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Marcom, Paul Kelly

Overview:

Basic Science:
-Germline and somatic genetic changes in cancer, particularly breast cancer. Ongoing efforts with Dr. Joseph R. Nevins in Department of Genetics.

Translational:
-Identification and management of individuals and families with hereditary cancer risk.
-Communication of cancer risk information to individuals and families.
-Breast cancer prevention.
-Optimizing management of early breast cancer.
-Treatment of metastatic breast cancer

Dr. Marcom's research has focused on two main areas. First, in the laboratory of Dr. Joseph Nevins in the Department of Genetics, he has been investigating alterations in cell cycle control in cancer. Primarily, these experiments have looked for primary alterations in the E2F family of genes, and their possible contribution to developing cancer. More recently, he has been involved with issues regarding genetic predisposition to developing cancer.

Investigations of cell cycle alterations have employed standard molecular biology techniques to analyze both cell lines and primary tumors for alterations in control of the retinoblastoma pathway, and consequent effects on E2F control.

Clinically, Dr. Marcom works as a medical oncologist in the multidisciplinary breast cancer clinic. He participates in clinical trials investigating new chemotherapeutic and biologic treatments. In addition, he is developing a new high risk, familial cancer clinic. This clinic will see patients and families thought to be at high risk of developing malignancies, and will interface with the forming Cancer Genetics Network. Patients and families will be counseled about their cancer risk, and identified for studying issues related to cancer genetics: determining penetrance of identified gene mutations, determining factors modifying genetic risk, prevention studies, etc. Finally, he also plans to be involved in clinical evaluation of drugs inhibiting tumor angiogenesis.

Areas of developing expertise include cell cycle alterations in malignancy, breast cancer, and hereditary cancer genetics.

Breast cancer, cell cycle, genetics, familial cancer, prognostic factors, angiogenesis

Positions:

Associate Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1989

M.D. — Baylor University

Medical Resident, Medicine

Duke University

Fellow In Hematology Oncology, Medicine

Duke University

Grants:

Merck KEYNOTE 522 (MK-3475)

Administered By
Duke Cancer Institute
AwardedBy
Merck Sharp & Dohme
Role
Principal Investigator
Start Date
July 07, 2017
End Date
July 12, 2022

Postdoctoral training in genomic medicine research

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
June 14, 2017
End Date
May 31, 2022

Targeting precursor neural (N)-cadherin to eliminate chemotherapy-resistant triple-negative breast tumor cells

Administered By
Pathology
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
March 01, 2017
End Date
February 29, 2020

Kastan Gray Foundation Project

Administered By
Duke Cancer Institute
AwardedBy
Gray Foundation
Role
Researcher
Start Date
October 01, 2017
End Date
September 30, 2019

TBCRC 031 INFORM

Administered By
Duke Cancer Institute
AwardedBy
Johns Hopkins University
Role
Principal Investigator
Start Date
September 01, 2015
End Date
August 31, 2019

TBCRC 031 INFORM (Beth Israel)

Administered By
Duke Cancer Institute
AwardedBy
Beth Israel Deaconess Medical Center
Role
Principal Investigator
Start Date
September 01, 2015
End Date
August 31, 2019

Can contrast dynamics in breast MRI predict genomic intra-tumor heterogeneity

Administered By
Radiology
AwardedBy
Bracco Diagnostics, Inc.
Role
Investigator
Start Date
July 18, 2016
End Date
June 30, 2018

A randomized phase II study of adjuvant Trastuzumab emtansine (T-DM1) vs Paclitaxel

Administered By
Duke Cancer Institute
AwardedBy
Dana Farber Cancer Institute
Role
Principal Investigator
Start Date
June 01, 2014
End Date
May 30, 2018

A RANDOMIZED PHASE II STUDY OF PREOPERATIVE CISPLATIN VS PACLITAXEL IN PATIENTS WITH TRIPLE NEGATIVE BREAST CANCER

Administered By
Duke Cancer Institute
AwardedBy
Dana Farber Cancer Institute
Role
Principal Investigator
Start Date
October 01, 2014
End Date
March 01, 2018

Novartis BYL719A2201

Administered By
Duke Cancer Institute
AwardedBy
Novartis Pharmaceuticals Corporation
Role
Principal Investigator
Start Date
September 16, 2013
End Date
December 31, 2017

Commericialization of a computational imaging-based biomarker for prognostication in breast cancer

Administered By
Radiology
AwardedBy
North Carolina Biotechnology Center
Role
Clinical Consultant
Start Date
February 01, 2016
End Date
October 31, 2017

Targeting nuclear FGF receptor to improve chemotherapy response in triple-negative breast cancer

Administered By
Pathology
AwardedBy
Department of Defense
Role
Investigator
Start Date
September 30, 2013
End Date
September 29, 2016

Clinical Oncology Research Career Development Program

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 29, 2009
End Date
July 31, 2015

Randomized Trial of Optimal Type of Aerobic Training in Breast Cancer

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 01, 2010
End Date
February 14, 2014

Programs in Clinical Effectiveness of Cancer Pharmacogenomics

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 30, 2009
End Date
August 31, 2012

Markers of short term breast cancer risk in FNA

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 30, 1995
End Date
June 30, 2008

Phase II trial of Cetuximab & Carboplatin in Basal-like Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1995
End Date
June 30, 2008

Carolina and Georgia Genetics Network Center

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 01, 1998
End Date
April 30, 2008

Phase II Trial of Estradiol Therapy for Advanced Breast Cancer

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
January 01, 2003
End Date
December 31, 2005

Carolina and Georgia Genetics Network Center

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 01, 1998
End Date
July 31, 2004
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Publications:

Can algorithmically assessed MRI features predict which patients with a preoperative diagnosis of ductal carcinoma in situ are upstaged to invasive breast cancer?

To assess the ability of algorithmically assessed magnetic resonance imaging (MRI) features to predict the likelihood of upstaging to invasive cancer in newly diagnosed ductal carcinoma in situ (DCIS).We identified 131 patients at our institution from 2000-2014 with a core needle biopsy-confirmed diagnosis of pure DCIS, a 1.5 or 3T preoperative bilateral breast MRI with nonfat-saturated T1 -weighted MRI sequences, no preoperative therapy before breast MRI, and no prior history of breast cancer. A fellowship-trained radiologist identified the lesion on each breast MRI using a bounding box. Twenty-nine imaging features were then computed automatically using computer algorithms based on the radiologist's annotation.The rate of upstaging of DCIS to invasive cancer in our study was 26.7% (35/131). Out of all imaging variables tested, the information measure of correlation 1, which quantifies spatial dependency in neighboring voxels of the tumor, showed the highest predictive value of upstaging with an area under the curve (AUC) = 0.719 (95% confidence interval [CI]: 0.609-0.829). This feature was statistically significant after adjusting for tumor size (P < 0.001).Automatically assessed MRI features may have a role in triaging which patients with a preoperative diagnosis of DCIS are at highest risk for occult invasive disease.4 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1332-1340.

Authors
Harowicz, MR; Saha, A; Grimm, LJ; Marcom, PK; Marks, JR; Hwang, ES; Mazurowski, MA
MLA Citation
Harowicz, MR, Saha, A, Grimm, LJ, Marcom, PK, Marks, JR, Hwang, ES, and Mazurowski, MA. "Can algorithmically assessed MRI features predict which patients with a preoperative diagnosis of ductal carcinoma in situ are upstaged to invasive breast cancer? (Accepted)." Journal of magnetic resonance imaging : JMRI 46.5 (November 2017): 1332-1340.
PMID
28181348
Source
epmc
Published In
Journal of Magnetic Resonance Imaging
Volume
46
Issue
5
Publish Date
2017
Start Page
1332
End Page
1340
DOI
10.1002/jmri.25655

Adherence to Recommended Risk Management among Unaffected Women with a BRCA Mutation.

Identifying unaffected women with a BRCA mutation can have a significant individual and population health impact on morbidity and mortality if these women adhere to guidelines for managing cancer risk. But, little is known about whether such women are adherent to current guidelines. We conducted telephone surveys of 97 unaffected BRCA mutation carriers who had genetic counseling at least one year prior to the survey to assess adherence to current guidelines, factors associated with adherence, and common reasons for performing and not performing recommended risk management. More than half of participants reported being adherent with current risk management recommendations for breast cancer (69 %, n = 67), ovarian cancer (82 %, n = 74) and both cancers (66 %, n = 64). Older age (OR = 10.53, p = 0.001), white race (OR = 8.93, p = 0.019), higher breast cancer genetics knowledge (OR = 1.67, p = 0.030), higher cancer-specific distress (OR = 1.07, p = 0.002) and higher physical functioning (OR = 1.09, p = 0.009) were significantly associated with adherence to recommended risk management for both cancers. Responses to open-ended questions about reasons for performing and not performing risk management behaviors indicated that participants recognized the clinical utility of these behaviors. Younger individuals and those with lower physical functioning may require targeted interventions to improve adherence, perhaps in the setting of long-term follow-up at a multi-disciplinary hereditary cancer clinic.

Authors
Buchanan, AH; Voils, CI; Schildkraut, JM; Fine, C; Horick, NK; Marcom, PK; Wiggins, K; Skinner, CS
MLA Citation
Buchanan, AH, Voils, CI, Schildkraut, JM, Fine, C, Horick, NK, Marcom, PK, Wiggins, K, and Skinner, CS. "Adherence to Recommended Risk Management among Unaffected Women with a BRCA Mutation." Journal of genetic counseling 26.1 (February 2017): 79-92.
PMID
27265406
Source
epmc
Published In
Journal of Genetic Counseling
Volume
26
Issue
1
Publish Date
2017
Start Page
79
End Page
92
DOI
10.1007/s10897-016-9981-6

Algorithms for prediction of the Oncotype DX recurrence score using clinicopathologic data: a review and comparison using an independent dataset.

Given the potential savings in cost and resource utilization, several algorithms have been proposed to predict Oncotype DX recurrence score (ODX RS) using commonly acquired histopathologic variables. Although it is promising, additional independent validation of these surrogate markers is needed prior to guide the patient management.In this retrospective study, we analyzed 305 patients with invasive breast cancer at our institution who had ODX RS available. We selected five equations that provide a surrogate measure of ODX as previously published by Klein et al. (Magee equations 1-3), Gage et al., and Tang et al. All equations used estrogen receptor status and progesterone receptor status along with different combinations of grade, proliferation indices (Ki-67, mitotic rate), HER2 status, and tumor size.Of all surrogate scores tested, the Magee equation 2 provided the highest correlation with ODX both with regard to raw score (Pearson's correlation coefficient = 0.66 95% CI 0.59-0.72) and categorical correlation (Cohen's kappa = 0.43, 95% CI 0.33-0.53). Although Magee equation 2 provided a way to reliably identify high-risk disease by assigning 95% of the patients with high ODX RS to either the intermediate- or high-risk group, it was unable to reliably identify the potential for patients to have intermediate- or high-risk disease by ODX (66% of such patients identified).Although commonly available surrogates for ODX appear to predict high-risk ODX RS, they are unable to reliably rule out the presence of patients with intermediate-risk disease by ODX. Given the potential benefit of adjuvant chemotherapy in women with intermediate-risk disease by ODX, current surrogates are unable to safely substitute for ODX. Characterizing the true recurrence risk in patients with intermediate-risk disease by ODX is critical to the clinical adoption of current surrogate markers and is an area of ongoing clinical trials.

Authors
Harowicz, MR; Robinson, TJ; Dinan, MA; Saha, A; Marks, JR; Marcom, PK; Mazurowski, MA
MLA Citation
Harowicz, MR, Robinson, TJ, Dinan, MA, Saha, A, Marks, JR, Marcom, PK, and Mazurowski, MA. "Algorithms for prediction of the Oncotype DX recurrence score using clinicopathologic data: a review and comparison using an independent dataset." Breast cancer research and treatment 162.1 (February 2017): 1-10. (Review)
PMID
28064383
Source
epmc
Published In
Breast Cancer Research and Treatment
Volume
162
Issue
1
Publish Date
2017
Start Page
1
End Page
10
DOI
10.1007/s10549-016-4093-4

Chemotherapy enriches for an invasive triple-negative breast tumor cell subpopulation expressing a precursor form of N-cadherin on the cell surface.

Although most triple-negative breast cancer (TNBC) patients initially respond to chemotherapy, residual tumor cells frequently persist and drive recurrent tumor growth. Previous studies from our laboratory and others' indicate that TNBC is heterogeneous, being composed of chemo-sensitive and chemo-resistant tumor cell subpopulations. In the current work, we studied the invasive behaviors of chemo-resistant TNBC, and sought to identify markers of invasion in chemo-residual TNBC.The invasive behavior of TNBC tumor cells surviving short-term chemotherapy treatment in vitro was studied using transwell invasion assays and an experimental metastasis model. mRNA expression levels of neural cadherin (N-cadherin), an adhesion molecule that promotes invasion, was assessed by PCR. Expression of N-cadherin and its precursor form (pro-N-cadherin) was assessed by immunoblotting and flow cytometry. Pro-N-cadherin immunohistochemistry was performed on tumors obtained from patients pre- and post- neoadjuvant chemotherapy treatment.TNBC cells surviving short-term chemotherapy treatment exhibited increased invasive behavior and capacity to colonize metastatic sites compared to untreated tumor cells. The invasive behavior of chemo-resistant cells was associated with their increased cell surface expression of precursor N-cadherin (pro-N-cadherin). An antibody specific for the precursor domain of N-cadherin inhibited invasion of chemo-resistant TNBC cells. To begin to validate our findings in humans, we showed that the percent cell surface pro-N-cadherin (+) tumor cells increased in patients post- chemotherapy treatment.TNBC cells surviving short-term chemotherapy treatment are more invasive than bulk tumor cells. Cell surface pro-N-cadherin expression is associated with the invasive and chemo-resistant behaviors of this tumor cell subset. Our findings indicate the importance of future studies determining the value of cell surface pro-N-cadherin as: 1) a biomarker for TNBC recurrence and 2) a therapeutic target for eliminating chemo-residual disease.

Authors
Nelson, ER; Li, S; Kennedy, M; Payne, S; Kilibarda, K; Groth, J; Bowie, M; Parilla-Castellar, E; de Ridder, G; Marcom, PK; Lyes, M; Peterson, BL; Cook, M; Pizzo, SV; McDonnell, DP; Bachelder, RE
MLA Citation
Nelson, ER, Li, S, Kennedy, M, Payne, S, Kilibarda, K, Groth, J, Bowie, M, Parilla-Castellar, E, de Ridder, G, Marcom, PK, Lyes, M, Peterson, BL, Cook, M, Pizzo, SV, McDonnell, DP, and Bachelder, RE. "Chemotherapy enriches for an invasive triple-negative breast tumor cell subpopulation expressing a precursor form of N-cadherin on the cell surface." Oncotarget 7.51 (December 2016): 84030-84042.
PMID
27768598
Source
epmc
Published In
Oncotarget
Volume
7
Issue
51
Publish Date
2016
Start Page
84030
End Page
84042
DOI
10.18632/oncotarget.12767

Is advanced imaging in early-stage breast cancer ever warranted? Reconciling clinical judgment with common quality measures

© JNCCN-Journal of the National Comprehensive Cancer Network. Background: The American Board of Internal Medicine Foundation's Choosing Wisely initiative aims to reduce unnecessary advanced imaging for early-stage breast cancer (ESBC). Additionally, NCCN Clinical Practice Guidelines in Oncology for Breast Cancer permit such images when oncologists perceive clinical clues of advanced disease. The utility of advanced imaging in ESBC is not known. Patients and Methods: We analyzed all patients with ESBC from January 2010 to June 2012 at a large tertiary cancer center. Early-stage was defined as stage IIb or less. We included advanced imaging within 60 days after diagnosis. Three independent reviewers manually abstracted a sample of charts to determine reason for ordering. Results: A total of 1,143 ESBC cases were identified; 21.8% of which had at least one advanced imaging procedure performed. Imaging modalities varied widely (38% CT, 21% PET, 34% bone scans, and 6% MRI). Patients who underwent advanced imaging were more likely to have triple-negative disease, be younger (age < 50 years), and have higher stage disease (stage IIb vs. stage IIa; all P < .001). A total of 100 cases (40%) were abstracted; 5 were excluded due to bilateral disease. Of the 95 cases remaining, 62% of the imaging studies were performed for staging, 17% for significant concurrent disease, and 22% for findings atypical of ESBC. Of the studies performed for staging, 15% produced clinically meaningful findings. Overall, 45% of studies were ordered for suspicious findings, complex history, or produced a meaningful result. Conclusions: Of patients with ESBC, 21.8% had at least one advanced imaging procedure within 60 days of diagnosis; almost half were clinically useful. Chart abstraction helped clarify intent. Conversations between clinicians and patients are needed to balance patient preferences and clinician judgment.

Authors
Kamal, A; Zhang, T; Power, S; Marcom, PK
MLA Citation
Kamal, A, Zhang, T, Power, S, and Marcom, PK. "Is advanced imaging in early-stage breast cancer ever warranted? Reconciling clinical judgment with common quality measures." JNCCN Journal of the National Comprehensive Cancer Network 14.8 (August 1, 2016): 993-998.
Source
scopus
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
14
Issue
8
Publish Date
2016
Start Page
993
End Page
998

Is Advanced Imaging in Early-Stage Breast Cancer Ever Warranted? Reconciling Clinical Judgment With Common Quality Measures.

The American Board of Internal Medicine Foundation's Choosing Wisely initiative aims to reduce unnecessary advanced imaging for early-stage breast cancer (ESBC). Additionally, NCCN Clinical Practice Guidelines in Oncology for Breast Cancer permit such images when oncologists perceive clinical clues of advanced disease. The utility of advanced imaging in ESBC is not known.We analyzed all patients with ESBC from January 2010 to June 2012 at a large tertiary cancer center. Early-stage was defined as stage IIb or less. We included advanced imaging within 60 days after diagnosis. Three independent reviewers manually abstracted a sample of charts to determine reason for ordering.A total of 1,143 ESBC cases were identified; 21.8% of which had at least one advanced imaging procedure performed. Imaging modalities varied widely (38% CT, 21% PET, 34% bone scans, and 6% MRI). Patients who underwent advanced imaging were more likely to have triple-negative disease, be younger (age <50 years), and have higher stage disease (stage IIb vs ≤ stage IIa; all P<.001). A total of 100 cases (40%) were abstracted; 5 were excluded due to bilateral disease. Of the 95 cases remaining, 62% of the imaging studies were performed for staging, 17% for significant concurrent disease, and 22% for findings atypical of ESBC. Of the studies performed for staging, 15% produced clinically meaningful findings. Overall, 45% of studies were ordered for suspicious findings, complex history, or produced a meaningful result.Of patients with ESBC, 21.8% had at least one advanced imaging procedure within 60 days of diagnosis; almost half were clinically useful. Chart abstraction helped clarify intent. Conversations between clinicians and patients are needed to balance patient preferences and clinician judgment.

Authors
Kamal, A; Zhang, T; Power, S; Marcom, PK
MLA Citation
Kamal, A, Zhang, T, Power, S, and Marcom, PK. "Is Advanced Imaging in Early-Stage Breast Cancer Ever Warranted? Reconciling Clinical Judgment With Common Quality Measures." Journal of the National Comprehensive Cancer Network : JNCCN 14.8 (August 2016): 993-998.
PMID
27496115
Source
epmc
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
14
Issue
8
Publish Date
2016
Start Page
993
End Page
998
DOI
10.6004/jnccn.2016.0106

Genetic/familial high-risk assessment: Breast and ovarian, version 2.2015 Featured updates to the NCCN guidelines

© 2016 JNCCN-Journal of the National Comprehensive Cancer Network. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling and risk assessment and management for hereditary cancer syndromes. Guidelines focus on syndromes associated with an increased risk of breast and/or ovarian cancer and are intended to assist with clinical and shared decision-making. These NCCN Guidelines Insights summarize major discussion points of the 2015 NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meeting. Major discussion topics this year included multigene testing, risk management recommendations for less common genetic mutations, and salpingectomy for ovarian cancer risk reduction. The panel also discussed revisions to genetic testing criteria that take into account ovarian cancer histology and personal history of pancreatic cancer.

Authors
Daly, MB; Pilarski, R; Axilbund, JE; Berry, M; Buys, SS; Crawford, B; Farmer, M; Friedman, S; Garber, JE; Khan, S; Klein, C; Kohlmann, W; Kurian, A; Litton, JK; Madlensky, L; Marcom, PK; Merajver, SD; Offit, K; Pal, T; Rana, H; Reiser, G; Robson, ME; Shannon, KM; Swisher, E; Voian, NC; Weitzel, JN; Whelan, A; Wick, MJ; Wiesner, GL; Dwyer, M; Kumar, R; Darlow, S
MLA Citation
Daly, MB, Pilarski, R, Axilbund, JE, Berry, M, Buys, SS, Crawford, B, Farmer, M, Friedman, S, Garber, JE, Khan, S, Klein, C, Kohlmann, W, Kurian, A, Litton, JK, Madlensky, L, Marcom, PK, Merajver, SD, Offit, K, Pal, T, Rana, H, Reiser, G, Robson, ME, Shannon, KM, Swisher, E, Voian, NC, Weitzel, JN, Whelan, A, Wick, MJ, Wiesner, GL, Dwyer, M, Kumar, R, and Darlow, S. "Genetic/familial high-risk assessment: Breast and ovarian, version 2.2015 Featured updates to the NCCN guidelines." JNCCN Journal of the National Comprehensive Cancer Network 14.2 (February 1, 2016): 153-162. (Review)
Source
scopus
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
14
Issue
2
Publish Date
2016
Start Page
153
End Page
162

Breast cancer, version 1.2016 featured updates to the NCCN guidelines

© National Comprehensive Cancer Network, Inc. 2015, All rights reserved. These NCCN Guideline Insights highlight the important updates to the systemic therapy recommendations in the 2016 NCCN Guidelines for Breast Cancer. In the most recent version of these guidelines, the NCCN Breast Cancer Panel included a new section on the principles of preoperative systemic therapy. In addition, based on new evidence, the panel updated systemic therapy recommendations for women with hormone receptor-positive breast cancer in the adjuvant and metastatic disease settings and for patients with HER2-positive metastatic breast cancer. This report summarizes these recent updates and discusses the rationale behind them.

Authors
Gradishar, WJ; Anderson, BO; Balassanian, R; Blair, SL; Burstein, HJ; Cyr, A; Elias, AD; Farrar, WB; Forero, A; Giordano, SH; Goetz, M; Goldstein, LJ; Hudis, CA; Isakoff, SJ; Marcom, PK; Mayer, IA; McCormick, B; Moran, M; Patel, SA; Pierce, LJ; Reed, EC; Salerno, KE; Schwartzberg, LS; Smith, KL; Smith, ML; Soliman, H; Somlo, G; Telli, M; Ward, JH; Shead, DA; Kumar, R
MLA Citation
Gradishar, WJ, Anderson, BO, Balassanian, R, Blair, SL, Burstein, HJ, Cyr, A, Elias, AD, Farrar, WB, Forero, A, Giordano, SH, Goetz, M, Goldstein, LJ, Hudis, CA, Isakoff, SJ, Marcom, PK, Mayer, IA, McCormick, B, Moran, M, Patel, SA, Pierce, LJ, Reed, EC, Salerno, KE, Schwartzberg, LS, Smith, KL, Smith, ML, Soliman, H, Somlo, G, Telli, M, Ward, JH, Shead, DA, and Kumar, R. "Breast cancer, version 1.2016 featured updates to the NCCN guidelines." JNCCN Journal of the National Comprehensive Cancer Network 13.12 (December 1, 2015): 1475-1485.
Source
scopus
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
13
Issue
12
Publish Date
2015
Start Page
1475
End Page
1485

Randomized Trial of Telegenetics vs. In-Person Cancer Genetic Counseling: Cost, Patient Satisfaction and Attendance.

Telegenetics-genetic counseling via live videoconferencing-can improve access to cancer genetic counseling (CGC) in underserved areas, but studies on cancer telegenetics have not applied randomized methodology or assessed cost. We report cost, patient satisfaction and CGC attendance from a randomized trial comparing telegenetics with in-person CGC among individuals referred to CGC in four rural oncology clinics. Participants (n = 162) were randomized to receive CGC at their local oncology clinic in-person or via telegenetics. Cost analyses included telegenetics system; mileage; and personnel costs for genetic counselor, IT specialist, and clinic personnel. CGC attendance was tracked via study database. Patient satisfaction was assessed 1 week post-CGC via telephone survey using validated scales. Total costs were $106 per telegenetics patient and $244 per in-person patient. Patient satisfaction did not differ by group on either satisfaction scale. In-person patients were significantly more likely to attend CGC than telegenetics patients (89 vs. 79 %, p = 0.03), with bivariate analyses showing an association between lesser computer comfort and lower attendance rate (Chi-square = 5.49, p = 0.02). Our randomized trial of telegenetics vs. in-person counseling found that telegenetics cost less than in-person counseling, with high satisfaction among those who attended. This study provides support for future randomized trials comparing multiple service delivery models on longer-term psychosocial and behavioral outcomes.

Authors
Buchanan, AH; Datta, SK; Skinner, CS; Hollowell, GP; Beresford, HF; Freeland, T; Rogers, B; Boling, J; Marcom, PK; Adams, MB
MLA Citation
Buchanan, AH, Datta, SK, Skinner, CS, Hollowell, GP, Beresford, HF, Freeland, T, Rogers, B, Boling, J, Marcom, PK, and Adams, MB. "Randomized Trial of Telegenetics vs. In-Person Cancer Genetic Counseling: Cost, Patient Satisfaction and Attendance." Journal of genetic counseling 24.6 (December 2015): 961-970.
PMID
25833335
Source
epmc
Published In
Journal of Genetic Counseling
Volume
24
Issue
6
Publish Date
2015
Start Page
961
End Page
970
DOI
10.1007/s10897-015-9836-6

Recurrence-free survival in breast cancer is associated with MRI tumor enhancement dynamics quantified using computer algorithms.

The purpose of this study is to investigate the association between breast cancer recurrence-free survival and breast magnetic resonance imaging (MRI) tumor enhancement dynamics which are quantified semi-automatically using computer algorithms.In this retrospective IRB-approved study, we analyzed data from 275 breast cancer patients at a single institution. Recurrence-free survival data were obtained from the medical record. Routine clinical pre-operative breast MRIs were performed in all patients. The tumors were marked on the MRIs by fellowship-trained breast radiologists. A previously developed computer algorithm was applied to the marked tumors to quantify the enhancement dynamics relative to the automatically assessed background parenchymal enhancement. To establish whether the contrast enhancement feature quantified by the algorithm was associated with recurrence-free survival, we constructed a Cox proportional hazards regression model with the computer-extracted feature as a covariate. We controlled for tumor grade and size (major axis length), patient age, patient race/ethnicity, and menopausal status.The analysis showed that the semi-automatically obtained feature quantifying MRI tumor enhancement dynamics was independently predictive of recurrence-free survival (p=0.024).Semi-automatically quantified tumor enhancement dynamics on MRI are predictive of recurrence-free survival in breast cancer patients.

Authors
Mazurowski, MA; Grimm, LJ; Zhang, J; Marcom, PK; Yoon, SC; Kim, C; Ghate, SV; Johnson, KS
MLA Citation
Mazurowski, MA, Grimm, LJ, Zhang, J, Marcom, PK, Yoon, SC, Kim, C, Ghate, SV, and Johnson, KS. "Recurrence-free survival in breast cancer is associated with MRI tumor enhancement dynamics quantified using computer algorithms." European journal of radiology 84.11 (November 2015): 2117-2122.
PMID
26210095
Source
epmc
Published In
European Journal of Radiology
Volume
84
Issue
11
Publish Date
2015
Start Page
2117
End Page
2122
DOI
10.1016/j.ejrad.2015.07.012

Medication taking behaviors among breast cancer patients on adjuvant endocrine therapy.

To explore how symptoms and psychosocial factors are related to intentional and unintentional non-adherent medication taking behaviors.Included were postmenopausal women with hormone receptor positive, stage I-IIIA breast cancer, who had completed surgery, chemotherapy, and radiation, and were taking endocrine therapy. Self-administered, standardized measures were completed during a routine clinic visit: Brief Fatigue Inventory, Brief Pain Inventory, Menopause Specific Quality of Life Questionnaire, Functional Assessment of Cancer Therapy General and Neurotoxicity scales, and Self-Efficacy for Appropriate Medication Use Scale. Regression analyses were performed to determine the degree to which demographic, medical, symptom, and psychosocial variables, explain intentional, such as changing one's doses or stopping medication, and unintentional, such as forgetting to take one's medication, non-adherent behaviors.Participants were 112 women: mean age 64 (SD = 9) years; 81% white; mean time from surgery 40 (SD = 28) months; 49% received chemotherapy (39% including a taxane); mean time on endocrine therapy, 35 (SD = 29.6) months; 82% taking an aromatase inhibitor. Intentional and unintentional non-adherent behaviors were described in 33.9% and 58.9% of participants, respectively. Multivariate analysis showed that higher self-efficacy for taking medication was associated with lower levels of unintentional (p = 0.002) and intentional (p = 0.004) non-adherent behaviors. The presence of symptoms (p = 0.03) and lower self-efficacy for physician communication (p = 0.009) were associated with higher levels of intentional non-adherent behaviors.These results suggest that women who report greater symptoms, lower self-efficacy for communicating with their physician, and lower self-efficacy for taking their medication are more likely to engage in both intentional and unintentional non-adherent behaviors.

Authors
Kimmick, G; Edmond, SN; Bosworth, HB; Peppercorn, J; Marcom, PK; Blackwell, K; Keefe, FJ; Shelby, RA
MLA Citation
Kimmick, G, Edmond, SN, Bosworth, HB, Peppercorn, J, Marcom, PK, Blackwell, K, Keefe, FJ, and Shelby, RA. "Medication taking behaviors among breast cancer patients on adjuvant endocrine therapy." Breast (Edinburgh, Scotland) 24.5 (October 2015): 630-636.
PMID
26189978
Source
epmc
Published In
The Breast
Volume
24
Issue
5
Publish Date
2015
Start Page
630
End Page
636
DOI
10.1016/j.breast.2015.06.010

CHAMBER: A Regional Performance Improvement CME Initiative for Breast Cancer Health Care Providers.

CHAMBER was a regional educational initiative for providers of care to patients with HER2+ breast cancer. The study goals were to (1) enhance testing for HER2/neu overexpression in patients with invasive breast cancer; (2) increase the appropriate use of targeted therapy for patients with HER2+ breast cancer; and (3) enhance patients' coping ability. This Performance Improvement Continuing Medical Education (PI-CME) initiative included clinical practice assessment, educational activities, and reassessment. Chart review revealed a high rate of HER2 testing (98%) before and after education. Targeted therapy for patients with HER2+ breast cancer declined after the program (from 96% to 61%), perhaps attributable to an increase in awareness of medical reasons to avoid use of targeted therapy. Assessment for patients' emotional coping ability increased after education (from 55% to 76%; P=.01). Rates of testing for HER2 amplification and assessment of emotional well-being after education were consistent with ASCO Quality Oncology Practice Initiative benchmark values. Documentation of actions to address emotional problems remained an area for improvement.

Authors
Sutton, LM; Geradts, J; Hamilton, EP; Havlin, KA; Kimmick, GG; Marcom, PK; Spector, NL; Watson, M; Rabin, DU; Bruno, TO; Noe, A; Miller, S; Subramaniam, C; Layton, S; Grichnik, K
MLA Citation
Sutton, LM, Geradts, J, Hamilton, EP, Havlin, KA, Kimmick, GG, Marcom, PK, Spector, NL, Watson, M, Rabin, DU, Bruno, TO, Noe, A, Miller, S, Subramaniam, C, Layton, S, and Grichnik, K. "CHAMBER: A Regional Performance Improvement CME Initiative for Breast Cancer Health Care Providers." J Natl Compr Canc Netw 13.8 (August 2015): 1005-1011.
PMID
26285246
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
13
Issue
8
Publish Date
2015
Start Page
1005
End Page
1011

Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance.

Chemotherapy remains the only available treatment for triple-negative (TN) breast cancer, and most patients exhibit an incomplete pathologic response. Half of patients exhibiting an incomplete pathologic response die within five years of treatment due to chemo-resistant, recurrent tumor growth. Defining molecules responsible for TN breast cancer chemo-resistance is crucial for developing effective combination therapies blocking tumor recurrence. Historically, chemo-resistance studies have relied on long-term chemotherapy selection models that drive genetic mutations conferring cell survival. Other models suggest that tumors are heterogeneous, being composed of both chemo-sensitive and chemo-resistant tumor cell populations. We previously described a short-term chemotherapy treatment model that enriches for chemo-residual TN tumor cells. In the current work, we use this enrichment strategy to identify a novel determinant of TN breast cancer chemotherapy resistance [a nuclear isoform of basic fibroblast growth factor (bFGF)].Studies are conducted using our in vitro model of chemotherapy resistance. Short-term chemotherapy treatment enriches for a chemo-residual TN subpopulation that over time resumes proliferation. By western blotting and real-time polymerase chain reaction, we show that this chemotherapy-enriched tumor cell subpopulation expresses nuclear bFGF. The importance of bFGF for survival of these chemo-residual cells is interrogated using short hairpin knockdown strategies. DNA repair capability is assessed by comet assay. Immunohistochemistry (IHC) is used to determine nuclear bFGF expression in TN breast cancer cases pre- and post- neoadjuvant chemotherapy.TN tumor cells surviving short-term chemotherapy treatment express increased nuclear bFGF. bFGF knockdown reduces the number of chemo-residual TN tumor cells. Adding back a nuclear bFGF construct to bFGF knockdown cells restores their chemo-resistance. Nuclear bFGF-mediated chemo-resistance is associated with increased DNA-dependent protein kinase (DNA-PK) expression and accelerated DNA repair. In fifty-six percent of matched TN breast cancer cases, percent nuclear bFGF-positive tumor cells either increases or remains the same post- neoadjuvant chemotherapy treatment (compared to pre-treatment). These data indicate that in a subset of TN breast cancers, chemotherapy enriches for nuclear bFGF-expressing tumor cells.These studies identify nuclear bFGF as a protein in a subset of TN breast cancers that likely contributes to drug resistance following standard chemotherapy treatment.

Authors
Li, S; Payne, S; Wang, F; Claus, P; Su, Z; Groth, J; Geradts, J; de Ridder, G; Alvarez, R; Marcom, PK; Pizzo, SV; Bachelder, RE
MLA Citation
Li, S, Payne, S, Wang, F, Claus, P, Su, Z, Groth, J, Geradts, J, de Ridder, G, Alvarez, R, Marcom, PK, Pizzo, SV, and Bachelder, RE. "Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance." Breast cancer research : BCR 17 (July 4, 2015): 91-.
PMID
26141457
Source
epmc
Published In
Breast Cancer Research
Volume
17
Publish Date
2015
Start Page
91
DOI
10.1186/s13058-015-0590-3

Cross-species DNA copy number analyses identifies multiple 1q21-q23 subtype-specific driver genes for breast cancer.

A large number of DNA copy number alterations (CNAs) exist in human breast cancers, and thus characterizing the most frequent CNAs is key to advancing therapeutics because it is likely that these regions contain breast tumor 'drivers' (i.e., cancer causal genes). This study aims to characterize the genomic landscape of breast cancer CNAs and identify potential subtype-specific drivers using a large set of human breast tumors and genetically engineered mouse (GEM) mammary tumors. Using a novel method called SWITCHplus, we identified subtype-specific DNA CNAs occurring at a 15% or greater frequency, which excluded many well-known breast cancer-related drivers such as amplification of ERBB2, and deletions of TP53 and RB1. A comparison of CNAs between mouse and human breast tumors identified regions with shared subtype-specific CNAs. Additional criteria that included gene expression-to-copy number correlation, a DawnRank network analysis, and RNA interference functional studies highlighted candidate driver genes that fulfilled these multiple criteria. Numerous regions of shared CNAs were observed between human breast tumors and GEM mammary tumor models that shared similar gene expression features. Specifically, we identified chromosome 1q21-23 as a Basal-like subtype-enriched region with multiple potential driver genes including PI4KB, SHC1, and NCSTN. This step-wise computational approach based on a cross-species comparison is applicable to any tumor type for which sufficient human and model system DNA copy number data exist, and in this instance, highlights that a single region of amplification may in fact harbor multiple driver genes.

Authors
Silva, GO; He, X; Parker, JS; Gatza, ML; Carey, LA; Hou, JP; Moulder, SL; Marcom, PK; Ma, J; Rosen, JM; Perou, CM
MLA Citation
Silva, GO, He, X, Parker, JS, Gatza, ML, Carey, LA, Hou, JP, Moulder, SL, Marcom, PK, Ma, J, Rosen, JM, and Perou, CM. "Cross-species DNA copy number analyses identifies multiple 1q21-q23 subtype-specific driver genes for breast cancer." Breast cancer research and treatment 152.2 (July 2015): 347-356.
PMID
26109346
Source
epmc
Published In
Breast Cancer Research and Treatment
Volume
152
Issue
2
Publish Date
2015
Start Page
347
End Page
356
DOI
10.1007/s10549-015-3476-2

Chemotherapy-related amenorrhea after adjuvant paclitaxel-trastuzumab (APT trial).

Chemotherapy-related amenorrhea (CRA) is associated with infertility and menopausal symptoms. Learning how frequently paclitaxel and trastuzumab cause amenorrhea is important. Most other adjuvant breast cancer therapies induce CRA in approximately 50 % of all premenopausal recipients [1]. 410 patients enrolled on the APT Trial, a single-arm phase 2 adjuvant study of 12 weeks of paclitaxel and trastuzumab followed by nine months of trastuzumab monotherapy. Eligible patients had ≤3 cm node-negative HER2 + breast cancers. Premenopausal enrollees were asked to complete menstrual surveys every 3-12 months for 72 months. Women who responded to at least one survey at least 15 months after chemotherapy initiation (and who did not undergo hysterectomy and/or bilateral oophorectomy or receive ovarian suppressing medications prior to 15 months) were included in this analysis. A participant was defined as having amenorrhea in follow-up if her self-reported last menstrual period at last follow-up was greater than 12 months prior to the survey. Among the 64 women in the evaluable population (median age at study entry 44 years, range 27-52 years), the median time between chemotherapy initiation and last menstrual survey was 51 months (range 16-79). 18 of 64 women (28 %, 95 % CI 18-41 %) were amenorrheic at that time point. Amenorrhea rates among premenopausal women treated with adjuvant paclitaxel and trastuzumab for early stage breast cancer appear lower than those seen historically with standard alkylator-based breast cancer regimens. Future studies are needed to understand the impact of this regimen on related issues of fertility and menopausal symptoms.

Authors
Ruddy, KJ; Guo, H; Barry, W; Dang, CT; Yardley, DA; Moy, B; Marcom, PK; Albain, KS; Rugo, HS; Ellis, MJ; Shapira, I; Wolff, AC; Carey, LA; Overmoyer, BA; Hudis, C; Krop, IE; Burstein, HJ; Winer, EP; Partridge, AH; Tolaney, SM
MLA Citation
Ruddy, KJ, Guo, H, Barry, W, Dang, CT, Yardley, DA, Moy, B, Marcom, PK, Albain, KS, Rugo, HS, Ellis, MJ, Shapira, I, Wolff, AC, Carey, LA, Overmoyer, BA, Hudis, C, Krop, IE, Burstein, HJ, Winer, EP, Partridge, AH, and Tolaney, SM. "Chemotherapy-related amenorrhea after adjuvant paclitaxel-trastuzumab (APT trial)." Breast cancer research and treatment 151.3 (June 2015): 589-596.
PMID
25981899
Source
epmc
Published In
Breast Cancer Research and Treatment
Volume
151
Issue
3
Publish Date
2015
Start Page
589
End Page
596
DOI
10.1007/s10549-015-3426-z

Implications of HER2-targeted therapy on extent of surgery for early-stage breast cancer.

Authors
Aziz, H; Marcom, PK; Hwang, ES
MLA Citation
Aziz, H, Marcom, PK, and Hwang, ES. "Implications of HER2-targeted therapy on extent of surgery for early-stage breast cancer." Annals of surgical oncology 22.5 (May 2015): 1404-1405.
PMID
25777094
Source
epmc
Published In
Annals of Surgical Oncology
Volume
22
Issue
5
Publish Date
2015
Start Page
1404
End Page
1405
DOI
10.1245/s10434-015-4503-6

Synchronous primary carcinoma of breast and ovary versus ovarian metastases.

Authors
Yadav, BS; Sharma, SC; Robin, TP; Sams, S; Elias, AD; Kaklamani, V; Kelly Marcom, P; Schaefer, S; Morris, GJ
MLA Citation
Yadav, BS, Sharma, SC, Robin, TP, Sams, S, Elias, AD, Kaklamani, V, Kelly Marcom, P, Schaefer, S, and Morris, GJ. "Synchronous primary carcinoma of breast and ovary versus ovarian metastases." Seminars in oncology 42.2 (April 2015): e13-e24. (Review)
PMID
25843740
Source
epmc
Published In
Seminars in Oncology
Volume
42
Issue
2
Publish Date
2015
Start Page
e13
End Page
e24
DOI
10.1053/j.seminoncol.2014.12.020

Circulating tumor cell analysis in metastatic triple-negative breast cancers.

Recent developments in rare-cell technology have led to improved blood-based assays that allow for the reliable detection, enumeration, and more recently, genomic profiling of circulating tumor cells (CTC). We evaluated two different approaches for enumeration of CTCs in a prospective therapeutic study of patients with metastatic triple-negative breast cancer (TNBC).The CellSearch system, a commercially available and U.S. Food and Drug Administration (FDA)-cleared assay for CTC enumeration, and IE/FC, an alternative method using EPCAM-based immunomagnetic enrichment and flow cytometry that maintains cell viability, were used to enumerate CTCs in the blood of patients with metastatic TNBC. CTC numbers were assessed at baseline and 7 to 14 days after initiation of therapy with cetuximab ± carboplatin in a phase II multicenter clinical trial (TBCRC 001).CTC numbers from two methods were significantly correlated at baseline (r = 0.62) and at 7 to 14 days (r = 0.53). Baseline CTCs showed no association with time-to-progression (TTP), whereas CTCs at 7 to 14 days were significantly correlated with TTP (CellSearch P = 0.02; IE/FC P = 0.03). CTCs at both time points were significantly associated with overall survival (OS) [CellSearch: baseline (P = 0.0001) and 7 to 14 days (P < 0.0001); IE/FC: baseline (P = 0.0009) and 7 to 14 days (P = 0.0086)].Our findings demonstrate that CTC enumeration by two different assays was highly concordant. In addition, results of both assays were significantly correlated with TTP and OS in patients with TNBC. The IE/FC method is also easily adapted to isolation of pure populations of CTCs for genomic profiling.

Authors
Magbanua, MJM; Carey, LA; DeLuca, A; Hwang, J; Scott, JH; Rimawi, MF; Mayer, EL; Marcom, PK; Liu, MC; Esteva, FJ; Park, JW; Rugo, HS; Translational Breast Cancer Research Consortium,
MLA Citation
Magbanua, MJM, Carey, LA, DeLuca, A, Hwang, J, Scott, JH, Rimawi, MF, Mayer, EL, Marcom, PK, Liu, MC, Esteva, FJ, Park, JW, Rugo, HS, and Translational Breast Cancer Research Consortium, . "Circulating tumor cell analysis in metastatic triple-negative breast cancers." Clinical cancer research : an official journal of the American Association for Cancer Research 21.5 (March 2015): 1098-1105.
PMID
25524311
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
21
Issue
5
Publish Date
2015
Start Page
1098
End Page
1105
DOI
10.1158/1078-0432.ccr-14-1948

Can breast cancer molecular subtype help to select patients for preoperative MR imaging?

PURPOSE: To assess whether breast cancer molecular subtype classified by surrogate markers can be used to predict the extent of clinically relevant disease with preoperative breast magnetic resonance (MR) imaging. MATERIALS AND METHODS: In this HIPAA-compliant, institutional review board-approved study, informed consent was waived. Preoperative breast MR imaging reports from 441 patients were reviewed for multicentric and/or multifocal disease, lymph node involvement, skin and/or nipple invasion, chest wall and/or pectoralis muscle invasion, or contralateral disease. Pathologic reports were reviewed to confirm the MR imaging findings and for hormone receptors (estrogen and progesterone subtypes), human epidermal growth factor receptor type 2 (HER2 subtype), tumor size, and tumor grade. Surrogates were used to categorize tumors by molecular subtype: hormone receptor positive and HER2 negative (luminal A subtype); hormone receptor positive and HER2 positive (luminal B subtype); hormone receptor negative and HER2 positive (HER2 subtype); hormone receptor negative and HER2 negative (basal subtype). All patients included in the study had a histologic correlation with MR imaging findings or they were excluded. χ(2) analysis was used to compare differences between subtypes, with multivariate logistic regression analysis used to assess for variable independence. RESULTS: Identified were 289 (65.5%) luminal A, 45 (10.2%) luminal B, 26 (5.9%) HER2, and 81 (18.4%) basal subtypes. Among subtypes, significant differences were found in the frequency of multicentric and/or multifocal disease (luminal A, 27.3% [79 of 289]; luminal B, 53.3% [24 of 45]; HER2, 65.4% [17 of 26]; basal, 27.2% [22 of 81]; P < .001) and lymph node involvement (luminal A, 17.3% [50 of 289]; luminal B, 35.6% [26 of 45]; HER2, 34.6% [nine of 26]; basal 24.7% [20 of 81]; P = .014). Multivariate analysis showed that molecular subtype was independently predictive of multifocal and/or multicentric disease. CONCLUSION: Preoperative breast MR imaging is significantly more likely to help detect multifocal and/or multicentric disease and lymph node involvement in luminal B and HER2 molecular subtype breast cancers. Molecular subtype may help to select patients for preoperative breast MR imaging.

Authors
Grimm, LJ; Johnson, KS; Marcom, PK; Baker, JA; Soo, MS
MLA Citation
Grimm, LJ, Johnson, KS, Marcom, PK, Baker, JA, and Soo, MS. "Can breast cancer molecular subtype help to select patients for preoperative MR imaging?." Radiology 274.2 (February 2015): 352-358.
PMID
25325325
Source
epmc
Published In
Radiology
Volume
274
Issue
2
Publish Date
2015
Start Page
352
End Page
358
DOI
10.1148/radiol.14140594

Breast cancer version 2.2015: Clinical practice guidelines in oncology

© JNCCN - Journal of the National Comprehensive Cancer Network. Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. This portion of the NCCN Guidelines discusses recommendations specific to the locoregional management of clinical stage I, II, and IIIA (T3N1M0) tumors.

Authors
Gradishar, WJ; Anderson, BO; Balassanian, R; Blair, SL; Burstein, HJ; Cyr, A; Elias, AD; Farrar, WB; Forero, A; Giordano, SH; Goetz, M; Goldstein, LJ; Hudis, CA; Isakoff, SJ; Marcom, PK; Mayer, IA; McCormick, B; Moran, M; Patel, SA; Pierce, LJ; Reed, EC; Salerno, KE; Schwartzberg, LS; Smith, KL; Smith, ML; Soliman, H; Somlo, G; Telli, M; Ward, JH; Shead, DA; Kumar, R
MLA Citation
Gradishar, WJ, Anderson, BO, Balassanian, R, Blair, SL, Burstein, HJ, Cyr, A, Elias, AD, Farrar, WB, Forero, A, Giordano, SH, Goetz, M, Goldstein, LJ, Hudis, CA, Isakoff, SJ, Marcom, PK, Mayer, IA, McCormick, B, Moran, M, Patel, SA, Pierce, LJ, Reed, EC, Salerno, KE, Schwartzberg, LS, Smith, KL, Smith, ML, Soliman, H, Somlo, G, Telli, M, Ward, JH, Shead, DA, and Kumar, R. "Breast cancer version 2.2015: Clinical practice guidelines in oncology." JNCCN Journal of the National Comprehensive Cancer Network 13.4 (January 1, 2015): 448-475. (Review)
Source
scopus
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
13
Issue
4
Publish Date
2015
Start Page
448
End Page
475

Ethinylestradiol is beneficial for postmenopausal patients with heavily pre-treated metastatic breast cancer after prior aromatase inhibitor treatment: A prospective study

Authors
Gwin, WR; Marcom, PK
MLA Citation
Gwin, WR, and Marcom, PK. "Ethinylestradiol is beneficial for postmenopausal patients with heavily pre-treated metastatic breast cancer after prior aromatase inhibitor treatment: A prospective study." Breast Diseases 25.4 (January 1, 2015): 326-327.
Source
scopus
Published In
Breast Diseases: A Year Book Quarterly
Volume
25
Issue
4
Publish Date
2015
Start Page
326
End Page
327

The use of Bayesian hierarchical models for adaptive randomization in biomarker-driven phase II studies.

The role of biomarkers has increased in cancer clinical trials such that novel designs are needed to efficiently answer questions of both drug effects and biomarker performance. We advocate Bayesian hierarchical models for response-adaptive randomized phase II studies integrating single or multiple biomarkers. Prior selection allows one to control a gradual and seamless transition from randomized-blocks to marker-enrichment during the trial. Adaptive randomization is an efficient design for evaluating treatment efficacy within biomarker subgroups, with less variable final sample sizes when compared to nested staged designs. Inference based on the Bayesian hierarchical model also has improved performance in identifying the sub-population where therapeutics are effective over independent analyses done within each biomarker subgroup.

Authors
Barry, WT; Perou, CM; Marcom, PK; Carey, LA; Ibrahim, JG
MLA Citation
Barry, WT, Perou, CM, Marcom, PK, Carey, LA, and Ibrahim, JG. "The use of Bayesian hierarchical models for adaptive randomization in biomarker-driven phase II studies." Journal of biopharmaceutical statistics 25.1 (January 2015): 66-88.
PMID
24836519
Source
epmc
Published In
Journal of Biopharmaceutical Statistics
Volume
25
Issue
1
Publish Date
2015
Start Page
66
End Page
88
DOI
10.1080/10543406.2014.919933

Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer.

No single standard treatment exists for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)-positive breast cancers, because most of these patients have been ineligible for the pivotal trials of adjuvant trastuzumab.We performed an uncontrolled, single-group, multicenter, investigator-initiated study of adjuvant paclitaxel and trastuzumab in 406 patients with tumors measuring up to 3 cm in greatest dimension. Patients received weekly treatment with paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy. The primary end point was survival free from invasive disease.The median follow-up period was 4.0 years. The 3-year rate of survival free from invasive disease was 98.7% (95% confidence interval [CI], 97.6 to 99.8). Among the 12 relapses seen, 2 were due to distant metastatic breast cancer. Excluding contralateral HER2-negative breast cancers and nonbreast cancers, 7 disease-specific events were noted. A total of 13 patients (3.2%; 95% CI, 1.7 to 5.4) reported at least one episode of grade 3 neuropathy, and 2 had symptomatic congestive heart failure (0.5%; 95% CI, 0.1 to 1.8), both of whom had normalization of the left ventricular ejection fraction after discontinuation of trastuzumab. A total of 13 patients had significant asymptomatic declines in ejection fraction (3.2%; 95% CI, 1.7 to 5.4), as defined by the study, but 11 of these patients were able to resume trastuzumab therapy after a brief interruption.Among women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of about 2%; 6% of patients withdrew from the study because of protocol-specified adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT00542451.).

Authors
Tolaney, SM; Barry, WT; Dang, CT; Yardley, DA; Moy, B; Marcom, PK; Albain, KS; Rugo, HS; Ellis, M; Shapira, I; Wolff, AC; Carey, LA; Overmoyer, BA; Partridge, AH; Guo, H; Hudis, CA; Krop, IE; Burstein, HJ; Winer, EP
MLA Citation
Tolaney, SM, Barry, WT, Dang, CT, Yardley, DA, Moy, B, Marcom, PK, Albain, KS, Rugo, HS, Ellis, M, Shapira, I, Wolff, AC, Carey, LA, Overmoyer, BA, Partridge, AH, Guo, H, Hudis, CA, Krop, IE, Burstein, HJ, and Winer, EP. "Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer." The New England journal of medicine 372.2 (January 2015): 134-141.
PMID
25564897
Source
epmc
Published In
The New England journal of medicine
Volume
372
Issue
2
Publish Date
2015
Start Page
134
End Page
141
DOI
10.1056/nejmoa1406281

Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance

© 2015 Li et al.Introduction: Chemotherapy remains the only available treatment for triple-negative (TN) breast cancer, and most patients exhibit an incomplete pathologic response. Half of patients exhibiting an incomplete pathologic response die within five years of treatment due to chemo-resistant, recurrent tumor growth. Defining molecules responsible for TN breast cancer chemo-resistance is crucial for developing effective combination therapies blocking tumor recurrence. Historically, chemo-resistance studies have relied on long-term chemotherapy selection models that drive genetic mutations conferring cell survival. Other models suggest that tumors are heterogeneous, being composed of both chemo-sensitive and chemo-resistant tumor cell populations. We previously described a short-term chemotherapy treatment model that enriches for chemo-residual TN tumor cells. In the current work, we use this enrichment strategy to identify a novel determinant of TN breast cancer chemotherapy resistance [a nuclear isoform of basic fibroblast growth factor (bFGF)]. Methods: Studies are conducted using our in vitro model of chemotherapy resistance. Short-term chemotherapy treatment enriches for a chemo-residual TN subpopulation that over time resumes proliferation. By western blotting and real-time polymerase chain reaction, we show that this chemotherapy-enriched tumor cell subpopulation expresses nuclear bFGF. The importance of bFGF for survival of these chemo-residual cells is interrogated using short hairpin knockdown strategies. DNA repair capability is assessed by comet assay. Immunohistochemistry (IHC) is used to determine nuclear bFGF expression in TN breast cancer cases pre- and post- neoadjuvant chemotherapy. Results: TN tumor cells surviving short-term chemotherapy treatment express increased nuclear bFGF. bFGF knockdown reduces the number of chemo-residual TN tumor cells. Adding back a nuclear bFGF construct to bFGF knockdown cells restores their chemo-resistance. Nuclear bFGF-mediated chemo-resistance is associated with increased DNA-dependent protein kinase (DNA-PK) expression and accelerated DNA repair. In fifty-six percent of matched TN breast cancer cases, percent nuclear bFGF-positive tumor cells either increases or remains the same post- neoadjuvant chemotherapy treatment (compared to pre-treatment). These data indicate that in a subset of TN breast cancers, chemotherapy enriches for nuclear bFGF-expressing tumor cells. Conclusion: These studies identify nuclear bFGF as a protein in a subset of TN breast cancers that likely contributes to drug resistance following standard chemotherapy treatment.

Authors
Li, S; Payne, S; Wang, F; Claus, P; Su, Z; Groth, J; Geradts, J; Ridder, GD; Alvarez, R; Marcom, PK; Pizzo, SV; Bachelder, RE
MLA Citation
Li, S, Payne, S, Wang, F, Claus, P, Su, Z, Groth, J, Geradts, J, Ridder, GD, Alvarez, R, Marcom, PK, Pizzo, SV, and Bachelder, RE. "Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance." Breast Cancer Research (2015).
Source
scival
Published In
Breast Cancer Research
Publish Date
2015
DOI
10.1186/s13058-015-0590-3

Recurrence-free survival in breast cancer is associated with MRI tumor enhancement dynamics quantified using computer algorithms

© 2015 Elsevier Ireland Ltd. All rights reserved.Purpose The purpose of this study is to investigate the association between breast cancer recurrence-free survival and breast magnetic resonance imaging (MRI) tumor enhancement dynamics which are quantified semi-automatically using computer algorithms. Methods In this retrospective IRB-approved study, we analyzed data from 275 breast cancer patients at a single institution. Recurrence-free survival data were obtained from the medical record. Routine clinical pre-operative breast MRIs were performed in all patients. The tumors were marked on the MRIs by fellowship-trained breast radiologists. A previously developed computer algorithm was applied to the marked tumors to quantify the enhancement dynamics relative to the automatically assessed background parenchymal enhancement. To establish whether the contrast enhancement feature quantified by the algorithm was associated with recurrence-free survival, we constructed a Cox proportional hazards regression model with the computer-extracted feature as a covariate. We controlled for tumor grade and size (major axis length), patient age, patient race/ethnicity, and menopausal status. Results The analysis showed that the semi-automatically obtained feature quantifying MRI tumor enhancement dynamics was independently predictive of recurrence-free survival (p = 0.024). Conclusion Semi-automatically quantified tumor enhancement dynamics on MRI are predictive of recurrence-free survival in breast cancer patients.

Authors
Mazurowski, MA; Grimm, LJ; Zhang, J; Marcom, PK; Yoon, SC; Kim, C; Ghate, SV; Johnson, KS
MLA Citation
Mazurowski, MA, Grimm, LJ, Zhang, J, Marcom, PK, Yoon, SC, Kim, C, Ghate, SV, and Johnson, KS. "Recurrence-free survival in breast cancer is associated with MRI tumor enhancement dynamics quantified using computer algorithms." European Journal of Radiology 84.11 (2015): 2117-2122.
Source
scival
Published In
European Journal of Radiology
Volume
84
Issue
11
Publish Date
2015
Start Page
2117
End Page
2122
DOI
10.1016/j.ejrad.2015.07.012

Patient experience and attitudes toward addressing the cost of breast cancer care.

The American Society of Clinical Oncology views patient-physician discussion of costs as a component of high-quality care. Few data exist on patients' views regarding how cost should be addressed in the clinic.We distributed a self-administered, anonymous, paper survey to consecutive patients with breast cancer presenting for a routine visit within 5 years of diagnosis at an academic cancer center. Survey questions addressed experience and preferences concerning discussions of cost and views on cost control. Results are primarily descriptive, with comparison among participants on the basis of disease stage, using chi-square and Fisher's exact tests. All p values are two-sided.We surveyed 134 participants (response rate 86%). Median age was 61 years, and 28% had stage IV disease. Although 44% of participants reported at least a moderate level of financial distress, only 14% discussed costs with their doctor; 94% agreed doctors should talk to patients about costs of care. Regarding the impact of costs on decision making, 53% felt doctors should consider direct costs to the patient, but only 38% felt doctors should consider costs to society. Moreover, 88% reported concern about costs of care, but there was no consensus on how to control costs.Most breast cancer patients want to discuss costs of care, but there is little consensus on the desired content or goal of these discussions. Further research is needed to define the role of cost discussions at the bedside and how they will contribute to the goal of high-quality and sustainable cancer care.

Authors
Irwin, B; Kimmick, G; Altomare, I; Marcom, PK; Houck, K; Zafar, SY; Peppercorn, J
MLA Citation
Irwin, B, Kimmick, G, Altomare, I, Marcom, PK, Houck, K, Zafar, SY, and Peppercorn, J. "Patient experience and attitudes toward addressing the cost of breast cancer care." November 2014.
PMID
25273078
Source
epmc
Published In
The oncologist
Volume
19
Issue
11
Publish Date
2014
Start Page
1135
End Page
1140
DOI
10.1634/theoncologist.2014-0117

Patient Experience and Attitudes Toward Addressing the Cost of Breast Cancer Care

Authors
Irwin, B; Kimmick, G; Altomare, I; Marcom, PK; Houck, K; Zafar, SY; Peppercorn, J
MLA Citation
Irwin, B, Kimmick, G, Altomare, I, Marcom, PK, Houck, K, Zafar, SY, and Peppercorn, J. "Patient Experience and Attitudes Toward Addressing the Cost of Breast Cancer Care." ONCOLOGIST 19.11 (November 2014): 1135-1140.
Source
wos-lite
Published In
The oncologist
Volume
19
Issue
11
Publish Date
2014
Start Page
1135
End Page
1140
DOI
10.1634/theoncologist.2014-0117

Self-efficacy for coping with symptoms moderates the relationship between physical symptoms and well-being in breast cancer survivors taking adjuvant endocrine therapy.

This study examined the relationships between physical symptoms, self-efficacy for coping with symptoms, and functional, emotional, and social well-being in women who were taking adjuvant endocrine therapy for breast cancer.One hundred and twelve women who were taking adjuvant endocrine therapy (tamoxifen or an aromatase inhibitor) for breast cancer completed measures of physical symptoms, self-efficacy for coping with symptoms, and functional, social, and emotional well-being at the time of routine medical follow-up (women were on average 3.4 years post-surgery; range 3 months to 11 years).Multiple linear regression analyses showed that higher self-efficacy for coping with symptoms was associated with greater functional, emotional, and social well-being after controlling for physical symptoms (p < 0.05). Self-efficacy for coping with symptoms moderated the relationship between physical symptoms and functional (B = 0.05, SE = 0.02, t = 2.67, p = 0.009) and emotional well-being (B = 0.03, SE = 0.01, t = 2.45, p = 0.02). As self-efficacy increased, the relationship between greater physical symptoms and lower well-being became weaker. Among women with high levels of self-efficacy, physical symptoms were not related to functional and emotional well-being.Self-efficacy for coping with symptoms may reduce the negative impact of physical symptoms and contribute to well-being in breast cancer survivors taking adjuvant endocrine therapy. Future studies could examine whether psychosocial interventions aimed at increasing self-efficacy for managing symptoms help women better cope with treatment side effects and improve quality of life.

Authors
Shelby, RA; Edmond, SN; Wren, AA; Keefe, FJ; Peppercorn, JM; Marcom, PK; Blackwell, KL; Kimmick, GG
MLA Citation
Shelby, RA, Edmond, SN, Wren, AA, Keefe, FJ, Peppercorn, JM, Marcom, PK, Blackwell, KL, and Kimmick, GG. "Self-efficacy for coping with symptoms moderates the relationship between physical symptoms and well-being in breast cancer survivors taking adjuvant endocrine therapy." Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 22.10 (October 2014): 2851-2859.
PMID
24821365
Source
epmc
Published In
Supportive Care in Cancer
Volume
22
Issue
10
Publish Date
2014
Start Page
2851
End Page
2859
DOI
10.1007/s00520-014-2269-1

Genetic/familial high-risk assessment: breast and ovarian, version 1.2014.

During the past few years, several genetic aberrations that may contribute to increased risks for development of breast and/or ovarian cancers have been identified. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian focus specifically on the assessment of genetic mutations in BRCA1/BRCA2, TP53, and PTEN, and recommend approaches to genetic testing/counseling and management strategies in individuals with these mutations. This portion of the NCCN Guidelines includes recommendations regarding diagnostic criteria and management of patients with Cowden Syndrome/PTEN hamartoma tumor syndrome.

Authors
Daly, MB; Pilarski, R; Axilbund, JE; Buys, SS; Crawford, B; Friedman, S; Garber, JE; Horton, C; Kaklamani, V; Klein, C; Kohlmann, W; Kurian, A; Litton, J; Madlensky, L; Marcom, PK; Merajver, SD; Offit, K; Pal, T; Pasche, B; Reiser, G; Shannon, KM; Swisher, E; Voian, NC; Weitzel, JN; Whelan, A; Wiesner, GL; Dwyer, MA; Kumar, R; National comprehensive cancer network,
MLA Citation
Daly, MB, Pilarski, R, Axilbund, JE, Buys, SS, Crawford, B, Friedman, S, Garber, JE, Horton, C, Kaklamani, V, Klein, C, Kohlmann, W, Kurian, A, Litton, J, Madlensky, L, Marcom, PK, Merajver, SD, Offit, K, Pal, T, Pasche, B, Reiser, G, Shannon, KM, Swisher, E, Voian, NC, Weitzel, JN, Whelan, A, Wiesner, GL, Dwyer, MA, Kumar, R, and National comprehensive cancer network, . "Genetic/familial high-risk assessment: breast and ovarian, version 1.2014." Journal of the National Comprehensive Cancer Network : JNCCN 12.9 (September 2014): 1326-1338.
PMID
25190698
Source
epmc
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
12
Issue
9
Publish Date
2014
Start Page
1326
End Page
1338
DOI
10.6004/jnccn.2014.0127

TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases.

Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3 weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14 months and median OS was 7.8 months. Intracranial RR was 12 %, while intracranial CBR was 27 %. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 diarrhea was rare (3 %). Intrinsic subtyping revealed 19 of 21 tumors (79 %) were basal-like, and intracranial response was associated with high expression of proliferation-related genes. This study suggests a modest benefit of irinotecan plus iniparib in progressive TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease.

Authors
Anders, C; Deal, AM; Abramson, V; Liu, MC; Storniolo, AM; Carpenter, JT; Puhalla, S; Nanda, R; Melhem-Bertrandt, A; Lin, NU; Kelly Marcom, P; Van Poznak, C; Stearns, V; Melisko, M; Smith, JK; Karginova, O; Parker, J; Berg, J; Winer, EP; Peterman, A; Prat, A; Perou, CM; Wolff, AC; Carey, LA
MLA Citation
Anders, C, Deal, AM, Abramson, V, Liu, MC, Storniolo, AM, Carpenter, JT, Puhalla, S, Nanda, R, Melhem-Bertrandt, A, Lin, NU, Kelly Marcom, P, Van Poznak, C, Stearns, V, Melisko, M, Smith, JK, Karginova, O, Parker, J, Berg, J, Winer, EP, Peterman, A, Prat, A, Perou, CM, Wolff, AC, and Carey, LA. "TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases." Breast cancer research and treatment 146.3 (August 2014): 557-566.
PMID
25001612
Source
epmc
Published In
Breast Cancer Research and Treatment
Volume
146
Issue
3
Publish Date
2014
Start Page
557
End Page
566
DOI
10.1007/s10549-014-3039-y

Breast cancer version 3.2014.

Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. The NCCN Guidelines specific to management of large clinical stage II and III tumors are discussed in this article. These guidelines are the work of the members of the NCCN Breast Cancer Panel. Expert medical clinical judgment is required to apply these guidelines in the context of an individual patient to provide optimal care. Although not stated at every decision point of the guidelines, patient participation in prospective clinical trials is the preferred option of treatment for all stages of breast cancer.

Authors
Gradishar, WJ; Anderson, BO; Blair, SL; Burstein, HJ; Cyr, A; Elias, AD; Farrar, WB; Forero, A; Giordano, SH; Goldstein, LJ; Hayes, DF; Hudis, CA; Isakoff, SJ; Ljung, B-ME; Marcom, PK; Mayer, IA; McCormick, B; Miller, RS; Pegram, M; Pierce, LJ; Reed, EC; Salerno, KE; Schwartzberg, LS; Smith, ML; Soliman, H; Somlo, G; Ward, JH; Wolff, AC; Zellars, R; Shead, DA; Kumar, R; National Comprehensive Cancer Network Breast Cancer Panel,
MLA Citation
Gradishar, WJ, Anderson, BO, Blair, SL, Burstein, HJ, Cyr, A, Elias, AD, Farrar, WB, Forero, A, Giordano, SH, Goldstein, LJ, Hayes, DF, Hudis, CA, Isakoff, SJ, Ljung, B-ME, Marcom, PK, Mayer, IA, McCormick, B, Miller, RS, Pegram, M, Pierce, LJ, Reed, EC, Salerno, KE, Schwartzberg, LS, Smith, ML, Soliman, H, Somlo, G, Ward, JH, Wolff, AC, Zellars, R, Shead, DA, Kumar, R, and National Comprehensive Cancer Network Breast Cancer Panel, . "Breast cancer version 3.2014." Journal of the National Comprehensive Cancer Network : JNCCN 12.4 (April 2014): 542-590.
PMID
24717572
Source
epmc
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
12
Issue
4
Publish Date
2014
Start Page
542
End Page
590
DOI
10.6004/jnccn.2014.0058

Breast Cancer Version 3.2014 Clinical Practice Guidelines in Oncology

Authors
Gradishar, WJ; Anderson, BO; Blair, SL; Burstein, HJ; Cyr, A; Elias, AD; Farrar, WB; Forero, A; Giordano, SH; Goldstein, LJ; Hayes, DF; Hudis, CA; Isakoff, SJ; Ljung, B-ME; Marcom, PK; Mayer, IA; McCormick, B; Miller, RS; Pegram, M; Pierce, LJ; Reed, EC; Salerno, KE; Schwartzberg, LS; Smith, ML; Soliman, H; Somlo, G; Ward, JH; Wolff, AC; Zellars, R; Shead, DA; Kumar, R; NCCN,
MLA Citation
Gradishar, WJ, Anderson, BO, Blair, SL, Burstein, HJ, Cyr, A, Elias, AD, Farrar, WB, Forero, A, Giordano, SH, Goldstein, LJ, Hayes, DF, Hudis, CA, Isakoff, SJ, Ljung, B-ME, Marcom, PK, Mayer, IA, McCormick, B, Miller, RS, Pegram, M, Pierce, LJ, Reed, EC, Salerno, KE, Schwartzberg, LS, Smith, ML, Soliman, H, Somlo, G, Ward, JH, Wolff, AC, Zellars, R, Shead, DA, Kumar, R, and NCCN, . "Breast Cancer Version 3.2014 Clinical Practice Guidelines in Oncology." JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK 12.4 (April 2014): 542-590.
Source
wos-lite
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
12
Issue
4
Publish Date
2014
Start Page
542
End Page
590

Optimizing the quality of breast cancer biomarker use at Duke Cancer Institute.

Advances in identifying biomarker profiles in patients with early-stage breast cancer have improved 5-year curative rates. Identification of the HER2 receptor provides valuable information that has been shown to extend survival in adjuvant and metastatic settings. Current clinical guidelines discuss when confirmatory testing may be inappropriate. Using a quality improvement approach, the team at Duke Cancer Institute determined HER2 ordering practices in a large academic cancer center. HER2 ordering using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) was abstracted from the charts of 314 patients with early-stage breast cancer. Qualitative responses to current clinical practices were obtained from clinicians. Of the patients included, duplicate IHC was performed for 36% and in triplicate for 6%; repeat testing resulted in clinically significant change in HER2 status for approximately 20%. Repeat biomarker testing on metastatic biopsy sites "all of the time" was favored by the surveyed physicians. FISH was ordered for each grade of IHC: 0+ (>20% of cases), 1+ (>20%), 2+ (99%), 3+ (54%). Most physicians "strongly" or "somewhat" favored solutions that integrate order sets and care pathways into the electronic medical record. This quality improvement project identified root causes and solutions to practice variance in breast cancer biomarker ordering and interpretation. Further investigations are planned to standardize best practices while appreciating the clinical challenges posed by discordant test results.

Authors
Kamal, AH; Power, S; Broadwater, G; Holland, AR; Marcom, PK
MLA Citation
Kamal, AH, Power, S, Broadwater, G, Holland, AR, and Marcom, PK. "Optimizing the quality of breast cancer biomarker use at Duke Cancer Institute." Journal of the National Comprehensive Cancer Network : JNCCN 12 Suppl 1 (February 2014): S21-S24.
PMID
24614047
Source
epmc
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
12 Suppl 1
Publish Date
2014
Start Page
S21
End Page
S24
DOI
10.6004/jnccn.2014.0209

TBCRC 018: Phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases

Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3 weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14 months and median OS was 7.8 months. Intracranial RR was 12 %, while intracranial CBR was 27 %. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 diarrhea was rare (3 %). Intrinsic subtyping revealed 19 of 21 tumors (79 %) were basal-like, and intracranial response was associated with high expression of proliferation-related genes. This study suggests a modest benefit of irinotecan plus iniparib in progressive TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease. © 2014 The Author(s).

Authors
Anders, C; Deal, AM; Abramson, V; Liu, MC; Storniolo, AM; Carpenter, JT; Puhalla, S; Nanda, R; Melhem-Bertrandt, A; Lin, NU; Kelly Marcom, P; Van Poznak, C; Stearns, V; Melisko, M; Smith, JK; Karginova, O; Parker, J; Berg, J; Winer, EP; Peterman, A; Prat, A; Perou, CM; Wolff, AC; Carey, LA
MLA Citation
Anders, C, Deal, AM, Abramson, V, Liu, MC, Storniolo, AM, Carpenter, JT, Puhalla, S, Nanda, R, Melhem-Bertrandt, A, Lin, NU, Kelly Marcom, P, Van Poznak, C, Stearns, V, Melisko, M, Smith, JK, Karginova, O, Parker, J, Berg, J, Winer, EP, Peterman, A, Prat, A, Perou, CM, Wolff, AC, and Carey, LA. "TBCRC 018: Phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases." Breast Cancer Research and Treatment 146.3 (January 1, 2014): 557-566.
Source
scopus
Published In
Breast Cancer Research and Treatment
Volume
146
Issue
3
Publish Date
2014
Start Page
557
End Page
566
DOI
10.1007/s10549-014-3039-y

Self-efficacy for coping with symptoms moderates the relationship between physical symptoms and well-being in breast cancer survivors taking adjuvant endocrine therapy

© 2014, Springer-Verlag Berlin Heidelberg.Purpose: This study examined the relationships between physical symptoms, self-efficacy for coping with symptoms, and functional, emotional, and social well-being in women who were taking adjuvant endocrine therapy for breast cancer.Methods: One hundred and twelve women who were taking adjuvant endocrine therapy (tamoxifen or an aromatase inhibitor) for breast cancer completed measures of physical symptoms, self-efficacy for coping with symptoms, and functional, social, and emotional well-being at the time of routine medical follow-up (women were on average 3.4 years post-surgery; range 3 months to 11 years).Results: Multiple linear regression analyses showed that higher self-efficacy for coping with symptoms was associated with greater functional, emotional, and social well-being after controlling for physical symptoms (p < 0.05). Self-efficacy for coping with symptoms moderated the relationship between physical symptoms and functional (B = 0.05, SE = 0.02, t = 2.67, p = 0.009) and emotional well-being (B = 0.03, SE = 0.01, t = 2.45, p = 0.02). As self-efficacy increased, the relationship between greater physical symptoms and lower well-being became weaker. Among women with high levels of self-efficacy, physical symptoms were not related to functional and emotional well-being.Conclusions: Self-efficacy for coping with symptoms may reduce the negative impact of physical symptoms and contribute to well-being in breast cancer survivors taking adjuvant endocrine therapy. Future studies could examine whether psychosocial interventions aimed at increasing self-efficacy for managing symptoms help women better cope with treatment side effects and improve quality of life.

Authors
Shelby, RA; Edmond, SN; Wren, AA; Keefe, FJ; Peppercorn, JM; Marcom, PK; Blackwell, KL; Kimmick, GG
MLA Citation
Shelby, RA, Edmond, SN, Wren, AA, Keefe, FJ, Peppercorn, JM, Marcom, PK, Blackwell, KL, and Kimmick, GG. "Self-efficacy for coping with symptoms moderates the relationship between physical symptoms and well-being in breast cancer survivors taking adjuvant endocrine therapy." Supportive Care in Cancer 22.10 (2014): 2851-2859.
Source
scival
Published In
Supportive Care in Cancer
Volume
22
Issue
10
Publish Date
2014
Start Page
2851
End Page
2859
DOI
10.1007/s00520-014-2269-1

Nab-paclitaxel/bevacizumab/carboplatin chemotherapy in first-line triple negative metastatic breast cancer

Background Triple negative metastatic breast cancer can be difficult to treat with primarily cytotoxic options. Nab-paclitaxel has demonstrated improved PFS and tolerability compared with standard cremophor-solubilized paclitaxel; based on this, we examined the efficacy and safety of combining weekly nab-paclitaxel with carboplatin and bevacizumab in TNMBC. Patients and Methods In this phase II, multicenter trial, patients with first-line TNMBC received nab-paclitaxel (100 mg/m 2 ) and carboplatin (area under the curve = 2) on days 1, 8, 15, and bevacizumab (10 mg/kg) on days 1 and 15 of a 28-day cycle. The primary end point was safety and tolerability and secondary end points included PFS, ORR, and CBR. PFS was calculated using the Kaplan-Meier method. Results Between July 16, 2007, and October 3, 2011, 34 patients were enrolled at 4 centers. Median age was 50.0 (range, 30-76) years and 77% (n = 26) of patients received previous adjuvant therapy. Median PFS was 9.2 months (95% confidence interval [CI], 7.8-25.1 months). The CBR was 94% (95% CI, 80%-99%), and ORR was 85% (95% CI, 69%-95%) for the combination. The regimen was well tolerated with the most common grade 3/4 adverse events being neutropenia (n = 18; 53%) and thrombocytopenia (n = 6; 18%), with other serous events including 1 grade 3 and 1 grade 4 thrombotic event and 1 febrile neutropenia. Conclusion The combination of nab-paclitaxel, bevacizumab, and carboplatin as first-line treatment for TNMBC was efficacious and well tolerated. The PFS, CBR, and ORR, and tolerability of the regimen, compares favorably with other standard first-line therapies. © 2013 Elsevier Inc. All rights reserved.

Authors
Hamilton, E; Kimmick, G; Hopkins, J; Marcom, PK; Rocha, G; Welch, R; Broadwater, G; Blackwell, K
MLA Citation
Hamilton, E, Kimmick, G, Hopkins, J, Marcom, PK, Rocha, G, Welch, R, Broadwater, G, and Blackwell, K. "Nab-paclitaxel/bevacizumab/carboplatin chemotherapy in first-line triple negative metastatic breast cancer." Clinical Breast Cancer 13.6 (December 1, 2013): 416-420.
Source
scopus
Published In
Clinical Breast Cancer
Volume
13
Issue
6
Publish Date
2013
Start Page
416
End Page
420
DOI
10.1016/j.clbc.2013.08.003

Nab-paclitaxel/bevacizumab/carboplatin chemotherapy in first-line triple negative metastatic breast cancer.

BACKGROUND: Triple negative metastatic breast cancer can be difficult to treat with primarily cytotoxic options. Nab-paclitaxel has demonstrated improved PFS and tolerability compared with standard cremophor-solubilized paclitaxel; based on this, we examined the efficacy and safety of combining weekly nab-paclitaxel with carboplatin and bevacizumab in TNMBC. PATIENTS AND METHODS: In this phase II, multicenter trial, patients with first-line TNMBC received nab-paclitaxel (100 mg/m(2)) and carboplatin (area under the curve = 2) on days 1, 8, 15, and bevacizumab (10 mg/kg) on days 1 and 15 of a 28-day cycle. The primary end point was safety and tolerability and secondary end points included PFS, ORR, and CBR. PFS was calculated using the Kaplan-Meier method. RESULTS: Between July 16, 2007, and October 3, 2011, 34 patients were enrolled at 4 centers. Median age was 50.0 (range, 30-76) years and 77% (n = 26) of patients received previous adjuvant therapy. Median PFS was 9.2 months (95% confidence interval [CI], 7.8-25.1 months). The CBR was 94% (95% CI, 80%-99%), and ORR was 85% (95% CI, 69%-95%) for the combination. The regimen was well tolerated with the most common grade 3/4 adverse events being neutropenia (n = 18; 53%) and thrombocytopenia (n = 6; 18%), with other serous events including 1 grade 3 and 1 grade 4 thrombotic event and 1 febrile neutropenia. CONCLUSION: The combination of nab-paclitaxel, bevacizumab, and carboplatin as first-line treatment for TNMBC was efficacious and well tolerated. The PFS, CBR, and ORR, and tolerability of the regimen, compares favorably with other standard first-line therapies.

Authors
Hamilton, E; Kimmick, G; Hopkins, J; Marcom, PK; Rocha, G; Welch, R; Broadwater, G; Blackwell, K
MLA Citation
Hamilton, E, Kimmick, G, Hopkins, J, Marcom, PK, Rocha, G, Welch, R, Broadwater, G, and Blackwell, K. "Nab-paclitaxel/bevacizumab/carboplatin chemotherapy in first-line triple negative metastatic breast cancer." Clin Breast Cancer 13.6 (December 2013): 416-420.
PMID
24099649
Source
pubmed
Published In
Clinical Breast Cancer
Volume
13
Issue
6
Publish Date
2013
Start Page
416
End Page
420
DOI
10.1016/j.clbc.2013.08.003

Pharmacogenetic testing in the face of unclear clinical efficacy: lessons from cytochrome P450 2D6 for tamoxifen.

BACKGROUND: This study evaluated self-reported knowledge, practice, and attitudes toward commercially available cytochrome P450 2D6 (CYP2D6) pharmacogenomic testing for patients on tamoxifen for breast cancer (CYPT) among US oncologists while evidence for the use of the test was evolving. METHODS: A self-administered survey of medical oncology breast cancer specialists at National Comprehensive Cancer Network (NCCNO) centers and a random sample of community-based oncologists (CBOs) was undertaken. The survey evaluated knowledge and use of the CYP2D6 test and response to hypothetical test results. RESULTS: In total, 201 of 459 (44%) oncologists responded. At a time when CYPT remained experimental, 31% of oncologists reported use of CYPT and 56% reported willingness to order CYPT outside of a clinical trial if requested by a patient. Compared to oncologists specializing in breast cancer, oncologists in community-based practice were more likely to use CYPT routinely (21% versus 11%, P< .06), to order CYPT on patient request (66% versus 44%, P< .001), and to change management for premenopausal women with intermediate metabolism (34% CBO versus 8% NCCN, P< .001). Oncologists cited data from randomized trials and professional guidelines as most influential when considering use of a genetic test. CONCLUSIONS: Prior to definitive evidence, a minority of oncologists reported using the CYP2D6 test routinely, and many indicated willingness to change management of patients based on test results. There is a need to educate clinicians and the public regarding the uncertain benefits of commercially available genetic tests in clinical practice when evidence from ongoing trials is still emerging.

Authors
Peppercorn, J; Hamilton, E; Marcom, PK; Beskow, L; Lyman, GH
MLA Citation
Peppercorn, J, Hamilton, E, Marcom, PK, Beskow, L, and Lyman, GH. "Pharmacogenetic testing in the face of unclear clinical efficacy: lessons from cytochrome P450 2D6 for tamoxifen." Cancer 119.20 (October 15, 2013): 3703-3709.
PMID
23893861
Source
pubmed
Published In
Cancer
Volume
119
Issue
20
Publish Date
2013
Start Page
3703
End Page
3709
DOI
10.1002/cncr.28263

Modulation of circulating angiogenic factors and tumor biology by aerobic training in breast cancer patients receiving neoadjuvant chemotherapy.

Aerobic exercise training (AET) is an effective adjunct therapy to attenuate the adverse side-effects of adjuvant chemotherapy in women with early breast cancer. Whether AET interacts with the antitumor efficacy of chemotherapy has received scant attention. We carried out a pilot study to explore the effects of AET in combination with neoadjuvant doxorubicin-cyclophosphamide (AC+AET), relative to AC alone, on: (i) host physiology [exercise capacity (VO2 peak), brachial artery flow-mediated dilation (BA-FMD)], (ii) host-related circulating factors [circulating endothelial progenitor cells (CEP) cytokines and angiogenic factors (CAF)], and (iii) tumor phenotype [tumor blood flow ((15)O-water PET), tissue markers (hypoxia and proliferation), and gene expression] in 20 women with operable breast cancer. AET consisted of three supervised cycle ergometry sessions/week at 60% to 100% of VO2 peak, 30 to 45 min/session, for 12 weeks. There was significant time × group interactions for VO2 peak and BA-FMD, favoring the AC+AET group (P < 0.001 and P = 0.07, respectively). These changes were accompanied by significant time × group interactions in CEPs and select CAFs [placenta growth factor, interleukin (IL)-1β, and IL-2], also favoring the AC+AET group (P < 0.05). (15)O-water positron emission tomography (PET) imaging revealed a 38% decrease in tumor blood flow in the AC+AET group. There were no differences in any tumor tissue markers (P > 0.05). Whole-genome microarray tumor analysis revealed significant differential modulation of 57 pathways (P < 0.01), including many that converge on NF-κB. Data from this exploratory study provide initial evidence that AET can modulate several host- and tumor-related pathways during standard chemotherapy. The biologic and clinical implications remain to be determined.

Authors
Jones, LW; Fels, DR; West, M; Allen, JD; Broadwater, G; Barry, WT; Wilke, LG; Masko, E; Douglas, PS; Dash, RC; Povsic, TJ; Peppercorn, J; Marcom, PK; Blackwell, KL; Kimmick, G; Turkington, TG; Dewhirst, MW
MLA Citation
Jones, LW, Fels, DR, West, M, Allen, JD, Broadwater, G, Barry, WT, Wilke, LG, Masko, E, Douglas, PS, Dash, RC, Povsic, TJ, Peppercorn, J, Marcom, PK, Blackwell, KL, Kimmick, G, Turkington, TG, and Dewhirst, MW. "Modulation of circulating angiogenic factors and tumor biology by aerobic training in breast cancer patients receiving neoadjuvant chemotherapy." Cancer Prev Res (Phila) 6.9 (September 2013): 925-937.
PMID
23842792
Source
pubmed
Published In
Cancer Prevention Research
Volume
6
Issue
9
Publish Date
2013
Start Page
925
End Page
937
DOI
10.1158/1940-6207.CAPR-12-0416

Breast cancer, version 3.2013: featured updates to the NCCN guidelines.

These NCCN Guidelines Insights highlight the important updates specific to the management of HER2-positive metastatic breast cancer in the 2013 version of the NCCN Clinical Practice Guidelines in Oncology for Breast Cancer. These include new first-line and subsequent therapy options for patients with HER2-positive metastatic breast cancer.

Authors
Theriault, RL; Carlson, RW; Allred, C; Anderson, BO; Burstein, HJ; Edge, SB; Farrar, WB; Forero, A; Giordano, SH; Goldstein, LJ; Gradishar, WJ; Hayes, DF; Hudis, CA; Isakoff, SJ; Ljung, B-ME; Mankoff, DA; Marcom, PK; Mayer, IA; McCormick, B; Pierce, LJ; Reed, EC; Schwartzberg, LS; Smith, ML; Soliman, H; Somlo, G; Ward, JH; Wolff, AC; Zellars, R; Shead, DA; Kumar, R; National Comprehensive Cancer Network,
MLA Citation
Theriault, RL, Carlson, RW, Allred, C, Anderson, BO, Burstein, HJ, Edge, SB, Farrar, WB, Forero, A, Giordano, SH, Goldstein, LJ, Gradishar, WJ, Hayes, DF, Hudis, CA, Isakoff, SJ, Ljung, B-ME, Mankoff, DA, Marcom, PK, Mayer, IA, McCormick, B, Pierce, LJ, Reed, EC, Schwartzberg, LS, Smith, ML, Soliman, H, Somlo, G, Ward, JH, Wolff, AC, Zellars, R, Shead, DA, Kumar, R, and National Comprehensive Cancer Network, . "Breast cancer, version 3.2013: featured updates to the NCCN guidelines." J Natl Compr Canc Netw 11.7 (July 2013): 753-760.
PMID
23847214
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
11
Issue
7
Publish Date
2013
Start Page
753
End Page
760

Prevalence of BRCA mutations among women with triple-negative breast cancer (TNBC) in a genetic counseling cohort

Background: Revised NCCN guidelines recommend that women ≤60 years with triple-negative breast cancer (TNBC) be referred for consideration of genetic counseling. Small, homogeneous samples have limited evaluation of BRCA mutation prevalence among different ethnicities affected by TNBC subtype. We sought to determine whether the prevalence of BRCA mutations within a TNBC cohort differs by demographic factors. Methods: We performed a retrospective review of patients with TNBC referred for genetic counseling at two academic Hereditary Cancer Clinics between 2000 and 2012. Demographic data were collected, including age at diagnosis and race/ethnicity. Race was categorized as African American (AA), Ashkenazi Jewish (AJ), Asian, Caucasian, Hispanic, or other. Primary outcome was BRCA mutation status, analyzed by race/ethnicity and age at diagnosis. Results: A total of 469 patients with TNBC who underwent testing for BRCA genetic mutations were identified, of which 450 patients had evaluable BRCA testing results; 139 (30.8 %) had confirmed BRCA1 (n = 106) or BRCA2 (n = 32) mutations. BRCA mutation prevalence differed by ethnicity and race: AA (20.4 %), AJ (50 %), Asian (28.5 %), Caucasian (33.3 %), and Hispanic (20 %). The prevalence of genetic mutations also differed by age at diagnosis: <40 years (43.8 %), 40-49 years (27.4 %), 50-59 years (25.3 %), 60-69 years (12.5 %), and >70 years (16.6 %). Conclusions: The prevalence of genetic mutations among women with TNBC referred for genetic counseling is high and differs significantly by ethnicity/race and age. This data helps to refine mutation risk estimates among women with TNBC, allowing for more personalized genetic counseling potentially aiding in improved patient decision-making. © 2013 Society of Surgical Oncology.

Authors
Greenup, R; Buchanan, A; Lorizio, W; Rhoads, K; Chan, S; Leedom, T; King, R; McLennan, J; Crawford, B; Marcom, PK; al, E
MLA Citation
Greenup, R, Buchanan, A, Lorizio, W, Rhoads, K, Chan, S, Leedom, T, King, R, McLennan, J, Crawford, B, Marcom, PK, and al, E. "Prevalence of BRCA mutations among women with triple-negative breast cancer (TNBC) in a genetic counseling cohort." Annals of Surgical Oncology 20.10 (2013): 3254-3258.
Source
scival
Published In
Annals of Surgical Oncology
Volume
20
Issue
10
Publish Date
2013
Start Page
3254
End Page
3258
DOI
10.1245/s10434-013-3205-1

Prevalence of BRCA Mutations Among Women with Triple-Negative Breast Cancer (TNBC) in a Genetic Counseling Cohort

Background: Revised NCCN guidelines recommend that women ≤60 years with triple-negative breast cancer (TNBC) be referred for consideration of genetic counseling. Small, homogeneous samples have limited evaluation of BRCA mutation prevalence among different ethnicities affected by TNBC subtype. We sought to determine whether the prevalence of BRCA mutations within a TNBC cohort differs by demographic factors. Methods: We performed a retrospective review of patients with TNBC referred for genetic counseling at two academic Hereditary Cancer Clinics between 2000 and 2012. Demographic data were collected, including age at diagnosis and race/ethnicity. Race was categorized as African American (AA), Ashkenazi Jewish (AJ), Asian, Caucasian, Hispanic, or other. Primary outcome was BRCA mutation status, analyzed by race/ethnicity and age at diagnosis. Results: A total of 469 patients with TNBC who underwent testing for BRCA genetic mutations were identified, of which 450 patients had evaluable BRCA testing results; 139 (30.8 %) had confirmed BRCA1 (n = 106) or BRCA2 (n = 32) mutations. BRCA mutation prevalence differed by ethnicity and race: AA (20.4 %), AJ (50 %), Asian (28.5 %), Caucasian (33.3 %), and Hispanic (20 %). The prevalence of genetic mutations also differed by age at diagnosis: <40 years (43.8 %), 40-49 years (27.4 %), 50-59 years (25.3 %), 60-69 years (12.5 %), and >70 years (16.6 %). Conclusions: The prevalence of genetic mutations among women with TNBC referred for genetic counseling is high and differs significantly by ethnicity/race and age. This data helps to refine mutation risk estimates among women with TNBC, allowing for more personalized genetic counseling potentially aiding in improved patient decision-making. © 2013 Society of Surgical Oncology.

Authors
Greenup, R; Buchanan, A; Lorizio, W; Rhoads, K; Chan, S; Leedom, T; King, R; McLennan, J; Crawford, B; Marcom, PK; al, E
MLA Citation
Greenup, R, Buchanan, A, Lorizio, W, Rhoads, K, Chan, S, Leedom, T, King, R, McLennan, J, Crawford, B, Marcom, PK, and al, E. "Prevalence of BRCA Mutations Among Women with Triple-Negative Breast Cancer (TNBC) in a Genetic Counseling Cohort." Annals of Surgical Oncology (2013): 1-5.
PMID
23975317
Source
scival
Published In
Annals of Surgical Oncology
Publish Date
2013
Start Page
1
End Page
5
DOI
10.1245/s10434-013-3205-1

Symptom communication in breast cancer: relationships of holding back and self-efficacy for communication to symptoms and adjustment.

Adjuvant endocrine therapy improves overall survival for women with breast cancer. However, side effects may compromise patients' quality of life (QOL). This study examined how two communication variables (self-efficacy for symptom communication [SE] and holding back from discussing cancer-related concerns [HB]) relate to QOL, pain and menopausal symptoms. Participants with breast cancer (N = 61) completed questionnaires regarding symptoms, communication, and QOL. SE was positively related to QOL and negatively related to pain interference. HB from discussing cancer-related concerns was related negatively to QOL and positively to pain interference. HB mediated the relationship between SE and QOL as well as between SE and pain interference. Increased SE is beneficial among women on endocrine therapy for breast cancer. Future research should determine if interventions to improve SE are feasible and can improve QOL and symptom tolerability.

Authors
Edmond, SN; Shelby, RA; Kimmick, GG; Marcom, PK; Peppercorn, JM; Keefe, FJ
MLA Citation
Edmond, SN, Shelby, RA, Kimmick, GG, Marcom, PK, Peppercorn, JM, and Keefe, FJ. "Symptom communication in breast cancer: relationships of holding back and self-efficacy for communication to symptoms and adjustment." J Psychosoc Oncol 31.6 (2013): 698-711.
PMID
24175903
Source
pubmed
Published In
Journal of Psychosocial Oncology
Volume
31
Issue
6
Publish Date
2013
Start Page
698
End Page
711
DOI
10.1080/07347332.2013.835023

Pharmacogenetic testing in the face of unclear clinical efficacy: Lessons from cytochrome P450 2D6 for tamoxifen

BACKGROUND This study evaluated self-reported knowledge, practice, and attitudes toward commercially available cytochrome P450 2D6 (CYP2D6) pharmacogenomic testing for patients on tamoxifen for breast cancer (CYPT) among US oncologists while evidence for the use of the test was evolving. METHODS A self-administered survey of medical oncology breast cancer specialists at National Comprehensive Cancer Network (NCCNO) centers and a random sample of community-based oncologists (CBOs) was undertaken. The survey evaluated knowledge and use of the CYP2D6 test and response to hypothetical test results. RESULTS In total, 201 of 459 (44%) oncologists responded. At a time when CYPT remained experimental, 31% of oncologists reported use of CYPT and 56% reported willingness to order CYPT outside of a clinical trial if requested by a patient. Compared to oncologists specializing in breast cancer, oncologists in community-based practice were more likely to use CYPT routinely (21% versus 11%, P <.06), to order CYPT on patient request (66% versus 44%, P <.001), and to change management for premenopausal women with intermediate metabolism (34% CBO versus 8% NCCN, P <.001). Oncologists cited data from randomized trials and professional guidelines as most influential when considering use of a genetic test. CONCLUSIONS Prior to definitive evidence, a minority of oncologists reported using the CYP2D6 test routinely, and many indicated willingness to change management of patients based on test results. There is a need to educate clinicians and the public regarding the uncertain benefits of commercially available genetic tests in clinical practice when evidence from ongoing trials is still emerging. Cancer 2013;119:3703-3709. © 2013 American Cancer Society.

Authors
Peppercorn, J; Hamilton, E; Marcom, PK; Beskow, L; Lyman, GH
MLA Citation
Peppercorn, J, Hamilton, E, Marcom, PK, Beskow, L, and Lyman, GH. "Pharmacogenetic testing in the face of unclear clinical efficacy: Lessons from cytochrome P450 2D6 for tamoxifen." Cancer 119.20 (2013): 3703-3709.
Source
scival
Published In
Cancer
Volume
119
Issue
20
Publish Date
2013
Start Page
3703
End Page
3709
DOI
10.1002/cncr.28263

Pseudoangiomatous stromal hyperplasia (PASH) causing massive breast enlargement: MRI findings.

Authors
Johnson, KS; Bentley, RC; Kelly Marcom, P; Baker, JA
MLA Citation
Johnson, KS, Bentley, RC, Kelly Marcom, P, and Baker, JA. "Pseudoangiomatous stromal hyperplasia (PASH) causing massive breast enlargement: MRI findings." Breast J 18.6 (November 2012): 600-601.
PMID
23110315
Source
pubmed
Published In
The Breast Journal
Volume
18
Issue
6
Publish Date
2012
Start Page
600
End Page
601
DOI
10.1111/tbj.12026

Impact of hormone receptor status on patterns of recurrence and clinical outcomes among patients with human epidermal growth factor-2-positive breast cancer in the National Comprehensive Cancer Network: a prospective cohort study.

INTRODUCTION: In gene expression experiments, hormone receptor (HR)-positive/human epidermal growth factor-2 (HER2)-positive tumors generally cluster within the luminal B subset; whereas HR-negative/HER2-positive tumors reside in the HER2-enriched subset. We investigated whether the clinical behavior of HER2-positive tumors differs by HR status. METHODS: We evaluated 3,394 patients who presented to National Comprehensive Cancer Network (NCCN) centers with stage I to III HER2-positive breast cancer between 2000 and 2007. Tumors were grouped as HR-positive/HER2-positive (HR+/HER2+) or HR-negative/HER2-positive (HR-/HER2+). Chi-square, logistic regression and Cox hazard proportional regression were used to compare groups. RESULTS: Median follow-up was four years. Patients with HR-/HER2+ tumors (n = 1,379, 41% of total) were more likely than those with HR+/HER-2+ disease (n = 2,015, 59% of total) to present with high histologic grade and higher stages (P <0.001). Recurrences were recorded for 458 patients. HR-/HER2+ patients were less likely to experience first recurrence in bone (univariate Odds Ratio (OR) = 0.53, 95% Confidence Interval (CI): 0.34 to 0.82, P = 0.005) and more likely to recur in brain (univariate OR = 1.75, 95% CI: 1.05 to 2.93, P = 0.033). A lower risk of recurrence in bone persisted after adjusting for age, stage and adjuvant trastuzumab therapy (OR = 0.53, 95% CI: 0.34 to 0.83, P = 0.005) and when first and subsequent sites of recurrence were both considered (multivariable OR = 0.55, 95% CI: 0.37 to 0.80, P = 0.002). CONCLUSIONS: Presenting features, patterns of recurrence and survival of HER2-positive breast cancer differed by HR status. These differences should be further explored and integrated in the design of clinical trials.

Authors
Vaz-Luis, I; Ottesen, RA; Hughes, ME; Marcom, PK; Moy, B; Rugo, HS; Theriault, RL; Wilson, J; Niland, JC; Weeks, JC; Lin, NU
MLA Citation
Vaz-Luis, I, Ottesen, RA, Hughes, ME, Marcom, PK, Moy, B, Rugo, HS, Theriault, RL, Wilson, J, Niland, JC, Weeks, JC, and Lin, NU. "Impact of hormone receptor status on patterns of recurrence and clinical outcomes among patients with human epidermal growth factor-2-positive breast cancer in the National Comprehensive Cancer Network: a prospective cohort study. (Published online)" Breast Cancer Res 14.5 (October 1, 2012): R129-.
PMID
23025714
Source
pubmed
Published In
Breast Cancer Research
Volume
14
Issue
5
Publish Date
2012
Start Page
R129
DOI
10.1186/bcr3324

Phase I study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors.

PURPOSE: To define the maximum tolerated dose, clinical toxicities, and pharmacodynamics of bevacizumab, everolimus, and panobinostat (LBH-589) when administered in combination to patients with advanced solid tumor malignancies. EXPERIMENT DESIGN: Subjects received 10 mg of panobinostat three times weekly, 5 or 10 mg everolimus daily, and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Protein acetylation was assessed in peripheral blood mononuclear cells (PBMC) both at baseline and on treatment. RESULTS: Twelve subjects were evaluable for toxicity and nine subjects for response. DLTs in cohort 1 included grade 2 esophagitis and grade 3 oral mucositis; DLTs in cohort -1 were grade 2 ventricular arrhythmia and grade 2 intolerable skin rash. Common adverse events were diarrhea (50 %), headache (33 %), mucositis/stomatitis (25 %), hyperlipidemia (25 %), and thrombocytopenia (25 %). There was 1 partial response; an additional 2 subjects had stable disease as best response. No consistent changes in protein acetylation in PBMC were observed in samples available from eight patients on treatment compared with baseline. CONCLUSIONS: Bevacizumab, everolimus, and panobinostat in combination at the lowest proposed doses did not have an acceptable safety and tolerability profile and did not consistently inhibit HDAC activity; therefore, we do not recommend further evaluation.

Authors
Strickler, JH; Starodub, AN; Jia, J; Meadows, KL; Nixon, AB; Dellinger, A; Morse, MA; Uronis, HE; Marcom, PK; Zafar, SY; Haley, ST; Hurwitz, HI
MLA Citation
Strickler, JH, Starodub, AN, Jia, J, Meadows, KL, Nixon, AB, Dellinger, A, Morse, MA, Uronis, HE, Marcom, PK, Zafar, SY, Haley, ST, and Hurwitz, HI. "Phase I study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors." Cancer Chemother Pharmacol 70.2 (August 2012): 251-258.
PMID
22744359
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
70
Issue
2
Publish Date
2012
Start Page
251
End Page
258
DOI
10.1007/s00280-012-1911-1

TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer.

PURPOSE: Epidermal growth factor receptor (EGFR) is a targetable receptor frequently overexpressed in basal-like breast cancer, which comprises most triple-negative breast cancers (TNBCs), the only subtype without established targeted therapy. PATIENTS AND METHODS: In this randomized phase II trial, patients with metastatic TNBC received anti-EGFR antibody cetuximab (400 mg/m(2) load then 250 mg/m(2) per week intravenously [IV]) alone, with carboplatin (area under the curve of 2, once per week IV) added after progression or as concomitant therapy from the beginning. Response rate (RR) was the primary end point; others included time to progression (TTP), overall survival (OS), and toxicity. Embedded correlative studies included molecular subtyping on archival tissue. Fresh tumor tissue before and after 7 to 14 days of therapy was used for microarray analyses exploring EGFR pathway activity and inhibition. RESULTS: In 102 patients with TNBC, RRs were 6% (two of 31) to cetuximab and 16% (four of 25) to cetuximab plus carboplatin after progression. RR to those treated from the beginning with cetuximab plus carboplatin was 17% (12 of 71); 31% of patients responded or had prolonged disease stabilization. The cetuximab plus carboplatin regimen was well tolerated, but both TTP and OS were short at 2.1 months (95% CI, 1.8 to 5.5 months) and 10.4 months (95% CI, 7.7 to 13.1 months), respectively. Of 73 patients with archival tissue for analysis, 74% had basal-like molecular subtype. Sixteen patients had tumor biopsies before and 1 week after therapy; genomic patterns of the EGFR pathway showed activation in 13 and inhibition by therapy in five. CONCLUSION: Despite strong preclinical data, combination cetuximab plus carboplatin in metastatic TNBC produced responses in fewer than 20% of patients. EGFR pathway analysis showed that most TNBCs involved activation. However, cetuximab blocked expression of the EGFR pathway in only a minority, suggesting that most had alternate mechanisms for pathway activation.

Authors
Carey, LA; Rugo, HS; Marcom, PK; Mayer, EL; Esteva, FJ; Ma, CX; Liu, MC; Storniolo, AM; Rimawi, MF; Forero-Torres, A; Wolff, AC; Hobday, TJ; Ivanova, A; Chiu, W-K; Ferraro, M; Burrows, E; Bernard, PS; Hoadley, KA; Perou, CM; Winer, EP
MLA Citation
Carey, LA, Rugo, HS, Marcom, PK, Mayer, EL, Esteva, FJ, Ma, CX, Liu, MC, Storniolo, AM, Rimawi, MF, Forero-Torres, A, Wolff, AC, Hobday, TJ, Ivanova, A, Chiu, W-K, Ferraro, M, Burrows, E, Bernard, PS, Hoadley, KA, Perou, CM, and Winer, EP. "TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer." J Clin Oncol 30.21 (July 20, 2012): 2615-2623.
PMID
22665533
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
30
Issue
21
Publish Date
2012
Start Page
2615
End Page
2623
DOI
10.1200/JCO.2010.34.5579

Metastatic breast cancer, version 1.2012: featured updates to the NCCN guidelines.

These NCCN Guidelines Insights highlight the important updates/changes specific to the management of metastatic breast cancer in the 2012 version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer. These changes/updates include the issue of retesting of biomarkers (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2) on recurrent disease, new information regarding first-line combination endocrine therapy for metastatic disease, a new section on monitoring of patients with metastatic disease, and new information on endocrine therapy combined with an mTOR inhibitor as a subsequent therapeutic option.

Authors
Carlson, RW; Allred, DC; Anderson, BO; Burstein, HJ; Edge, SB; Farrar, WB; Forero, A; Giordano, SH; Goldstein, LJ; Gradishar, WJ; Hayes, DF; Hudis, CA; Isakoff, SJ; Ljung, B-ME; Mankoff, DA; Marcom, PK; Mayer, IA; McCormick, B; Pierce, LJ; Reed, EC; Smith, ML; Soliman, H; Somlo, G; Theriault, RL; Ward, JH; Wolff, AC; Zellars, R; Kumar, R; Shead, DA; National Comprehensive Cancer Network,
MLA Citation
Carlson, RW, Allred, DC, Anderson, BO, Burstein, HJ, Edge, SB, Farrar, WB, Forero, A, Giordano, SH, Goldstein, LJ, Gradishar, WJ, Hayes, DF, Hudis, CA, Isakoff, SJ, Ljung, B-ME, Mankoff, DA, Marcom, PK, Mayer, IA, McCormick, B, Pierce, LJ, Reed, EC, Smith, ML, Soliman, H, Somlo, G, Theriault, RL, Ward, JH, Wolff, AC, Zellars, R, Kumar, R, Shead, DA, and National Comprehensive Cancer Network, . "Metastatic breast cancer, version 1.2012: featured updates to the NCCN guidelines." J Natl Compr Canc Netw 10.7 (July 1, 2012): 821-829.
PMID
22773798
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
10
Issue
7
Publish Date
2012
Start Page
821
End Page
829

Adoption of gene expression profile testing and association with use of chemotherapy among women with breast cancer.

PURPOSE: Gene expression profile (GEP) testing is a relatively new technology that offers the potential of personalized medicine to patients, yet little is known about its adoption into routine practice. One of the first commercially available GEP tests, a 21-gene profile, was developed to estimate the benefit of adjuvant chemotherapy for hormone receptor-positive breast cancer (HR-positive BC). PATIENTS AND METHODS: By using a prospective registry data set outlining the routine care provided to women diagnosed from 2006 to 2008 with HR-positive BC at 17 comprehensive and community-based cancer centers, we assessed GEP test adoption and the association between testing and chemotherapy use. RESULTS: Of 7,375 women, 20.4% had GEP testing and 50.2% received chemotherapy. Over time, testing increased (14.7% in 2006 to 27.5% in 2008; P < .01) and use of chemotherapy decreased (53.9% in 2006 to 47.0% in 2008; P < .01). Characteristics independently associated with lower odds of testing included African American versus white race (odds ratio [OR], 0.70; 95% CI, 0.54 to 0.92) and high school or less versus more than high school education (OR, 0.63; 95% CI, 0.52 to 0.76). Overall, testing was associated with lower odds of chemotherapy use (OR, 0.70; 95% CI, 0.62 to 0.80). Stratified analyses demonstrated that for small, node-negative cancers, testing was associated with higher odds of chemotherapy use (OR, 11.13; 95% CI, 5.39 to 22.99), whereas for node-positive and large node-negative cancers, testing was associated with lower odds of chemotherapy use (OR, 0.11; 95% CI, 0.07 to 0.17). CONCLUSION: There has been a progressive increase in use of this GEP test and an associated shift in the characteristics of and overall reduction in the proportion of women with HR-positive BC receiving adjuvant chemotherapy.

Authors
Hassett, MJ; Silver, SM; Hughes, ME; Blayney, DW; Edge, SB; Herman, JG; Hudis, CA; Marcom, PK; Pettinga, JE; Share, D; Theriault, R; Wong, Y-N; Vandergrift, JL; Niland, JC; Weeks, JC
MLA Citation
Hassett, MJ, Silver, SM, Hughes, ME, Blayney, DW, Edge, SB, Herman, JG, Hudis, CA, Marcom, PK, Pettinga, JE, Share, D, Theriault, R, Wong, Y-N, Vandergrift, JL, Niland, JC, and Weeks, JC. "Adoption of gene expression profile testing and association with use of chemotherapy among women with breast cancer." J Clin Oncol 30.18 (June 20, 2012): 2218-2226.
PMID
22585699
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
30
Issue
18
Publish Date
2012
Start Page
2218
End Page
2226
DOI
10.1200/JCO.2011.38.5740

Whole-genome analysis informs breast cancer response to aromatase inhibition.

To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.

Authors
Ellis, MJ; Ding, L; Shen, D; Luo, J; Suman, VJ; Wallis, JW; Van Tine, BA; Hoog, J; Goiffon, RJ; Goldstein, TC; Ng, S; Lin, L; Crowder, R; Snider, J; Ballman, K; Weber, J; Chen, K; Koboldt, DC; Kandoth, C; Schierding, WS; McMichael, JF; Miller, CA; Lu, C; Harris, CC; McLellan, MD; Wendl, MC; DeSchryver, K; Allred, DC; Esserman, L; Unzeitig, G; Margenthaler, J; Babiera, GV; Marcom, PK; Guenther, JM; Leitch, M; Hunt, K; Olson, J; Tao, Y; Maher, CA; Fulton, LL; Fulton, RS; Harrison, M; Oberkfell, B et al.
MLA Citation
Ellis, MJ, Ding, L, Shen, D, Luo, J, Suman, VJ, Wallis, JW, Van Tine, BA, Hoog, J, Goiffon, RJ, Goldstein, TC, Ng, S, Lin, L, Crowder, R, Snider, J, Ballman, K, Weber, J, Chen, K, Koboldt, DC, Kandoth, C, Schierding, WS, McMichael, JF, Miller, CA, Lu, C, Harris, CC, McLellan, MD, Wendl, MC, DeSchryver, K, Allred, DC, Esserman, L, Unzeitig, G, Margenthaler, J, Babiera, GV, Marcom, PK, Guenther, JM, Leitch, M, Hunt, K, Olson, J, Tao, Y, Maher, CA, Fulton, LL, Fulton, RS, Harrison, M, and Oberkfell, B et al. "Whole-genome analysis informs breast cancer response to aromatase inhibition. (Published online)" Nature 486.7403 (June 10, 2012): 353-360.
PMID
22722193
Source
pubmed
Published In
Nature
Volume
486
Issue
7403
Publish Date
2012
Start Page
353
End Page
360
DOI
10.1038/nature11143

Retraction: Acharya CR, et al. Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer. JAMA. 2008;299(13):1574-1587.

Authors
Acharya, CR; Hsu, DS; Anders, CK; Anguiano, A; Salter, KH; Walters, KS; Redman, RC; Tuchman, SA; Moylan, CA; Mukherjee, S; Barry, WT; Dressman, HK; Ginsburg, GS; Marcom, KP; Garman, KS; Lyman, GH; Nevins, JR; Potti, A
MLA Citation
Acharya, CR, Hsu, DS, Anders, CK, Anguiano, A, Salter, KH, Walters, KS, Redman, RC, Tuchman, SA, Moylan, CA, Mukherjee, S, Barry, WT, Dressman, HK, Ginsburg, GS, Marcom, KP, Garman, KS, Lyman, GH, Nevins, JR, and Potti, A. "Retraction: Acharya CR, et al. Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer. JAMA. 2008;299(13):1574-1587." JAMA 307.5 (February 1, 2012): 453-.
PMID
22228686
Source
pubmed
Published In
JAMA : the journal of the American Medical Association
Volume
307
Issue
5
Publish Date
2012
Start Page
453
DOI
10.1001/jama.2012.2

Phase II trial of dasatinib in patients with metastatic breast cancer using real-time pharmacodynamic tissue biomarkers of Src inhibition to escalate dosing.

PURPOSE: A phase II study of dasatinib, an inhibitor of multiple oncogenic tyrosine kinases including Src, was conducted to evaluate 16-week progression-free rate and tolerability in patients with previously treated metastatic breast cancer (MBC). Real-time assessment of potential tissue biomarkers of Src inhibition was used to optimize dosing. EXPERIMENTAL DESIGN: Eligibility criteria required that patients have measurable MBC, biopsiable tumor, and unlimited prior therapies. For the analysis of change in protein biomarkers of Src inhibition, focal adhesion kinase, paxillin, and p-Src, patients underwent metastatic biopsies at baseline and 4 weeks. Patients who tolerated the starting dose of dasatinib (50 or 70 mg orally twice daily) for the first 28-day cycle, and displayed suboptimal Src inhibition, were escalated to a higher dose (70 or 100 mg). RESULTS: The trial was closed early with 31 patients because of a statistical boundary that required at least 4 (13%) patients without disease progression to continue accrual. These 31 patients had a median of 2 prior lines of chemotherapy for MBC. The most notable toxicity was pleural effusions in 16 patients (52%). Twenty patients had evaluable metastatic biopsies. None of the tumors showed the predefined optimal level of Src inhibition at week 4. CONCLUSIONS: Single-agent dasatinib did not exhibit significant antitumor activity in patients with heavily pretreated MBC. There were no clinically meaningful decreases before and after dasatinib exposure between exploratory tissue biomarkers of Src inhibition which may be attributable to challenges in defining biomarker endpoints for multitargeted tyrosine kinase inhibitors.

Authors
Herold, CI; Chadaram, V; Peterson, BL; Marcom, PK; Hopkins, J; Kimmick, GG; Favaro, J; Hamilton, E; Welch, RA; Bacus, S; Blackwell, KL
MLA Citation
Herold, CI, Chadaram, V, Peterson, BL, Marcom, PK, Hopkins, J, Kimmick, GG, Favaro, J, Hamilton, E, Welch, RA, Bacus, S, and Blackwell, KL. "Phase II trial of dasatinib in patients with metastatic breast cancer using real-time pharmacodynamic tissue biomarkers of Src inhibition to escalate dosing." Clin Cancer Res 17.18 (September 15, 2011): 6061-6070.
PMID
21810917
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
18
Publish Date
2011
Start Page
6061
End Page
6070
DOI
10.1158/1078-0432.CCR-11-1071

Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers.

During cancer progression, malignant cells undergo epithelial-mesenchymal transitions (EMT) and mesenchymal-epithelial transitions (MET) as part of a broad invasion and metastasis program. We previously observed MET events among lung metastases in a preclinical model of prostate adenocarcinoma that suggested a relationship between epithelial plasticity and metastatic spread. We thus sought to translate these findings into clinical evidence by examining the existence of EMT in circulating tumor cells (CTC) from patients with progressive metastatic solid tumors, with a focus on men with castration-resistant prostate cancer (CRPC) and women with metastatic breast cancer. We showed that the majority (> 80%) of these CTCs in patients with metastatic CRPC coexpress epithelial proteins such as epithelial cell adhesion molecule (EpCAM), cytokeratins (CK), and E-cadherin, with mesenchymal proteins including vimentin, N-cadherin and O-cadherin, and the stem cell marker CD133. Equally, we found that more than 75% of CTCs from women with metastatic breast cancer coexpress CK, vimentin, and N-cadherin. The existence and high frequency of these CTCs coexpressing epithelial, mesenchymal, and stem cell markers in patients with progressive metastases has important implications for the application and interpretation of approved methods to detect CTCs.

Authors
Armstrong, AJ; Marengo, MS; Oltean, S; Kemeny, G; Bitting, RL; Turnbull, JD; Herold, CI; Marcom, PK; George, DJ; Garcia-Blanco, MA
MLA Citation
Armstrong, AJ, Marengo, MS, Oltean, S, Kemeny, G, Bitting, RL, Turnbull, JD, Herold, CI, Marcom, PK, George, DJ, and Garcia-Blanco, MA. "Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers." Mol Cancer Res 9.8 (August 2011): 997-1007.
PMID
21665936
Source
pubmed
Published In
Molecular cancer research : MCR
Volume
9
Issue
8
Publish Date
2011
Start Page
997
End Page
1007
DOI
10.1158/1541-7786.MCR-10-0490

Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031.

PURPOSE: Preoperative aromatase inhibitor (AI) treatment promotes breast-conserving surgery (BCS) for estrogen receptor (ER)-positive breast cancer. To study this treatment option, responses to three AIs were compared in a randomized phase II neoadjuvant trial designed to select agents for phase III investigations. PATIENTS AND METHODS: Three hundred seventy-seven postmenopausal women with clinical stage II to III ER-positive (Allred score 6-8) breast cancer were randomly assigned to receive neoadjuvant exemestane, letrozole, or anastrozole. The primary end point was clinical response. Secondary end points included BCS, Ki67 proliferation marker changes, the Preoperative Endocrine Prognostic Index (PEPI), and PAM50-based intrinsic subtype analysis. RESULTS: On the basis of clinical response rates, letrozole and anastrozole were selected for further investigation; however, no other differences in surgical outcome, PEPI score, or Ki67 suppression were detected. The BCS rate for mastectomy-only patients at presentation was 51%. PAM50 analysis identified AI-unresponsive nonluminal subtypes (human epidermal growth factor receptor 2 enriched or basal-like) in 3.3% of patients. Clinical response and surgical outcomes were similar in luminal A (LumA) versus luminal B tumors; however, a PEPI of 0 (best prognostic group) was highest in the LumA subset (27.1% v 10.7%; P = .004). CONCLUSION: Neoadjuvant AI treatment markedly improved surgical outcomes. Ki67 and PEPI data demonstrated that the three agents tested are biologically equivalent and therefore likely to have similar adjuvant activities. LumA tumors were more likely to have favorable biomarker characteristics after treatment; however, occasional paradoxical increases in Ki67 (12% of tumors with > 5% increase after therapy) suggest treatment-resistant cells, present in some LumA tumors, can be detected by post-treatment profiling.

Authors
Ellis, MJ; Suman, VJ; Hoog, J; Lin, L; Snider, J; Prat, A; Parker, JS; Luo, J; DeSchryver, K; Allred, DC; Esserman, LJ; Unzeitig, GW; Margenthaler, J; Babiera, GV; Marcom, PK; Guenther, JM; Watson, MA; Leitch, M; Hunt, K; Olson, JA
MLA Citation
Ellis, MJ, Suman, VJ, Hoog, J, Lin, L, Snider, J, Prat, A, Parker, JS, Luo, J, DeSchryver, K, Allred, DC, Esserman, LJ, Unzeitig, GW, Margenthaler, J, Babiera, GV, Marcom, PK, Guenther, JM, Watson, MA, Leitch, M, Hunt, K, and Olson, JA. "Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031." J Clin Oncol 29.17 (June 10, 2011): 2342-2349.
PMID
21555689
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
17
Publish Date
2011
Start Page
2342
End Page
2349
DOI
10.1200/JCO.2010.31.6950

Individual responses to chemotherapy-induced oxidative stress.

Differences in redox homeostatic control between cancer patients may underlie predisposition to drug resistance and toxicities. To evaluate interindividual differences in redox response among newly diagnosed breast cancer patients undergoing standard chemotherapy, urine samples were collected before (T0), and at 1 (T1) and 24 h (T24) after chemotherapy administration. Oxidative status was assessed by urinary levels of allantoin and four F2-isoprostanes, quantified by LC-MS/MS. In all subjects, biomarker levels increased at T1 and returned to baseline at T24. Analyzing individual responses, two patterns were revealed: 10 subjects showed uniform increases of biomarker levels at T1 ("increase" pattern) and 8 subjects showed mixed (increase/unchanged/decrease) responses for different biomarkers ("mixed" pattern). The increase-pattern group had lower pre-treatment (T0) levels of the biomarkers and showed a sharp increase at T1 (64-141%) with a subsequent decrease at T24. The mixed-pattern group had higher pre-treatment biomarker levels and showed no change in biomarkers either at T1 or at T24. These findings indicate that there may be at least two distinct redox phenotypes with different homeostatic mechanisms balancing oxidative stress in humans. Recognizing redox phenotypes in human populations may lead to more precise assessment of health risks and benefits associated with individual redox make-up, and may also help to identify cancer patients who are especially susceptible to drug resistance and/or drug toxicity.

Authors
Il'yasova, D; Kennedy, K; Spasojevic, I; Wang, F; Tolun, AA; Base, K; Young, SP; Kelly Marcom, P; Marks, J; Millington, DS; Dewhirst, MW
MLA Citation
Il'yasova, D, Kennedy, K, Spasojevic, I, Wang, F, Tolun, AA, Base, K, Young, SP, Kelly Marcom, P, Marks, J, Millington, DS, and Dewhirst, MW. "Individual responses to chemotherapy-induced oxidative stress." Breast Cancer Res Treat 125.2 (January 2011): 583-589.
PMID
20830514
Source
pubmed
Published In
Breast Cancer Research and Treatment
Volume
125
Issue
2
Publish Date
2011
Start Page
583
End Page
589
DOI
10.1007/s10549-010-1158-7

Surgery of the primary tumor does not improve survival in stage IV breast cancer

We sought to evaluate the survival of patients who received breast surgery prior to any other breast cancer therapy following a metastatic diagnosis. Standard treatment for stage IV breast cancer is systemic therapy without resection of the primary tumor. Registry-based studies suggest that resection of the primary tumor may improve survival in stage IV cancer. We performed a retrospective analysis using data from the National Comprehensive Cancer Network (NCCN) Breast Cancer Outcomes Database. Patients were eligible if they had a metastatic breast cancer diagnosis at presentation with disease at a distant site and either received surgery prior to any systemic therapy or received systemic therapy only. Eligible patients who did not receive surgery were matched to those who received surgery based on age at diagnosis, ER, HER2, and number of metastatic sites. To determine whether estimates from the matched analysis were consistent with estimates that could be obtained without matching univariate and multivariable analyses of the unmatched sample were also conducted. There were 1,048 patients in the NCCN database diagnosed with stage IV breast cancer from 1997 to 2007. 609 metastatic breast cancer patients were identified as eligible for the study. Among the 551 patients who had data available for matching, 236 patients who did not receive surgery were matched to 54 patients who received surgery. Survival was similar between the groups with a median of 3.4 years in the nonsurgery group and 3.5 years in the surgery group. The groups were similar after adjusting for the presence of lung metastases and use of trastuzumab therapy (HR = 0.94, CI 0.83-1.08, P = 0.38). When matching for the variables associated with a survival benefit in previous studies, surgery was not shown to improve survival in the stage IV setting for this subset © 2011 Springer Science+Business Media, LLC.

Authors
Dominici, L; Najita, J; Hughes, M; Niland, J; Marcom, P; Wong, Y-N; Carter, B; Javid, S; Edge, S; Burstein, H; Golshan, M
MLA Citation
Dominici, L, Najita, J, Hughes, M, Niland, J, Marcom, P, Wong, Y-N, Carter, B, Javid, S, Edge, S, Burstein, H, and Golshan, M. "Surgery of the primary tumor does not improve survival in stage IV breast cancer." Breast Cancer Research and Treatment 129.2 (2011): 459-465.
PMID
21713372
Source
scival
Published In
Breast Cancer Research and Treatment
Volume
129
Issue
2
Publish Date
2011
Start Page
459
End Page
465
DOI
10.1007/s10549-011-1648-2

Correction: An integration of complementary strategies for gene-expression analysis to reveal novel therapeutic opportunities for breast cancer

Authors
Bild, AH; Parker, JS; Gustafson, AM; Acharya, CR; Hoadley, KA; Anders, C; Marcom, PK; Carey, LA; Potti, A; Nevins, JR; Perou, CM
MLA Citation
Bild, AH, Parker, JS, Gustafson, AM, Acharya, CR, Hoadley, KA, Anders, C, Marcom, PK, Carey, LA, Potti, A, Nevins, JR, and Perou, CM. "Correction: An integration of complementary strategies for gene-expression analysis to reveal novel therapeutic opportunities for breast cancer." Breast Cancer Research 13.4 (2011).
Source
scival
Published In
Breast Cancer Research
Volume
13
Issue
4
Publish Date
2011
DOI
10.1186/bcr2909

Invasive breast cancer: Clinical practice guidelines in oncology

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. In many situations, the patient and physician have the responsibility to jointly explore and select the most appropriate option from among the available alternatives. With few exceptions, the evaluation, treatment, and follow-up recommendations in these NCCN Guidelines are based on the results of past and present clinical trials. However, not a single clinical situation exists in which the treatment of breast cancer has been optimized with respect to either maximizing cure or minimizing toxicity and disfigurement. Therefore, patient/physician participation in prospective clinical trials allows patients to not only receive state-of-the-art cancer treatment but also contribute to improving the treatment of future patients. © JNCCN - Journal of the National Comprehensive Cancer Network.

Authors
Carlson, RW; Allred, DC; Anderson, BO; Burstein, HJ; Carter, WB; Edge, SB; Erban, JK; Farrar, WB; Forero, A; Giordano, SH; Goldstein, LJ; Gradishar, WJ; Hayes, DF; Hudis, CA; Ljung, B-M; Mankoff, DA; Marcom, PK; Mayer, IA; McCormick, B; Pierce, LJ; Reed, EC; Sachdev, J; Smith, ML; Somlo, G; Ward, JH; Wolff, AC; Zellars, R
MLA Citation
Carlson, RW, Allred, DC, Anderson, BO, Burstein, HJ, Carter, WB, Edge, SB, Erban, JK, Farrar, WB, Forero, A, Giordano, SH, Goldstein, LJ, Gradishar, WJ, Hayes, DF, Hudis, CA, Ljung, B-M, Mankoff, DA, Marcom, PK, Mayer, IA, McCormick, B, Pierce, LJ, Reed, EC, Sachdev, J, Smith, ML, Somlo, G, Ward, JH, Wolff, AC, and Zellars, R. "Invasive breast cancer: Clinical practice guidelines in oncology." JNCCN Journal of the National Comprehensive Cancer Network 9.2 (2011): 136-222.
PMID
21310842
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
9
Issue
2
Publish Date
2011
Start Page
136
End Page
222

An Integrated Approach to the Prediction of Chemotherapeutic Response in Patients with Breast Cancer

Background: A major challenge in oncology is the selection of the most effective chemotherapeutic agents for individual patients, while the administration of ineffective chemotherapy increases mortality and decreases quality of life in cancer patients. This emphasizes the need to evaluate every patient's probability of responding to each chemotherapeutic agent and limiting the agents used to those most likely to be effective. Methods and Results: Using gene expression data on the NCI-60 and corresponding drug sensitivity, mRNA and microRNA profiles were developed representing sensitivity to individual chemotherapeutic agents. The mRNA signatures were tested in an independent cohort of 133 breast cancer patients treated with the TFAC (paclitaxel, 5-fluorouracil, adriamycin, and cyclophosphamide) chemotherapy regimen. To further dissect the biology of resistance, we applied signatures of oncogenic pathway activation and performed hierarchical clustering. We then used mRNA signatures of chemotherapy sensitivity to identify alternative therapeutics for patients resistant to TFAC. Profiles from mRNA and microRNA expression data represent distinct biologic mechanisms of resistance to common cytotoxic agents. The individual mRNA signatures were validated in an independent dataset of breast tumors (P = 0.002, NPV = 82%). When the accuracy of the signatures was analyzed based on molecular variables, the predictive ability was found to be greater in basal-like than non basal-like patients (P = 0.03 and P = 0.06). Samples from patients with co-activated Myc and E2F represented the cohort with the lowest percentage (8%) of responders. Using mRNA signatures of sensitivity to other cytotoxic agents, we predict that TFAC non-responders are more likely to be sensitive to docetaxel (P = 0.04), representing a viable alternative therapy. Conclusions: Our results suggest that the optimal strategy for chemotherapy sensitivity prediction integrates molecular variables such as ER and HER2 status with corresponding microRNA and mRNA expression profiles. Importantly, we also present evidence to support the concept that analysis of molecular variables can present a rational strategy to identifying alternative therapeutic opportunities. © 2008 Salter et al.

Authors
Salter, KH; Acharya, CR; Walters, KS; Redman, R; Anguiano, A; Garman, KS; Anders, CK; Mukherjee, S; Dressman, HK; Barry, WT; Marcom, KP; Olson, J; Nevins, JR; Potti, A
MLA Citation
Salter, KH, Acharya, CR, Walters, KS, Redman, R, Anguiano, A, Garman, KS, Anders, CK, Mukherjee, S, Dressman, HK, Barry, WT, Marcom, KP, Olson, J, Nevins, JR, and Potti, A. "An Integrated Approach to the Prediction of Chemotherapeutic Response in Patients with Breast Cancer." PLoS ONE 6.9 (2011).
Source
scival
Published In
PloS one
Volume
6
Issue
9
Publish Date
2011
DOI
10.1371/journal.pone.0001908

Evaluation of established breast cancer risk factors as modifiers of BRCA1 or BRCA2: a multi-center case-only analysis.

The incomplete penetrance of mutations in BRCA1 and BRCA2 suggests that some combination of environmental and genetic factors modifies the risk of breast cancer in mutation carriers. This study sought to identify possible interactions between established breast cancer risk factors and BRCA1 or BRCA2 mutations using a case-only study design. Breast cancer cases that had been tested for BRCA1 and BRCA2 mutations were identified from 11 collaborating centers. Comparisons of reproductive and lifestyle risk factors were made between women with breast cancer who were positive for BRCA1 mutations (n = 283), BRCA2 mutations (n = 204), or negative for both BRCA1 and BRCA2 mutations (n = 894). Interaction risk ratios (IRRs) were calculated using multinominal logistic regression models. Compared with non-carriers, statistically significant IRRs were observed for later age at menarche among BRCA2 mutation carriers, for a greater number of pregnancies among both BRCA1 and BRCA2 mutation carriers, and for alcohol use among BRCA1 mutation carriers. Our data suggest that the risk for breast cancer among BRCA1 or BRCA2 carriers may be modified by reproductive characteristics and alcohol use. However, our results should be interpreted cautiously given the overall inconsistency in the epidemiologic literature on modifiers of BRCA1 and BRCA2.

Authors
Moorman, PG; Iversen, ES; Marcom, PK; Marks, JR; Wang, F; Kathleen Cuningham Consortium for Research into Familial Breast Cancer, ; Lee, E; Ursin, G; Rebbeck, TR; Domchek, SM; Arun, B; Susswein, L; Isaacs, C; Garber, JE; Visvanathan, K; Griffin, CA; Sutphen, R; Brzosowicz, J; Gruber, S; Finkelstein, DM; Schildkraut, JM
MLA Citation
Moorman, PG, Iversen, ES, Marcom, PK, Marks, JR, Wang, F, Kathleen Cuningham Consortium for Research into Familial Breast Cancer, , Lee, E, Ursin, G, Rebbeck, TR, Domchek, SM, Arun, B, Susswein, L, Isaacs, C, Garber, JE, Visvanathan, K, Griffin, CA, Sutphen, R, Brzosowicz, J, Gruber, S, Finkelstein, DM, and Schildkraut, JM. "Evaluation of established breast cancer risk factors as modifiers of BRCA1 or BRCA2: a multi-center case-only analysis." Breast Cancer Res Treat 124.2 (November 2010): 441-451.
PMID
20309627
Source
pubmed
Published In
Breast Cancer Research and Treatment
Volume
124
Issue
2
Publish Date
2010
Start Page
441
End Page
451
DOI
10.1007/s10549-010-0842-y

Rationale and design of the Exercise Intensity Trial (EXCITE): A randomized trial comparing the effects of moderate versus moderate to high-intensity aerobic training in women with operable breast cancer.

BACKGROUND: The Exercise Intensity Trial (EXcITe) is a randomized trial to compare the efficacy of supervised moderate-intensity aerobic training to moderate to high-intensity aerobic training, relative to attention control, on aerobic capacity, physiologic mechanisms, patient-reported outcomes, and biomarkers in women with operable breast cancer following the completion of definitive adjuvant therapy. METHODS/DESIGN: Using a single-center, randomized design, 174 postmenopausal women (58 patients/study arm) with histologically confirmed, operable breast cancer presenting to Duke University Medical Center (DUMC) will be enrolled in this trial following completion of primary therapy (including surgery, radiation therapy, and chemotherapy). After baseline assessments, eligible participants will be randomized to one of two supervised aerobic training interventions (moderate-intensity or moderate/high-intensity aerobic training) or an attention-control group (progressive stretching). The aerobic training interventions will include 150 mins.wk⁻¹ of supervised treadmill walking per week at an intensity of 60%-70% (moderate-intensity) or 60% to 100% (moderate to high-intensity) of the individually determined peak oxygen consumption (VO₂peak) between 20-45 minutes/session for 16 weeks. The progressive stretching program will be consistent with the exercise interventions in terms of program length (16 weeks), social interaction (participants will receive one-on-one instruction), and duration (20-45 mins/session). The primary study endpoint is VO₂peak, as measured by an incremental cardiopulmonary exercise test. Secondary endpoints include physiologic determinants that govern VO₂peak, patient-reported outcomes, and biomarkers associated with breast cancer recurrence/mortality. All endpoints will be assessed at baseline and after the intervention (16 weeks). DISCUSSION: EXCITE is designed to investigate the intensity of aerobic training required to induce optimal improvements in VO₂peak and other pertinent outcomes in women who have completed definitive adjuvant therapy for operable breast cancer. Overall, this trial will inform and refine exercise guidelines to optimize recovery in breast and other cancer survivors following the completion of primary cytotoxic therapy. TRIAL REGISTRATION: NCT01186367.

Authors
Jones, LW; Douglas, PS; Eves, ND; Marcom, PK; Kraus, WE; Herndon, JE; Inman, BA; Allen, JD; Peppercorn, J
MLA Citation
Jones, LW, Douglas, PS, Eves, ND, Marcom, PK, Kraus, WE, Herndon, JE, Inman, BA, Allen, JD, and Peppercorn, J. "Rationale and design of the Exercise Intensity Trial (EXCITE): A randomized trial comparing the effects of moderate versus moderate to high-intensity aerobic training in women with operable breast cancer. (Published online)" BMC Cancer 10 (October 6, 2010): 531-.
Website
http://hdl.handle.net/10161/4358
PMID
20925920
Source
pubmed
Published In
BMC Cancer
Volume
10
Publish Date
2010
Start Page
531
DOI
10.1186/1471-2407-10-531

Breast cancer: noninvasive and special situations.

Authors
Carlson, RW; Allred, DC; Anderson, BO; Burstein, HJ; Carter, WB; Edge, SB; Erban, JK; Farrar, WB; Forero, A; Giordano, SH; Goldstein, LJ; Gradishar, WJ; Hayes, DF; Hudis, CA; Ljung, B-M; Marcom, PK; Mayer, IA; McCormick, B; Pierce, LJ; Reed, EC; Smith, ML; Somlo, G; Topham, NS; Ward, JH; Winer, EP; Wolff, AC
MLA Citation
Carlson, RW, Allred, DC, Anderson, BO, Burstein, HJ, Carter, WB, Edge, SB, Erban, JK, Farrar, WB, Forero, A, Giordano, SH, Goldstein, LJ, Gradishar, WJ, Hayes, DF, Hudis, CA, Ljung, B-M, Marcom, PK, Mayer, IA, McCormick, B, Pierce, LJ, Reed, EC, Smith, ML, Somlo, G, Topham, NS, Ward, JH, Winer, EP, and Wolff, AC. "Breast cancer: noninvasive and special situations." J Natl Compr Canc Netw 8.10 (October 2010): 1182-1207.
PMID
20971842
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
8
Issue
10
Publish Date
2010
Start Page
1182
End Page
1207

Breast cancer patients' treatment expectations after exposure to the decision aid program adjuvant online: the influence of numeracy.

The decision aid called ''Adjuvant Online'' (Adjuvant! for short) helps breast cancer patients make treatment decisions by providing numerical estimates of treatment efficacy (e.g., 10-y relapse or survival). Studies exploring how patients' numeracy interacts with the estimates provided by Adjuvant! are lacking. Pooling across 2 studies totaling 105 women with estrogen receptor-positive, early-stage breast cancer, the authors explored patients' treatment expectations, perceived benefit from treatments, and confidence of personal benefit from treatments. Patients who were more numerate were more likely to provide estimates of cancer-free survival that matched the estimates provided by Adjuvant! for each treatment option compared with patients with lower numeracy (odds ratios of 1.6 to 2.4). As estimates of treatment efficacy provided by Adjuvant! increased, so did patients' estimates of cancer-free survival (0.37 > r(s) > 0.48) and their perceptions of treatment benefit from hormonal therapy (r(s) = 0.28) and combined therapy (r(s) = 0.27). These relationships were significantly more pronounced for those with higher numeracy, especially for perceived benefit of combined therapy. Results suggest that numeracy influences a patient's ability to interpret numerical estimates of treatment efficacy from decision aids such as Adjuvant!.

Authors
Lipkus, IM; Peters, E; Kimmick, G; Liotcheva, V; Marcom, P
MLA Citation
Lipkus, IM, Peters, E, Kimmick, G, Liotcheva, V, and Marcom, P. "Breast cancer patients' treatment expectations after exposure to the decision aid program adjuvant online: the influence of numeracy." Med Decis Making 30.4 (July 2010): 464-473.
PMID
20160070
Source
pubmed
Published In
Medical Decision Making
Volume
30
Issue
4
Publish Date
2010
Start Page
464
End Page
473
DOI
10.1177/0272989X09360371

Urinary biomarkers of oxidative status in a clinical model of oxidative assault.

BACKGROUND: We used doxorubicin-based chemotherapy as a clinical model of oxidative assault in humans. METHODS: The study recruited newly diagnosed breast cancer patients (n = 23). Urine samples were collected immediately before (T0) and at 1 hour (T1) and 24 hours (T24) after i.v. administration of treatment. Measurements included allantoin and the isoprostanes iPF(2alpha)-III, iPF(2alpha)-VI, and 8,12-iso-iPF(2alpha)-VI along with the prostaglandin 2,3-dinor-iPF(2alpha)-III, a metabolite of iPF(2alpha)-III. All biomarkers were quantified using liquid chromatography-tandem mass spectrometry. RESULTS: In all subjects, the levels of the biomarkers increased at T1: allantoin by 22% (P = 0.06), iPF(2alpha)-III by 62% (P < 0.05), iPF(2alpha)-VI by 41% (P < 0.05), 8,12-iso-iPF(2alpha)-VI by 58% (P < 0.05), and 2,3-dinor-iPF(2alpha)-III by 52% (P < 0.05). At T24, the F2-isoprostanes returned to their baseline levels; the levels of allantoin continued to increase, although the T24-T0 difference was not statistically significant. CONCLUSIONS: These results indicate that urinary F2-isoprostanes are valid biomarkers and allantoin is a promising biomarker of oxidative status in humans. IMPACT: The levels of biomarkers change quickly in response to oxidative assault and can be used to monitor oxidative status in humans in response to treatments related either to generation of free radicals (chemotherapy and radiation therapy) or to antioxidants (inborn metabolic diseases and Down syndrome).

Authors
Il'yasova, D; Spasojevic, I; Wang, F; Tolun, AA; Base, K; Young, SP; Marcom, PK; Marks, J; Mixon, G; DiGiulio, R; Millington, DS
MLA Citation
Il'yasova, D, Spasojevic, I, Wang, F, Tolun, AA, Base, K, Young, SP, Marcom, PK, Marks, J, Mixon, G, DiGiulio, R, and Millington, DS. "Urinary biomarkers of oxidative status in a clinical model of oxidative assault." Cancer Epidemiol Biomarkers Prev 19.6 (June 2010): 1506-1510.
PMID
20501773
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
19
Issue
6
Publish Date
2010
Start Page
1506
End Page
1510
DOI
10.1158/1055-9965.EPI-10-0211

Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome.

PURPOSE: Identifying sources of variation in expression microarray data and the effect of variance in gene expression measurements on complex predictive and diagnostic models is essential when translating microarray-based experimental approaches into clinical assays. The technical reproducibility of microarray platforms is well established. Here, we investigate the additional impact of intratumor heterogeneity, a largely unstudied component of variance, on the performance of several microarray-based assays in breast cancer. PATIENTS AND METHODS: Genome-wide expression profiling was performed on 50 core needle biopsies from 18 breast cancer patients using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Global profiles of expression were characterized using unsupervised clustering methods and variance components models. Array-based measures of estrogen receptor (ER) and progesterone receptor (PR) status were compared with immunohistochemistry. The precision of genomic predictors of ER pathway status, recurrence risk, and sensitivity to chemotherapeutics was evaluated by interclass correlation. RESULTS: Global patterns of gene expression demonstrated that intratumor variation was substantially less than the total variation observed across the patient population. Nevertheless, a fraction of genes exhibited significant intratumor heterogeneity in expression. A high degree of reproducibility was observed in single-gene predictors of ER (intraclass correlation coefficient [ICC] = 0.94) and PR expression (ICC = 0.90), and in a multigene predictor of ER pathway activation (ICC = 0.98) with high concordance with immunohistochemistry. Substantial agreement was also observed for multigene signatures of cancer recurrence (ICC = 0.71) and chemotherapeutic sensitivity (ICC = 0.72 and 0.64). CONCLUSION: Intratumor heterogeneity, although present at the level of individual gene expression, does not preclude precise microarray-based predictions of tumor behavior or clinical outcome in breast cancer patients.

Authors
Barry, WT; Kernagis, DN; Dressman, HK; Griffis, RJ; Hunter, JD; Olson, JA; Marks, JR; Ginsburg, GS; Marcom, PK; Nevins, JR; Geradts, J; Datto, MB
MLA Citation
Barry, WT, Kernagis, DN, Dressman, HK, Griffis, RJ, Hunter, JD, Olson, JA, Marks, JR, Ginsburg, GS, Marcom, PK, Nevins, JR, Geradts, J, and Datto, MB. "Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome." J Clin Oncol 28.13 (May 1, 2010): 2198-2206.
PMID
20368555
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
28
Issue
13
Publish Date
2010
Start Page
2198
End Page
2206
DOI
10.1200/JCO.2009.26.7245

Contribution of cancer symptoms, dysfunctional sleep related thoughts, and sleep inhibitory behaviors to the insomnia process in breast cancer survivors: A daily process analysis

Study Objectives: Using a comprehensive cognitive-behavioral model of insomnia and a daily process approach, this study was conducted to examine the contribution of cancer symptoms and dysfunctional sleep related thoughts and behaviors to the process of insomnia in breast cancer survivors. Design: Within-group longitudinal research design. Setting: An academic medical center. Participants: 41 women with breast cancer who had completed their primary cancer treatment and met Research Diagnostic Criteria for primary insomnia or insomnia comorbid with breast cancer. Interventions: NA Measurements and Results: For 28 days, participants completed morning diaries assessing sleep, nighttime pain and hot flashes, and dysfunctional sleep related thoughts and behaviors during the day and night, and evening diaries assessing daytime pain, fatigue, hot flashes, and mood. All diaries were collected using an automated telephone-based system. Results revealed that poorer sleep was related to nighttime pain and hot flashes in breast cancer patients. Time-lagged effects were also found. The current study identified higher levels of dysfunctional sleep related thoughts and sleep inhibitory behaviors during the day and night as antecedents of insomnia, and higher levels of pain, fatigue, and hot flashes and lower levels of positive mood and dysfunctional sleep related thoughts as consequences of insomnia in this population. Conclusions: The current study found support for a comprehensive cognitive-behavioral model of insomnia, which has several theoretical, practice, and research implications.

Authors
Rumble, ME; Keefe, FJ; Edinger, JD; Affleck, G; Marcom, PK; Shaw, HS
MLA Citation
Rumble, ME, Keefe, FJ, Edinger, JD, Affleck, G, Marcom, PK, and Shaw, HS. "Contribution of cancer symptoms, dysfunctional sleep related thoughts, and sleep inhibitory behaviors to the insomnia process in breast cancer survivors: A daily process analysis." Sleep 33.11 (2010): 1501-1509.
PMID
21102992
Source
scival
Published In
Sleep
Volume
33
Issue
11
Publish Date
2010
Start Page
1501
End Page
1509

Genetic/familial high-risk assessment: Breast and ovarian - Clinical practice guidelines in oncology™

All cancers develop as a result of mutations in certain genes, such as those involved in the regulation of cell growth and/or DNA repair, but not all mutations are inherited. However, family studies have long documented an increased risk for several forms of cancer among first and second-degree relatives . Hereditary cancers are often characterized by mutations associated with a high probability of cancer development, vertical transmission through either mother or father, and an association with other types of tumors. They often have an early age of onset and exhibit an autosomal dominant inheritance pattern. Familial cancers share only some features of hereditary cancers. Although other cancers are associated with these hereditary syndromes, these guidelines mainly focus on management of breast and ovarian cancer risk in these individuals. © Journal of the National Comprehensive Cancer Network.

Authors
Daly, MB; Axilbund, JE; Buys, S; Crawford, B; Farrell, CD; Friedman, S; Garber, JE; Goorha, S; Gruber, SB; Hampel, H; Kaklamani, V; Kohlmann, W; Kurian, A; Litton, J; Marcom, PK; Nussbaum, R; Offit, K; Pal, T; Pasche, B; Pilarski, R; Reiser, G; Shannon, KM; Smith, JR; Swisher, E; Weitzel, JN
MLA Citation
Daly, MB, Axilbund, JE, Buys, S, Crawford, B, Farrell, CD, Friedman, S, Garber, JE, Goorha, S, Gruber, SB, Hampel, H, Kaklamani, V, Kohlmann, W, Kurian, A, Litton, J, Marcom, PK, Nussbaum, R, Offit, K, Pal, T, Pasche, B, Pilarski, R, Reiser, G, Shannon, KM, Smith, JR, Swisher, E, and Weitzel, JN. "Genetic/familial high-risk assessment: Breast and ovarian - Clinical practice guidelines in oncology™." JNCCN Journal of the National Comprehensive Cancer Network 8.5 (2010): 562-594.
PMID
20495085
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
8
Issue
5
Publish Date
2010
Start Page
562
End Page
594

Novel tumor sampling strategies to enable microarray gene expression signatures in breast cancer: a study to determine feasibility and reproducibility in the context of clinical care.

Feasibility and reproducibility of microarray biomarkers in clinical settings are doubted because of reliance on fresh frozen tissue. We sought to develop and validate a paradigm of frozen tissue collection from early breast tumors to enable use of microarray in oncology practice. Frozen core needle biopsies (CNBx) were collected from 150 clinical stage I patients during image-guided diagnostic biopsy and/or surgery. Histology and tumor content from frozen cores were compared to diagnostic specimens. Twenty-eight patients had microarray analysis to examine accuracy and reproducibility of predictive gene signatures developed for estrogen receptor (ER) and HER2. One hundred twenty-seven (85%) of 150 patients had at least one frozen core containing cancer suitable for microarray analysis. Larger tumor size, ex vivo biopsy, and use of a new specimen device increased the likelihood of obtaining adequate specimens. Sufficient quality RNA was obtained from 90% of tumor cores. Microarray signatures predicting ER and HER2 expression were developed in training sets of up to 363 surgical samples and were applied to microarray data obtained from core samples collected in clinical settings. In these samples, prediction of ER and HER2 expression achieved a sensitivity/specificity of 94%/100%, and 82%/72%, respectively. Predictions were reproducible in 83-100% of paired samples. Frozen CNBx can be readily obtained from most breast cancers without interfering with pathologic evaluation in routine clinical settings. Collection of tumor tissue at diagnostic biopsy and/or at surgery from lumpectomy specimens using image guidance resulted in sufficient samples for array analysis from over 90% of patients. Sampling of breast cancer for microarray data is reproducible and feasible in clinical practice and can yield signatures predictive of multiple breast cancer phenotypes.

Authors
Tebbit, CL; Zhai, J; Untch, BR; Ellis, MJ; Dressman, HK; Bentley, RC; Baker, JA; Marcom, PK; Nevins, JR; Marks, JR; Olson, JA
MLA Citation
Tebbit, CL, Zhai, J, Untch, BR, Ellis, MJ, Dressman, HK, Bentley, RC, Baker, JA, Marcom, PK, Nevins, JR, Marks, JR, and Olson, JA. "Novel tumor sampling strategies to enable microarray gene expression signatures in breast cancer: a study to determine feasibility and reproducibility in the context of clinical care." Breast Cancer Res Treat 118.3 (December 2009): 635-643.
PMID
19224362
Source
pubmed
Published In
Breast Cancer Research and Treatment
Volume
118
Issue
3
Publish Date
2009
Start Page
635
End Page
643
DOI
10.1007/s10549-008-0301-1

Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study.

CONTEXT: Estrogen deprivation therapy with aromatase inhibitors has been hypothesized to paradoxically sensitize hormone-receptor-positive breast cancer tumor cells to low-dose estradiol therapy. OBJECTIVE: To determine whether 6 mg of estradiol (daily) is a viable therapy for postmenopausal women with advanced aromatase inhibitor-resistant hormone receptor-positive breast cancer. DESIGN, SETTING, AND PATIENTS: A phase 2 randomized trial of 6 mg vs 30 mg of oral estradiol used daily (April 2004-February 2008 [enrollment closed]). Eligible patients (66 randomized) had metastatic breast cancer treated with an aromatase inhibitor with progression-free survival (> or = 24 wk) or relapse (after > or = 2 y) of adjuvant aromatase inhibitor use. Patients at high risk of estradiol-related adverse events were excluded. Patients were examined after 1 and 2 weeks for clinical and laboratory toxicities and flare reactions and thereafter every 4 weeks. Tumor radiological assessment occurred every 12 weeks. At least 1 measurable lesion or 4 measurable lesions (bone-only disease) were evaluated for tumor response. INTERVENTION: Randomization to receive 1 oral 2-mg generic estradiol tablet 3 times daily or five 2-mg tablets 3 times daily. MAIN OUTCOME MEASURES: Primary end point: clinical benefit rate (response plus stable disease at 24 weeks). SECONDARY OUTCOMES: toxicity, progression-free survival, time to treatment failure, quality of life, and the predictive properties of the metabolic flare reaction detected by positron emission tomography/computed tomography with fluorodeoxyglucose F 18. RESULTS: The adverse event rate (> or = grade 3) in the 30-mg group (11/32 [34%]; 95% confidence interval [CI], 23%-47%) was higher than in the 6-mg group (4/34 [18%]; 95% CI, 5%-22%; P = .03). Clinical benefit rates were 9 of 32 (28%; 95% CI, 18%-41%) in the 30-mg group and 10 of 34 (29%; 95% CI, 19%-42%) in the 6-mg group. An estradiol-stimulated increase in fluorodeoxyglucose F 18 uptake (> or = 12% prospectively defined) was predictive of response (positive predictive value, 80%; 95% CI, 61%-92%). Seven patients with estradiol-sensitive disease were re-treated with aromatase inhibitors at estradiol progression, among which 2 had partial response and 1 had stable disease, suggesting resensitization to estrogen deprivation. CONCLUSIONS: In women with advanced breast cancer and acquired resistance to aromatase inhibitors, a daily dose of 6 mg of estradiol provided a similar clinical benefit rate as 30 mg, with fewer serious adverse events. The efficacy of treatment with the lower dose should be further examined in phase 3 clinical trials. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00324259.

Authors
Ellis, MJ; Gao, F; Dehdashti, F; Jeffe, DB; Marcom, PK; Carey, LA; Dickler, MN; Silverman, P; Fleming, GF; Kommareddy, A; Jamalabadi-Majidi, S; Crowder, R; Siegel, BA
MLA Citation
Ellis, MJ, Gao, F, Dehdashti, F, Jeffe, DB, Marcom, PK, Carey, LA, Dickler, MN, Silverman, P, Fleming, GF, Kommareddy, A, Jamalabadi-Majidi, S, Crowder, R, and Siegel, BA. "Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study." JAMA 302.7 (August 19, 2009): 774-780.
PMID
19690310
Source
pubmed
Published In
JAMA : the journal of the American Medical Association
Volume
302
Issue
7
Publish Date
2009
Start Page
774
End Page
780
DOI
10.1001/jama.2009.1204

Markers of oxidative status in a clinical model of oxidative assault: a pilot study in human blood following doxorubicin administration.

We used doxorubicin-based chemotherapy as a clinical model for oxidative assault. Study recruited 23 breast cancer patients and collected blood samples before (T0), at 1 (T1) and 24 hours (T24) after treatment administration. Measurements included protein carbonyl content (PPCC), malondialdehyde (MDA), and alpha- and gamma-tocopherols in plasma and total glutathione content in erythrocytes (erGSHt). In all subjects, PPCC and MDA levels did not change. erGSHt levels increased at T24 by 8% (p=0.03). Levels of alpha, gamma, and total tocopherols progressively decreased by 7%-15% (p <0.05). In subjects with low erGSHt levels (below median), PPCC mean levels progressively increased from 0.35 (T0) to 0.56 (T1) and 0.72 nmol carbonyl/mg protein (T24) (p =0.2). These results indicate that (1) plasma MDA is not a sensitive biomarker in humans; (2) PPCC potentially may be used, if antioxidant reserves are taken into account; (3) antioxidant reserves play an important role in the reaction to oxidative stress.

Authors
Il'yasova, D; Mixon, G; Wang, F; Marcom, PK; Marks, J; Spasojevich, I; Craft, N; Arredondo, F; DiGiulio, R
MLA Citation
Il'yasova, D, Mixon, G, Wang, F, Marcom, PK, Marks, J, Spasojevich, I, Craft, N, Arredondo, F, and DiGiulio, R. "Markers of oxidative status in a clinical model of oxidative assault: a pilot study in human blood following doxorubicin administration." Biomarkers 14.5 (August 2009): 321-325.
PMID
19476408
Source
pubmed
Published In
Biomarkers (Informa)
Volume
14
Issue
5
Publish Date
2009
Start Page
321
End Page
325
DOI
10.1080/13547500902946757

Improved surgical outcomes for breast cancer patients receiving neoadjuvant aromatase inhibitor therapy: results from a multicenter phase II trial.

BACKGROUND: Neoadjuvant aromatase inhibitor therapy has been reported to improve surgical outcomes for postmenopausal women with clinical stage II or III hormone receptor-positive breast cancer. A multicenter phase II clinical trial was conducted to investigate the value of this approach for US surgical practice. STUDY DESIGN: One hundred fifteen postmenopausal women with >2 cm, estrogen receptor (ER) or progesterone receptor (PgR)-positive breast cancer were enrolled in a trial of 16 to 24 weeks of letrozole 2.5 mg daily before operation. RESULTS: One hundred six patients were eligible for primary analysis, 96 underwent operations, 7 received chemotherapy after progressive disease, and 3 did not undergo an operation. Baseline surgical status was marginal for breast-conserving surgery (BCS) in 48 (45%), 47 were definitely ineligible for BCS (44%), and 11 were inoperable by standard mastectomy (10%). Overall Response Evaluation Criteria In Solid Tumors clinical response rate in the breast was 62%, with 12% experiencing progressive disease. Fifty percent underwent BCS, including 30 of 46 (65%) patients who were initially marginal for BCS and 15 of 39 (38%) patients who were initially ineligible for BCS. All 11 inoperable patients successfully underwent operations, including 3 (27%) who had BCS. Nineteen percent of patients undergoing mastectomy had a pathologic T1 tumor, suggesting that some highly responsive tumors were overtreated surgically. CONCLUSIONS: Neoadjuvant aromatase inhibitor improves operability and facilitates BCS, but there was considerable variability in responsiveness. Better techniques to predict response, determine residual tumor burden before operation, and greater willingness to attempt BCS in responsive patients could additionally improve the rate of successful BCS.

Authors
Olson, JA; Budd, GT; Carey, LA; Harris, LA; Esserman, LJ; Fleming, GF; Marcom, PK; Leight, GS; Giuntoli, T; Commean, P; Bae, K; Luo, J; Ellis, MJ
MLA Citation
Olson, JA, Budd, GT, Carey, LA, Harris, LA, Esserman, LJ, Fleming, GF, Marcom, PK, Leight, GS, Giuntoli, T, Commean, P, Bae, K, Luo, J, and Ellis, MJ. "Improved surgical outcomes for breast cancer patients receiving neoadjuvant aromatase inhibitor therapy: results from a multicenter phase II trial." J Am Coll Surg 208.5 (May 2009): 906-914.
PMID
19476859
Source
pubmed
Published In
Journal of the American College of Surgeons
Volume
208
Issue
5
Publish Date
2009
Start Page
906
End Page
914
DOI
10.1016/j.jamcollsurg.2009.01.035

The impact of sharing results of a randomized breast cancer clinical trial with study participants.

BACKGROUND: There has been growing interest in providing clinical trial participants with study results yet only limited information exists regarding the process and impact of sharing results. We sought to evaluate patient perceptions of how results had been shared from a large randomized cooperative group trial, and the impact of learning results. PATIENTS AND METHODS: A subset of women who participated in NCCTG 9831 (A Phase III Trial of Adjuvant Chemotherapy with or without Trastuzumab for Women with HER2-positive Breast Cancer) were mailed surveys after the preliminary study results were released to the public and mailed to participants. RESULTS: One hundred and 67 of 228 surveys sent (73%) were returned; 61% reported receiving trastuzumab on study; 4% reported recurrent disease. Ninety-five percent of participants were glad they received results; 81% were satisfied with how results were shared; 23% were more anxious after learning the results. Sixty-nine percent correctly interpreted the results. Logistic regression revealed that satisfaction with the process of receiving results was associated with satisfaction with treatment (P = 0.04), and increased anxiety was associated with dissatisfaction with treatment (0.02), incorrect interpretation of results (0.04), and not having received trastuzumab (P < 0.0001). CONCLUSION: Sharing results directly with study participants is met with overwhelmingly favorable responses from patients, although some may not initially understand the findings. The potential for increased anxiety should be considered, and psychosocial support may be required by some. A plan to share results should be routinely and prospectively considered in the design of cancer clinical trials.

Authors
Partridge, AH; Wolff, AC; Marcom, PK; Kaufman, PA; Zhang, L; Gelman, R; Moore, C; Lake, D; Fleming, GF; Rugo, HS; Atkins, J; Sampson, E; Collyar, D; Winer, EP
MLA Citation
Partridge, AH, Wolff, AC, Marcom, PK, Kaufman, PA, Zhang, L, Gelman, R, Moore, C, Lake, D, Fleming, GF, Rugo, HS, Atkins, J, Sampson, E, Collyar, D, and Winer, EP. "The impact of sharing results of a randomized breast cancer clinical trial with study participants." Breast Cancer Res Treat 115.1 (May 2009): 123-129.
PMID
18543100
Source
pubmed
Published In
Breast Cancer Research and Treatment
Volume
115
Issue
1
Publish Date
2009
Start Page
123
End Page
129
DOI
10.1007/s10549-008-0057-7

Breast cancer. Clinical practice guidelines in oncology.

Authors
Carlson, RW; Allred, DC; Anderson, BO; Burstein, HJ; Carter, WB; Edge, SB; Erban, JK; Farrar, WB; Goldstein, LJ; Gradishar, WJ; Hayes, DF; Hudis, CA; Jahanzeb, M; Kiel, K; Ljung, B-M; Marcom, PK; Mayer, IA; McCormick, B; Nabell, LM; Pierce, LJ; Reed, EC; Smith, ML; Somlo, G; Theriault, RL; Topham, NS; Ward, JH; Winer, EP; Wolff, AC; NCCN Breast Cancer Clinical Practice Guidelines Panel,
MLA Citation
Carlson, RW, Allred, DC, Anderson, BO, Burstein, HJ, Carter, WB, Edge, SB, Erban, JK, Farrar, WB, Goldstein, LJ, Gradishar, WJ, Hayes, DF, Hudis, CA, Jahanzeb, M, Kiel, K, Ljung, B-M, Marcom, PK, Mayer, IA, McCormick, B, Nabell, LM, Pierce, LJ, Reed, EC, Smith, ML, Somlo, G, Theriault, RL, Topham, NS, Ward, JH, Winer, EP, Wolff, AC, and NCCN Breast Cancer Clinical Practice Guidelines Panel, . "Breast cancer. Clinical practice guidelines in oncology." J Natl Compr Canc Netw 7.2 (February 2009): 122-192. (Review)
PMID
19200416
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
7
Issue
2
Publish Date
2009
Start Page
122
End Page
192

An integration of complementary strategies for gene-expression analysis to reveal novel therapeutic opportunities for breast cancer.

INTRODUCTION: Perhaps the major challenge in developing more effective therapeutic strategies for the treatment of breast cancer patients is confronting the heterogeneity of the disease, recognizing that breast cancer is not one disease but multiple disorders with distinct underlying mechanisms. Gene-expression profiling studies have been used to dissect this complexity, and our previous studies identified a series of intrinsic subtypes of breast cancer that define distinct populations of patients with respect to survival. Additional work has also used signatures of oncogenic pathway deregulation to dissect breast cancer heterogeneity as well as to suggest therapeutic opportunities linked to pathway activation. METHODS: We used genomic analyses to identify relations between breast cancer subtypes, pathway deregulation, and drug sensitivity. For these studies, we use three independent breast cancer gene-expression data sets to measure an individual tumor phenotype. Correlation between pathway status and subtype are examined and linked to predictions for response to conventional chemotherapies. RESULTS: We reveal patterns of pathway activation characteristic of each molecular breast cancer subtype, including within the more aggressive subtypes in which novel therapeutic opportunities are critically needed. Whereas some oncogenic pathways have high correlations to breast cancer subtype (RAS, CTNNB1, p53, HER1), others have high variability of activity within a specific subtype (MYC, E2F3, SRC), reflecting biology independent of common clinical factors. Additionally, we combined these analyses with predictions of sensitivity to commonly used cytotoxic chemotherapies to provide additional opportunities for therapeutics specific to the intrinsic subtype that might be better aligned with the characteristics of the individual patient. CONCLUSIONS: Genomic analyses can be used to dissect the heterogeneity of breast cancer. We use an integrated analysis of breast cancer that combines independent methods of genomic analyses to highlight the complexity of signaling pathways underlying different breast cancer phenotypes and to identify optimal therapeutic opportunities.

Authors
Bild, AH; Parker, JS; Gustafson, AM; Acharya, CR; Hoadley, KA; Anders, C; Marcom, PK; Carey, LA; Potti, A; Nevins, JR; Perou, CM
MLA Citation
Bild, AH, Parker, JS, Gustafson, AM, Acharya, CR, Hoadley, KA, Anders, C, Marcom, PK, Carey, LA, Potti, A, Nevins, JR, and Perou, CM. "An integration of complementary strategies for gene-expression analysis to reveal novel therapeutic opportunities for breast cancer." Breast Cancer Res 11.4 (2009): R55-.
PMID
19638211
Source
pubmed
Published In
Breast Cancer Research
Volume
11
Issue
4
Publish Date
2009
Start Page
R55
DOI
10.1186/bcr2344

Cancer genetic counseling in rural north carolina oncology clinics: Program establishment and patient characteristics

Cancer genetic counseling (CGC) has become standard of care for individuals at increased risk of hereditary cancer. However, because access to CGC is limited in rural communities, several groups are underserved by CGC, and little knowledge exists about characteristics and decisions of individuals who have CGC in a rural setting. We describe pilot data from an outreach CGC program from the Duke Hereditary Cancer Clinic to six rural North Carolina oncology clinics. We assessed whether the program was successfully established and whether outreach patients' characteristics differed from those of patients seen in the tertiary care center. Between February 2005 and February 2006, genetic counseling was provided to 57 patients in the outreach clinics and 275 patients in the tertiary care clinic. We found the program reached individuals less likely to receive CGC otherwise and that patients were satisfied with it. Differences found between outreach and tertiary care patients in race, insurance type, risk of having a hereditary cancer syndrome, and genetic testing decision highlight the importance of continued research to characterize rural CGC patients and understand their decisions. © 2009 Elsevier Inc. All rights reserved.

Authors
Buchanan, AH; Skinner, CS; Calingaert, B; Schildkraut, JM; King, RH; Marcom, PK
MLA Citation
Buchanan, AH, Skinner, CS, Calingaert, B, Schildkraut, JM, King, RH, and Marcom, PK. "Cancer genetic counseling in rural north carolina oncology clinics: Program establishment and patient characteristics." Community Oncology 6.2 (2009): 70-77.
Source
scival
Published In
Community Oncology
Volume
6
Issue
2
Publish Date
2009
Start Page
70
End Page
77

Primary systemic therapy in breast cancer: past lessons and new approaches.

Primary systemic therapy (PST) is a common treatment strategy used to optimize surgical outcomes for women with locally advanced breast cancer. Several cooperative group trials have shown equivalent survival outcomes between neoadjuvant and adjuvant chemotherapy and have identified pathologic complete response (pCR) as a biologic marker for survival. Research efforts to optimize PST include the development of strategies to predict individual response and to guide the choice of chemotherapy. These emerging approaches are informed by our knowledge of subtypes of breast cancer, as well as genomic technologies, such as chemosensitivity signatures. Following definitive surgery, the management of residual disease is controversial.

Authors
Herold, CI; Marcom, PK
MLA Citation
Herold, CI, and Marcom, PK. "Primary systemic therapy in breast cancer: past lessons and new approaches." Cancer Invest 26.10 (December 2008): 1052-1059.
PMID
19093262
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
26
Issue
10
Publish Date
2008
Start Page
1052
End Page
1059
DOI
10.1080/07357900802123260

Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression.

PURPOSE: Breast cancer arising in young women is correlated with inferior survival and higher incidence of negative clinicopathologic features. The biology driving this aggressive disease has yet to be defined. PATIENTS AND METHODS: Clinically annotated, microarray data from 784 early-stage breast cancers were identified, and prospectively defined, age-specific cohorts (young: /= 65 years, n = 211) were compared by prognosis, clinicopathologic variables, mRNA expression values, single-gene analysis, and gene set enrichment analysis (GSEA). Univariate and multivariate analyses were performed. RESULTS: Using clinicopathologic variables, young women illustrated lower estrogen receptor (ER) positivity (immunohistochemistry [IHC], P = .027), larger tumors (P = .012), higher human epidermal growth factor receptor 2 (HER-2) overexpression (IHC, P = .075), lymph node positivity (P = .008), higher grade tumors (P < .0001), and trends toward inferior disease-free survival (DFS; hazard ratio = 1.32; P = .094). Using genomic expression analysis, tumors arising in young women had significantly lower ERalpha mRNA (P < .0001), ERbeta (P = .02), and progesterone receptor (PR) expression (P < .0001), but higher HER-2 (P < .0001) and epidermal growth factor receptor (EGFR) expression (P < .0001). Exploratory analysis (GSEA) revealed 367 biologically relevant gene sets significantly distinguishing breast tumors arising in young women. Combining clinicopathologic and genomic variables among tumors arising in young women demonstrated that younger age and lower ERbeta and higher EGFR mRNA expression were significant predictors of inferior DFS. CONCLUSION: This large-scale genomic analysis illustrates that breast cancer arising in young women is a unique biologic entity driven by unifying oncogenic signaling pathways, is characterized by less hormone sensitivity and higher HER-2/EGFR expression, and warrants further study to offer this poor-prognosis group of women better preventative and therapeutic options.

Authors
Anders, CK; Hsu, DS; Broadwater, G; Acharya, CR; Foekens, JA; Zhang, Y; Wang, Y; Marcom, PK; Marks, JR; Febbo, PG; Nevins, JR; Potti, A; Blackwell, KL
MLA Citation
Anders, CK, Hsu, DS, Broadwater, G, Acharya, CR, Foekens, JA, Zhang, Y, Wang, Y, Marcom, PK, Marks, JR, Febbo, PG, Nevins, JR, Potti, A, and Blackwell, KL. "Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression." J Clin Oncol 26.20 (July 10, 2008): 3324-3330.
PMID
18612148
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
20
Publish Date
2008
Start Page
3324
End Page
3330
DOI
10.1200/JCO.2007.14.2471

TU-C-332-04: Pilot Patient Studies Using a Dedicated Dual-Modality SPECT-CT System for Breast Imaging

Authors
Madhav, P; Cutler, S; Crotty, D; Perez, K; McKinley, R; Marcom, P; Wong, T; Tornai, M
MLA Citation
Madhav, P, Cutler, S, Crotty, D, Perez, K, McKinley, R, Marcom, P, Wong, T, and Tornai, M. "TU-C-332-04: Pilot Patient Studies Using a Dedicated Dual-Modality SPECT-CT System for Breast Imaging." June 2008.
Source
crossref
Published In
Medical physics
Volume
35
Issue
6Part21
Publish Date
2008
Start Page
2894
End Page
2894
DOI
10.1118/1.2962498

Benefit or bias? The role of surgery to remove the primary tumor in patients with metastatic breast cancer.

Authors
Olson, JA; Marcom, PK
MLA Citation
Olson, JA, and Marcom, PK. "Benefit or bias? The role of surgery to remove the primary tumor in patients with metastatic breast cancer." Ann Surg 247.5 (May 2008): 739-740.
PMID
18438109
Source
pubmed
Published In
Annals of Surgery
Volume
247
Issue
5
Publish Date
2008
Start Page
739
End Page
740
DOI
10.1097/SLA.0b013e3181706140

Dose-escalation of filgrastim does not improve efficacy: clinical tolerability and long-term follow-up on CALGB study 9141 adjuvant chemotherapy for node-positive breast cancer patients using dose-intensified doxorubicin plus cyclophosphamide followed by paclitaxel.

PURPOSE: To assess the safety, tolerability, and clinical outcomes of an adjuvant chemotherapy regimen designed to incorporate a non-cross-resistant agent (paclitaxel, T) with a maximally dose-intensified regimen of doxorubicin and cyclophosphamide (AC) in conjunction with hematopoietic growth factor support (recombinant human granulocyte-colony stimulating factor; G-CSF; Filgrastim). A secondary aim was to assess if a higher dose (10 mcg/kg/day) of G-CSF is more efficacious than the conventional dose (5 mcg/kg/day) in this setting. PATIENTS AND METHODS: Female patients with early-stage, node-positive invasive breast cancer were eligible for this multicenter, cooperative group feasibility trial that was designed as the pilot study for a larger randomized clinical trial. The protocol treatment comprised five cycles of dose-intensified AC (75 and 2000 mg/m(2)/cycle, respectively, intravenously every three weeks) with G-CSF support, followed by an additional four cycles of T (175 mg/m(2) by 3h intravenous infusion, every three weeks). Patients were randomized to receive one of two dose levels of G-CSF (5 vs. 10 mcg/kg/day) during AC chemotherapy. Data on both short-term toxicity and long-term survival were collected. RESULTS: One hundred and seventy two node-positive patients with operable primary breast cancer were accrued to this trial between February 1993 and April 1994. 130 of the 172 patients (76%) completed all protocol-specified therapy. Of the 42 early study withdrawals, 23 were due to unacceptable acute treatment-related toxicity. No differences in toxicities or clinical outcomes were noted between the two different dose levels of G-CSF support. At 6.8 years median follow-up, relapse-free survival (RFS) and overall survival (OS) rates for all patients are 70% and 78%, respectively. Ten patients developed second malignancies during follow-up, including three cases with a hematologic malignancy (2% incidence). CONCLUSION: The delivery of dose-intensified AC followed by T was feasible in this large-scale pilot trial, although significant acute toxicities were commonly encountered. The data confirmed the acceptable tolerability of T after aggressive myelotoxic therapy in the adjuvant setting, leading to a larger randomized clinical trial comparing three dose levels of doxorubicin in AC with or without the addition of T (CALGB 9344). Supportive care using twice the conventional dose of G-CSF did not significantly improve the tolerability or change the toxicities of this regimen, and the occurrence of secondary malignancies is consistent with the emerging risk profile of dose-intensive regimens with growth factor support. With long-term follow-up, the clinical outcomes remain relatively favorable and correlate with such expected prognostic factors as the number of involved nodes and hormone receptor status.

Authors
Liu, MC; Demetri, GD; Berry, DA; Norton, L; Broadwater, G; Robert, NJ; Duggan, D; Hayes, DF; Henderson, IC; Lyss, A; Hopkins, J; Kaufman, PA; Marcom, PK; Younger, J; Lin, N; Tkaczuk, K; Winer, EP; Hudis, CA; Cancer and Leukemia Group B,
MLA Citation
Liu, MC, Demetri, GD, Berry, DA, Norton, L, Broadwater, G, Robert, NJ, Duggan, D, Hayes, DF, Henderson, IC, Lyss, A, Hopkins, J, Kaufman, PA, Marcom, PK, Younger, J, Lin, N, Tkaczuk, K, Winer, EP, Hudis, CA, and Cancer and Leukemia Group B, . "Dose-escalation of filgrastim does not improve efficacy: clinical tolerability and long-term follow-up on CALGB study 9141 adjuvant chemotherapy for node-positive breast cancer patients using dose-intensified doxorubicin plus cyclophosphamide followed by paclitaxel." Cancer Treat Rev 34.3 (May 2008): 223-230.
PMID
18234424
Source
pubmed
Published In
Cancer Treatment Reviews
Volume
34
Issue
3
Publish Date
2008
Start Page
223
End Page
230
DOI
10.1016/j.ctrv.2007.11.004

Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer.

CONTEXT: Gene expression profiling may be useful for prognostic and therapeutic strategies in breast carcinoma. OBJECTIVES: To demonstrate the value in integrating genomic information with clinical and pathological risk factors, to refine prognosis, and to improve therapeutic strategies for early stage breast cancer. DESIGN, SETTING, AND PATIENTS: Retrospective study of patients with early stage breast carcinoma who were candidates for adjuvant chemotherapy; 964 clinically annotated breast tumor samples (573 in the initial discovery set and 391 in the validation cohort) with corresponding microarray data were used. All patients were assigned relapse risk scores based on their respective clinicopathological features. Signatures representing oncogenic pathway activation and tumor biology/microenvironment status were applied to these samples to obtain patterns of deregulation that correspond with relapse risk scores to refine prognosis with the clinicopathological prognostic model alone. Predictors of chemotherapeutic response were also applied to further characterize clinically relevant heterogeneity in early stage breast cancer. MAIN OUTCOME MEASURES: Gene expression signatures and clinicopathological variables in early stage breast cancer to determine a refined estimation of relapse-free survival and sensitivity to chemotherapy. RESULTS: In the initial data set of 573 patients, prognostically significant clusters representing patterns of oncogenic pathway activation and tumor biology/microenvironment states were identified within the low-risk (log-rank P = .004), intermediate-risk (log-rank P = .01), and high-risk (log-rank P = .003) model cohorts, representing clinically important genomic subphenotypes of breast cancer. As an example, in the low-risk cohort, of 6 prognostically significant clusters, patients in cluster 4 had an inferior relapse-free survival vs patients in cluster 1 (log-rank P = .004) and cluster 5 (log-rank P = .03). Median relapse-free survival for patients in cluster 4 was 16 months less than for patients in cluster 1 (95% CI, 7.5-24.5 months) and 19 months less than for patients in cluster 5 (95% CI, 10.5-27.5 months). Multivariate analyses confirmed the independent prognostic value of the genomic clusters (low risk, P = .05; high risk, P = .02). The reproducibility and validity of these patterns of pathway deregulation in predicting relapse risk was established using related but not identical clusters in the independent validation cohort. The prognostic clinicogenomic clusters also have unique sensitivity patterns to commonly used cytotoxic therapies. CONCLUSIONS: These results provide preliminary evidence that incorporation of gene expression signatures into clinical risk stratification can refine prognosis. Prospective studies are needed to determine the value of this approach for individualizing therapeutic strategies.

Authors
Acharya, CR; Hsu, DS; Anders, CK; Anguiano, A; Salter, KH; Walters, KS; Redman, RC; Tuchman, SA; Moylan, CA; Mukherjee, S; Barry, WT; Dressman, HK; Ginsburg, GS; Marcom, KP; Garman, KS; Lyman, GH; Nevins, JR; Potti, A
MLA Citation
Acharya, CR, Hsu, DS, Anders, CK, Anguiano, A, Salter, KH, Walters, KS, Redman, RC, Tuchman, SA, Moylan, CA, Mukherjee, S, Barry, WT, Dressman, HK, Ginsburg, GS, Marcom, KP, Garman, KS, Lyman, GH, Nevins, JR, and Potti, A. "Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer." JAMA 299.13 (April 2, 2008): 1574-1587.
PMID
18387932
Source
pubmed
Published In
JAMA : the journal of the American Medical Association
Volume
299
Issue
13
Publish Date
2008
Start Page
1574
End Page
1587
DOI
10.1001/jama.299.13.1574

An integrated approach to the prediction of chemotherapeutic response in patients with breast cancer.

BACKGROUND: A major challenge in oncology is the selection of the most effective chemotherapeutic agents for individual patients, while the administration of ineffective chemotherapy increases mortality and decreases quality of life in cancer patients. This emphasizes the need to evaluate every patient's probability of responding to each chemotherapeutic agent and limiting the agents used to those most likely to be effective. METHODS AND RESULTS: Using gene expression data on the NCI-60 and corresponding drug sensitivity, mRNA and microRNA profiles were developed representing sensitivity to individual chemotherapeutic agents. The mRNA signatures were tested in an independent cohort of 133 breast cancer patients treated with the TFAC (paclitaxel, 5-fluorouracil, adriamycin, and cyclophosphamide) chemotherapy regimen. To further dissect the biology of resistance, we applied signatures of oncogenic pathway activation and performed hierarchical clustering. We then used mRNA signatures of chemotherapy sensitivity to identify alternative therapeutics for patients resistant to TFAC. Profiles from mRNA and microRNA expression data represent distinct biologic mechanisms of resistance to common cytotoxic agents. The individual mRNA signatures were validated in an independent dataset of breast tumors (P = 0.002, NPV = 82%). When the accuracy of the signatures was analyzed based on molecular variables, the predictive ability was found to be greater in basal-like than non basal-like patients (P = 0.03 and P = 0.06). Samples from patients with co-activated Myc and E2F represented the cohort with the lowest percentage (8%) of responders. Using mRNA signatures of sensitivity to other cytotoxic agents, we predict that TFAC non-responders are more likely to be sensitive to docetaxel (P = 0.04), representing a viable alternative therapy. CONCLUSIONS: Our results suggest that the optimal strategy for chemotherapy sensitivity prediction integrates molecular variables such as ER and HER2 status with corresponding microRNA and mRNA expression profiles. Importantly, we also present evidence to support the concept that analysis of molecular variables can present a rational strategy to identifying alternative therapeutic opportunities.

Authors
Salter, KH; Acharya, CR; Walters, KS; Redman, R; Anguiano, A; Garman, KS; Anders, CK; Mukherjee, S; Dressman, HK; Barry, WT; Marcom, KP; Olson, J; Nevins, JR; Potti, A
MLA Citation
Salter, KH, Acharya, CR, Walters, KS, Redman, R, Anguiano, A, Garman, KS, Anders, CK, Mukherjee, S, Dressman, HK, Barry, WT, Marcom, KP, Olson, J, Nevins, JR, and Potti, A. "An integrated approach to the prediction of chemotherapeutic response in patients with breast cancer. (Published online)" PLoS One 3.4 (April 2, 2008): e1908-.
Website
http://hdl.handle.net/10161/4486
PMID
18382681
Source
pubmed
Published In
PloS one
Volume
3
Issue
4
Publish Date
2008
Start Page
e1908
DOI
10.1371/journal.pone.0001908

Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840.

PURPOSE: Phase II trials suggested that weekly paclitaxel might be more effective and less toxic than every-3-weeks administration for metastatic breast cancer (MBC). Cancer and Leukemia Group B (CALGB) protocol 9840 was initiated to address this question. Subsequently trastuzumab was demonstrated to improve outcomes of paclitaxel therapy for human epidermal growth factor receptor-2 (HER-2)-positive patients, and was therefore incorporated. Because inhibition of HER-family signaling had potential efficacy even without HER-2 overexpression, we randomly assigned for trastuzumab in this population. PATIENTS AND METHODS: Patients were randomly assigned to paclitaxel 175 mg/m(2) every 3 weeks or 80 mg/m(2) weekly. After the first 171 patients, all HER-2-positive patients received trastuzumab; HER-2 nonoverexpressors were randomly assigned for trastuzumab, in addition to paclitaxel schedule. A total of 577 patients were treated on 9840. An additional 158 patients were included in analyses, for combined sample of 735. The primary end point was response rate (RR); secondary end points were time to progression (TTP), overall survival, and toxicity. Primary comparisons were between weekly versus every-3-weeks paclitaxel, and trastuzumab versus no trastuzumab in HER-2 nonoverexpressors. RESULTS: In the combined sample, weekly paclitaxel was superior to every-3-weeks administration: RR (42% v 29%, unadjusted odds ratio [OR] = 1.75; P = .0004), TTP (median, 9 v 5 months; adjusted HR = 1.43; P < .0001), and survival (median, 24 v 12 months; adjusted HR = 1.28; P = .0092). For HER-2 nonoverexpressors, trastuzumab did not improve efficacy. Grade 3 neuropathy was more common with weekly dosing (24% v 12%; P = .0003). CONCLUSION: Weekly paclitaxel is more effective than every-3-weeks administration for MBC. Trastuzumab did not improve efficacy for HER-2 nonoverexpressors. Neurotoxicity is a treatment-limiting toxicity for weekly paclitaxel.

Authors
Seidman, AD; Berry, D; Cirrincione, C; Harris, L; Muss, H; Marcom, PK; Gipson, G; Burstein, H; Lake, D; Shapiro, CL; Ungaro, P; Norton, L; Winer, E; Hudis, C
MLA Citation
Seidman, AD, Berry, D, Cirrincione, C, Harris, L, Muss, H, Marcom, PK, Gipson, G, Burstein, H, Lake, D, Shapiro, CL, Ungaro, P, Norton, L, Winer, E, and Hudis, C. "Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840." J Clin Oncol 26.10 (April 1, 2008): 1642-1649.
PMID
18375893
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
10
Publish Date
2008
Start Page
1642
End Page
1649
DOI
10.1200/JCO.2007.11.6699

A pilot study of predictive markers of chemotherapy-related amenorrhea among premenopausal women with early stage breast cancer.

BACKGROUND: Premenopausal women treated for early stage breast cancer (ESBC) are at risk for chemotherapy-related amenorrhea (CRA). Prospectively-validated, predictive markers of CRA are needed. PATIENTS AND METHODS: Premenopausal women with ESBC and planned chemotherapy (>/= 25% risk of amenorrhea) were evaluated. Follicle stimulating hormone (FSH), estradiol, Inhibin A and B, anti-Müllerian hormone (AMH), and quality of life (QOL) were prospectively evaluated pre-, post-, 6 months and 1 year post-chemotherapy and correlated with age and menstrual status. CRA was defined as absence of menses 1 year post-chemotherapy. RESULTS: Forty-four women were evaluated at the time of analysis. Median age at diagnosis and FSH 1 year post-chemotherapy were higher among women with CRA (44 yrs [33-51] vs. 40 yrs [31-43]; p = 0.03; 39.8 vs. 5.0 mLU/mL, p = 0.0058, respectively). Median estradiol 1 year post-chemotherapy was higher among women who resumed menses (108.3 vs. 41.3 pg/mL, p = 0.01). Pre-chemotherapy median Inhibin B and AMH were lower among women with CRA (33.2 vs. 108.8 pg/mL; p = 0.03; 0.16 vs. 1.09 ng/mL, p = 0.02, respectively). The risk of CRA was increased among women with lower pre-chemotherapy Inhibin B (RR = 1.67, p = 0.15) and AMH (RR = 1.83, p = 0.05). Amongst women whose pre-chemotherapy Inhibin B and AMH values were below the median, the incidence of CRA was 87.5%. CONCLUSIONS: RESULTS indicate that pre-chemotherapy Inhibin B and AMH are lower among women experiencing CRA and may be predictive of CRA among premenopausal women facing chemotherapy for ESBC.

Authors
Anders, C; Marcom, PK; Peterson, B; Gu, L; Unruhe, S; Welch, R; Lyons, P; Behera, M; Copland, S; Kimmick, G; Shaw, H; Snyder, S; Antenos, M; Woodruff, T; Blackwell, K
MLA Citation
Anders, C, Marcom, PK, Peterson, B, Gu, L, Unruhe, S, Welch, R, Lyons, P, Behera, M, Copland, S, Kimmick, G, Shaw, H, Snyder, S, Antenos, M, Woodruff, T, and Blackwell, K. "A pilot study of predictive markers of chemotherapy-related amenorrhea among premenopausal women with early stage breast cancer." Cancer Invest 26.3 (April 2008): 286-295.
PMID
18317970
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
26
Issue
3
Publish Date
2008
Start Page
286
End Page
295
DOI
10.1080/07357900701829777

Results of a diet/exercise feasibility trial to prevent adverse body composition change in breast cancer patients on adjuvant chemotherapy.

PURPOSE: Patients with breast cancer on adjuvant chemotherapy can experience weight gain and concurrent losses in muscle mass. Exercise interventions can prevent these changes, but time and travel pose barriers to participation. The Survivor Training for Enhancing Total Health (STRENGTH) trial assessed the feasibility and impact of 2 home-based interventions. PATIENTS AND METHODS: Ninety premenopausal patients with breast cancer on adjuvant chemotherapy were randomized to a calcium-rich diet (CA) intervention (attention control) or to 2 experimental arms: a CA + exercise (EX) arm or a CA + EX and high fruit and vegetable, low-fat diet (FVLF) arm. Exercise arms included aerobic and strength-training exercises. Body composition, weight status, waist circumference, dietary intake, physical activity, quality of life, anxiety, depression, serum lipids, sex hormone binding globulin, insulin, proinsulin, C-reactive protein, interleukin-1B, and tumor-necrosis factor receptor-II were measured at baseline and at 6-month follow-up. RESULTS: Accrual targets were achieved and modest attrition was observed (8.8%). Self-reports suggest increased calcium intakes in all arms, and higher fruit and vegetable and lower fat intake in the CA + EX + FVLF arm; no differences in physical activity were observed. While measures of adiposity were generally lower in the CA + EX + FVLF arm, the only significant difference was in percentage of body fat (arms and legs); change in scores (mean +/- standard deviation) were +0.7% +/- 2.3% (CA); +1.2% +/- 2.7% (CA + EX); and +0.1% +/- 2% (CA + EX + FVLF; P = .047). Lean body mass was largely preserved, even in the control arm (net gain of 452 g +/- 2395 g). No differences were observed in other endpoints. CONCLUSION: Diet and exercise interventions can prevent weight gain and adverse body composition changes, but more research is needed to determine optimally effective interventions that can be implemented during active treatment and that promote adherence.

Authors
Demark-Wahnefried, W; Case, LD; Blackwell, K; Marcom, PK; Kraus, W; Aziz, N; Snyder, DC; Giguere, JK; Shaw, E
MLA Citation
Demark-Wahnefried, W, Case, LD, Blackwell, K, Marcom, PK, Kraus, W, Aziz, N, Snyder, DC, Giguere, JK, and Shaw, E. "Results of a diet/exercise feasibility trial to prevent adverse body composition change in breast cancer patients on adjuvant chemotherapy." Clin Breast Cancer 8.1 (February 2008): 70-79.
PMID
18501061
Source
pubmed
Published In
Clinical Breast Cancer
Volume
8
Issue
1
Publish Date
2008
Start Page
70
End Page
79
DOI
10.3816/CBC.2008.n.005

Age-specific differences in oncogenic pathway deregulation seen in human breast tumors.

PURPOSE: To define the biology driving the aggressive nature of breast cancer arising in young women. EXPERIMENTAL DESIGN: Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young or=65 years), 411 eligible patients (n = 200or=65 years) with clinically-annotated Affymetrix microarray data were identified. GSEA, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts. RESULTS: In comparing deregulation of oncogenic pathways between age groups, a higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in breast tumors arising in younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with a higher probability of PI3K, Myc, and beta-catenin, conferred a worse prognosis (HR = 4.15). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, with concurrent low probability of PI3K, Myc and beta-catenin deregulation, was associated with poorer outcome (HR = 2.7). In multivariate analyses, genomic clusters of pathway deregulation illustrate prognostic value. CONCLUSION: Results demonstrate that breast cancer arising in young women represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that are prognostic, independent of currently available clinico-pathologic variables. These results should enable refinement of targeted treatment strategies in this clinically challenging situation.

Authors
Anders, CK; Acharya, CR; Hsu, DS; Broadwater, G; Garman, K; Foekens, JA; Zhang, Y; Wang, Y; Marcom, K; Marks, JR; Mukherjee, S; Nevins, JR; Blackwell, KL; Potti, A
MLA Citation
Anders, CK, Acharya, CR, Hsu, DS, Broadwater, G, Garman, K, Foekens, JA, Zhang, Y, Wang, Y, Marcom, K, Marks, JR, Mukherjee, S, Nevins, JR, Blackwell, KL, and Potti, A. "Age-specific differences in oncogenic pathway deregulation seen in human breast tumors. (Published online)" PLoS One 3.1 (January 2, 2008): e1373-.
Website
http://hdl.handle.net/10161/4481
PMID
18167534
Source
pubmed
Published In
PloS one
Volume
3
Issue
1
Publish Date
2008
Start Page
e1373
DOI
10.1371/journal.pone.0001373

A pilot study of predictive markers of chemotherapy-related amenorrhea among premenopausal women with early stage breast cancer (Cancer Investigation 26, 3, (286-295))

Authors
Anders, C; Marcom, PK; Peterson, B; Gu, L; Unruhe, S; Welch, R; Lyons, P; Behera, M; Copland, S; Kimmick, G; Shaw, H; Snyder, S; Antenos, M; Woodruff, T; Blackwell, K
MLA Citation
Anders, C, Marcom, PK, Peterson, B, Gu, L, Unruhe, S, Welch, R, Lyons, P, Behera, M, Copland, S, Kimmick, G, Shaw, H, Snyder, S, Antenos, M, Woodruff, T, and Blackwell, K. "A pilot study of predictive markers of chemotherapy-related amenorrhea among premenopausal women with early stage breast cancer (Cancer Investigation 26, 3, (286-295))." Cancer Investigation 26.10 (2008): 1068--.
Source
scival
Published In
Cancer Investigation (Informa)
Volume
26
Issue
10
Publish Date
2008
Start Page
1068-
DOI
10.1080/07357900802660220

Racial differences in clinical outcomes from metastatic breast cancer: A pooled analysis of CALGB 9342 and 9840 - Cancer and leukemia group B

Purpose: African American women are more likely to be diagnosed with metastatic breast cancer at the time of presentation than whites, and have shorter survival once diagnosed. This study examines racial differences in clinical outcomes in the setting of two large cooperative group randomized clinical trials. Patients and Methods: The study cohort consisted of 787 white (80%) and 195 African American (20%) patients with metastatic breast cancer enrolled in two successive Cancer and Leukemia Group B (CALGB) trials using taxanes in the metastatic setting. Differences in overall survival (OS), response incidence, and time to treatment failure (TTF) were examined by race. In addition, differences in the incidence of baseline and treatment-related toxicities were examined. Results: With 779 deaths (166 African Americans and 613 whites), median OS was 14.3 months for African Americans and 18.75 months for whites (hazard ratio [HR] = 1.37; 95% CI, 1.15 to 1.63). When adjusted for prognostic factors, African Americans had a 24% increase in the hazard of death compared with whites (HR = 1.24; 95% CI, 1.02 to 1.51). No significant differences in TTF or overall response to therapy were seen. No clinically significant toxicity differences were seen. Conclusion: African Americans with metastatic breast cancer have an increased hazard of death compared with whites despite the receipt of similar per-protocol treatment, but experience no differences in TTF or overall response to therapy. We hypothesize that more direct and robust measures of comorbidities, and perhaps other factors such as receipt of subsequent therapy could help further explain the observed survival difference. © 2008 by American Society of Clinical Oncology.

Authors
Polite, BN; Cirrincione, C; Fleming, GF; Berry, DA; Seidman, A; Muss, H; Norton, L; Shapiro, C; Bakri, K; Marcom, K; Lake, D; Schwartz, JH; Hudis, C; Winer, EP
MLA Citation
Polite, BN, Cirrincione, C, Fleming, GF, Berry, DA, Seidman, A, Muss, H, Norton, L, Shapiro, C, Bakri, K, Marcom, K, Lake, D, Schwartz, JH, Hudis, C, and Winer, EP. "Racial differences in clinical outcomes from metastatic breast cancer: A pooled analysis of CALGB 9342 and 9840 - Cancer and leukemia group B." Journal of Clinical Oncology 26.16 (2008): 2659-2665.
PMID
18509177
Source
scival
Published In
Journal of Clinical Oncology
Volume
26
Issue
16
Publish Date
2008
Start Page
2659
End Page
2665
DOI
10.1200/JCO.2007.13.9782

Long term disease-free survival and T cell and antibody responses in women with high-risk Her2+ breast cancer following vaccination against Her2.

BACKGROUND: The HER2-inhibiting antibody trastuzumab, in combination with chemotherapy, significantly improves survival of women with resected, HER2-overexpressing breast cancers, but is associated with toxicities including a risk of cardiomyopathy. Additionally, the beneficial effect of trastuzumab is expected to decrease once the drug is discontinued. We proposed to address these concerns by using cancer vaccines to stimulate HER2 intracellular domain (ICD)-specific T cell and antibody responses. METHODS: Subjects with stage II (> or = 6 +LN), III, or stage IV breast cancer with > 50% HER2 overexpressing tumor cells who were disease-free after surgery and adjuvant therapy were eligible. Vaccines consisted of immature, cultured DC (n = 3), mature cultured DC (n = 3), or mature Flt3-ligand mobilized peripheral blood DC (n = 1) loaded with ICD, or tetanus toxoid, keyhole limpet hemocyanin or CMV peptide as controls, and were administered intradermally/subcutaneously four times at 3 week intervals. ICD-specific T cell and antibody responses were measured. Cardiac function was determined by MUGA or ECHO; long term disease status was obtained from patient contact. RESULTS: All seven patients successfully underwent DC generation and five received all 4 immunizations. There were no toxicities greater than grade 1 or ejection fraction decrements below normal. Delayed-type hypersensitivity (DTH) reactions at the injection site occurred in 6/7 patients and HER2 specificity was detected by cytokine flow cytometry or ELISPOT in 5 patients. At more than 5 years of follow-up, 6/7 had detectable anti-ICD antibodies. One patient experienced a pulmonary recurrence at 4 years from their study immunizations. This recurrence was resected and they are without evidence of disease. All patients are alive and disease-free at 4.6-6.7 years of follow-up. CONCLUSION: Although this was a small pilot study, the well-tolerated nature of the vaccines, the lack of cardiac toxicity, significant immunogenicity, and a 100% 4.5-year survival rate suggest that vaccination with HER2 ICD protein-containing DC is appropriate for further study in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00005956.

Authors
Morse, MA; Hobeika, A; Osada, T; Niedzwiecki, D; Marcom, PK; Blackwell, KL; Anders, C; Devi, GR; Lyerly, HK; Clay, TM
MLA Citation
Morse, MA, Hobeika, A, Osada, T, Niedzwiecki, D, Marcom, PK, Blackwell, KL, Anders, C, Devi, GR, Lyerly, HK, and Clay, TM. "Long term disease-free survival and T cell and antibody responses in women with high-risk Her2+ breast cancer following vaccination against Her2. (Published online)" J Transl Med 5 (September 6, 2007): 42-.
PMID
17822557
Source
pubmed
Published In
Journal of Translational Medicine
Volume
5
Publish Date
2007
Start Page
42
DOI
10.1186/1479-5876-5-42

Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study.

BACKGROUND: The optimal trastuzumab-based chemotherapy regimen for HER2-overexpressing, metastatic breast cancer is not known. The trastuzumab and vinorelbine or taxane (TRAVIOTA) study was a prospective, multicenter, randomized trial that was designed to compare these regimens. METHODS: Eligible patients had HER2-overexpressing, metastatic breast cancer and had received no prior chemotherapy for advanced disease. Patients were randomized 1:1 to receive either trastuzumab with weekly vinorelbine therapy or weekly taxane therapy (paclitaxel or docetaxel at the investigator's choice). Originally planned for 250 patients, the study was closed because of poor accrual with 81 evaluable patients, including 41 patients who received vinorelbine and 40 patients who received taxane. RESULTS: Response rates were 51% and 40% for the vinorelbine/trastuzumab arm and the taxane/trastuzumab arm, respectively (Fisher exact test; P = .37). The median time to disease progression was 8.5 months and 6.0 months for the vinorelbine- and taxane-based arms, respectively (log-rank test; P = .09). Treatment with either regimen generally was well tolerated, yielding comparable rates of neurologic and gastrointestinal toxicity. Vinorelbine-based treatment was associated with more anemia and neutropenia and with 2 episodes of cardiotoxicity. Taxane-based therapy was associated with more dermatologic toxicity, myalgias, and fluid retention. CONCLUSIONS: Both vinorelbine/trastuzumab and taxane/trastuzumab treatments were active as first-line therapy for HER2-positive, metastatic breast cancer and had comparable rates of efficacy and tolerability. The toxicities observed were the result of recognized side effects associated with each of the chemotherapy agents and schedules. These data can inform treatment decision making in this clinical setting.

Authors
Burstein, HJ; Keshaviah, A; Baron, AD; Hart, RD; Lambert-Falls, R; Marcom, PK; Gelman, R; Winer, EP
MLA Citation
Burstein, HJ, Keshaviah, A, Baron, AD, Hart, RD, Lambert-Falls, R, Marcom, PK, Gelman, R, and Winer, EP. "Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study." Cancer 110.5 (September 1, 2007): 965-972.
PMID
17614302
Source
pubmed
Published In
Cancer
Volume
110
Issue
5
Publish Date
2007
Start Page
965
End Page
972
DOI
10.1002/cncr.22885

Cancer yield of mammography, MR, and US in high-risk women: prospective multi-institution breast cancer screening study.

PURPOSE: To prospectively determine cancer yield, callback and biopsy rates, and positive predictive value (PPV) of mammography, magnetic resonance (MR) imaging, and ultrasonography (US) in women at high risk for breast cancer. MATERIALS AND METHODS: The study was approved by the institutional review board and was HIPAA compliant, and informed consent was obtained. We conducted a prospective pilot study of screening mammography, MR, and US in asymptomatic women 25 years of age or older who were genetically at high risk, defined as BRCA1/BRCA2 carriers or with at least a 20% probability of carrying a BRCA1/BRCA2 mutation. All imaging modalities were performed within 90 days of each other. Data were analyzed by using exact confidence intervals (CIs) and the McNemar test. RESULTS: A total of 195 women were enrolled in this study over a 6-month period, and 171 completed all study examinations (mammography, US, and MR). Average age of the 171 participants was 46 years +/- 10.2 (standard deviation). Sixteen biopsies were performed and six cancers were detected, for an overall 3.5% cancer yield. MR enabled detection of all six cancers; mammography, two; and US, one. The diagnostic yields for each test were 3.5% for MR, 0.6% for US, and 1.2% for mammography. MR, US, and mammography findings prompted biopsy in 8.2%, 2.3%, and 2.3% of patients, respectively. None of the pairwise comparisons were statistically significant. The PPV of biopsies performed as a result of MR was 43%. CONCLUSION: Screening MR imaging had a higher biopsy rate but helped detect more cancers than either mammography or US. US had the highest false-negative rate compared with mammography and MR, enabling detection of only one in six cancers in high-risk women.

Authors
Lehman, CD; Isaacs, C; Schnall, MD; Pisano, ED; Ascher, SM; Weatherall, PT; Bluemke, DA; Bowen, DJ; Marcom, PK; Armstrong, DK; Domchek, SM; Tomlinson, G; Skates, SJ; Gatsonis, C
MLA Citation
Lehman, CD, Isaacs, C, Schnall, MD, Pisano, ED, Ascher, SM, Weatherall, PT, Bluemke, DA, Bowen, DJ, Marcom, PK, Armstrong, DK, Domchek, SM, Tomlinson, G, Skates, SJ, and Gatsonis, C. "Cancer yield of mammography, MR, and US in high-risk women: prospective multi-institution breast cancer screening study." Radiology 244.2 (August 2007): 381-388.
PMID
17641362
Source
pubmed
Published In
Radiology
Volume
244
Issue
2
Publish Date
2007
Start Page
381
End Page
388
DOI
10.1148/radiol.2442060461

The combination of letrozole and trastuzumab as first or second-line biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers.

BACKGROUND: Estrogen receptor (ER) and/or progesterone receptor expression occurs in approximately 50% HER2 positive (HER2+) breast cancers and cross-talk between the estrogen and HER2 pathways promotes endocrine therapy resistance. The efficacy of the aromatase inhibitor letrozole in combination with trastuzumab was therefore tested in a Phase 2 study. METHODS: Patients with ER+ and/or PgR+ and HER2+ (IHC 2+ or 3+ or FISH+) advanced breast cancer were treated with trastuzumab plus letrozole until disease progression or unacceptable toxicity. RESULTS: Thirty-three patients were enrolled, of which thirty one were considered evaluable. The majority of patients (82%) had received tamoxifen and 82% had HER2 FISH+ and/or IHC 3+ tumors. Eight patients responded (1 CR and 7 PR) for an overall response rate (ORR) of 26% and a clinical benefit rate (CBR) of 52%. The median time to progression (TTP) was 5.8 months and the median duration of response (DOR) was 20.6+ months. Excluding IHC 2+, FISH- tumors, the OR was 24%, CBR 44%, TTP 5.5 months and DOR 17+ months. The combination was well tolerated with only two toxicity events requiring termination of study medication. CONCLUSIONS: Combined trastuzumab and letrozole treatment for patients with HER2+ and ER+ advanced breast cancer produced durable responses consistently lasting at least 1 year in one quarter of the patients. While these data are promising for a subgroup, for half the patients, trastuzumab plus letrozole was inactive. This finding demonstrates ER+ HER2+ advanced disease is heterogeneous and additional agents will be required for optimal management based on targeted therapeutics alone.

Authors
Marcom, PK; Isaacs, C; Harris, L; Wong, ZW; Kommarreddy, A; Novielli, N; Mann, G; Tao, Y; Ellis, MJ
MLA Citation
Marcom, PK, Isaacs, C, Harris, L, Wong, ZW, Kommarreddy, A, Novielli, N, Mann, G, Tao, Y, and Ellis, MJ. "The combination of letrozole and trastuzumab as first or second-line biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers." Breast Cancer Res Treat 102.1 (March 2007): 43-49.
PMID
16897431
Source
pubmed
Published In
Breast Cancer Research and Treatment
Volume
102
Issue
1
Publish Date
2007
Start Page
43
End Page
49
DOI
10.1007/s10549-006-9307-8

Hypermethylation of the breast cancer-associated gene 1 promoter does not predict cytologic atypia or correlate with surrogate end points of breast cancer risk.

Mutation of the breast cancer-associated gene 1 (BRCA1) plays an important role in familial breast cancer. Although hypermethylation of the BRCA1 promoter has been observed in sporadic breast cancer, its exact role in breast cancer initiation and association with breast cancer risk is unknown. The frequency of BRCA1 promoter hypermethylation was tested in (a) 14 primary breast cancer biopsies and (b) the initial random periareolar fine-needle aspiration (RPFNA) cytologic samples obtained from 61 asymptomatic women who were at increased risk for breast cancer. BRCA1 promoter hypermethylation was assessed from nucleotide -150 to nucleotide +32 relative to the transcription start site. RPFNA specimens were stratified for cytologic atypia using the Masood cytology index. BRCA1 promoter hypermethylation was observed at similar frequency in nonproliferative (normal; Masood

Authors
Bean, GR; Ibarra Drendall, C; Goldenberg, VK; Baker, JC; Troch, MM; Paisie, C; Wilke, LG; Yee, L; Marcom, PK; Kimler, BF; Fabian, CJ; Zalles, CM; Broadwater, G; Scott, V; Seewaldt, VL
MLA Citation
Bean, GR, Ibarra Drendall, C, Goldenberg, VK, Baker, JC, Troch, MM, Paisie, C, Wilke, LG, Yee, L, Marcom, PK, Kimler, BF, Fabian, CJ, Zalles, CM, Broadwater, G, Scott, V, and Seewaldt, VL. "Hypermethylation of the breast cancer-associated gene 1 promoter does not predict cytologic atypia or correlate with surrogate end points of breast cancer risk." Cancer Epidemiol Biomarkers Prev 16.1 (January 2007): 50-56.
PMID
17220331
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
16
Issue
1
Publish Date
2007
Start Page
50
End Page
56
DOI
10.1158/1055-9965.EPI-06-0598

Genetic Nurse Counsellors Can Be An Acceptable and Cost-effective Alternative to Clinical Geneticists for Breast Cancer Risk Genetic Counselling. Evidence From Two Parallel Randomised Controlled Equivalence Trials

Authors
Marcom, PK
MLA Citation
Marcom, PK. "Genetic Nurse Counsellors Can Be An Acceptable and Cost-effective Alternative to Clinical Geneticists for Breast Cancer Risk Genetic Counselling. Evidence From Two Parallel Randomised Controlled Equivalence Trials." Breast Diseases 18.2 (2007): 212--.
Source
scival
Published In
Breast Diseases: A Year Book Quarterly
Volume
18
Issue
2
Publish Date
2007
Start Page
212-
DOI
10.1016/S1043-321X(07)80287-6

Gene expression profiles of multiple breast cancer phenotypes and response to neoadjuvant chemotherapy.

PURPOSE: Breast cancer is a heterogeneous disease, and markers for disease subtypes and therapy response remain poorly defined. For that reason, we employed a prospective neoadjuvant study in locally advanced breast cancer to identify molecular signatures of gene expression correlating with known prognostic clinical phenotypes, such as inflammatory breast cancer or the presence of hypoxia. In addition, we defined molecular signatures that correlate with response to neoadjuvant chemotherapy. EXPERIMENTAL DESIGN: Tissue was collected under ultrasound guidance from patients with stage IIB/III breast cancer before four cycles of neoadjuvant liposomal doxorubicin paclitaxel chemotherapy combined with local whole breast hyperthermia. Gene expression analysis was done using Affymetrix U133 Plus 2.0 GeneChip arrays. RESULTS: Gene expression patterns were identified that defined the phenotypes of inflammatory breast cancer as well as tumor hypoxia. In addition, molecular signatures were identified that predicted the persistence of malignancy in the axillary lymph nodes after neoadjuvant chemotherapy. This persistent lymph node signature significantly correlated with disease-free survival in two separate large populations of breast cancer patients. CONCLUSIONS: Gene expression signatures have the capacity to identify clinically significant features of breast cancer and can predict which individual patients are likely to be resistant to neoadjuvant therapy, thus providing the opportunity to guide treatment decisions.

Authors
Dressman, HK; Hans, C; Bild, A; Olson, JA; Rosen, E; Marcom, PK; Liotcheva, VB; Jones, EL; Vujaskovic, Z; Marks, J; Dewhirst, MW; West, M; Nevins, JR; Blackwell, K
MLA Citation
Dressman, HK, Hans, C, Bild, A, Olson, JA, Rosen, E, Marcom, PK, Liotcheva, VB, Jones, EL, Vujaskovic, Z, Marks, J, Dewhirst, MW, West, M, Nevins, JR, and Blackwell, K. "Gene expression profiles of multiple breast cancer phenotypes and response to neoadjuvant chemotherapy." Clin Cancer Res 12.3 Pt 1 (February 1, 2006): 819-826.
PMID
16467094
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
3 Pt 1
Publish Date
2006
Start Page
819
End Page
826
DOI
10.1158/1078-0432.CCR-05-1447

Genetic/familial high-risk assessment: breast and ovarian.

Authors
Daly, MB; Axilbund, JE; Bryant, E; Buys, S; Eng, C; Friedman, S; Esserman, LJ; Farrell, CD; Ford, JM; Garber, JE; Jeter, JM; Kohlmann, W; Lynch, PM; Marcom, PK; Nabell, LM; Offit, K; Osarogiagbon, RU; Pasche, B; Reiser, G; Sutphen, R; Weitzel, JN; National Comprehensive Cancer Network,
MLA Citation
Daly, MB, Axilbund, JE, Bryant, E, Buys, S, Eng, C, Friedman, S, Esserman, LJ, Farrell, CD, Ford, JM, Garber, JE, Jeter, JM, Kohlmann, W, Lynch, PM, Marcom, PK, Nabell, LM, Offit, K, Osarogiagbon, RU, Pasche, B, Reiser, G, Sutphen, R, Weitzel, JN, and National Comprehensive Cancer Network, . "Genetic/familial high-risk assessment: breast and ovarian." J Natl Compr Canc Netw 4.2 (February 2006): 156-176.
PMID
16451772
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
4
Issue
2
Publish Date
2006
Start Page
156
End Page
176

Genetic/familial high-risk assessment: Breast and ovarian. Clinical Practice Guidelines in Oncology™

Recent advances in molecular genetics have identified several genes associated with inherited susceptibility to cancer and have provided a means to begin identifying individuals and families with an increased risk of cancer. This rapid expansion of knowledge about cancer genetics has implications for all aspects of cancer management, including prevention, screening, and treatment. These guidelines specifically address hereditary breast/ovarian cancer syndrome (HBOC), Li-Fraumeni syndrome, and Cowden syndrome. These guidelines were developed understanding that much of our knowledge of how the rapidly emerging field of molecular genetics can be applied clinically is preliminary and that flexibility is needed when applying these guidelines to individual families. © Journal of the National Comprehensive Cancer Network.

Authors
Daly, MB; Axilbund, JE; Bryant, E; Buys, S; Eng, C; Friedman, S; Esserman, LJ; Farrell, CD; Ford, JM; Garber, JE; Jeter, JM; Kohlmann, W; Lynch, PM; Marcom, PK; Nabell, LM; Offit, K; Osarogiagbon, RU; Pasche, B; Reiser, G; Sutphen, R; Weitzel, JN
MLA Citation
Daly, MB, Axilbund, JE, Bryant, E, Buys, S, Eng, C, Friedman, S, Esserman, LJ, Farrell, CD, Ford, JM, Garber, JE, Jeter, JM, Kohlmann, W, Lynch, PM, Marcom, PK, Nabell, LM, Offit, K, Osarogiagbon, RU, Pasche, B, Reiser, G, Sutphen, R, and Weitzel, JN. "Genetic/familial high-risk assessment: Breast and ovarian. Clinical Practice Guidelines in Oncology™." JNCCN Journal of the National Comprehensive Cancer Network 4.2 (2006): 156-176.
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
4
Issue
2
Publish Date
2006
Start Page
156
End Page
176

Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas.

PURPOSE: This study (EGF10004) assessed the safety/tolerability, pharmacokinetics, and clinical activity of daily oral dosing with lapatinib (GW572016) in patients with ErbB1-expressing and/or ErbB2-overexpressing advanced-stage refractory solid tumors. PATIENTS AND METHODS: Heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers were randomly assigned to one of five dose cohorts of lapatinib administered once daily. Pharmacokinetic samples were obtained on days 1 and 20. Clinical response was assessed every 8 weeks. RESULTS: Sixty-seven patients with metastatic solid tumors were treated with lapatinib. The most frequently reported drug-related adverse events were diarrhea (42%) and rash (31%). No grade 4 drug-related adverse events were reported. Five grade 3 drug-related toxicities (gastrointestinal events and rash) were experienced by four patients. Drug-related interstitial pneumonitis or cardiac dysfunction associated with other ErbB-targeted therapies was not reported. Four patients with trastuzumab-resistant metastatic breast cancer-two of whom were classified as having inflammatory breast cancer-had partial responses (PRs). Twenty-four patients with various other carcinomas experienced stable disease, of whom 10 received lapatinib for > or = 6 months. The relationships between lapatinib dose or serum concentration and clinical response could not be adequately characterized due to the limited response data. The incidence of diarrhea increased with increasing dose, whereas the incidence of rash was not related to dose. CONCLUSION: Lapatinib was well tolerated at doses ranging from 500 to 1,600 mg once daily. Clinical activity was observed in heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers, including four PRs in patients with trastuzumab-resistant breast cancers and prolonged stable disease in 10 patients.

Authors
Burris, HA; Hurwitz, HI; Dees, EC; Dowlati, A; Blackwell, KL; O'Neil, B; Marcom, PK; Ellis, MJ; Overmoyer, B; Jones, SF; Harris, JL; Smith, DA; Koch, KM; Stead, A; Mangum, S; Spector, NL
MLA Citation
Burris, HA, Hurwitz, HI, Dees, EC, Dowlati, A, Blackwell, KL, O'Neil, B, Marcom, PK, Ellis, MJ, Overmoyer, B, Jones, SF, Harris, JL, Smith, DA, Koch, KM, Stead, A, Mangum, S, and Spector, NL. "Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas." J Clin Oncol 23.23 (August 10, 2005): 5305-5313.
PMID
15955900
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
23
Publish Date
2005
Start Page
5305
End Page
5313
DOI
10.1200/JCO.2005.16.584

Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies.

PURPOSE: This was a pilot study to assess the biologic effects of lapatinib on various tumor growth/survival pathways in patients with advanced ErbB1 and/or ErbB2-overexpressing solid malignancies. PATIENTS AND METHODS: Heavily pretreated patients with metastatic cancers overexpressing ErbB2 and/or expressing ErbB1 were randomly assigned to one of five dose cohorts of lapatinib (GW572016) administered orally once daily continuously. The biologic effects of lapatinib on tumor growth and survival pathways were assessed in tumor biopsies obtained before and after 21 days of therapy. Clinical response was determined at 8 weeks. RESULTS: Sequential tumor biopsies from 33 patients were examined. Partial responses occurred in four patients with breast cancer, and disease stabilization occurred in 11 others with various malignancies. Responders exhibited variable levels of inhibition of p-ErbB1, p-ErbB2, p-Erk1/2, p-Akt, cyclin D1, and transforming growth factor alpha. Even some nonresponders demonstrated varying degrees of biomarker inhibition. Increased tumor cell apoptosis (TUNEL) occurred in patients with evidence of tumor regression but not in nonresponders (progressive disease). Clinical response was associated with a pretreatment TUNEL score > 0 and increased pretreatment expression of ErbB2, p-ErbB2, Erk1/2, p-Erk1/2, insulin-like growth factor receptor-1, p70 S6 kinase, and transforming growth factor alpha compared with nonresponders. CONCLUSION: Lapatinib exhibited preliminary evidence of biologic and clinical activity in ErbB1 and/or ErbB2-overexpressing tumors. However, the limited sample size of this study and the variability of the biologic endpoints suggest that further work is needed to prioritize biomarkers for disease-directed studies, and underscores the need for improved trial design strategies in early clinical studies of targeted agents.

Authors
Spector, NL; Xia, W; Burris, H; Hurwitz, H; Dees, EC; Dowlati, A; O'Neil, B; Overmoyer, B; Marcom, PK; Blackwell, KL; Smith, DA; Koch, KM; Stead, A; Mangum, S; Ellis, MJ; Liu, L; Man, AK; Bremer, TM; Harris, J; Bacus, S
MLA Citation
Spector, NL, Xia, W, Burris, H, Hurwitz, H, Dees, EC, Dowlati, A, O'Neil, B, Overmoyer, B, Marcom, PK, Blackwell, KL, Smith, DA, Koch, KM, Stead, A, Mangum, S, Ellis, MJ, Liu, L, Man, AK, Bremer, TM, Harris, J, and Bacus, S. "Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies." J Clin Oncol 23.11 (April 10, 2005): 2502-2512.
PMID
15684311
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
11
Publish Date
2005
Start Page
2502
End Page
2512
DOI
10.1200/JCO.2005.12.157

Retinoic acid receptor-beta2 promoter methylation in random periareolar fine needle aspiration.

Methylation of the retinoic acid receptor-beta2 (RARbeta2) P2 promoter is hypothesized to be an important mechanism for loss of RARbeta2 function during early mammary carcinogenesis. The frequency of RARbeta2 P2 methylation was tested in (a) 16 early stage breast cancers and (b) 67 random periareolar fine needle aspiration (RPFNA) samples obtained from 38 asymptomatic women who were at increased risk for breast cancer. Risk was defined as either (a) 5-year Gail risk calculation > or = 1.7%; (b) prior biopsy exhibiting atypical hyperplasia, lobular carcinoma in situ, or ductal carcinoma in situ; or (c) known BRCA1/2 mutation carrier. RARbeta2 P2 promoter methylation was assessed at two regions, M3 (-51 to 162 bp) and M4 (104-251 bp). In early stage cancers, M4 methylation was observed in 11 of 16 (69%) cases; in RPFNA samples, methylation was present at M3 and M4 in 28 of 56 (50%) and 19 of 56 (38%) cases, respectively. RPFNAs were stratified for cytologic atypia using the Masood cytology index. The distribution of RARbeta2 P2 promoter methylation was reported as a function of increased cytologic abnormality. Methylation at both M3 and M4 was observed in (a) 0 of 10 (0%) of RPFNAs with Masood scores of < or = 10 (nonproliferative), (b) 3 of 20 (15%) with Masood scores of 11 to 12 (low-grade proliferative), (c) 3 of 10 (30%) with Masood scores of 13 (high-grade proliferative), and (d) 7 of 14 (50%) with Masood scores of 14 of 15 (atypia). Results from this study indicate that the RARbeta2 P2 promoter is frequently methylated (69%) in primary breast cancers and shows a positive association with increasing cytologic abnormality in RPFNA.

Authors
Bean, GR; Scott, V; Yee, L; Ratliff-Daniel, B; Troch, MM; Seo, P; Bowie, ML; Marcom, PK; Slade, J; Kimler, BF; Fabian, CJ; Zalles, CM; Broadwater, G; Baker, JC; Wilke, LG; Seewaldt, VL
MLA Citation
Bean, GR, Scott, V, Yee, L, Ratliff-Daniel, B, Troch, MM, Seo, P, Bowie, ML, Marcom, PK, Slade, J, Kimler, BF, Fabian, CJ, Zalles, CM, Broadwater, G, Baker, JC, Wilke, LG, and Seewaldt, VL. "Retinoic acid receptor-beta2 promoter methylation in random periareolar fine needle aspiration." Cancer Epidemiol Biomarkers Prev 14.4 (April 2005): 790-798.
PMID
15824145
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
14
Issue
4
Publish Date
2005
Start Page
790
End Page
798
DOI
10.1158/1055-9965.EPI-04-0580

Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer.

PURPOSE: This randomized phase III trial compared the efficacy and safety of capecitabine with or without bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. PATIENTS AND METHODS: Patients were randomly assigned to receive capecitabine (2,500 mg/m2/d) twice daily on day 1 through 14 every 3 weeks, alone or in combination with bevacizumab (15 mg/kg) on day 1. The primary end point was progression-free survival (PFS), as determined by an independent review facility. RESULTS: From November 2000 to March 2002, 462 patients were enrolled. Treatment arms were balanced. No significant differences were found in the incidence of diarrhea, hand-foot syndrome, thromboembolic events, or serious bleeding episodes between treatment groups. Of other grade 3 or 4 adverse events, only hypertension requiring treatment (17.9% v 0.5%) was more frequent in patients receiving bevacizumab. Combination therapy significantly increased the response rates (19.8% v 9.1%; P = .001); however, this did not result in a longer PFS (4.86 v 4.17 months; hazard ratio = 0.98). Overall survival (15.1 v 14.5 months) and time to deterioration in quality of life as measured by the Functional Assessment Of Cancer Treatment--Breast were comparable in both treatment groups. CONCLUSION: Bevacizumab was well tolerated in this heavily pretreated patient population. Although the addition of bevacizumab to capecitabine produced a significant increase in response rates, this did not translate into improved PFS or overall survival.

Authors
Miller, KD; Chap, LI; Holmes, FA; Cobleigh, MA; Marcom, PK; Fehrenbacher, L; Dickler, M; Overmoyer, BA; Reimann, JD; Sing, AP; Langmuir, V; Rugo, HS
MLA Citation
Miller, KD, Chap, LI, Holmes, FA, Cobleigh, MA, Marcom, PK, Fehrenbacher, L, Dickler, M, Overmoyer, BA, Reimann, JD, Sing, AP, Langmuir, V, and Rugo, HS. "Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer." J Clin Oncol 23.4 (February 1, 2005): 792-799.
PMID
15681523
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
4
Publish Date
2005
Start Page
792
End Page
799
DOI
10.1200/JCO.2005.05.098

Thermochemoradiotherapy improves oxygenation in locally advanced breast cancer.

PURPOSE: The purpose of this research was to evaluate toxicity, response, and changes in oxygenation (pO(2)) in patients with locally advanced breast cancer (LABC) treated with concurrent taxol, hyperthermia (HT), and radiation therapy (RT) followed by mastectomy. EXPERIMENTAL DESIGN: Eighteen patients with LABC were enrolled from October 1995 through February 1999. Treatment consisted of taxol (175 mg/m(2)) given every 3 weeks for three cycles. Radiation therapy included the breast and regional nodes with a dose of 50 Gy, followed by a boost to 60-65 Gy for those not undergoing surgery. Mastectomy was performed for patients deemed resectable after this neoadjuvant program. HT was administered twice per week. Oxygenation was measured before the first HT treatment and 24 h after the first HT treatment. RESULTS: Fifteen of 18 patients responded, 6 with a clinical complete response, 9 with a partial clinical response, and 3 nonresponders. Thirteen underwent mastectomy with 3 pathological complete responses. Tumor hypoxia was present in 8 of 13 patients (pO(2) = 4.7 +/- 1.2 mmHg). Five patients had well-oxygenated tumors (pO(2) = 27.6 +/- 7.8 mmHg). Patients with well-oxygenated tumors before treatment as well as those with significant reoxygenation had a favorable clinical response. Tumor reoxygenation appeared to be temperature dependent and associated with the lower thermal doses. CONCLUSIONS: This novel therapeutic program resulted in a high response rate in patients with LABC. Hyperthermia may offer a strategy for improving tumor reoxygenation with consequent treatment response. However, the effect of hyperthermia on tumor reoxygenation appears to depend on thermal dose and requires additional investigation.

Authors
Jones, EL; Prosnitz, LR; Dewhirst, MW; Marcom, PK; Hardenbergh, PH; Marks, LB; Brizel, DM; Vujaskovic, Z
MLA Citation
Jones, EL, Prosnitz, LR, Dewhirst, MW, Marcom, PK, Hardenbergh, PH, Marks, LB, Brizel, DM, and Vujaskovic, Z. "Thermochemoradiotherapy improves oxygenation in locally advanced breast cancer." Clin Cancer Res 10.13 (July 1, 2004): 4287-4293.
PMID
15240513
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
10
Issue
13
Publish Date
2004
Start Page
4287
End Page
4293
DOI
10.1158/1078-0432.CCR-04-0133

Capecitabine plus paclitaxel as front-line combination therapy for metastatic breast cancer: a multicenter phase II study.

PURPOSE: The goal of this multicenter, open-label phase II study was the clinical evaluation of combination therapy with the oral fluoropyrimidine capecitabine and the taxane paclitaxel in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-seven patients with MBC received oral capecitabine at 1650 mg/m(2)/d (825 mg/m(2) twice daily) on days 1 through 14, and intravenous infusion of paclitaxel at 175 mg/m(2) on day 1 of each 21-day treatment cycle. Treatment continued until disease progression, intolerable toxicity, or patient' s decision to discontinue. Patients (35 to 76 years old) had a median Karnofsky performance status of 90%. Forty-four patients (94%) received study treatment as first-line therapy for metastatic disease. RESULTS: Objective responses occurred in 24 (51%) patients; seven (15%) complete responses and 17 (36%) partial responses. Stable disease lasting 180 days or more was observed in nine (19%); the clinical response rate was 70%. Median duration of response was 12.6 months, median time to disease progression was 10.6 months, and median overall survival time was 29.9 months. The most common treatment-related adverse events, regardless of severity, were alopecia, hand-foot syndrome, nausea, and fatigue. Neutropenia (15%), alopecia (13%), and hand-foot syndrome (11%) were the only grade 3 or 4 treatment-related adverse events that occurred in more than 10% of patients. CONCLUSION: The combination of capecitabine plus paclitaxel is a highly active and generally well-tolerated regimen for first-line treatment of MBC.

Authors
Gradishar, WJ; Meza, LA; Amin, B; Samid, D; Hill, T; Chen, Y-M; Lower, EE; Marcom, PK
MLA Citation
Gradishar, WJ, Meza, LA, Amin, B, Samid, D, Hill, T, Chen, Y-M, Lower, EE, and Marcom, PK. "Capecitabine plus paclitaxel as front-line combination therapy for metastatic breast cancer: a multicenter phase II study." J Clin Oncol 22.12 (June 15, 2004): 2321-2327.
PMID
15197193
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
22
Issue
12
Publish Date
2004
Start Page
2321
End Page
2327
DOI
10.1200/JCO.2004.12.128

Thermochemoradiotherapy improves oxygenation in locally advanced breast cancer

Authors
Jones, EL; Prosnitz, LR; Dewhirst, MW; Marcom, PK; Hardenbergh, PH; Marks, LB; Brizel, DM; Vujaskovic, Z; Buchholz, TA
MLA Citation
Jones, EL, Prosnitz, LR, Dewhirst, MW, Marcom, PK, Hardenbergh, PH, Marks, LB, Brizel, DM, Vujaskovic, Z, and Buchholz, TA. "Thermochemoradiotherapy improves oxygenation in locally advanced breast cancer." Women's Oncology Review 4.3 (2004): 221-222.
Source
scival
Published In
Women's Oncology Review
Volume
4
Issue
3
Publish Date
2004
Start Page
221
End Page
222
DOI
10.1080/14733400400012958

Capecitabine plus paclitaxel as front-line combination therapy for metastatic breast cancer: A multicenter phase II study

Authors
Gradishar, WJ; Meza, LA; Amin, B; Samid, D; Hill, T; Chen, Y-M; Lower, EE; Marcom, PK; Iqbal, S
MLA Citation
Gradishar, WJ, Meza, LA, Amin, B, Samid, D, Hill, T, Chen, Y-M, Lower, EE, Marcom, PK, and Iqbal, S. "Capecitabine plus paclitaxel as front-line combination therapy for metastatic breast cancer: A multicenter phase II study." Women's Oncology Review 4.4 (2004): 283-285.
Source
scival
Published In
Women's Oncology Review
Volume
4
Issue
4
Publish Date
2004
Start Page
283
End Page
285
DOI
10.1080/14733400500034472

Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm.

PURPOSE: Trastuzumab-based therapy improves survival for women with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. We conducted a multicenter phase II study to evaluate the efficacy and safety of trastuzumab combined with vinorelbine, and to assess cardiac surveillance algorithms and tumor markers as prognostic tools. PATIENTS AND METHODS: Patients with HER2-positive (immunohistochemistry [IHC] 3+-positive or fluorescence in situ hybridization [FISH]-positive) metastatic breast cancer received first-line chemotherapy with trastuzumab and vinorelbine to determine response rate. Eligibility criteria were measurable disease and baseline ejection fraction >or= 50%. Serial testing for HER2 extracellular domain (ECD) was performed. RESULTS: Fifty-four women from 17 participating centers were entered onto the study. The overall response rate was 68% (95% confidence interval, 54% to 80%). Response rates were not affected by method of HER2 status determination (FISH v IHC) or by prior adjuvant chemotherapy. Median time to treatment failure was 5.6 months; 38% of patients were progression free after 1 year. Concurrent therapy was quite feasible with maintained dose-intensity. Patients received both chemotherapy and trastuzumab on 90% of scheduled treatment dates. Two patients experienced cardiotoxicity in excess of grade 1; one patient experienced symptomatic heart failure. A surveillance algorithm of screening left ventricular ejection fraction (LVEF) at 16 weeks successfully identified women at risk for experiencing cardiotoxicity. Other acute and chronic side effects were tolerable. Lack of decline in HER2 ECD during cycle 1 predicted tumor progression. CONCLUSION: Trastuzumab and vinorelbine constitute effective and well-tolerated first-line treatment for HER2-positive metastatic breast cancer. Patients with normal LVEF can be observed with surveillance of LVEF at 16 weeks to identify those at risk for cardiotoxicity.

Authors
Burstein, HJ; Harris, LN; Marcom, PK; Lambert-Falls, R; Havlin, K; Overmoyer, B; Friedlander, RJ; Gargiulo, J; Strenger, R; Vogel, CL; Ryan, PD; Ellis, MJ; Nunes, RA; Bunnell, CA; Campos, SM; Hallor, M; Gelman, R; Winer, EP
MLA Citation
Burstein, HJ, Harris, LN, Marcom, PK, Lambert-Falls, R, Havlin, K, Overmoyer, B, Friedlander, RJ, Gargiulo, J, Strenger, R, Vogel, CL, Ryan, PD, Ellis, MJ, Nunes, RA, Bunnell, CA, Campos, SM, Hallor, M, Gelman, R, and Winer, EP. "Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm." J Clin Oncol 21.15 (August 1, 2003): 2889-2895.
PMID
12885806
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
21
Issue
15
Publish Date
2003
Start Page
2889
End Page
2895
DOI
10.1200/JCO.2003.02.018

Do patients participating in clinical trials want to know study results?

Authors
Partridge, AH; Burstein, HJ; Gelman, RS; Marcom, PK; Winer, EP
MLA Citation
Partridge, AH, Burstein, HJ, Gelman, RS, Marcom, PK, and Winer, EP. "Do patients participating in clinical trials want to know study results?." J Natl Cancer Inst 95.6 (March 19, 2003): 491-492. (Letter)
PMID
12644548
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
95
Issue
6
Publish Date
2003
Start Page
491
End Page
492

Retinoids and retinoic acid receptors regulate growth arrest and apoptosis in human mammary epithelial cells and modulate expression of CBP/p300.

Retinoids and retinoic acid receptors (RARs) are important mediators of normal epithelial cell homeostasis. To assess the role of retinoids and RARs in regulating growth arrest and apoptosis in benign and malignant mammary epithelial cells, two model systems were developed: 1) RAR function was suppressed in retinoid-sensitive normal human mammary epithelial cells (HMECs) by the dominant-negative retinoic acid receptor, RARalpha403 (DNRAR), and 2) retinoid-resistant MCF-7 breast cancer cells were transduced with a functional RARbeta2. Inhibition of RAR function by the DNRAR in HMECs resulted in retinoid-resistance, increased proliferation, and dysregulated growth when cells were cultured in reconstituted extracellular matrix (rECM). Expression of RARbeta2 in MCF-7 cells resulted in sensitivity to retinoid-induced growth arrest and apoptosis. The CREB-binding protein (CBP) and the homologous protein p300 are tightly regulated, rate-limiting integrators of diverse signaling pathways and are recruited during retinoid-mediated transcriptional activation. The relationship between retinoid receptor expression, growth regulation, and transcriptional regulation of CBP/p300 is poorly understood. Inhibition of RAR function in HMECs by DNRAR suppressed expression of CBP/p300 and expression of RARbeta2 in MCF-7 cells promoted induction of CBP/p300 when cells were treated with 1.0 microM all-trans-retinoic acid (ATRA). These results suggest that ATRA and RARs regulate growth arrest of HMECs and modulate CBP/p300 protein expression. Since CBP and p300 are normally present in limiting amounts, their regulation by ATRA and RARs may be an important element in the control of transcriptional activation of genes regulating growth arrest and apoptosis.

Authors
Dietze, EC; Caldwell, LE; Marcom, K; Collins, SJ; Yee, L; Swisshelm, K; Hobbs, KB; Bean, GR; Seewaldt, VL
MLA Citation
Dietze, EC, Caldwell, LE, Marcom, K, Collins, SJ, Yee, L, Swisshelm, K, Hobbs, KB, Bean, GR, and Seewaldt, VL. "Retinoids and retinoic acid receptors regulate growth arrest and apoptosis in human mammary epithelial cells and modulate expression of CBP/p300." Microsc Res Tech 59.1 (October 1, 2002): 23-40.
PMID
12242694
Source
pubmed
Published In
Microscopy Research and Technique
Volume
59
Issue
1
Publish Date
2002
Start Page
23
End Page
40
DOI
10.1002/jemt.10174

Pre-counseling education materials for BRCA testing: does tailoring make a difference?

Although tailored print materials (TPMs) have been assessed for a variety of behavioral targets, their effectiveness as decision aids for genetic testing had not been evaluated at the time this study began. We compared TPMs and non-tailored print material (NPMs) that included similar content about genetic testing for breast and ovarian cancer susceptibility. TPMs were prepared especially for an individual based on information from and about her. We mailed baseline surveys to 461 women referred by physicians or identified through a tumor registry. All had personal and family histories of breast and/or ovarian cancer and, on the basis of these histories, an estimated > or =10% probability of carrying a mutation in the breast/ovarian cancer genes BRCA1 or BRCA2. The 325 (70%) who responded were randomly assigned to receive TPM or NPM. Followup surveys, mailed 2 weeks following receipt of print materials, were returned by 262 women (81% of baseline responders). Participants were predominately white (94%) and well-educated (50% college graduates). The mean age was 49 years. At follow-up, TPM recipients exhibited significantly greater improvement in percent of correct responses for the 13-item true/false measure of knowledge (24% increase for TPM vs. 16% for NPM; p < 0.0001) and significantly less over-estimation of risk of being a mutation carrier (40% TPM group overestimated vs. 70% NPM; p < 0.0001). Anxiety did not differ significantly between groups. Reactions to materials differed on two items: "seemed to be prepared just for me" (76% TPM vs. 52% NPM; p < 0.001) and "told me what I wanted to know about BRCA1 and 2 testing" (98% TPM vs. 91% NPM; p < 0.05). TPMs showed an advantage in increasing knowledge and enhancing accuracy of perceived risk. Both are critical components of informed decision making.

Authors
Skinner, CS; Schildkraut, JM; Berry, D; Calingaert, B; Marcom, PK; Sugarman, J; Winer, EP; Iglehart, JD; Futreal, PA; Rimer, BK
MLA Citation
Skinner, CS, Schildkraut, JM, Berry, D, Calingaert, B, Marcom, PK, Sugarman, J, Winer, EP, Iglehart, JD, Futreal, PA, and Rimer, BK. "Pre-counseling education materials for BRCA testing: does tailoring make a difference?." Genet Test 6.2 (2002): 93-105.
PMID
12215248
Source
pubmed
Published In
Genetic Testing
Volume
6
Issue
2
Publish Date
2002
Start Page
93
End Page
105
DOI
10.1089/10906570260199348

Changes in weight, body composition, and factors influencing energy balance among premenopausal breast cancer patients receiving adjuvant chemotherapy.

PURPOSE: Weight gain is a common problem among breast cancer patients who receive adjuvant chemotherapy (CT). We undertook a study to determine the causes of this energy imbalance. PATIENTS AND METHODS: Factors related to energy balance were assessed at baseline (within 3 weeks of diagnosis) and throughout 1 year postdiagnosis among 53 premenopausal women with operable breast carcinoma. Thirty-six patients received CT and 17 received only localized treatment (LT). Measures included body composition (dual energy x-ray absorptiometry), resting energy expenditure (REE; indirect calorimetry), dietary intake (2-day dietary recalls and food frequency questionnaires) and physical activity (physical activity records). RESULTS: Mean weight gain in the LT patients was 1.0 kg versus 2.1 kg in the CT group (P =.02). No significant differences between groups in trend over time were observed for REE and energy intake; however, a significant difference was noted for physical activity (P =.01). Several differences between groups in 1-year change scores were detected. The mean change (+/- SE) in LT versus CT groups and P values for uncontrolled/controlled (age, race, radiation therapy, baseline body mass index, and end point under consideration) analysis are as follows: percentage of body fat (-0.1 +/- 0.4 v +2.2 +/- 0.6%; P =.001/0.04); fat mass (+0.1 +/- 0.3 v +2.3 +/- 0.7 kg; P =.002/0.04); lean body mass (+0.8 +/- 0.2 v -0.4 +/- 0.3 kg; P =.02/0.30); and leg lean mass (+0.5 +/- 0.1 v -0.2 +/- 0.1 kg; P =.01/0.11). CONCLUSION: These data do not support overeating as a cause of weight gain among breast cancer patients who receive CT. The data suggest, however, that CT-induced weight gain is distinctive and indicative of sarcopenic obesity (weight gain in the presence of lean tissue loss or absence of lean tissue gain). The development of sarcopenic obesity with evidence of reduced physical activity supports the need for interventions focused on exercise, especially resistance training in the lower body, to prevent weight gain.

Authors
Demark-Wahnefried, W; Peterson, BL; Winer, EP; Marks, L; Aziz, N; Marcom, PK; Blackwell, K; Rimer, BK
MLA Citation
Demark-Wahnefried, W, Peterson, BL, Winer, EP, Marks, L, Aziz, N, Marcom, PK, Blackwell, K, and Rimer, BK. "Changes in weight, body composition, and factors influencing energy balance among premenopausal breast cancer patients receiving adjuvant chemotherapy." J Clin Oncol 19.9 (May 1, 2001): 2381-2389.
PMID
11331316
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
19
Issue
9
Publish Date
2001
Start Page
2381
End Page
2389
DOI
10.1200/JCO.2001.19.9.2381

Testing for hereditary breast and ovarian cancer in the southeastern United States.

OBJECTIVES: To detail characterization of mutations and uncharacterized variants in the breast cancer susceptibility genes BRCA1 and BRCA2, as observed in a population of breast cancer patients from the southeastern United States, and to examine baseline characteristics of women referred for counseling and testing and provide a preliminary look at how counseling and testing affected intentions toward prophylactic surgery. BACKGROUND: Mutations in the BRCA1 and BRCA2 genes give rise to a dramatically increased risk of developing breast or ovarian cancer or both. There are many reports about special populations in which deleterious mutations are present at a high frequency. It is useful to study these genes in more heterogeneous populations, reflecting different geographic regions. Interest in preventive surgery for gene carriers is high in women and their surgeons. METHODS: Women were recruited through a prospective clinical trial of counseling and free genetic testing. BRCA1 and BRCA2 were screened for mutations using standard techniques, and results were given to participants. Baseline questionnaires determined interest in preventive surgery at the beginning of the study. Follow-up questionnaires for those who completed testing surveyed interest in prophylactic surgery after counseling and receiving test results. RESULTS: Of 213 women who completed counseling and testing, 44 (20.6%) had 29 separate mutations; there were 11 Jewish women carrying three founder mutations. Twenty-eight women (13.1%) had uncharacterized variants in BRCA1 or BRCA2; nine were not previously reported. Women overestimated their chances of possessing a deleterious gene mutation compared to a statistical estimate of carrier risk. A number of women changed their intentions toward preventive surgery after genetic counseling and testing. CONCLUSIONS: Hereditary breast cancer due to mutations in BRCA1 and BRCA2 was a heterogeneous syndrome in the southeastern United States. Most mutations were seen just once, and uncharacterized variants were common and of uncertain clinical significance. In general, positive test results tended to reinforce intentions toward prophylactic surgery. In contrast, women not interested in surgery at the time of entry tended to remain reluctant after testing and counseling.

Authors
Miron, A; Schildkraut, JM; Rimer, BK; Winer, EP; Sugg Skinner, C; Futreal, PA; Culler, D; Calingaert, B; Clark, S; Kelly Marcom, P; Iglehart, JD
MLA Citation
Miron, A, Schildkraut, JM, Rimer, BK, Winer, EP, Sugg Skinner, C, Futreal, PA, Culler, D, Calingaert, B, Clark, S, Kelly Marcom, P, and Iglehart, JD. "Testing for hereditary breast and ovarian cancer in the southeastern United States." Ann Surg 231.5 (May 2000): 624-634.
PMID
10767783
Source
pubmed
Published In
Annals of Surgery
Volume
231
Issue
5
Publish Date
2000
Start Page
624
End Page
634

Phase I study of Doxil and vinorelbine in metastatic breast cancer.

BACKGROUND: Vinorelbine and Doxil (liposomal doxorubicin) are active chemotherapeutic agents in metastatic breast cancer. A phase I study was designed to evaluate combination therapy. PATIENTS AND METHODS: Thirty women with metastatic breast cancer were enrolled. Dose-limiting toxicity was determined through a dose escalation scheme, and defined for the first treatment cycle, only. Pharmacokinetic studies were performed during the first cycle of treatment. RESULTS: In the first cohort of Doxil 30 mg/m2 day 1 and vinorelbine 25 mg/m2 days 1 and 8, patients experienced severe neutropenia. Vinorelbine administration was changed thereafter to days 1 and 15 of each cycle. Dose limiting toxicity was observed at Doxil 50 mg/m2 and vinorelbine 25 mg/m2. Doxil 40 mg/m2 and vinorelbine 30 mg/m2 was defined as the maximally tolerated dose. Few toxicities (principally neutro penia) were seen at this dose level, with the notable absence of significant nausea, vomiting, or alopecia. Though 63% of patients had received prior anthracycline-based chemotherapy, only one patient developed grade 2 cardiac toxicity. Pharmacokinetic studies revealed prolonged exposure to high doxorubicin concentrations for several days following Doxil administration. CONCLUSIONS: Combination chemotherapy with Doxil and vinorelbine affords treatment with two active drugs in women with metastatic breast cancer, and appears to have a favorable toxicity profile. A schedule of Doxil 40 mg/m2 day 1 and vinorelbine 30 mg/m2 days 1 and 15 given every 28 days is recommended for phase II studies.

Authors
Burstein, HJ; Ramirez, MJ; Petros, WP; Clarke, KD; Warmuth, MA; Marcom, PK; Matulonis, UA; Parker, LM; Harris, LN; Winer, EP
MLA Citation
Burstein, HJ, Ramirez, MJ, Petros, WP, Clarke, KD, Warmuth, MA, Marcom, PK, Matulonis, UA, Parker, LM, Harris, LN, and Winer, EP. "Phase I study of Doxil and vinorelbine in metastatic breast cancer." Ann Oncol 10.9 (September 1999): 1113-1116.
PMID
10572612
Source
pubmed
Published In
Annals of Oncology
Volume
10
Issue
9
Publish Date
1999
Start Page
1113
End Page
1116

Topical thrombin and acquired coagulation factor inhibitors: clinical spectrum and laboratory diagnosis.

Topical bovine thrombin preparations are used extensively in cardiovascular, neurosurgical, and otolaryngologic procedures. Patients who are treated with these topical thrombin preparations may develop antibodies to bovine coagulation factors that may cross-react with the endogenous human clotting proteins. We have identified four patients with acquired factor inhibitors following exposure to topical thrombin at Duke University Medical Center and summarize these cases in addition to 13 patients previously reported in the literature. In most cases, the inhibitor developed following a second (or subsequent) exposure to topical thrombin. The clinical course was extremely variable, ranging from totally asymptomatic to life-threatening hemorrhage. The most consistent laboratory abnormality was a prolonged bovine thrombin clotting time, which corrected, at least partially, when human thrombin was substituted for bovine thrombin. Some of these patients also developed factor V inhibitors with prolonged prothrombin and activated partial thromboplastin times. Although these patients have prolonged clotting times, they should not be considered "autoanticoagulated," since thromboembolic complications can still occur. Therapeutic intervention is largely empirical and depends on the clinical manifestations of the individual patient.

Authors
Ortel, TL; Charles, LA; Keller, FG; Marcom, PK; Oldham, HN; Kane, WH; Macik, BG
MLA Citation
Ortel, TL, Charles, LA, Keller, FG, Marcom, PK, Oldham, HN, Kane, WH, and Macik, BG. "Topical thrombin and acquired coagulation factor inhibitors: clinical spectrum and laboratory diagnosis." Am J Hematol 45.2 (February 1994): 128-135. (Review)
PMID
8141118
Source
pubmed
Published In
American Journal of Hematology
Volume
45
Issue
2
Publish Date
1994
Start Page
128
End Page
135

Rocky Mountain spotted fever complicated by gangrene: report of six cases and review.

Although mortality due to fulminant Rocky Mountain spotted fever (RMSF) is well appreciated, the ability of the disease to cause survivors to become permanently disabled is not as widely known. We report six cases of RMSF complicated by gangrene. Although four patients required multiple limb and/or digital amputations, only one death resulted. Our review of the English-language literature revealed 23 additional cases of RMSF complicated by gangrene. Pathophysiologically, gangrene is most likely related to small-vessel occlusion. Skin necrosis and gangrene in association with RMSF are the extreme end on a continuum from reversible to irreversible skin and tissue damage caused by Rickettsia rickettsii. Most patients with RMSF have a typical skin rash that resolves without sequelae. Some patients develop minute cicatrices marking the location of focal cutaneous necrosis; for other patients, digital ischemia occurs transiently or evolves to produce severe ischemic changes without gangrene that result in permanent impairment. At the far end of this clinical continuum are patients who develop gangrene requiring amputation.

Authors
Kirkland, KB; Marcom, PK; Sexton, DJ; Dumler, JS; Walker, DH
MLA Citation
Kirkland, KB, Marcom, PK, Sexton, DJ, Dumler, JS, and Walker, DH. "Rocky Mountain spotted fever complicated by gangrene: report of six cases and review." Clin Infect Dis 16.5 (May 1993): 629-634. (Review)
PMID
8507753
Source
pubmed
Published In
Clinical Infectious Diseases
Volume
16
Issue
5
Publish Date
1993
Start Page
629
End Page
634

Sodium channel density in hypomyelinated brain increased by myelin basic protein gene deletion.

Trophic control over the expression and membrane distribution of voltage-dependent ion channels is one of the principal organizing events underlying the maturation of excitable cells. The myelin sheath is a major structural determinant of regional ion channel topography in central axons, but the exact molecular signals that mediate local interactions between the oligodendrocyte and axolemma are not known. We have found that large caliber fibre pathways in the brain of the mutant mouse shiverer (shi, gene on chromosome 18), whose developmental fate of myelination is averted by deletion of five exons in the myelin basic protein gene, have a striking excess of sodium channels. As cytoplasmic membranes of shiverer oligodendroglia still adhere to axons, the evidence indicates that myelin basic protein or a myelin basic protein-dependent glial transmembrane signal associated with compact myelin formation, rather than a simple glial-axon contact inhibition or an intrinsic genetic program of neuronal differentiation, could be critical in downregulating sodium channel density in axons. Here we use the shiverer mutant to show that mature central nervous system projection neurons with large caliber unmyelinated fibres sustain functional excitability by increasing sodium channel density. This axon plasticity, triggered by the absence of a single glial protein, contributes to the unexpectedly mild degree of neurological impairment in the mutant brain without myelin, and may be a potentially inducible mechanism determining the recovery of function from dysmyelinating disease.

Authors
Noebels, JL; Marcom, PK; Jalilian-Tehrani, MH
MLA Citation
Noebels, JL, Marcom, PK, and Jalilian-Tehrani, MH. "Sodium channel density in hypomyelinated brain increased by myelin basic protein gene deletion." Nature 352.6334 (August 1, 1991): 431-434.
PMID
1713650
Source
pubmed
Published In
Nature
Volume
352
Issue
6334
Publish Date
1991
Start Page
431
End Page
434
DOI
10.1038/352431a0
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