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Blackwell, Kimberly Lynn

Overview:

Breast cancer angiogenesis
Breast cancer in younger women
Hormonal therapy
Neoadjurant therapy for breast cancer

Current Clinical Investigations

Principal Investigator, A Phase I-II Study of Neoadjuvant Evacet/Paclitaxel/Hyperthermia in Locally Advanced Breast Cancer Patients.

Investigator, Development of Screening Markers for Breast Cancer using Circulating Immune Complexes: Collaborative Study with Diagen Medical Technologies.

Principal Investigator, Use of Plasma D-Dimer as a Predictive Marker in Colorectal Carcinoma: Correlative Science Study with Genentech, Inc.

Principal Investigator, A randomized, Phase II study of gabapentin or glutamine to prevent the peripheral neuropathy/myalgia associated with weekly taxol administration in metastatic breast and lung cancer.

Investigator, A Phase 2, Randomized, Double-Masked, Multicenter Study of Two Dose Levels of ERA-923 for the treatment of Metastatic Breast Cancer in Postmenopausal Women who have failed Tamoxifen therapy. Genetics Institute.

Investigator, A Phase I Study of Combined Doxil/Hyperthermia in Stage IV Breast Cancer.

Positions:

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Assistant Professor in Radiation Oncology

Radiation Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1994

M.D. — Mayo School of Health Sciences

Medical Resident, Medicine

Duke University

Fellow In Hematology Oncology, Medicine

Duke University

News:

Grants:

Defining the Rules of Breast Cancer Cell Traffic Through Bone

Administered By
Medicine, Hematological Malignancies
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
January 09, 2017
End Date
December 31, 2021

Translational Research in Surgical Oncology

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
January 01, 2002
End Date
August 31, 2021

Regional Oncolytic Poliovirus Immunotherapy for Breast Cancer

Administered By
Surgery, Surgical Sciences
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
August 01, 2016
End Date
July 31, 2021

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Collaborating Investigator
Start Date
September 01, 1985
End Date
December 31, 2020

Innocrin VT-464

Administered By
Duke Cancer Institute
AwardedBy
Innocrin Pharmaceutical, Inc.
Role
Principal Investigator
Start Date
August 26, 2016
End Date
August 25, 2020

Targeting differential apoptosis regulation in triple negative breast cancer

Administered By
Pharmacology & Cancer Biology
AwardedBy
Department of Defense
Role
Collaborator
Start Date
September 30, 2016
End Date
September 29, 2019

A RANDOMIZED, MULTICENTER, OPEN-LABEL, PHASE III TRIAL COMPARING TRASTUZUMAB PLUS

Administered By
Duke Cancer Institute
AwardedBy
Genentech, Inc.
Role
Principal Investigator
Start Date
September 01, 2014
End Date
August 31, 2019

Genentech Intrathecal

Administered By
Duke Cancer Institute
AwardedBy
Genentech, Inc.
Role
Principal Investigator
Start Date
March 01, 2016
End Date
December 31, 2018

Determining the clinical efficacy and predictive biomarkers of mirvetuximab soravtansine (IMGN853) in folate receptor alpha (FRA) expressing, chemotherapy refractory triple negative breast cance

Administered By
Medicine, Medical Oncology
AwardedBy
National Comprehensive Cancer Network
Role
Principal Investigator
Start Date
December 01, 2016
End Date
November 30, 2018

Genentech Anti PD-L1

Administered By
Duke Cancer Institute
AwardedBy
F. Hoffmann-La Roche Ltd
Role
Principal Investigator
Start Date
December 05, 2016
End Date
November 29, 2018

Oncothyreon ONT 380-206

Administered By
Duke Cancer Institute
AwardedBy
Cascadian Therapeutics Inc.
Role
Principal Investigator
Start Date
October 11, 2016
End Date
October 11, 2018

Monaleesa 7 LEE011-E2301

Administered By
Duke Cancer Institute
AwardedBy
Novartis Pharmaceuticals Corporation
Role
Principal Investigator
Start Date
July 01, 2015
End Date
September 02, 2018

MonaLEEsa 3 LEE011-F2301

Administered By
Duke Cancer Institute
AwardedBy
Novartis Pharmaceuticals Corporation
Role
Principal Investigator
Start Date
April 20, 2015
End Date
September 02, 2018

Celldex CDX 011-04

Administered By
Duke Cancer Institute
AwardedBy
Celldex Therapeutics, Inc.
Role
Principal Investigator
Start Date
September 01, 2014
End Date
August 31, 2018

A Phase II Study of Neratinib in Metastatic HER2 Non-amplified by HER2 Mutant Breast Cancer

Administered By
Duke Cancer Institute
AwardedBy
Washington University
Role
Principal Investigator
Start Date
January 01, 2014
End Date
December 31, 2017

Examining the Role of Cholesterol Metabolites on the Estrogen Receptor Signaling Pathway

Administered By
Medicine, Medical Oncology
AwardedBy
Susan G. Komen Breast Cancer Foundation
Role
Principal Investigator
Start Date
October 23, 2015
End Date
October 22, 2017

Developing a HER3 Vaccine to Prevent Resistance to Endocrine Therapy

Administered By
Surgery, Surgical Sciences
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
September 30, 2012
End Date
September 29, 2017

Directed Chemotherapy Delivery for Leptomeningeal Metastases

Administered By
Neurosurgery
AwardedBy
Minnetronix, Inc
Role
Co Investigator
Start Date
September 01, 2016
End Date
August 31, 2017

Enhancing Efficacy of Chemotherapy in Triple Negatiave/Basal-like Breast Cancer

Administered By
Duke Cancer Institute
AwardedBy
University of California - San Francisco
Role
Principal Investigator
Start Date
August 08, 2013
End Date
April 30, 2017

Innovative Biomarker-Integrated Clinical Trial Design and Analysis

Administered By
Biostatistics & Bioinformatics
AwardedBy
University of North Carolina - Chapel Hill
Role
Clinical Investigator
Start Date
May 15, 2015
End Date
March 31, 2017

Merrimack MM-302

Administered By
Duke Cancer Institute
AwardedBy
Merrimack Pharmaceuticals
Role
Principal Investigator
Start Date
June 01, 2016
End Date
March 09, 2017

EISAI BREAST CANCER ADVANCED TRAINING

Administered By
Medicine, Medical Oncology
AwardedBy
Eisai, Inc.
Role
Principal Investigator
Start Date
September 27, 2016
End Date
October 12, 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

Novartis Breast Cancer Practicum

Administered By
Medicine, Medical Oncology
AwardedBy
Novartis Pharmaceuticals Corporation
Role
Principal Investigator
Start Date
October 27, 2014
End Date
November 06, 2014

Understanding Patient Expectations of Treatment Outcomes

Administered By
Duke Clinical Research Institute
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
June 08, 2009
End Date
November 30, 2011

Role of XIAP in Therapeutic Resistance in Inflammatory Breast Cancer

Administered By
Surgery
AwardedBy
Dept. of the Army -- USAMRAA
Role
Consultant
Start Date
July 01, 2008
End Date
August 31, 2010

Antiestrogenic Effects on Tumor Angiogenesis

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 2001
End Date
April 30, 2006
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Publications:

Phase II, randomized, placebo-controlled study of dovitinib in combination with fulvestrant in postmenopausal patients with HR+, HER2- breast cancer that had progressed during or after prior endocrine therapy.

Overexpression of fibroblast growth factor receptor 1 (FGFR1), found in ≤8% of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer cases, is correlated with decreased overall survival and resistance to endocrine therapy (ET). Dovitinib, a potent FGFR inhibitor, has demonstrated antitumor activity in heavily pretreated patients with FGFR pathway-amplified breast cancer.In this randomized, placebo-controlled phase II trial, we evaluated whether the addition of dovitinib to fulvestrant would improve outcomes in postmenopausal patients with HR+, HER2- advanced breast cancer that had progressed during or after prior ET. Patients were stratified by FGF pathway amplification and presence of visceral disease, and they were randomized 1:1 to receive fulvestrant plus dovitinib or placebo. The primary endpoint was progression-free survival (PFS).From 15 May 2012 to 26 November 2014, 97 patients from 36 centers were enrolled. The frequency of FGF pathway amplification was lower than anticipated, and the study was terminated early owing to slow accrual of patients with FGF pathway amplification. The median PFS (95% CI) was 5.5 (3.8-14.0) months vs 5.5 (3.5-10.7) months in the dovitinib vs placebo arms, respectively (HR, 0.68; did not meet predefined efficacy criteria). For the FGF pathway-amplified subgroup (n = 31), the median PFS (95% CI) was 10.9 (3.5-16.5) months vs 5.5 (3.5-16.4) months in the dovitinib vs placebo arms, respectively (HR, 0.64; met the predefined superiority criteria). Frequently reported adverse events in the dovitinib (diarrhea, nausea, vomiting, asthenia, and headache) and placebo (diarrhea, fatigue, nausea, and asthenia) arms were mostly low grade.The safety profile of dovitinib plus fulvestrant was consistent with the known safety profile of single-agent dovitinib. Dovitinib in combination with fulvestrant showed promising clinical activity in the FGF pathway-amplified subgroup. However, the data reported herein should be interpreted with caution, given that fewer PFS events occurred in the FGF pathway-amplified patients than was expected and that an effect of dovitinib regardless of FGR pathway amplification status cannot be excluded, because the population was smaller than expected.ClinicalTrials.gov identifier: NCT01528345 . Registered 31 January 2012.

Authors
Musolino, A; Campone, M; Neven, P; Denduluri, N; Barrios, CH; Cortes, J; Blackwell, K; Soliman, H; Kahan, Z; Bonnefoi, H; Squires, M; Zhang, Y; Deudon, S; Shi, MM; André, F
MLA Citation
Musolino, A, Campone, M, Neven, P, Denduluri, N, Barrios, CH, Cortes, J, Blackwell, K, Soliman, H, Kahan, Z, Bonnefoi, H, Squires, M, Zhang, Y, Deudon, S, Shi, MM, and André, F. "Phase II, randomized, placebo-controlled study of dovitinib in combination with fulvestrant in postmenopausal patients with HR+, HER2- breast cancer that had progressed during or after prior endocrine therapy." Breast cancer research : BCR 19.1 (February 10, 2017): 18-.
PMID
28183331
Source
epmc
Published In
Breast Cancer Research
Volume
19
Issue
1
Publish Date
2017
Start Page
18
DOI
10.1186/s13058-017-0807-8

TBCRC-010: Phase I/II Study of Dasatinib in Combination with Zoledronic Acid for the Treatment of Breast Cancer Bone Metastasis

Authors
Mitri, Z; Nanda, R; Blackwell, K; Costelloe, CM; Hood, I; Wei, C; Brewster, AM; Ibrahim, NK; Koenig, KB; Hortobagyi, GN; Van Poznak, C; Rimawi, MF; Moulder-Thompson, S
MLA Citation
Mitri, Z, Nanda, R, Blackwell, K, Costelloe, CM, Hood, I, Wei, C, Brewster, AM, Ibrahim, NK, Koenig, KB, Hortobagyi, GN, Van Poznak, C, Rimawi, MF, and Moulder-Thompson, S. "TBCRC-010: Phase I/II Study of Dasatinib in Combination with Zoledronic Acid for the Treatment of Breast Cancer Bone Metastasis." Clinical Cancer Research 22.23 (December 1, 2016): 5706-5712.
Source
crossref
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
22
Issue
23
Publish Date
2016
Start Page
5706
End Page
5712
DOI
10.1158/1078-0432.CCR-15-2845

PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation.

Therapies that efficiently induce apoptosis are likely to be required for durable clinical responses in patients with solid tumors. Using a pharmacological screening approach, we discovered that combined inhibition of B cell lymphoma-extra large (BCL-XL) and the mammalian target of rapamycin (mTOR)/4E-BP axis results in selective and synergistic induction of apoptosis in cellular and animal models of PIK3CA mutant breast cancers, including triple-negative tumors. Mechanistically, inhibition of mTOR/4E-BP suppresses myeloid cell leukemia-1 (MCL-1) protein translation only in PIK3CA mutant tumors, creating a synthetic dependence on BCL-XL This dual dependence on BCL-XL and MCL-1, but not on BCL-2, appears to be a fundamental property of diverse breast cancer cell lines, xenografts, and patient-derived tumors that is independent of the molecular subtype or PIK3CA mutational status. Furthermore, this dependence distinguishes breast cancers from normal breast epithelial cells, which are neither primed for apoptosis nor dependent on BCL-XL/MCL-1, suggesting a potential therapeutic window. By tilting the balance of pro- to antiapoptotic signals in the mitochondria, dual inhibition of MCL-1 and BCL-XL also sensitizes breast cancer cells to standard-of-care cytotoxic and targeted chemotherapies. Together, these results suggest that patients with PIK3CA mutant breast cancers may benefit from combined treatment with inhibitors of BCL-XL and the mTOR/4E-BP axis, whereas alternative methods of inhibiting MCL-1 and BCL-XL may be effective in tumors lacking PIK3CA mutations.

Authors
Anderson, GR; Wardell, SE; Cakir, M; Crawford, L; Leeds, JC; Nussbaum, DP; Shankar, PS; Soderquist, RS; Stein, EM; Tingley, JP; Winter, PS; Zieser-Misenheimer, EK; Alley, HM; Yllanes, A; Haney, V; Blackwell, KL; McCall, SJ; McDonnell, DP; Wood, KC
MLA Citation
Anderson, GR, Wardell, SE, Cakir, M, Crawford, L, Leeds, JC, Nussbaum, DP, Shankar, PS, Soderquist, RS, Stein, EM, Tingley, JP, Winter, PS, Zieser-Misenheimer, EK, Alley, HM, Yllanes, A, Haney, V, Blackwell, KL, McCall, SJ, McDonnell, DP, and Wood, KC. "PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation." Science translational medicine 8.369 (December 2016): 369ra175-.
Website
http://hdl.handle.net/10161/13335
PMID
27974663
Source
epmc
Published In
Science Translational Medicine
Volume
8
Issue
369
Publish Date
2016
Start Page
369ra175
DOI
10.1126/scitranslmed.aae0348

Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer.

Background The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). Methods In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10-5. Results The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10-6 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively. Conclusions Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).

Authors
Hortobagyi, GN; Stemmer, SM; Burris, HA; Yap, Y-S; Sonke, GS; Paluch-Shimon, S; Campone, M; Blackwell, KL; André, F; Winer, EP; Janni, W; Verma, S; Conte, P; Arteaga, CL; Cameron, DA; Petrakova, K; Hart, LL; Villanueva, C; Chan, A; Jakobsen, E; Nusch, A; Burdaeva, O; Grischke, E-M; Alba, E; Wist, E; Marschner, N; Favret, AM; Yardley, D; Bachelot, T; Tseng, L-M; Blau, S; Xuan, F; Souami, F; Miller, M; Germa, C; Hirawat, S; O'Shaughnessy, J
MLA Citation
Hortobagyi, GN, Stemmer, SM, Burris, HA, Yap, Y-S, Sonke, GS, Paluch-Shimon, S, Campone, M, Blackwell, KL, André, F, Winer, EP, Janni, W, Verma, S, Conte, P, Arteaga, CL, Cameron, DA, Petrakova, K, Hart, LL, Villanueva, C, Chan, A, Jakobsen, E, Nusch, A, Burdaeva, O, Grischke, E-M, Alba, E, Wist, E, Marschner, N, Favret, AM, Yardley, D, Bachelot, T, Tseng, L-M, Blau, S, Xuan, F, Souami, F, Miller, M, Germa, C, Hirawat, S, and O'Shaughnessy, J. "Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer." The New England journal of medicine 375.18 (November 2016): 1738-1748.
PMID
27717303
Source
epmc
Published In
The New England journal of medicine
Volume
375
Issue
18
Publish Date
2016
Start Page
1738
End Page
1748
DOI
10.1056/nejmoa1609709

Embracing rejection: Immunologic trends in brain metastasis.

Brain metastases represent the most common type of brain tumor. These tumors offer a dismal prognosis and significantly impact quality of life for patients. Their capacity for central nervous system (CNS) invasion is dependent upon induced disruptions to the blood-brain barrier (BBB), alterations to the brain microenvironment, and mechanisms for escaping CNS immunosurveillance. In the emerging era of immunotherapy, understanding how metastases are influenced by the immunologic peculiarities of the CNS will be crucial to forging therapeutic advances. In this review, the immunology of brain metastasis is explored.

Authors
Farber, SH; Tsvankin, V; Narloch, JL; Kim, GJ; Salama, AKS; Vlahovic, G; Blackwell, KL; Kirkpatrick, JP; Fecci, PE
MLA Citation
Farber, SH, Tsvankin, V, Narloch, JL, Kim, GJ, Salama, AKS, Vlahovic, G, Blackwell, KL, Kirkpatrick, JP, and Fecci, PE. "Embracing rejection: Immunologic trends in brain metastasis." Oncoimmunology 5.7 (July 2016): e1172153-. (Review)
PMID
27622023
Source
epmc
Published In
OncoImmunology
Volume
5
Issue
7
Publish Date
2016
Start Page
e1172153
DOI
10.1080/2162402x.2016.1172153

A Comparison of Proposed Biosimilar LA-EP2006 and Reference Pegfilgrastim for the Prevention of Neutropenia in Patients With Early-Stage Breast Cancer Receiving Myelosuppressive Adjuvant or Neoadjuvant Chemotherapy: Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2), a Phase III, Randomized, Double-Blind Trial

Authors
Blackwell, K; Donskih, R; Jones, CM; Nixon, A; Vidal, MJ; Nakov, R; Singh, P; Schaffar, G; Gascón, P; Harbeck, N
MLA Citation
Blackwell, K, Donskih, R, Jones, CM, Nixon, A, Vidal, MJ, Nakov, R, Singh, P, Schaffar, G, Gascón, P, and Harbeck, N. "A Comparison of Proposed Biosimilar LA-EP2006 and Reference Pegfilgrastim for the Prevention of Neutropenia in Patients With Early-Stage Breast Cancer Receiving Myelosuppressive Adjuvant or Neoadjuvant Chemotherapy: Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2), a Phase III, Randomized, Double-Blind Trial." The Oncologist 21.7 (July 2016): 789-794.
Source
crossref
Published In
The oncologist
Volume
21
Issue
7
Publish Date
2016
Start Page
789
End Page
794
DOI
10.1634/theoncologist.2016-0011

Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer

Authors
Harbeck, N; Lipatov, O; Frolova, M; Udovitsa, D; Topuzov, E; Ganea-Motan, DE; Nakov, R; Singh, P; Rudy, A; Blackwell, K
MLA Citation
Harbeck, N, Lipatov, O, Frolova, M, Udovitsa, D, Topuzov, E, Ganea-Motan, DE, Nakov, R, Singh, P, Rudy, A, and Blackwell, K. "Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer." Future Oncology 12.11 (June 2016): 1359-1367.
Source
crossref
Published In
Future oncology (London, England)
Volume
12
Issue
11
Publish Date
2016
Start Page
1359
End Page
1367
DOI
10.2217/fon-2016-0016

Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases.

Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial.Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥ 50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression--the threshold for success was five of 40 responders.Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time.Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.

Authors
Freedman, RA; Gelman, RS; Wefel, JS; Melisko, ME; Hess, KR; Connolly, RM; Van Poznak, CH; Niravath, PA; Puhalla, SL; Ibrahim, N; Blackwell, KL; Moy, B; Herold, C; Liu, MC; Lowe, A; Agar, NYR; Ryabin, N; Farooq, S; Lawler, E; Rimawi, MF; Krop, IE; Wolff, AC; Winer, EP; Lin, NU
MLA Citation
Freedman, RA, Gelman, RS, Wefel, JS, Melisko, ME, Hess, KR, Connolly, RM, Van Poznak, CH, Niravath, PA, Puhalla, SL, Ibrahim, N, Blackwell, KL, Moy, B, Herold, C, Liu, MC, Lowe, A, Agar, NYR, Ryabin, N, Farooq, S, Lawler, E, Rimawi, MF, Krop, IE, Wolff, AC, Winer, EP, and Lin, NU. "Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 34.9 (March 2016): 945-952.
PMID
26834058
Source
epmc
Published In
Journal of Clinical Oncology
Volume
34
Issue
9
Publish Date
2016
Start Page
945
End Page
952
DOI
10.1200/jco.2015.63.0343

Increased Fiber Intake Decreases Premenopausal Breast Cancer Risk.

Authors
Harnden, KK; Blackwell, KL
MLA Citation
Harnden, KK, and Blackwell, KL. "Increased Fiber Intake Decreases Premenopausal Breast Cancer Risk." Pediatrics 137.3 (March 2016): e20154376-.
PMID
26908710
Source
epmc
Published In
Pediatrics
Volume
137
Issue
3
Publish Date
2016
Start Page
e20154376
DOI
10.1542/peds.2015-4376

Phase I/II dose-escalation study of PI3K inhibitors pilaralisib or voxtalisib in combination with letrozole in patients with hormone-receptor-positive and HER2-negative metastatic breast cancer refractory to a non-steroidal aromatase inhibitor.

This phase I/II dose-escalation study evaluated the efficacy, safety, and pharmacokinetics of pilaralisib (SAR245408), a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, or voxtalisib (SAR245409), a PI3K and mammalian target of rapamycin inhibitor, in combination with letrozole in hormone-receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative, non-steroidal aromatase inhibitor-refractory, recurrent or metastatic breast cancer. Maximum tolerated doses (MTDs) were determined using a 3 + 3 design in phase I. Efficacy was evaluated at the MTDs in phase II. Twenty-one patients were enrolled in phase I; MTDs were determined to be pilaralisib tablets 400 mg once daily (QD) or voxtalisib capsules 50 mg twice daily in combination with letrozole tablets 2.5 mg QD. Fifty-one patients were enrolled in phase II; one patient had a partial response in the pilaralisib arm. Rates of progression-free survival at 6 months were 17 and 8 % in the pilaralisib and voxtalisib arms, respectively. The most frequently reported treatment-related grade ≥ 3 adverse events were aspartate aminotransferase increased (5 %) and rash (5 %) in the pilaralisib arm, and alanine aminotransferase increased (11 %) and rash (9 %) in the voxtalisib arm. Pilaralisib and voxtalisib did not interact pharmacokinetically with letrozole. Pilaralisib had a greater pharmacodynamic impact than voxtalisib, as demonstrated by its impact on glucose homeostasis. There was no association between molecular alterations in the PI3K pathway and efficacy. In summary, pilaralisib or voxtalisib, in combination with letrozole, was associated with an acceptable safety profile and limited efficacy in endocrine therapy-resistant HR+ , HER2-negative metastatic breast cancer.

Authors
Blackwell, K; Burris, H; Gomez, P; Lynn Henry, N; Isakoff, S; Campana, F; Gao, L; Jiang, J; Macé, S; Tolaney, SM
MLA Citation
Blackwell, K, Burris, H, Gomez, P, Lynn Henry, N, Isakoff, S, Campana, F, Gao, L, Jiang, J, Macé, S, and Tolaney, SM. "Phase I/II dose-escalation study of PI3K inhibitors pilaralisib or voxtalisib in combination with letrozole in patients with hormone-receptor-positive and HER2-negative metastatic breast cancer refractory to a non-steroidal aromatase inhibitor." Breast cancer research and treatment 154.2 (November 2015): 287-297.
PMID
26497877
Source
epmc
Published In
Breast Cancer Research and Treatment
Volume
154
Issue
2
Publish Date
2015
Start Page
287
End Page
297
DOI
10.1007/s10549-015-3615-9

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

Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy

Authors
Blackwell, K; Semiglazov, V; Krasnozhon, D; Davidenko, I; Nelyubina, L; Nakov, R; Stiegler, G; Singh, P; Schwebig, A; Kramer, S; Harbeck, N
MLA Citation
Blackwell, K, Semiglazov, V, Krasnozhon, D, Davidenko, I, Nelyubina, L, Nakov, R, Stiegler, G, Singh, P, Schwebig, A, Kramer, S, and Harbeck, N. "Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy." Annals of Oncology 26.9 (September 2015): 1948-1953.
Source
crossref
Published In
Annals of Oncology
Volume
26
Issue
9
Publish Date
2015
Start Page
1948
End Page
1953
DOI
10.1093/annonc/mdv281

Genomic profiling in locally advanced and inflammatory breast cancer and its link to DCE-MRI and overall survival.

We have previously reported that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion patterns obtained from locally advanced breast cancer (LABC) patients prior to neoadjuvant therapy predicted pathologic clinical response. Genomic analyses were also independently conducted on the same patient population. This retrospective study was performed to test two hypotheses: (1) gene expression profiles are associated with DCE-MRI perfusion patterns, and (2) association between long-term overall survival data and gene expression profiles can lead to the identification of novel predictive biomarkers.We utilised RNA microarray and DCE-MRI data from 47 LABC patients, including 13 inflammatory breast cancer (IBC) patients. Association between gene expression profile and DCE-MRI perfusion patterns (centrifugal and centripetal) was determined by Wilcoxon rank sum test. Association between gene expression level and survival was assessed using a Cox rank score test. Additional genomic analysis of the IBC subset was conducted, with a period of follow-up of up to 11 years. Associations between gene expression and overall survival were further assessed in The Cancer Genome Atlas Data Portal.Differences in gene expression profiles were seen between centrifugal and centripetal perfusion patterns in the sulphotransferase family, cytosolic, 1 A, phenol-preferring, members 1 and 2 (SULT1A1, SULT1A2), poly (ADP-ribose) polymerase, member 6 (PARP6), and metastasis tumour antigen1 (MTA1). In the IBC subset our analyses demonstrated that differential expression of 45 genes was associated with long-term survival.Here we have demonstrated an association between DCE-MRI perfusion patterns and gene expression profiles. In addition we have reported on candidate prognostic biomarkers in IBC patients, with some of the genes being significantly associated with survival in IBC and LABC.

Authors
Siamakpour-Reihani, S; Owzar, K; Jiang, C; Scarbrough, PM; Craciunescu, OI; Horton, JK; Dressman, HK; Blackwell, KL; Dewhirst, MW
MLA Citation
Siamakpour-Reihani, S, Owzar, K, Jiang, C, Scarbrough, PM, Craciunescu, OI, Horton, JK, Dressman, HK, Blackwell, KL, and Dewhirst, MW. "Genomic profiling in locally advanced and inflammatory breast cancer and its link to DCE-MRI and overall survival." International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 31.4 (June 2015): 386-395.
PMID
25811737
Source
epmc
Published In
International Journal of Hyperthermia (Informa)
Volume
31
Issue
4
Publish Date
2015
Start Page
386
End Page
395
DOI
10.3109/02656736.2015.1016557

Routine use of zoledronic acid in early-stage breast cancer.

Zoledronic acid, a potent nitrogen-containing bisphosphonate, plays a key role in preventing complications of bone metastases in metastatic breast cancer, but its affect on early-stage breast cancer has been unclear. The preclinical data supporting the anticancer effects of zoledronic acid are compelling and several recent clinical trials have suggested that it reduces breast cancer recurrence in certain patient subgroups. Given these anticancer effects and reasonable safety profile, this therapeutic option could be discussed with patients. This article focuses on the results of supporting preclinical and clinical data evaluating the role of zoledronic acid in adjuvant breast cancer therapy.

Authors
Harnden, K; Blackwell, K
MLA Citation
Harnden, K, and Blackwell, K. "Routine use of zoledronic acid in early-stage breast cancer." Journal of the National Comprehensive Cancer Network : JNCCN 13.4 (April 2015): 480-486. (Review)
PMID
25870382
Source
epmc
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
13
Issue
4
Publish Date
2015
Start Page
480
End Page
486

Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA.

We characterized the incidence of central nervous system (CNS) metastases after treatment with trastuzumab emtansine (T-DM1) versus capecitabine-lapatinib (XL), and treatment efficacy among patients with pre-existing CNS metastases in the phase III EMILIA study.In EMILIA, patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer previously treated with trastuzumab and a taxane were randomized to T-DM1 or XL until disease progression. Patients with treated, asymptomatic CNS metastases at baseline and patients developing postbaseline CNS metastases were identified retrospectively by independent review; exploratory analyses were carried out.Among 991 randomized patients (T-DM1 = 495; XL = 496), 95 (T-DM1 = 45; XL = 50) had CNS metastases at baseline. CNS progression occurred in 9 of 450 (2.0%) and 3 of 446 (0.7%) patients without CNS metastases at baseline in the T-DM1 and XL arms, respectively, and in 10 of 45 (22.2%) and 8 of 50 (16.0%) patients with CNS metastases at baseline. Among patients with CNS metastases at baseline, a significant improvement in overall survival (OS) was observed in the T-DM1 arm compared with the XL arm [hazard ratio (HR) = 0.38; P = 0.008; median, 26.8 versus 12.9 months]. Progression-free survival by independent review was similar in the two treatment arms (HR = 1.00; P = 1.000; median, 5.9 versus 5.7 months). Multivariate analyses demonstrated similar results. Grade ≥3 adverse events were reported in 48.8% and 63.3% of patients with CNS metastases at baseline administered T-DM1 and XL, respectively; no new safety signals were observed.In this retrospective, exploratory analysis, the rate of CNS progression in patients with HER2-positive advanced breast cancer was similar for T-DM1 and for XL, and higher overall in patients with CNS metastases at baseline compared with those without CNS metastases at baseline. In patients with treated, asymptomatic CNS metastases at baseline, T-DM1 was associated with significantly improved OS compared with XL.

Authors
Krop, IE; Lin, NU; Blackwell, K; Guardino, E; Huober, J; Lu, M; Miles, D; Samant, M; Welslau, M; Diéras, V
MLA Citation
Krop, IE, Lin, NU, Blackwell, K, Guardino, E, Huober, J, Lu, M, Miles, D, Samant, M, Welslau, M, and Diéras, V. "Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA." Annals of oncology : official journal of the European Society for Medical Oncology 26.1 (January 2015): 113-119.
PMID
25355722
Source
epmc
Published In
Annals of Oncology
Volume
26
Issue
1
Publish Date
2015
Start Page
113
End Page
119
DOI
10.1093/annonc/mdu486

Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor.

The paradigm shift in cancer treatment from cytotoxic drugs to tumor targeted therapies poses new challenges, including optimization of dose and schedule based on a biologically effective dose, rather than the historical maximum tolerated dose. Optimal dosing is currently determined using concentrations of tyrosine kinase inhibitors in plasma as a surrogate for tumor concentrations. To examine this plasma-tumor relationship, we explored the association between lapatinib levels in tumor and plasma in mice and humans, and those effects on phosphorylation of human epidermal growth factor receptors (HER) in human tumors.Mice bearing BT474 HER2+ human breast cancer xenografts were dosed once or twice daily (BID) with lapatinib. Drug concentrations were measured in blood, tumor, liver, and kidney. In a randomized phase I clinical trial, 28 treatment-naïve female patients with early stage HER2+ breast cancer received lapatinib 1000 or 1500 mg once daily (QD) or 500 mg BID before evaluating steady-state lapatinib levels in plasma and tumor.In mice, lapatinib levels were 4-fold higher in tumor than blood with a 4-fold longer half-life. Tumor concentrations exceeded the in vitro IC90 (~ 900 nM or 500 ng/mL) for inhibition of HER2 phosphorylation throughout the 12-hour dosing interval. In patients, tumor levels were 6- and 10-fold higher with QD and BID dosing, respectively, compared to plasma trough levels. The relationship between tumor and plasma concentration was complex, indicating multiple determinants. HER receptor phosphorylation varied depending upon lapatinib tumor concentrations, suggestive of changes in the repertoire of HER homo- and heterodimers.Plasma lapatinib concentrations underestimated tumor drug levels, suggesting that optimal dosing should be focused on the site of action to avoid to inappropriate dose escalation. Larger clinical trials are required to determine optimal dose and schedule to achieve tumor concentrations that maximally inhibit HER receptors.NCT00359190.

Authors
Spector, NL; Robertson, FC; Bacus, S; Blackwell, K; Smith, DA; Glenn, K; Cartee, L; Harris, J; Kimbrough, CL; Gittelman, M; Avisar, E; Beitsch, P; Koch, KM
MLA Citation
Spector, NL, Robertson, FC, Bacus, S, Blackwell, K, Smith, DA, Glenn, K, Cartee, L, Harris, J, Kimbrough, CL, Gittelman, M, Avisar, E, Beitsch, P, and Koch, KM. "Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor." PloS one 10.11 (January 2015): e0142845-.
PMID
26571496
Source
epmc
Published In
PloS one
Volume
10
Issue
11
Publish Date
2015
Start Page
e0142845
DOI
10.1371/journal.pone.0142845

Endocrine therapy with or without inhibition of epidermal growth factor receptor and human epidermal growth factor receptor 2: a randomized, double-blind, placebo-controlled phase III trial of fulvestrant with or without lapatinib for postmenopausal women with hormone receptor-positive advanced breast cancer-CALGB 40302 (Alliance).

CALGB 40302 sought to determine whether lapatinib would improve progression-free survival (PFS) among women with hormone receptor-positive metastatic breast cancer treated with fulvestrant.Eligible women had estrogen receptor-positive and/or progesterone receptor-positive tumors, regardless of human epidermal growth factor receptor 2 (HER2) status, and prior aromatase inhibitor treatment. Patients received fulvestrant 500 mg intramuscularly on day 1, followed by 250 mg on days 15 and 28 and every 4 weeks thereafter, and either lapatinib 1,500 mg or placebo daily. The study planned to accrue 324 patients and was powered for a 50% improvement in PFS with lapatinib from 5 to 7.5 months.At the third planned interim analysis, the futility boundary was crossed, and the data and safety monitoring board recommend study closure, having accrued 295 patients. At the final analysis, there was no difference in PFS (hazard ratio [HR] of placebo to lapatinib, 1.04; 95% CI, 0.82 to 1.33; P = .37); median PFS was 4.7 months for fulvestrant plus lapatinib versus 3.8 months for fulvestrant plus placebo. There was no difference in overall survival (OS) (HR, 0.91; 95% CI, 0.68 to 1.21; P = .25). For HER2-normal tumors, median PFS did not differ by treatment arm (4.1 v 3.8 months). For HER2-positive tumors, lapatinib was associated with longer median PFS (5.9 v 3.3 months), but the differential treatment effect by HER2 status was not significant (P = .53). The most frequent toxicities were diarrhea, fatigue, and rash associated with lapatinib.Adding lapatinib to fulvestrant does not improve PFS or OS in advanced ER-positive breast cancer and is more toxic.

Authors
Burstein, HJ; Cirrincione, CT; Barry, WT; Chew, HK; Tolaney, SM; Lake, DE; Ma, C; Blackwell, KL; Winer, EP; Hudis, CA
MLA Citation
Burstein, HJ, Cirrincione, CT, Barry, WT, Chew, HK, Tolaney, SM, Lake, DE, Ma, C, Blackwell, KL, Winer, EP, and Hudis, CA. "Endocrine therapy with or without inhibition of epidermal growth factor receptor and human epidermal growth factor receptor 2: a randomized, double-blind, placebo-controlled phase III trial of fulvestrant with or without lapatinib for postmenopausal women with hormone receptor-positive advanced breast cancer-CALGB 40302 (Alliance)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 32.35 (December 2014): 3959-3966.
PMID
25348000
Source
epmc
Published In
Journal of Clinical Oncology
Volume
32
Issue
35
Publish Date
2014
Start Page
3959
End Page
3966
DOI
10.1200/jco.2014.56.7941

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

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 : 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

ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2)†.

Authors
Cardoso, F; Costa, A; Norton, L; Senkus, E; Aapro, M; André, F; Barrios, CH; Bergh, J; Biganzoli, L; Blackwell, KL; Cardoso, MJ; Cufer, T; El Saghir, N; Fallowfield, L; Fenech, D; Francis, P; Gelmon, K; Giordano, SH; Gligorov, J; Goldhirsch, A; Harbeck, N; Houssami, N; Hudis, C; Kaufman, B; Krop, I; Kyriakides, S; Lin, UN; Mayer, M; Merjaver, SD; Nordström, EB; Pagani, O; Partridge, A; Penault-Llorca, F; Piccart, MJ; Rugo, H; Sledge, G; Thomssen, C; Van't Veer, L; Vorobiof, D; Vrieling, C et al.
MLA Citation
Cardoso, F, Costa, A, Norton, L, Senkus, E, Aapro, M, André, F, Barrios, CH, Bergh, J, Biganzoli, L, Blackwell, KL, Cardoso, MJ, Cufer, T, El Saghir, N, Fallowfield, L, Fenech, D, Francis, P, Gelmon, K, Giordano, SH, Gligorov, J, Goldhirsch, A, Harbeck, N, Houssami, N, Hudis, C, Kaufman, B, Krop, I, Kyriakides, S, Lin, UN, Mayer, M, Merjaver, SD, Nordström, EB, Pagani, O, Partridge, A, Penault-Llorca, F, Piccart, MJ, Rugo, H, Sledge, G, Thomssen, C, Van't Veer, L, Vorobiof, D, and Vrieling, C et al. "ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2)†." Annals of oncology : official journal of the European Society for Medical Oncology 25.10 (October 2014): 1871-1888.
PMID
25234545
Source
epmc
Published In
Annals of Oncology
Volume
25
Issue
10
Publish Date
2014
Start Page
1871
End Page
1888
DOI
10.1093/annonc/mdu385

ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2).

Authors
Cardoso, F; Costa, A; Norton, L; Senkus, E; Aapro, M; André, F; Barrios, CH; Bergh, J; Biganzoli, L; Blackwell, KL; Cardoso, MJ; Cufer, T; El Saghir, N; Fallowfield, L; Fenech, D; Francis, P; Gelmon, K; Giordano, SH; Gligorov, J; Goldhirsch, A; Harbeck, N; Houssami, N; Hudis, C; Kaufman, B; Krop, I; Kyriakides, S; Lin, UN; Mayer, M; Merjaver, SD; Nordström, EB; Pagani, O; Partridge, A; Penault-Llorca, F; Piccart, MJ; Rugo, H; Sledge, G; Thomssen, C; Van't Veer, L; Vorobiof, D; Vrieling, C et al.
MLA Citation
Cardoso, F, Costa, A, Norton, L, Senkus, E, Aapro, M, André, F, Barrios, CH, Bergh, J, Biganzoli, L, Blackwell, KL, Cardoso, MJ, Cufer, T, El Saghir, N, Fallowfield, L, Fenech, D, Francis, P, Gelmon, K, Giordano, SH, Gligorov, J, Goldhirsch, A, Harbeck, N, Houssami, N, Hudis, C, Kaufman, B, Krop, I, Kyriakides, S, Lin, UN, Mayer, M, Merjaver, SD, Nordström, EB, Pagani, O, Partridge, A, Penault-Llorca, F, Piccart, MJ, Rugo, H, Sledge, G, Thomssen, C, Van't Veer, L, Vorobiof, D, and Vrieling, C et al. "ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2)." Breast (Edinburgh, Scotland) 23.5 (October 2014): 489-502.
PMID
25244983
Source
epmc
Published In
The Breast
Volume
23
Issue
5
Publish Date
2014
Start Page
489
End Page
502
DOI
10.1016/j.breast.2014.08.009

Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer.

Unresectable chest wall recurrences of breast cancer (CWR) in heavily pretreated patients are especially difficult to treat. We hypothesised that thermally enhanced drug delivery using low temperature liposomal doxorubicin (LTLD), given with mild local hyperthermia (MLHT), will be safe and effective in this population.This paper combines the results of two similarly designed phase I trials. Eligible CWR patients had progressed on the chest wall after prior hormone therapy, chemotherapy, and radiotherapy. Patients were to get six cycles of LTLD every 21-35 days, followed immediately by chest wall MLHT for 1 hour at 40-42 °C. In the first trial 18 subjects received LTLD at 20, 30, or 40 mg/m2; in the second trial, 11 subjects received LTLD at 40 or 50 mg/m2.The median age of all 29 patients enrolled was 57 years. Thirteen patients (45%) had distant metastases on enrolment. Patients had received a median dose of 256 mg/m2 of prior anthracyclines and a median dose of 61 Gy of prior radiation. The median number of study treatments that subjects completed was four. The maximum tolerated dose was 50 mg/m2, with seven subjects (24%) developing reversible grade 3-4 neutropenia and four (14%) reversible grade 3-4 leucopenia. The rate of overall local response was 48% (14/29, 95% CI: 30-66%), with. five patients (17%) achieving complete local responses and nine patients (31%) having partial local responses.LTLD at 50 mg/m2 and MLHT is safe. This combined therapy produces objective responses in heavily pretreated CWR patients. Future work should test thermally enhanced LTLD delivery in a less advanced patient population.

Authors
Zagar, TM; Vujaskovic, Z; Formenti, S; Rugo, H; Muggia, F; O'Connor, B; Myerson, R; Stauffer, P; Hsu, I-C; Diederich, C; Straube, W; Boss, M-K; Boico, A; Craciunescu, O; Maccarini, P; Needham, D; Borys, N; Blackwell, KL; Dewhirst, MW
MLA Citation
Zagar, TM, Vujaskovic, Z, Formenti, S, Rugo, H, Muggia, F, O'Connor, B, Myerson, R, Stauffer, P, Hsu, I-C, Diederich, C, Straube, W, Boss, M-K, Boico, A, Craciunescu, O, Maccarini, P, Needham, D, Borys, N, Blackwell, KL, and Dewhirst, MW. "Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer." International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 30.5 (August 2014): 285-294.
PMID
25144817
Source
epmc
Published In
International Journal of Hyperthermia (Informa)
Volume
30
Issue
5
Publish Date
2014
Start Page
285
End Page
294
DOI
10.3109/02656736.2014.936049

Adverse event management in patients with advanced cancer receiving oral everolimus: focus on breast cancer.

Everolimus, an orally administered rapamycin analogue, inhibits the mammalian target of rapamycin (mTOR), a highly conserved intracellular serine-threonine kinase that is a central node in a network of signaling pathways controlling cellular metabolism, growth, survival, proliferation, angiogenesis, and immune function. Everolimus has demonstrated substantial clinical benefit in randomized, controlled, phase III studies leading to approval for the treatment of advanced renal cell carcinoma, advanced neuroendocrine tumors of pancreatic origin, renal angiomyolipoma and subependymal giant-cell astrocytoma associated with tuberous sclerosis complex, as well as advanced hormone-receptor-positive (HR(+)) and human epidermal growth factor receptor-2-negative advanced breast cancer.We discuss clinically relevant everolimus-related adverse events from the phase III studies, including stomatitis, noninfectious pneumonitis, rash, selected metabolic abnormalities, and infections, with focus on appropriate clinical management of these events and specific considerations in patients with breast cancer.The majority of adverse events experienced during everolimus therapy are of mild to moderate severity. The safety profile and protocols for toxicity management are well established. The class-effect adverse event profile observed with everolimus plus endocrine therapy in breast cancer is (as expected) distinct from that of endocrine therapy alone, but is similar to that observed with everolimus in other solid tumors. Information gained from the experience in other carcinomas on prompt diagnosis and treatments to optimize drug exposure, treatment outcomes, and patients' quality of life also applies to the patient population with advanced breast cancer.As with all orally administered agents, education of both physicians and patients in the management of adverse events for patients receiving everolimus is critical to achieving optimal exposure and clinical benefit. Active monitoring for early identification of everolimus-related adverse events combined with aggressive and appropriate intervention should lead to a reduction in the severity and duration of the event.

Authors
Aapro, M; Andre, F; Blackwell, K; Calvo, E; Jahanzeb, M; Papazisis, K; Porta, C; Pritchard, K; Ravaud, A
MLA Citation
Aapro, M, Andre, F, Blackwell, K, Calvo, E, Jahanzeb, M, Papazisis, K, Porta, C, Pritchard, K, and Ravaud, A. "Adverse event management in patients with advanced cancer receiving oral everolimus: focus on breast cancer." Annals of oncology : official journal of the European Society for Medical Oncology 25.4 (April 2014): 763-773. (Review)
PMID
24667713
Source
epmc
Published In
Annals of Oncology
Volume
25
Issue
4
Publish Date
2014
Start Page
763
End Page
773
DOI
10.1093/annonc/mdu021

αb-crystallin: A novel regulator of breast cancer metastasis to the Brain

Purpose: Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone αB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of αB-crystallin in brain metastasis in TNBCs. Experimental Design: αB-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among patients with breast cancer with brain metastases. αB-crystallin was overexpressed or silenced in two different TNBC cell lines. The effects on cell adhesion to human brain microvascular endothelial cells (HBMEC) or extracellular matrix proteins, transendothelial migration, and transmigration across a HBMEC/astrocyte coculture blood-brain barrier (BBB) model were examined. In addition, the effects of overexpressing or silencing αB-crystallin on brain metastasis in vivo were investigated using orthotopic TNBC models. Results: In a cohort of women with breast cancer brain metastasis, αB-crystallin expression in primary breast carcinomas was associated with poor overall survival and poor survival after brain metastasis, even among patients with TNBC. Stable overexpression of αB-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, whereas silencing αB-crystallin inhibited these events. αB-crystallin promoted adhesion of TNBC cells to HBMECs, at least in part, through an α3β1 integrin-dependent mechanism. αB-crystallin overexpression promoted brain metastasis, whereas silencing αB-crystallin inhibited brain metastasis in orthotopic TNBC models. Conclusion: αB-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease. Clin Cancer Res; 1-12. © 2013 AACR.

Authors
Malin, D; Strekalova, E; Petrovic, V; Deal, AM; Al Ahmad, A; Adamo, B; Miller, CR; Ugolkov, A; Livasy, C; Fritchie, K; Hamilton, E; Blackwell, K; Geradts, J; Ewend, M; Carey, L; Shusta, EV; Anders, CK; Cryns, VL
MLA Citation
Malin, D, Strekalova, E, Petrovic, V, Deal, AM, Al Ahmad, A, Adamo, B, Miller, CR, Ugolkov, A, Livasy, C, Fritchie, K, Hamilton, E, Blackwell, K, Geradts, J, Ewend, M, Carey, L, Shusta, EV, Anders, CK, and Cryns, VL. "αb-crystallin: A novel regulator of breast cancer metastasis to the Brain." Clinical Cancer Research 20.1 (January 1, 2014): 1-12.
Source
scopus
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
20
Issue
1
Publish Date
2014
Start Page
1
End Page
12
DOI
10.1158/1078-0432.CCR-13-1255

αB-crystallin: a novel regulator of breast cancer metastasis to the brain.

PURPOSE: Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone αB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of αB-crystallin in brain metastasis in TNBCs. EXPERIMENTAL DESIGN: αB-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among patients with breast cancer with brain metastases. αB-crystallin was overexpressed or silenced in two different TNBC cell lines. The effects on cell adhesion to human brain microvascular endothelial cells (HBMEC) or extracellular matrix proteins, transendothelial migration, and transmigration across a HBMEC/astrocyte coculture blood-brain barrier (BBB) model were examined. In addition, the effects of overexpressing or silencing αB-crystallin on brain metastasis in vivo were investigated using orthotopic TNBC models. RESULTS: In a cohort of women with breast cancer brain metastasis, αB-crystallin expression in primary breast carcinomas was associated with poor overall survival and poor survival after brain metastasis, even among patients with TNBC. Stable overexpression of αB-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, whereas silencing αB-crystallin inhibited these events. αB-crystallin promoted adhesion of TNBC cells to HBMECs, at least in part, through an α3β1 integrin-dependent mechanism. αB-crystallin overexpression promoted brain metastasis, whereas silencing αB-crystallin inhibited brain metastasis in orthotopic TNBC models. CONCLUSION: αB-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease.

Authors
Malin, D; Strekalova, E; Petrovic, V; Deal, AM; Al Ahmad, A; Adamo, B; Miller, CR; Ugolkov, A; Livasy, C; Fritchie, K; Hamilton, E; Blackwell, K; Geradts, J; Ewend, M; Carey, L; Shusta, EV; Anders, CK; Cryns, VL
MLA Citation
Malin, D, Strekalova, E, Petrovic, V, Deal, AM, Al Ahmad, A, Adamo, B, Miller, CR, Ugolkov, A, Livasy, C, Fritchie, K, Hamilton, E, Blackwell, K, Geradts, J, Ewend, M, Carey, L, Shusta, EV, Anders, CK, and Cryns, VL. "αB-crystallin: a novel regulator of breast cancer metastasis to the brain." Clin Cancer Res 20.1 (January 1, 2014): 56-67.
PMID
24132917
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
20
Issue
1
Publish Date
2014
Start Page
56
End Page
67
DOI
10.1158/1078-0432.CCR-13-1255

Next generation sequencing and tumor mutation profiling: are we ready for routine use in the oncology clinic?

Next generation sequencing (NGS) coupled with sophisticated bioinformatics tools yields an unprecedented amount of information regarding tumor genetics, with the potential to reveal insights into tumor behavior. NGS and other multiplex genomic assays are rapidly spilling from the laboratory into the clinic through numerous commercial and academic entities. This raises the important question as to whether we are ready to use these data in clinical decision-making. While genetic lesions are clearly targeted by a new generation of biological cancer therapies, and certain regulatory approvals are actually coupled to single gene assays, we still do not know if the vast information on other genomic alterations is worth the added cost, or even worse, the inappropriate and unproven assignment of patients to treatment with an unapproved drug carrying potentially serious side effects. On the other hand, the trend toward a precision medicine pathway is clearly accelerating, and clinical trials validating pathway-driven personalized cancer therapeutics will be necessary in both the community and academic settings. Lower cost and wider availability of NGS now raises a debate over the merit of routine tumor genome-wide analysis.

Authors
Tripathy, D; Harnden, K; Blackwell, K; Robson, M
MLA Citation
Tripathy, D, Harnden, K, Blackwell, K, and Robson, M. "Next generation sequencing and tumor mutation profiling: are we ready for routine use in the oncology clinic?." BMC medicine 12 (January 2014): 140-.
PMID
25286031
Source
epmc
Published In
BMC Medicine
Volume
12
Publish Date
2014
Start Page
140
DOI
10.1186/s12916-014-0140-3

αB-crystallin: a novel regulator of breast cancer metastasis to the brain.

Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone αB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of αB-crystallin in brain metastasis in TNBCs. αB-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among patients with breast cancer with brain metastases. αB-crystallin was overexpressed or silenced in two different TNBC cell lines. The effects on cell adhesion to human brain microvascular endothelial cells (HBMEC) or extracellular matrix proteins, transendothelial migration, and transmigration across a HBMEC/astrocyte coculture blood-brain barrier (BBB) model were examined. In addition, the effects of overexpressing or silencing αB-crystallin on brain metastasis in vivo were investigated using orthotopic TNBC models. In a cohort of women with breast cancer brain metastasis, αB-crystallin expression in primary breast carcinomas was associated with poor overall survival and poor survival after brain metastasis, even among patients with TNBC. Stable overexpression of αB-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, whereas silencing αB-crystallin inhibited these events. αB-crystallin promoted adhesion of TNBC cells to HBMECs, at least in part, through an α3β1 integrin-dependent mechanism. αB-crystallin overexpression promoted brain metastasis, whereas silencing αB-crystallin inhibited brain metastasis in orthotopic TNBC models. αB-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease.

Authors
Malin, D; Strekalova, E; Petrovic, V; Deal, AM; Ahmad, AA; Adamo, B; Miller, CR; Ugolkov, A; Livasy, C; Fritchie, K; Hamilton, E; Blackwell, K; Geradts, J; Ewend, M; Carey, L; Shusta, EV; Anders, CK; Cryns, VL
MLA Citation
Malin, D, Strekalova, E, Petrovic, V, Deal, AM, Ahmad, AA, Adamo, B, Miller, CR, Ugolkov, A, Livasy, C, Fritchie, K, Hamilton, E, Blackwell, K, Geradts, J, Ewend, M, Carey, L, Shusta, EV, Anders, CK, and Cryns, VL. "αB-crystallin: a novel regulator of breast cancer metastasis to the brain." Clinical cancer research : an official journal of the American Association for Cancer Research 20.1 (2014): 56-67.
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
20
Issue
1
Publish Date
2014
Start Page
56
End Page
67
DOI
10.1158/1078-0432.CCR-13-1255

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/m2) 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

Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer.

PURPOSE: Patients with hormone receptor-negative breast cancer generally do not benefit from endocrine-targeted therapies. However, a subset with androgen receptor (AR) expression is predicted to respond to antiandrogen therapies. This phase II study explored bicalutamide in AR-positive, estrogen receptor (ER), and progesterone receptor (PgR)-negative metastatic breast cancer. EXPERIMENTAL DESIGN: Tumors from patients with ER/PgR-negative advanced breast cancer were tested centrally for AR [immunohistochemistry (IHC) > 10% nuclear staining considered positive]. If either the primary or a metastatic site was positive, patients were eligible to receive the AR antagonist bicalutamide at a dose of 150 mg daily. Clinical benefit rate (CBR), the primary endpoint, was defined as the total number of patients who show a complete response (CR), partial response (PR), or stable disease (SD) > 6 months; secondary endpoints included progression-free survival (PFS) and toxicity. Correlative studies included measurement of circulating endocrine markers and IHC surrogates for basal-like breast cancer. RESULTS: Of 424 patients with ER/PgR-negative breast cancer, 12% tested AR-positive. The 6-month CBR was 19% [95% confidence interval (CI), 7%-39%] for bicalutamide. The median PFS was 12 weeks (95% CI, 11-22 weeks). Bicalutamide was well-tolerated with no grade 4/5 treatment-related adverse events observed. CONCLUSION: AR was expressed in 12% of patients with ER/PgR-negative breast cancer screened for this trial. The CBR of 19% observed with bicalutamide shows proof of principle for the efficacy of minimally toxic androgen blockade in a select group of patients with ER/PgR-negative, AR-positive breast cancer.

Authors
Gucalp, A; Tolaney, S; Isakoff, SJ; Ingle, JN; Liu, MC; Carey, LA; Blackwell, K; Rugo, H; Nabell, L; Forero, A; Stearns, V; Doane, AS; Danso, M; Moynahan, ME; Momen, LF; Gonzalez, JM; Akhtar, A; Giri, DD; Patil, S; Feigin, KN; Hudis, CA; Traina, TA; Translational Breast Cancer Research Consortium (TBCRC 011),
MLA Citation
Gucalp, A, Tolaney, S, Isakoff, SJ, Ingle, JN, Liu, MC, Carey, LA, Blackwell, K, Rugo, H, Nabell, L, Forero, A, Stearns, V, Doane, AS, Danso, M, Moynahan, ME, Momen, LF, Gonzalez, JM, Akhtar, A, Giri, DD, Patil, S, Feigin, KN, Hudis, CA, Traina, TA, and Translational Breast Cancer Research Consortium (TBCRC 011), . "Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer." Clin Cancer Res 19.19 (October 1, 2013): 5505-5512.
PMID
23965901
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
19
Issue
19
Publish Date
2013
Start Page
5505
End Page
5512
DOI
10.1158/1078-0432.CCR-12-3327

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

How Can We Optimize Treatment of HER2-Positive Metastatic Breast Cancer?

Authors
Hamilton, EP; Blackwell, KL
MLA Citation
Hamilton, EP, and Blackwell, KL. "How Can We Optimize Treatment of HER2-Positive Metastatic Breast Cancer?." ONCOLOGY-NEW YORK 27.3 (March 2013): 180-182.
PMID
23687786
Source
wos-lite
Published In
Oncology
Volume
27
Issue
3
Publish Date
2013
Start Page
180
End Page
182

An option after pertuzumab and TDM-1

Authors
Blackwell, KL
MLA Citation
Blackwell, KL. "An option after pertuzumab and TDM-1." Oncology Report AUG (January 1, 2013): 3-.
Source
scopus
Published In
Oncology Report
Issue
AUG
Publish Date
2013
Start Page
3

A randomized phase II study of lapatinib plus pazopanib versus lapatinib in patients with HER2+ inflammatory breast cancer

Authors
Cristofanilli, M; Johnston, SRD; Manikhas, A; Gomez, HL; Gladkov, O; Shao, Z; Safina, S; Blackwell, KL; Alvarez, RH; Rubin, SD; Ranganathan, S; Redhu, S; Trudeau, ME
MLA Citation
Cristofanilli, M, Johnston, SRD, Manikhas, A, Gomez, HL, Gladkov, O, Shao, Z, Safina, S, Blackwell, KL, Alvarez, RH, Rubin, SD, Ranganathan, S, Redhu, S, and Trudeau, ME. "A randomized phase II study of lapatinib plus pazopanib versus lapatinib in patients with HER2+ inflammatory breast cancer." BREAST CANCER RESEARCH AND TREATMENT 137.2 (January 2013): 471-482.
PMID
23239151
Source
wos-lite
Published In
Breast Cancer Research and Treatment
Volume
137
Issue
2
Publish Date
2013
Start Page
471
End Page
482
DOI
10.1007/s10549-012-2369-x

Correction: phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibtion.

Authors
Hamilton, E; Blackwell, K; Hobeika, AC; Clay, TM; Broadwater, G; Ren, XR; Chen, W; Castro, H; Lehmann, F; Spector, N; Wei, J; Osada, T; Lyerly, HK; Morse, MA
MLA Citation
Hamilton, E, Blackwell, K, Hobeika, AC, Clay, TM, Broadwater, G, Ren, XR, Chen, W, Castro, H, Lehmann, F, Spector, N, Wei, J, Osada, T, Lyerly, HK, and Morse, MA. "Correction: phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibtion." J Transl Med 11 (2013): 82-.
PMID
23536971
Source
pubmed
Published In
Journal of Translational Medicine
Volume
11
Publish Date
2013
Start Page
82
DOI
10.1186/1479-5876-11-82

How can we optimize treatment of HER2-positive metastatic breast cancer?

Authors
Hamilton, EP; Blackwell, KL
MLA Citation
Hamilton, EP, and Blackwell, KL. "How can we optimize treatment of HER2-positive metastatic breast cancer?." Oncology (Williston Park, N.Y.) 27.3 (2013): 180-182.
Source
scival
Published In
Oncology
Volume
27
Issue
3
Publish Date
2013
Start Page
180
End Page
182

A randomized phase II study of lapatinib + pazopanib versus lapatinib in patients with HER2+ inflammatory breast cancer

This multi-center Phase II study evaluated lapatinib, pazopanib, and the combination in patients with relapsed HER2+ inflammatory breast cancer. In Cohort 1, 76 patients were randomized 1:1 to receive lapatinib 1,500 mg + placebo or lapatinib 1,500 mg + pazopanib 800 mg (double-blind) once daily until disease progression, unacceptable toxicity, or death. Due to high-grade diarrhea observed with this dose combination in another study (VEG20007), Cohort 1 was closed. The protocol was amended such that an additional 88 patients (Cohort 2) were randomized in a 5:5:2 ratio to receive daily monotherapy lapatinib 1,500 mg, lapatinib 1,000 mg + pazopanib 400 mg, or monotherapy pazopanib 800 mg, respectively. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival, and safety. In Cohort 1, ORR for the lapatinib (n = 38) and combination (n = 38) arms was 29 and 45 %, respectively; median PFS was 16.1 and 14.3 weeks, respectively. Grade ≥3 adverse events (AEs) were more frequent in the combination arm (71 %) than in the lapatinib arm (24 %). Dose reductions and interruptions due to AEs were also more frequent in the combination arm (45 and 53 %, respectively) than in the lapatinib monotherapy arm (0 and 11 %, respectively). In Cohort 2, ORR for patients treated with lapatinib (n = 36), lapatinib + pazopanib (n = 38), and pazopanib (n = 13) was 47, 58, and 31 %, respectively; median PFS was 16.0, 16.0, and 11.4 weeks, respectively. In the lapatinib, combination, and pazopanib therapy arms, grade ≥3 AEs were reported for 17, 50, and 46 % of patients, respectively, and the incidence of discontinuations due to AEs was 0, 24, and 23 %, respectively. The lapatinib-pazopanib combination was associated with a numerically higher ORR but no increase in PFS compared to lapatinib alone. The combination also had increased toxicity resulting in more dose reductions, modifications, and treatment delays. Activity with single-agent lapatinib was confirmed in this population. © 2012 The Author(s).

Authors
Cristofanilli, M; Johnston, SRD; Manikhas, A; Gomez, HL; Gladkov, O; Shao, Z; Safina, S; Blackwell, KL; Alvarez, RH; Rubin, SD; Ranganathan, S; Redhu, S; Trudeau, ME
MLA Citation
Cristofanilli, M, Johnston, SRD, Manikhas, A, Gomez, HL, Gladkov, O, Shao, Z, Safina, S, Blackwell, KL, Alvarez, RH, Rubin, SD, Ranganathan, S, Redhu, S, and Trudeau, ME. "A randomized phase II study of lapatinib + pazopanib versus lapatinib in patients with HER2+ inflammatory breast cancer." Breast Cancer Research and Treatment 137.2 (2013): 471-482.
Source
scival
Published In
Breast Cancer Research and Treatment
Volume
137
Issue
2
Publish Date
2013
Start Page
471
End Page
482
DOI
10.1007/s10549-012-2369-x

Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study.

PURPOSE: Phase III EGF104900 data demonstrated that lapatinib plus trastuzumab significantly improved progression-free survival (PFS) and clinical benefit rate versus lapatinib monotherapy, offering a chemotherapy-free option for patients with heavily pretreated human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC). Final planned overall survival (OS) analysis from EGF104900 is reported here. PATIENTS AND METHODS: Patients with HER2-positive MBC whose disease progressed during prior trastuzumab-based therapies were randomly assigned to receive lapatinib monotherapy or lapatinib in combination with trastuzumab. OS and updated PFS data are presented using Kaplan-Meier curves and log-rank tests stratified for hormone receptor and visceral disease status. Subgroup analyses were conducted to identify characteristics of patients deriving the greatest clinical benefit. RESULTS: In this updated final analysis of all patients randomly assigned with strata (n = 291), lapatinib plus trastuzumab continued to show superiority to lapatinib monotherapy in PFS (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.94; P = .011) and offered significant OS benefit (HR, 0.74; 95% CI, 0.57 to 0.97; P = .026). Improvements in absolute OS rates were 10% at 6 months and 15% at 12 months in the combination arm compared with the monotherapy arm. Multiple baseline factors, including Eastern Cooperative Oncology Group performance status of 0, nonvisceral disease, < three metastatic sites, and less time from initial diagnosis until random assignment, were associated with improved OS. Incidence of adverse events was consistent with previously reported rates. CONCLUSION: These data demonstrated a significant 4.5-month median OS advantage with the lapatinib and trastuzumab combination and support dual HER2 blockade in patients with heavily pretreated HER2-positive MBC.

Authors
Blackwell, KL; Burstein, HJ; Storniolo, AM; Rugo, HS; Sledge, G; Aktan, G; Ellis, C; Florance, A; Vukelja, S; Bischoff, J; Baselga, J; O'Shaughnessy, J
MLA Citation
Blackwell, KL, Burstein, HJ, Storniolo, AM, Rugo, HS, Sledge, G, Aktan, G, Ellis, C, Florance, A, Vukelja, S, Bischoff, J, Baselga, J, and O'Shaughnessy, J. "Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study." J Clin Oncol 30.21 (July 20, 2012): 2585-2592.
PMID
22689807
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
30
Issue
21
Publish Date
2012
Start Page
2585
End Page
2592
DOI
10.1200/JCO.2011.35.6725

Polyclonal HER2-specific antibodies induced by vaccination mediate receptor internalization and degradation in tumor cells.

INTRODUCTION: Sustained HER2 signaling at the cell surface is an oncogenic mechanism in a significant proportion of breast cancers. While clinically effective therapies targeting HER2 such as mAbs and tyrosine kinase inhibitors exist, tumors overexpressing HER2 eventually progress despite treatment. Thus, abrogation of persistent HER2 expression at the plasma membrane to synergize with current approaches may represent a novel therapeutic strategy. METHODS: We generated polyclonal anti-HER2 antibodies (HER2-VIA) by vaccinating mice with an adenovirus expressing human HER2, and assessed their signaling effects in vitro and anti-tumor effects in a xenograft model. In addition, we studied the signaling effects of human HER2-specific antibodies induced by vaccinating breast cancer patients with a HER2 protein vaccine. RESULTS: HER2-VIA bound HER2 at the plasma membrane, initially activating the downstream kinases extracellular signal-regulated protein kinase 1/2 and Akt, but subsequently inducing receptor internalization in clathrin-coated pits in a HER2 kinase-independent manner, followed by ubiquitination and degradation of HER2 into a 130 kDa fragment phosphorylated at tyrosine residues 1,221/1,222 and 1,248. Following vaccination of breast cancer patients with the HER2 protein vaccine, HER2-specific antibodies were detectable and these antibodies bound to cell surface-expressed HER2 and inhibited HER2 signaling through blocking tyrosine 877 phosphorylation of HER2. In contrast to the murine antibodies, human anti-HER2 antibodies induced by protein vaccination did not mediate receptor internalization and degradation. CONCLUSION: These data provide new insight into HER2 trafficking at the plasma membrane and the changes induced by polyclonal HER2-specific antibodies. The reduction of HER2 membrane expression and HER2 signaling by polyclonal antibodies induced by adenoviral HER2 vaccines supports human clinical trials with this strategy for those breast cancer patients with HER2 therapy-resistant disease.

Authors
Ren, X-R; Wei, J; Lei, G; Wang, J; Lu, J; Xia, W; Spector, N; Barak, LS; Clay, TM; Osada, T; Hamilton, E; Blackwell, K; Hobeika, AC; Morse, MA; Lyerly, HK; Chen, W
MLA Citation
Ren, X-R, Wei, J, Lei, G, Wang, J, Lu, J, Xia, W, Spector, N, Barak, LS, Clay, TM, Osada, T, Hamilton, E, Blackwell, K, Hobeika, AC, Morse, MA, Lyerly, HK, and Chen, W. "Polyclonal HER2-specific antibodies induced by vaccination mediate receptor internalization and degradation in tumor cells. (Published online)" Breast Cancer Res 14.3 (June 7, 2012): R89-.
PMID
22676470
Source
pubmed
Published In
Breast Cancer Research
Volume
14
Issue
3
Publish Date
2012
Start Page
R89
DOI
10.1186/bcr3204

Carbonic anhydrase IX is a predictive marker of doxorubicin resistance in early-stage breast cancer independent of HER2 and TOP2A amplification.

BACKGROUND: In early-stage breast cancer, adjuvant chemotherapy is associated with significant systemic toxicity with only a modest survival benefit. Therefore, there is considerable interest in identifying predictive markers of response to therapy. Doxorubicin, one of the most common drugs used to treat breast cancer, is an anthracycline chemotherapeutic agent, a class of drugs known to be affected by hypoxia. Accordingly, we examined whether expression of the endogenous hypoxia marker carbonic anhydrase IX (CA IX) is predictive of outcome in early-stage breast cancer patients treated with doxorubicin. METHODS: We obtained 209 early-stage pre-treatment surgically-resected breast tumours from patients, who received doxorubicin in their chemotherapeutic regimen and had >10 years of follow-up. Immunohistochemistry was used to detect CA IX, and we used fluorescence in situ hybridisation to detect both human epidermal growth factor receptor (HER2) and DNA topoisomerase II-alpha (TOP2A) gene amplification. RESULTS: Carbonic anhydrase IX intensity was significantly correlated with progression-free survival (PFS) and overall survival (OS) in patients receiving 300 mg m(-2) of doxorubicin (HR=1.82 and 3.77; P=0.0014 and 0.010, respectively). There was a significant, inverse correlation between CA IX score and oestrogen receptor expression, but no significant correlations were seen with either HER2 or TOP2A ratio. CONCLUSION: We demonstrate that CA IX expression is correlated with worse PFS and OS for breast cancer patients treated with doxorubicin, independent of HER2 or TOP2A gene amplification. This study provides evidence that using CA IX to detect hypoxia in surgically-resected breast tumours may be of clinical use in choosing an appropriate chemotherapy regimen.

Authors
Betof, AS; Rabbani, ZN; Hardee, ME; Kim, SJ; Broadwater, G; Bentley, RC; Snyder, SA; Vujaskovic, Z; Oosterwijk, E; Harris, LN; Horton, JK; Dewhirst, MW; Blackwell, KL
MLA Citation
Betof, AS, Rabbani, ZN, Hardee, ME, Kim, SJ, Broadwater, G, Bentley, RC, Snyder, SA, Vujaskovic, Z, Oosterwijk, E, Harris, LN, Horton, JK, Dewhirst, MW, and Blackwell, KL. "Carbonic anhydrase IX is a predictive marker of doxorubicin resistance in early-stage breast cancer independent of HER2 and TOP2A amplification." Br J Cancer 106.5 (February 28, 2012): 916-922.
PMID
22333602
Source
pubmed
Published In
British Journal of Cancer
Volume
106
Issue
5
Publish Date
2012
Start Page
916
End Page
922
DOI
10.1038/bjc.2012.32

Phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibition [corrected].

BACKGROUND: Patients with HER2-overexpressing metastatic breast cancer, despite initially benefiting from the monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib, will eventually have progressive disease. HER2-based vaccines induce polyclonal antibody responses against HER2 that demonstrate enhanced anti-tumor activity when combined with lapatinib in murine models. We wished to test the clinical safety, immunogenicity, and activity of a HER2-based cancer vaccine, when combined with lapatinib. METHODS: We immunized women (n = 12) with metastatic, trastuzumab-refractory, HER2-overexpressing breast cancer with dHER2, a recombinant protein consisting of extracellular domain (ECD) and a portion of the intracellular domain (ICD) of HER2 combined with the adjuvant AS15, containing MPL, QS21, CpG and liposome. Lapatinib (1250 mg/day) was administered concurrently. Peripheral blood antibody and T cell responses were measured. RESULTS: This regimen was well tolerated, with no cardiotoxicity. Anti-HER2-specific antibody was induced in all patients whereas HER2-specific T cells were detected in one patient. Preliminary analyses of patient serum demonstrated downstream signaling inhibition in HER2 expressing tumor cells. The median time to progression was 55 days, with the majority of patients progressing prior to induction of peak anti-HER2 immune responses; however, 300-day overall survival was 92% (95% CI: 77-100%). CONCLUSIONS: dHER2 combined with lapatinib was safe and immunogenic with promising long term survival in those with HER2-overexpressing breast cancers refractory to trastuzumab. Further studies to define the anticancer activity of the antibodies induced by HER2 vaccines along with lapatinib are underway. TRIAL REGISTRY: ClinicalTrials.gov NCT00952692.

Authors
Hamilton, E; Blackwell, K; Hobeika, AC; Clay, TM; Broadwater, G; Ren, X-R; Chen, W; Castro, H; Lehmann, F; Spector, N; Wei, J; Osada, T; Lyerly, HK; Morse, MA
MLA Citation
Hamilton, E, Blackwell, K, Hobeika, AC, Clay, TM, Broadwater, G, Ren, X-R, Chen, W, Castro, H, Lehmann, F, Spector, N, Wei, J, Osada, T, Lyerly, HK, and Morse, MA. "Phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibition [corrected]. (Published online)" J Transl Med 10 (February 10, 2012): 28-.
PMID
22325452
Source
pubmed
Published In
Journal of Translational Medicine
Volume
10
Publish Date
2012
Start Page
28
DOI
10.1186/1479-5876-10-28

Trastuzumab emtansine for HER2-positive advanced breast cancer

BACKGROUND: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker. METHODS: We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted. RESULTS: Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all additional secondary end points favored T-DM1. Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine. CONCLUSIONS: T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. (Funded by F. Hoffmann-La Roche/Genentech; EMILIA ClinicalTrials.gov number, NCT00829166.) Copyright © 2012 Massachusetts Medical Society.

Authors
Verma, S; Miles, D; Gianni, L; Krop, IE; Welslau, M; Baselga, J; Pegram, M; Oh, D-Y; Diéras, V; Guardino, E; Fang, L; Lu, MW; Olsen, S; Blackwell, K
MLA Citation
Verma, S, Miles, D, Gianni, L, Krop, IE, Welslau, M, Baselga, J, Pegram, M, Oh, D-Y, Diéras, V, Guardino, E, Fang, L, Lu, MW, Olsen, S, and Blackwell, K. "Trastuzumab emtansine for HER2-positive advanced breast cancer." New England Journal of Medicine 367.19 (2012): 1783-1791.
PMID
23020162
Source
scival
Published In
The New England journal of medicine
Volume
367
Issue
19
Publish Date
2012
Start Page
1783
End Page
1791
DOI
10.1056/NEJMoa1209124

New perspectives on zoledronic acid in breast cancer: potential augmentation of anticancer immune response.

A small subset of T cells (gamma-delta T cells) is able to recognize phosphoantigens that are overexpressed in some cancer cells and may selectively target and kill cancer cells with high levels of phosphoantigen. Moreover, nitrogen-containing bisphosphonates, such as zoledronic acid, are able to induce accumulation of specific phosphoantigens in some cancer cells. A recent preclinical study showed that gamma-delta T cells effectively targeted and killed zoledronic acid-treated estrogen-receptor-positive breast cancer cells. These new data provide growing insight into a potential mechanism of action for some of the anticancer activity demonstrated by zoledronic acid in breast cancer clinical trials.

Authors
Hamilton, E; Clay, TM; Blackwell, KL
MLA Citation
Hamilton, E, Clay, TM, and Blackwell, KL. "New perspectives on zoledronic acid in breast cancer: potential augmentation of anticancer immune response." Cancer Invest 29.8 (October 2011): 533-541. (Review)
PMID
21843051
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
29
Issue
8
Publish Date
2011
Start Page
533
End Page
541
DOI
10.3109/07357907.2011.605413

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

Truncated ErbB2 expressed in tumor cell nuclei contributes to acquired therapeutic resistance to ErbB2 kinase inhibitors.

ErbB2 tyrosine kinase inhibitors (TKI) block tyrosine autophosphorylation and activation of the full-length transmembrane ErbB2 receptor (p185(ErbB2)). In addition to p185(ErbB2), truncated forms of ErbB2 exist in breast cancer cell lines and clinical tumors. The contribution of these truncated forms, specifically those expressed in tumor cell nuclei, to the development of therapeutic resistance to ErbB2 TKIs has not been previously shown. Here, we show that expression of a 95-kDa tyrosine phosphorylated form of ErbB2, herein referred to as p95L (lapatinib-induced p95) was increased in ErbB2(+) breast cancer cells treated with potent ErbB2 TKIs (lapatinib, GW2974). Expressed in tumor cell nuclei, tyrosine phosphorylation of p95L was resistant to inhibition by ErbB2 TKIs. Furthermore, the expression of p95L was increased in ErbB2(+) breast cancer models of acquired therapeutic resistance to lapatinib that mimic the clinical setting. Pretreatment with proteasome inhibitors blocked p95L induction in response to ErbB2 TKIs, implicating the role of the proteasome in the regulation of p95L expression. In addition, tyrosine phosphorylated C-terminal fragments of ErbB2, generated by alternate initiation of translation and similar in molecular weight to p95L, were expressed in tumor cell nuclei, where they too were resistant to inhibition by ErbB2 TKIs. When expressed in the nuclei of lapatinib-sensitive ErbB2(+) breast cancer cells, truncated ErbB2 rendered cells resistant to lapatinib-induced apoptosis. Elucidating the function of nuclear, truncated forms of ErbB2, and developing therapeutic strategies to block their expression and/or activation may enhance the clinical efficacy of ErbB2 TKIs.

Authors
Xia, W; Liu, Z; Zong, R; Liu, L; Zhao, S; Bacus, SS; Mao, Y; He, J; Wulfkuhle, JD; Petricoin, EF; Osada, T; Yang, X-Y; Hartman, ZC; Clay, TM; Blackwell, KL; Lyerly, HK; Spector, NL
MLA Citation
Xia, W, Liu, Z, Zong, R, Liu, L, Zhao, S, Bacus, SS, Mao, Y, He, J, Wulfkuhle, JD, Petricoin, EF, Osada, T, Yang, X-Y, Hartman, ZC, Clay, TM, Blackwell, KL, Lyerly, HK, and Spector, NL. "Truncated ErbB2 expressed in tumor cell nuclei contributes to acquired therapeutic resistance to ErbB2 kinase inhibitors." Mol Cancer Ther 10.8 (August 2011): 1367-1374.
PMID
21673090
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
10
Issue
8
Publish Date
2011
Start Page
1367
End Page
1374
DOI
10.1158/1535-7163.MCT-10-0991

Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with Toll-like receptor stimulation to induce immunity to self-antigens in cancer patients.

PURPOSE: The use of tumor-derived proteins as cancer vaccines is complicated by tolerance to these self-antigens. Tolerance may be broken by immunization with activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting cells (APC); however, targeting tumor antigen directly to APC in vivo would be a less complicated strategy. We wished to test whether targeted delivery of an otherwise poorly immunogenic, soluble antigen to APC through their mannose receptors (MR) would induce clinically relevant immunity. EXPERIMENTAL DESIGN: Two phase I studies were conducted with CDX-1307, a vaccine composed of human chorionic gonadotropin beta-chain (hCG-β) fused to an MR-specific monoclonal antibody, administered either locally (intradermally) or systemically (intravenously) in patients with advanced epithelial malignancies. An initial dose escalation of single-agent CDX-1307 was followed by additional cohorts of CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC. RESULTS: CDX-1307 induced consistent humoral and T-cell responses to hCG-β when coadministered with TLR agonists. Greater immune responses and clinical benefit, including the longest duration of stable disease, were observed with immunization combined with local TLR agonists. Immune responses were induced equally efficiently in patients with elevated and nonelevated levels of serum hCG-β. Antibodies within the serum of vaccinated participants had tumor suppressive function in vitro. Toxicity consisted chiefly of mild injection site reactions. CONCLUSIONS: APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer immunotherapy.

Authors
Morse, MA; Chapman, R; Powderly, J; Blackwell, K; Keler, T; Green, J; Riggs, R; He, L-Z; Ramakrishna, V; Vitale, L; Zhao, B; Butler, SA; Hobeika, A; Osada, T; Davis, T; Clay, T; Lyerly, HK
MLA Citation
Morse, MA, Chapman, R, Powderly, J, Blackwell, K, Keler, T, Green, J, Riggs, R, He, L-Z, Ramakrishna, V, Vitale, L, Zhao, B, Butler, SA, Hobeika, A, Osada, T, Davis, T, Clay, T, and Lyerly, HK. "Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with Toll-like receptor stimulation to induce immunity to self-antigens in cancer patients." Clin Cancer Res 17.14 (July 15, 2011): 4844-4853.
PMID
21632857
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
14
Publish Date
2011
Start Page
4844
End Page
4853
DOI
10.1158/1078-0432.CCR-11-0891

Analysis of tumor environmental response and oncogenic pathway activation identifies distinct basal and luminal features in HER2-related breast tumor subtypes.

INTRODUCTION: Breast cancer heterogeneity occurs as a consequence of the dysregulation of numerous oncogenic pathways as well as many non-genetic factors, including tumor microenvironmental stresses such as hypoxia, lactic acidosis, and glucose deprivation. Although the importance of these non-genetic factors is well recognized, it is not clear how to integrate these factors within the genetic framework of cancer as the next logical step in understanding tumor heterogeneity. METHODS: We report here the development of a series of gene expression signatures to measure the influences of microenvironmental stresses. The pathway activities of hypoxia, lactic acidosis, acidosis and glucose deprivation were investigated in a collection of 1,143 breast tumors, which have been separated into 17 breast tumor subgroups defined by their distinct patterns of oncogenic pathways. A validation dataset comprised of 547 breast tumors was also used to confirm the major findings, and representative breast cancer cell lines were utilized to validate in silico results and mechanistic studies. RESULTS: Through the integrative pathway analysis of microenvironmental stresses and oncogenic events in breast tumors, we identified many known and novel correlations between these two sources of tumor heterogeneity. Focusing on differences between two human epidermal growth factor receptor 2 (HER2)-related subgroups, previously identified based on patterns of oncogenic pathway activity, we determined that these subgroups differ with regards to tumor microenvironmental signatures, including hypoxia. We further demonstrate that each of these subgroups have features consistent with basal and luminal breast tumors including patterns of oncogenic signaling pathways, expression of subtype specific genes, and cellular mechanisms that regulate the hypoxia response. Importantly, we also demonstrate that the correlated pattern of hypoxia-related gene expression and basal-associated gene expression are consistent across HER2-related tumors whether we analyze the tumors as a function of our pathway-based classification scheme, using the intrinsic gene list (ERBB2+), or based on HER2 IHC status. Our results demonstrate a cell lineage-specific phenomenon in which basal-like tumors, HER2-related tumors with high hypoxia, as well as normal basal epithelial cells express increased mRNA levels of HIF-1α compared to luminal types and silencing of HIF-1α results in decreased expression of hypoxia-induced genes. CONCLUSIONS: This study demonstrates differences in microenvironmental conditions in HER2-related subgroups defined by distinct oncogenic pathway activities, and provides a mechanistic explanation for differences in the observed hypoxia response between these subgroups. Collectively, these data demonstrate the potential of a pathway-based classification strategy as a framework to integrate genetic and non-genetic factors to investigate the basis of tumor heterogeneity.

Authors
Gatza, ML; Kung, H-N; Blackwell, KL; Dewhirst, MW; Marks, JR; Chi, J-T
MLA Citation
Gatza, ML, Kung, H-N, Blackwell, KL, Dewhirst, MW, Marks, JR, and Chi, J-T. "Analysis of tumor environmental response and oncogenic pathway activation identifies distinct basal and luminal features in HER2-related breast tumor subtypes. (Published online)" Breast Cancer Res 13.3 (June 7, 2011): R62-.
PMID
21672245
Source
pubmed
Published In
Breast Cancer Research
Volume
13
Issue
3
Publish Date
2011
Start Page
R62
DOI
10.1186/bcr2899

MHC class I-presented tumor antigens identified in ovarian cancer by immunoproteomic analysis are targets for T-cell responses against breast and ovarian cancer.

PURPOSE: The purpose of this study is to test whether peptide epitopes chosen from among those naturally processed and overpresented within MHC molecules by malignant, but not normal cells, when formulated into cancer vaccines, could activate antitumor T-cell responses in humans. EXPERIMENTAL DESIGN: Mixtures of human leukocyte antigen A2 (HLA-A2)-binding ovarian cancer-associated peptides were used to activate naive T cells to generate antigen-specific T cells that could recognize ovarian and breast cancers in vitro. Combinations of these peptides (0.3 mg of each peptide or 1 mg of each peptide) were formulated into vaccines in conjunction with Montanide ISA-51 and granulocyte monocyte colony stimulating factor which were used to vaccinate patients with ovarian and breast cancer without evidence of clinical disease in parallel pilot clinical trials. RESULTS: T cells specific for individual peptides could be generated in vitro by using mixtures of peptides, and these T cells recognized ovarian and breast cancers but not nonmalignant cells. Patient vaccinations were well tolerated with the exception of local erythema and induration at the injection site. Nine of the 14 vaccinated patients responded immunologically to their vaccine by inducing peptide-specific T-cell responses that were capable of recognizing HLA-matched breast and ovarian cancer cells. CONCLUSION: Mixtures of specific peptides identified as naturally presented on cancer cells and capable of activating tumor-specific T cells in vitro also initiate or augment immune responses toward solid tumors in cancer patients.

Authors
Morse, MA; Secord, AA; Blackwell, K; Hobeika, AC; Sinnathamby, G; Osada, T; Hafner, J; Philip, M; Clay, TM; Lyerly, HK; Philip, R
MLA Citation
Morse, MA, Secord, AA, Blackwell, K, Hobeika, AC, Sinnathamby, G, Osada, T, Hafner, J, Philip, M, Clay, TM, Lyerly, HK, and Philip, R. "MHC class I-presented tumor antigens identified in ovarian cancer by immunoproteomic analysis are targets for T-cell responses against breast and ovarian cancer." Clin Cancer Res 17.10 (May 15, 2011): 3408-3419.
PMID
21300761
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
10
Publish Date
2011
Start Page
3408
End Page
3419
DOI
10.1158/1078-0432.CCR-10-2614

Safety of bevacizumab in patients with metastatic breast cancer.

Five randomized phase III trials - AVF2119g, E2100, AVADO, RIBBON-1, and RIBBON-2 - have reported data on the efficacy and safety of bevacizumab, combined with a variety of chemotherapy agents and in various settings, in patients with metastatic breast cancer (MBC). The E2100 trial demonstrated a significant improvement in progression-free survival according to the independent review facility, from 5.8 to 11.3 months when bevacizumab was combined with paclitaxel (p < 0.0001) as first-line therapy in patients with HER2-nonamplified MBC; subsequent trials of bevacizumab as first-line (AVADO, RIBBON-1) and second-line (RIBBON-2) therapy for patients with HER2-nonamplified MBC have also met their primary end point of prolonging progression-free survival (PFS). Accumulating safety data for bevacizumab in MBC show that it is generally well tolerated and associated with predictable adverse events, including hypertension and proteinuria. The majority of adverse events are mild and manageable, but bevacizumab is also associated with some severe toxicities. The management of bevacizumab-related adverse events in MBC has improved with increased experience. This review summarizes bevacizumab efficacy in MBC and focuses on bevacizumab-related toxicities as reported in 5 phase III clinical trials. Current adverse event management strategies, based on guidelines and experience from these trials, are outlined.

Authors
Hamilton, EP; Blackwell, KL
MLA Citation
Hamilton, EP, and Blackwell, KL. "Safety of bevacizumab in patients with metastatic breast cancer." Oncology 80.5-6 (January 2011): 314-325.
PMID
21778772
Source
epmc
Published In
Oncology
Volume
80
Issue
5-6
Publish Date
2011
Start Page
314
End Page
325
DOI
10.1159/000328757

Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases.

INTRODUCTION: Activation status of the phosphatidylinositol 3-kinase (PI3K) pathway in breast cancer brain metastases (BCBMs) is largely unknown. We examined expression of phospho(p)-AKT, p-S6, and phosphatase and tensin homologue (PTEN) in BCBMs and their implications for overall survival (OS) and survival after BCBMs. Secondary analyses included PI3K pathway activation status and associations with time to distant recurrence (TTDR) and time to BCBMs. Similar analyses were also conducted among the subset of patients with triple-negative BCBMs. METHODS: p-AKT, p-S6, and PTEN expression was assessed with immunohistochemistry in 52 BCBMs and 12 matched primary BCs. Subtypes were defined as hormone receptor (HR)+/HER2-, HER2+, and triple-negative (TNBC). Survival analyses were performed by using a Cox model, and survival curves were estimated with the Kaplan-Meier method. RESULTS: Expression of p-AKT and p-S6 and lack of PTEN (PTEN-) was observed in 75%, 69%, and 25% of BCBMs. Concordance between primary BCs and matched BCBMs was 67% for p-AKT, 58% for p-S6, and 83% for PTEN. PTEN- was more common in TNBC compared with HR+/HER2- and HER2+. Expression of p-AKT, p-S6, and PTEN- was not associated with OS or survival after BCBMs (all, P > 0.06). Interestingly, among all patients, PTEN- correlated with shorter time to distant and brain recurrence. Among patients with TNBC, PTEN- in BCBMs was associated with poorer overall survival. CONCLUSIONS: The PI3K pathway is active in most BCBMs regardless of subtype. Inhibition of this pathway represents a promising therapeutic strategy for patients with BCBMs, a group of patients with poor prognosis and limited systemic therapeutic options. Although expression of the PI3K pathway did not correlate with OS and survival after BCBM, PTEN- association with time to recurrence and OS (among patients with TNBC) is worthy of further study.

Authors
Adamo, B; Deal, AM; Burrows, E; Geradts, J; Hamilton, E; Blackwell, KL; Livasy, C; Fritchie, K; Prat, A; Harrell, JC; Ewend, MG; Carey, LA; Miller, CR; Anders, CK
MLA Citation
Adamo, B, Deal, AM, Burrows, E, Geradts, J, Hamilton, E, Blackwell, KL, Livasy, C, Fritchie, K, Prat, A, Harrell, JC, Ewend, MG, Carey, LA, Miller, CR, and Anders, CK. "Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases." Breast Cancer Res 13.6 (2011): R125-.
PMID
22132754
Source
pubmed
Published In
Breast Cancer Research
Volume
13
Issue
6
Publish Date
2011
Start Page
R125
DOI
10.1186/bcr3071

Impact of lapatinib plus trastuzumab versus single-agent lapatinib on quality of life of patients with trastuzumab-refractory HER2+ metastatic breast cancer

Background: Progression-free survival (PFS) was significantly longer for the lapatinib plus trastuzumab (L+T) arm than for L alone in a phase III, randomized, open-label study of women with human epidermal growth factor receptor 2 positive metastatic breast cancer who had documented progression on at least one T-containing regimen in the metastatic setting. This analysis focused on impact of treatments on health-related quality of life (HRQOL).Methods: HRQOL was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. Changes from baseline and time to deterioration were analyzed in the intent-to-treat population.Results: Differences between the treatment arms in adjusted mean change from baseline favored the L+T arm, ranging from 0.0 to 4.1 (FACT-B), 1.0-4.0 [Functional Assessment of Cancer Therapy-General (FACT-G)], and 0.5-2.7 (Trial Outcome Index). Most differences were not statistically significant, except for FACT-G at week 12 (delta = 4.0, P = 0.037). Similar results were found in a sensitivity analysis that included HRQOL records up to patient withdrawal from original randomized treatment. The longer time to HRQOL deterioration in the L+T arm was not statistically significant (FACT-B hazard ratio, 0.82; 95% confidence interval 0.56-1.20).Conclusion: The addition of lapatinib to trastuzumab prolonged PFS while improving or maintaining near-term HRQOL, suggesting a meaningful clinical benefit to patients. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Authors
Wu, Y; Amonkar, MM; Sherrill, BH; O'shaughnessy, J; Ellis, C; Baselga, J; Blackwell, KL; Burstein, HJ
MLA Citation
Wu, Y, Amonkar, MM, Sherrill, BH, O'shaughnessy, J, Ellis, C, Baselga, J, Blackwell, KL, and Burstein, HJ. "Impact of lapatinib plus trastuzumab versus single-agent lapatinib on quality of life of patients with trastuzumab-refractory HER2+ metastatic breast cancer." Annals of Oncology 22.12 (2011): 2582-2590.
PMID
21406472
Source
scival
Published In
Annals of Oncology
Volume
22
Issue
12
Publish Date
2011
Start Page
2582
End Page
2590
DOI
10.1093/annonc/mdr014

Breast carcinomas arising at a young age: Unique biology or a surrogate for aggressive intrinsic subtypes?

Authors
Anders, CK; Fan, C; Parker, JS; Carey, LA; Blackwell, KL; Klauber-DeMore, N; Perou, CM
MLA Citation
Anders, CK, Fan, C, Parker, JS, Carey, LA, Blackwell, KL, Klauber-DeMore, N, and Perou, CM. "Breast carcinomas arising at a young age: Unique biology or a surrogate for aggressive intrinsic subtypes?." Journal of Clinical Oncology 29.1 (2011): e18-e20.
PMID
21115855
Source
scival
Published In
Journal of Clinical Oncology
Volume
29
Issue
1
Publish Date
2011
Start Page
e18
End Page
e20
DOI
10.1200/JCO.2010.28.9199

Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer.

PURPOSE: Preclinical studies in ErbB2-positive cell lines demonstrated a synergistic interaction between lapatinib and trastuzumab, suggesting that dual blockade is more effective than a single agent alone. EGF104900 compared the activity of lapatinib alone or in combination with trastuzumab in patients with ErbB2-positive, trastuzumab-refractory metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients with ErbB2-positive MBC who experienced progression on prior trastuzumab-containing regimens were randomly assigned to receive either lapatinib alone or in combination with trastuzumab. The primary end point was progression-free survival (PFS). Secondary efficacy end points included overall response rate (ORR), clinical benefit rate (CBR; complete response, partial response, and stable disease for >/= 24 weeks), and overall survival (OS). RESULTS: In the intent-to-treat population (N = 296) who received a median of three prior trastuzumab-containing regimens, the combination of lapatinib with trastuzumab was superior to lapatinib alone for PFS (hazard ratio [HR] = 0.73; 95% CI, 0.57 to 0.93; P = .008) and CBR (24.7% in the combination arm v 12.4% in the monotherapy arm; P = .01). A trend for improved OS in the combination arm was observed (HR = 0.75; 95% CI, 0.53 to 1.07; P = .106). There was no difference in ORR (10.3% in the combination arm v 6.9% in the monotherapy arm; P = .46). The most frequent adverse events were diarrhea, rash, nausea, and fatigue; diarrhea was higher in the combination arm (P = .03). The incidence of symptomatic and asymptomatic cardiac events was low (combination therapy = 2% and 3.4%; monotherapy = 0.7% and 1.4%, respectively). CONCLUSION: Despite disease progression on prior trastuzumab-based therapy, lapatinib in combination with trastuzumab significantly improved PFS and CBR versus lapatinib alone, thus offering a chemotherapy-free option with an acceptable safety profile to patients with ErbB2-positive MBC.

Authors
Blackwell, KL; Burstein, HJ; Storniolo, AM; Rugo, H; Sledge, G; Koehler, M; Ellis, C; Casey, M; Vukelja, S; Bischoff, J; Baselga, J; O'Shaughnessy, J
MLA Citation
Blackwell, KL, Burstein, HJ, Storniolo, AM, Rugo, H, Sledge, G, Koehler, M, Ellis, C, Casey, M, Vukelja, S, Bischoff, J, Baselga, J, and O'Shaughnessy, J. "Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer." J Clin Oncol 28.7 (March 1, 2010): 1124-1130.
PMID
20124187
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
28
Issue
7
Publish Date
2010
Start Page
1124
End Page
1130
DOI
10.1200/JCO.2008.21.4437

Hyperthermia for locally advanced breast cancer.

Hyperthermia (HT) has a proven benefit for treating superficial malignancies, particularly chest wall recurrences of breast cancer. There has been less research utilising HT in patients with locally advanced breast cancer (LABC), but available data are promising. HT has been combined with chemotherapy and/or radiotherapy in the neoadjuvant, definitive and adjuvant setting, albeit in series with small numbers of patients. There is only one phase III trial that examines hyperthermia in LABC, also with relatively small numbers of patients. The goal of this review is to highlight important research utilising HT in patients with LABC as well as to suggest future directions for its use.

Authors
Zagar, TM; Oleson, JR; Vujaskovic, Z; Dewhirst, MW; Craciunescu, OI; Blackwell, KL; Prosnitz, LR; Jones, EL
MLA Citation
Zagar, TM, Oleson, JR, Vujaskovic, Z, Dewhirst, MW, Craciunescu, OI, Blackwell, KL, Prosnitz, LR, and Jones, EL. "Hyperthermia for locally advanced breast cancer." Int J Hyperthermia 26.7 (2010): 618-624. (Review)
PMID
20849257
Source
pubmed
Published In
International Journal of Hyperthermia (Informa)
Volume
26
Issue
7
Publish Date
2010
Start Page
618
End Page
624
DOI
10.3109/02656736.2010.501051

A phase I/II study of neoadjuvant liposomal doxorubicin, paclitaxel, and hyperthermia in locally advanced breast cancer.

PURPOSE: The prognosis for locally advanced breast cancer (LABC) patients continues to be poor, with an estimated five-year survival of only 50-60%. Preclinical data demonstrates enhanced therapeutic efficacy with liposomal encapsulation of doxorubicin combined with hyperthermia (HT). Therefore this phase I/II study was designed to evaluate the safety and efficacy of a novel neoadjuvant combination treatment of paclitaxel, liposomal doxorubicin, and hyperthermia. MATERIALS AND METHODS: Eligible patients received four cycles of neoadjuvant liposomal doxorubicin (30-75 mg/m(2)), paclitaxel (100-175 mg/m(2)), and hyperthermia. They subsequently underwent either a modified radical mastectomy or lumpectomy with axillary node dissection followed by radiation therapy and then eight cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy. RESULTS: Forty-seven patients with stage IIB-III LABC were enrolled and 43 patients were evaluable. Fourteen patients (33%) had inflammatory breast cancer. Combined (partial + complete) clinical response rate was 72% and combined pathological response rate was 60%. Four patients achieved a pathologically complete response. Sixteen patients were eligible for breast-conserving surgery. The cumulative equivalent minutes (CEM 43) at T90 (tenth percentile of temperature distribution) was significantly greater for those with a pathological response. Four-year disease-free survival was 63% (95% CI, 46%-76%) and the four-year overall survival was 75% (95% CI, 58-86%). CONCLUSIONS: Neoadjuvant therapy using paclitaxel, liposomal doxorubicin and hyperthermia is a feasible and well tolerated treatment strategy in patients with LABC. The thermal dose parameter CEM 43 T90 was significantly correlated with attaining a pathological response.

Authors
Vujaskovic, Z; Kim, DW; Jones, E; Lan, L; McCall, L; Dewhirst, MW; Craciunescu, O; Stauffer, P; Liotcheva, V; Betof, A; Blackwell, K
MLA Citation
Vujaskovic, Z, Kim, DW, Jones, E, Lan, L, McCall, L, Dewhirst, MW, Craciunescu, O, Stauffer, P, Liotcheva, V, Betof, A, and Blackwell, K. "A phase I/II study of neoadjuvant liposomal doxorubicin, paclitaxel, and hyperthermia in locally advanced breast cancer." Int J Hyperthermia 26.5 (2010): 514-521.
PMID
20377362
Source
pubmed
Published In
International Journal of Hyperthermia (Informa)
Volume
26
Issue
5
Publish Date
2010
Start Page
514
End Page
521
DOI
10.3109/02656731003639364

Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: a review of the randomised data.

Hyperthermia has long been used in combination with radiation for the treatment of superficial malignancies, in part due to its radiosensitising capabilities. Patients who suffer superficial recurrences of breast cancer, be it in their chest wall following mastectomy, or in their breast after breast conservation, typically have poor clinical outcomes. They often develop distant metastatic disease, but one must not overlook the problems associated with an uncontrolled local failure. Morbidity is enormous, and can significantly impair quality of life. There is no accepted standard of care in treating superficial recurrences of breast cancer, particularly in patients that have previously been irradiated. There is a substantial literature regarding the combined use of hyperthermia and radiotherapy for these superficial recurrences. Most of it is retrospective in nature, but there are several larger phase III randomised trials that show an improved rate of clinical complete response in patients treated with both modalities. In this review article, we will highlight the important prospective data that has been published regarding the combined use of hyperthermia and radiation.

Authors
Zagar, TM; Oleson, JR; Vujaskovic, Z; Dewhirst, MW; Craciunescu, OI; Blackwell, KL; Prosnitz, LR; Jones, EL
MLA Citation
Zagar, TM, Oleson, JR, Vujaskovic, Z, Dewhirst, MW, Craciunescu, OI, Blackwell, KL, Prosnitz, LR, and Jones, EL. "Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: a review of the randomised data." Int J Hyperthermia 26.7 (2010): 612-617. (Review)
PMID
20849256
Source
pubmed
Published In
International Journal of Hyperthermia (Informa)
Volume
26
Issue
7
Publish Date
2010
Start Page
612
End Page
617
DOI
10.3109/02656736.2010.487194

Use of aromatase inhibitors and bisphosphonates as an anticancer therapy in postmenopausal breast cancer

Breast cancer is a major cause of morbidity and mortality in postmenopausal women worldwide. Reducing the risk of distant disease recurrence is a primary goal of adjuvant endocrine therapy. As we await data from ongoing Phase III comparison trials, an emerging body of evidence demonstrates important differences between third-generation aromatase inhibitors, particularly with respect to potency and prevention of early distant metastases. Furthermore, a growing body of evidence demonstrates anticancer benefits of bisphosphonates in adjuvant breast cancer and other settings. This article outlines the proceedings from an Expert Panel meeting of regionally diverse breast cancer specialists regarding the appropriate use of aromatase inhibitors in postmenopausal hormone-responsive early breast cancer and bisphosphonates as anticancer therapy in adjuvant breast cancer. © 2010 Expert Reviews Ltd.

Authors
Mouridsen, HT; Lønning, P; Beckmann, MW; Blackwell, K; Doughty, J; Gligorov, J; Llombart-Cussac, A; Robidoux, A; Thürlimann, B; Gnant, M
MLA Citation
Mouridsen, HT, Lønning, P, Beckmann, MW, Blackwell, K, Doughty, J, Gligorov, J, Llombart-Cussac, A, Robidoux, A, Thürlimann, B, and Gnant, M. "Use of aromatase inhibitors and bisphosphonates as an anticancer therapy in postmenopausal breast cancer." Expert Review of Anticancer Therapy 10.11 (2010): 1825-1836.
PMID
20883112
Source
scival
Published In
Expert Review of Anticancer Therapy
Volume
10
Issue
11
Publish Date
2010
Start Page
1825
End Page
1836
DOI
10.1586/era.10.160

Independent adjudication of symptomatic heart failure with the use of doxorubicin and cyclophosphamide followed by trastuzumab adjuvant therapy: A combined review of cardiac data from the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 clinical trials

Purpose: An independent Adjuvant Cardiac Review and Evaluation Committee (ACREC) systematically reviewed cases of symptomatic heart failure events to uniformly define the cardiac event rate across two large trials (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-31 and North Central Cancer Treatment Group [NCCTG] N9831) that assessed the addition of trastuzumab to standard adjuvant chemotherapy. Patients and Methods: The committee was composed of six independent oncologists and cardiologists. A retrospective review of patients with a cardiac event was performed by the primary investigators of the trials. The ACREC prospectively established criteria for determining a symptomatic heart failure event. Recovery status was determined from documented resolution of signs and symptoms. Potential risk factors were also assessed. Results: Medical records for a total of 173 patients were reviewed: 40 in the chemotherapy-alone arm and 133 in the trastuzumab arm. Trastuzumab-treated patients had a 2.0% incidence of symptomatic heart failure events compared with 0.45% in the chemotherapy-alone arm. Complete or partial recovery was observed in 86.1% of trastuzumab-treated patients with symptomatic heart failure events. Of five patients who died, only one patient had received trastuzumab. Independent predictors for cardiac events were age older than 50 years, a low ejection fraction at the start of paclitaxel treatment, and trastuzumab treatment. Conclusion: The incidence of symptomatic heart failure events is 2.0% in patients treated with adjuvant trastuzumab, and the majority of these patients recover with appropriate treatment. © 2010 by American Society of Clinical Oncology.

Authors
Russell, SD; Blackwell, KL; Lawrence, J; Jr, JEP; Roe, MT; Wood, F; Paton, V; Holmgren, E; Mahaffey, KW
MLA Citation
Russell, SD, Blackwell, KL, Lawrence, J, Jr, JEP, Roe, MT, Wood, F, Paton, V, Holmgren, E, and Mahaffey, KW. "Independent adjudication of symptomatic heart failure with the use of doxorubicin and cyclophosphamide followed by trastuzumab adjuvant therapy: A combined review of cardiac data from the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 clinical trials." Journal of Clinical Oncology 28.21 (2010): 3416-3421.
PMID
20530275
Source
scival
Published In
Journal of Clinical Oncology
Volume
28
Issue
21
Publish Date
2010
Start Page
3416
End Page
3421
DOI
10.1200/JCO.2009.23.6950

Reply to F. Bellati et al

Authors
Spector, NL; Blackwell, KL
MLA Citation
Spector, NL, and Blackwell, KL. "Reply to F. Bellati et al." Journal of Clinical Oncology 28.21 (2010): e371-.
Source
scival
Published In
Journal of Clinical Oncology
Volume
28
Issue
21
Publish Date
2010
Start Page
e371
DOI
10.1200/JCO.2010.28.8571

Third-generation aromatase inhibitors: Differences between the agents and their role in reducing the risk of distant metastasis and improving survival

There are now several efficacious treatments for early-stage hormone-receptor-positive breast cancer. Although tamoxifen reduces disease recurrence and death from breast cancer and previously was the standard of care for decades, third-generation aromatase inhibitors (AIs) are now the treatment of choice for postmenopausal women with early-stage breast cancer (ESBC). There are three commercially available AIs: letrozole, anastrozole, and exemestane. All three have been shown to bemore effective and at least as well tolerated as tamoxifen when used as adjuvant therapy. Preclinical studies suggest letrozole is the most potent inhibitor of aromatase and results in greater suppression of estrogen levels when compared to other AIs. However, the relationship between aromatase activity and clinical efficacy is unclear. In the absence of direct head-to-head comparisons between the AIs, cross-trial comparisons have been used to try to elucidate differences between the AIs. There is a wealth of data comparing each AI with tamoxifen; however, across these trials, differences in study populations, definition of trial endpoints, and treatment schedules exist. Definitive conclusions remain unreached; however, differences between the agents are emerging. Upfront letrozole appears particularly effective when used in the adjuvant setting, particularly for the prevention of early distant metastasis. Distant metastasis is associated with significant morbidity and is strongly associated with breast-cancer-related death. This article explores the clinical efficacy of the AIs, differences between the agents, and their safety profiles in addition to discussing optimal ESBC clinical trial endpoints.

Authors
Hamilton, EP; Blackwell, KL
MLA Citation
Hamilton, EP, and Blackwell, KL. "Third-generation aromatase inhibitors: Differences between the agents and their role in reducing the risk of distant metastasis and improving survival." European journal of Clinical and Medical Oncology 2.4 (2010).
Source
scival
Published In
European journal of Clinical and Medical Oncology
Volume
2
Issue
4
Publish Date
2010

Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer.

PURPOSE: Targeted therapy with the humanized monoclonal antibody trastuzumab has become a mainstay for human epidermal growth factor receptor 2 (HER2) -positive breast cancer (BC). The mechanisms of action of trastuzumab have not been fully elucidated, and data available to date are reviewed here. The impact of the mechanisms of action on clinical benefit also is discussed. METHODS: An extensive literature review of trastuzumab and proposed mechanisms of action was performed. RESULTS: At least five potential extracellular and intracellular antitumor mechanisms of trastuzumab have been identified in the preclinical setting. These include activation of antibody-dependent cellular cytotoxicity, inhibition of extracellular domain cleavage, abrogation of intracellular signaling, reduction of angiogenesis, and decreased DNA repair. These effects lead to tumor cell stasis and/or death. Clinical benefit from trastuzumab-based therapy in both early and advanced BC has been demonstrated. The benefit of trastuzumab use beyond progression has also been shown, which indicates the need for continuous suppression of the HER2 pathway. Targeting both HER2, with various approaches, and other pathways may enhance the clinical benefit observed with trastuzumab and overcome potential resistance. Novel combinations include pertuzumab (a HER2 dimerization inhibitor), lapatinib (a HER1/HER2 tyrosine kinase inhibitor), bevacizumab (an antiangiogenic agent), tanespimycin (a heat shock protein inhibitor), antiestrogen therapies, and an antibody-drug conjugate (trastuzumab-DM1). CONCLUSION: Trastuzumab is the foundation of care for patients with HER2-positive BC. Emerging data from studies of other targeted agents may provide alternative treatment combinations to maximize the clinical benefit from trastuzumab and prevent or delay resistance. The continued development of trastuzumab highlights promising treatment approaches for the future.

Authors
Spector, NL; Blackwell, KL
MLA Citation
Spector, NL, and Blackwell, KL. "Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer." J Clin Oncol 27.34 (December 1, 2009): 5838-5847. (Review)
PMID
19884552
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
34
Publish Date
2009
Start Page
5838
End Page
5847
DOI
10.1200/JCO.2009.22.1507

Comparative genome-wide screening identifies a conserved doxorubicin repair network that is diploid specific in Saccharomyces cerevisiae.

The chemotherapeutic doxorubicin (DOX) induces DNA double-strand break (DSB) damage. In order to identify conserved genes that mediate DOX resistance, we screened the Saccharomyces cerevisiae diploid deletion collection and identified 376 deletion strains in which exposure to DOX was lethal or severely reduced growth fitness. This diploid screen identified 5-fold more DOX resistance genes than a comparable screen using the isogenic haploid derivative. Since DSB damage is repaired primarily by homologous recombination in yeast, and haploid cells lack an available DNA homolog in G1 and early S phase, this suggests that our diploid screen may have detected the loss of repair functions in G1 or early S phase prior to complete DNA replication. To test this, we compared the relative DOX sensitivity of 30 diploid deletion mutants identified under our screening conditions to their isogenic haploid counterpart, most of which (n = 26) were not detected in the haploid screen. For six mutants (bem1Delta, ctf4Delta, ctk1Delta, hfi1Delta,nup133Delta, tho2Delta) DOX-induced lethality was absent or greatly reduced in the haploid as compared to the isogenic diploid derivative. Moreover, unlike WT, all six diploid mutants displayed severe G1/S phase cell cycle progression defects when exposed to DOX and some were significantly enhanced (ctk1Delta and hfi1Delta) or deficient (tho2Delta) for recombination. Using these and other "THO2-like" hypo-recombinogenic, diploid-specific DOX sensitive mutants (mft1Delta, thp1Delta, thp2Delta) we utilized known genetic/proteomic interactions to construct an interactive functional genomic network which predicted additional DOX resistance genes not detected in the primary screen. Most (76%) of the DOX resistance genes detected in this diploid yeast screen are evolutionarily conserved suggesting the human orthologs are candidates for mediating DOX resistance by impacting on checkpoint and recombination functions in G1 and/or early S phases.

Authors
Westmoreland, TJ; Wickramasekara, SM; Guo, AY; Selim, AL; Winsor, TS; Greenleaf, AL; Blackwell, KL; Olson, JA; Marks, JR; Bennett, CB
MLA Citation
Westmoreland, TJ, Wickramasekara, SM, Guo, AY, Selim, AL, Winsor, TS, Greenleaf, AL, Blackwell, KL, Olson, JA, Marks, JR, and Bennett, CB. "Comparative genome-wide screening identifies a conserved doxorubicin repair network that is diploid specific in Saccharomyces cerevisiae. (Published online)" PLoS One 4.6 (June 8, 2009): e5830-.
PMID
19503795
Source
pubmed
Published In
PloS one
Volume
4
Issue
6
Publish Date
2009
Start Page
e5830
DOI
10.1371/journal.pone.0005830

Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens.

BACKGROUND: This phase II study evaluated the efficacy and safety of lapatinib in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer that progressed during prior trastuzumab therapy. PATIENTS AND METHODS: Women with stage IIIB/IV HER2-overexpressing breast cancer were treated with single-agent lapatinib 1250 or 1500 mg once daily after protocol amendment. Tumor response according to RECIST was assessed every 8 weeks. HER2 expression was assessed in tumor tissue by immunohistochemistry and FISH. RESULTS: Seventy-eight patients were enrolled in the study. Investigator and independent review response rates [complete response (CR) or partial response (PR)] were 7.7% and 5.1%, and clinical benefit rates (CR, PR, or stable disease for >or=24 weeks) were 14.1% and 9.0%, respectively. Median time to progression was 15.3 weeks by independent review, and median overall survival was 79 weeks. The most common treatment-related adverse events were rash (47%), diarrhea (46%), nausea (31%), and fatigue (18%). CONCLUSIONS: Single-agent lapatinib has clinical activity with manageable toxic effects in HER2-overexpressing breast cancer that progressed on trastuzumab-containing therapy. Studies of lapatinib-based combination regimens with chemotherapy and other targeted therapies in metastatic and earlier stages of breast cancer are warranted.

Authors
Blackwell, KL; Pegram, MD; Tan-Chiu, E; Schwartzberg, LS; Arbushites, MC; Maltzman, JD; Forster, JK; Rubin, SD; Stein, SH; Burstein, HJ
MLA Citation
Blackwell, KL, Pegram, MD, Tan-Chiu, E, Schwartzberg, LS, Arbushites, MC, Maltzman, JD, Forster, JK, Rubin, SD, Stein, SH, and Burstein, HJ. "Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens." Ann Oncol 20.6 (June 2009): 1026-1031.
PMID
19179558
Source
pubmed
Published In
Annals of Oncology
Volume
20
Issue
6
Publish Date
2009
Start Page
1026
End Page
1031
DOI
10.1093/annonc/mdn759

Her2/neu signaling blockade improves tumor oxygenation in a multifactorial fashion in Her2/neu+ tumors.

PURPOSE: Tumor hypoxia reduces the efficacy of radiation and chemotherapy as well as altering gene expression that promotes cell survival and metastasis. The growth factor receptor, Her2/neu, is overexpressed in 25-30% of breast tumors. Tumors that are Her2(+) may have an altered state of oxygenation, relative to Her2(-) tumors, due to differences in tumor growth rate and angiogenesis. METHODS: Her2 blockade was accomplished using an antibody to the receptor (trastuzumab; Herceptin). This study examined the effects of Her2 blockade on tumor angiogenesis, vascular architecture, and hypoxia in Her2(+) and Her2(-) MCF7 xenograft tumors. RESULTS: Treatment with trastuzumab in Her2(+) tumors significantly improved tumor oxygenation, increased microvessel density, and improved vascular architecture compared with the control-treated Her2(+) tumors. The Her2(+) xenografts treated with trastuzumab also demonstrated decreased proliferation indices when compared with control-treated xenografts. These results indicate that Her2 blockade can improve tumor oxygenation by decreasing oxygen consumption (reducing tumor cell proliferation and inducing necrosis) and increasing oxygen delivery (vascular density and architecture). CONCLUSIONS: These results support the use of trastuzumab as an adjunct in the treatment of breast tumors with chemotherapy or radiotherapy, as improvements in tumor oxygenation should translate into improved treatment response.

Authors
Hardee, ME; Eapen, RJ; Rabbani, ZN; Dreher, MR; Marks, J; Blackwell, KL; Dewhirst, MW
MLA Citation
Hardee, ME, Eapen, RJ, Rabbani, ZN, Dreher, MR, Marks, J, Blackwell, KL, and Dewhirst, MW. "Her2/neu signaling blockade improves tumor oxygenation in a multifactorial fashion in Her2/neu+ tumors." Cancer Chemother Pharmacol 63.2 (January 2009): 219-228.
PMID
18365198
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
63
Issue
2
Publish Date
2009
Start Page
219
End Page
228
DOI
10.1007/s00280-008-0729-3

DCE-MRI parameters have potential to predict response of locally advanced breast cancer patients to neoadjuvant chemotherapy and hyperthermia: a pilot study.

UNLABELLED: Combined therapies represent a staple of modern medicine. For women treated with neoadjuvant chemotherapy (NA ChT) for locally advanced breast cancer (LABC), early determination of whether the patient will fail to respond can enable the use of alternative, more beneficial therapies. This is even more desirable when the combined therapy includes hyperthermia (HT), an efficient way to improve drug delivery, however, more costly and time consuming. There is data showing that this goal can be achieved using magnetic resonance imaging (MRI) with contrast agent (CA) enhancement. This work for the first time proposes combining the information extracted from pre-treatment MR imaging into a morpho-physiological tumour score (MPTS) with the hypothesis that this score will increase the prognostic efficacy, compared to each of its MR-derived components: morphological (derived from the shape of the tumour enhancement) and physiological (derived from the CA enhancement variance dynamics parameters). The MPTS was correlated with response as determined by both pathologic residual tumour and MRI imaging, and was shown to have potential to predict response. The MPTS was extracted from pre-treatment MRI parameters, so independent of the combined therapy used. PURPOSE: To use a novel morpho-physiological tumour score (MPTS) generated from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict response to treatment. MATERIALS AND METHODS: A protocol was designed to acquire DCE-MRI images of 20 locally advanced breast cancer (LABC) patients treated with neoadjuvant chemotherapy (NA ChT) and hyperthermia (HT). Imaging was done over 30 min following bolus injection of gadopentetate-based contrast agent. Parametric maps were generated by fitting the signal intensity to a double exponential curve and were used to derive a morphological characterisation of the lesions. Enhancement-variance dynamics parameters, wash-in and wash-out parameters (WiP, WoP), were extracted. The morphological characterisation and the WiP and WoP were combined into a MPTS with the intent of achieving better prognostic efficacy. The MPTS was correlated with response to NA therapy as determined by pathological residual tumour and MRI imaging. RESULTS: The contrast agent in all tumours typically peaked in the first 1-4 min. The tumours' WiP and WoP varied considerably. The MPTS was highly correlated with whether the patients had a pathological response. This scoring system has a specificity of 78% and a sensitivity of 91% for predicting response to NA chemotherapy. The kappa was 0.69 with a 95% confidence interval of [0.38, 1] and a p-value of 0.002. CONCLUSIONS: This pilot study shows that the MPTS derived using pre-treatment MRI images has the potential to predict response to NA ChT and HT in LABC patients. Further prospective studies are needed to confirm the validity of these results.

Authors
Craciunescu, OI; Blackwell, KL; Jones, EL; Macfall, JR; Yu, D; Vujaskovic, Z; Wong, TZ; Liotcheva, V; Rosen, EL; Prosnitz, LR; Samulski, TV; Dewhirst, MW
MLA Citation
Craciunescu, OI, Blackwell, KL, Jones, EL, Macfall, JR, Yu, D, Vujaskovic, Z, Wong, TZ, Liotcheva, V, Rosen, EL, Prosnitz, LR, Samulski, TV, and Dewhirst, MW. "DCE-MRI parameters have potential to predict response of locally advanced breast cancer patients to neoadjuvant chemotherapy and hyperthermia: a pilot study." Int J Hyperthermia 25.6 (2009): 405-415.
PMID
19657852
Source
pubmed
Published In
International Journal of Hyperthermia (Informa)
Volume
25
Issue
6
Publish Date
2009
Start Page
405
End Page
415
DOI
10.1080/02656730903022700

Lapatinib monotherapy in patients with HER2-overexpressing relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+ cohort in EGF103009, a phase II study

Background: Inflammatory breast cancer is an aggressive and biologically distinct form with a higher frequency of HER2 overexpression than other breast cancers. For patients with resistance to conventional anthracycline or taxane and trastuzumab treatment, options are limited. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor tyrosine kinases, previously had a 50% response rate in a cohort of 30 patients with HER2-overexpressing (HER2+) recurrent or anthracycline-refractory inflammatory breast cancer. We aimed to assess efficacy of lapatinib in an expanded cohort of patients with relapsed or refractory HER2+ disease. Methods: From March, 2005, to September, 2007, 126 patients with relapsed or refractory HER2+ inflammatory breast cancer were treated with lapatinib 1500 mg once daily in a non-randomised, open-label, phase II study. Pretreatment tumour biopsies were done to verify pathological features of inflammatory breast cancer. Skin disease was assessed every 4 weeks, and response in sites of measurable locally advanced or metastatic disease were assessed by response evaluation in solid tumours (RECIST) criteria every 8 weeks. The primary aim was to assess combined objective response rate, by clinically evaluable skin disease criteria and RECIST, if applicable. Analyses were done by intention to treat; patients with missing data were treated as non-responders. This study is registered with ClinicalTrials.gov, number NCT00105950. Findings: Clinical presentation and biomarker analysis showed a tumour molecular profile consistent with inflammatory breast cancer. No patients had complete response. 49 patients (39%; 95% CI 30-48) had partial response. Median progression-free survival was 14·6 weeks (95% CI 12·1-16·0), with median duration of response of 20·9 weeks (12·7-32·1). Likelihood of response to lapatinib was not affected by previous treatment with trastuzumab. 130 (92%) of 141 patients had at least one adverse event; 45 (32%) had serious adverse events, the most common were dyspnoea (eight patients) and pleural effusion (six). Five patients had fatal adverse events that were possibly treatment related. Interpretation: Lapatinib monotherapy is a potentially effective treatment for relapsed or refractory HER2+ inflammatory breast cancer. Funding: GlaxoSmithKline. © 2009 Elsevier Ltd. All rights reserved.

Authors
Kaufman, B; Trudeau, M; Awada, A; Blackwell, K; Bachelot, T; Salazar, V; DeSilvio, M; Westlund, R; Zaks, T; Spector, N; Johnston, S
MLA Citation
Kaufman, B, Trudeau, M, Awada, A, Blackwell, K, Bachelot, T, Salazar, V, DeSilvio, M, Westlund, R, Zaks, T, Spector, N, and Johnston, S. "Lapatinib monotherapy in patients with HER2-overexpressing relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+ cohort in EGF103009, a phase II study." The Lancet Oncology 10.6 (2009): 581-588.
PMID
19394894
Source
scival
Published In
The Lancet Oncology
Volume
10
Issue
6
Publish Date
2009
Start Page
581
End Page
588
DOI
10.1016/S1470-2045(09)70087-7

Analysis of dermatologic events in patients with cancer treated with lapatinib

Purpose Dermatologic events (DEs) in patients with cancer treated with lapatinib, a small-molecule dual tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR [ErbB1]) and HER2 (ErbB2), were characterized. Patients and methods Nine clinical trials of metastatic cancer were included in this analysis. Lapatinib was administered at doses ranging from 1000 to 1500 mg/day as monotherapy (n = 928) or in combination with paclitaxel or capecitabine (n = 491). Patients not treated with lapatinib comprised the control group. Dermatologic events included hand-foot syndrome, rash, hair disorder, dry skin, pruritus/urticaria, skin disorder, skin infection, and nail disorder; DEs were characterized based on type, time to onset, severity, duration, and required interventions. Results Fifty-eight percent of patients treated with lapatinib monotherapy, 74% treated with lapatinib plus paclitaxel or capecitabine, and 53% in the control group developed DEs. Among patients receiving lapatinib monotherapy, 55% experienced grade 1/2 DEs, 3% had grade 3 DEs, and no grade 4 DEs were observed. The most common DE was rash (43%); all other events occurred in ≤ 8% of patients. Most DEs developed between days 1 and 14 of starting treatment, with a median duration of 29 days. Three percent of DEs led to lapatinib dose reduction, 7% resulted in dose interruption, and 1% led to drug discontinuation. Conclusions Most DEs in lapatinib-treated patients present early, are mild to moderate in severity, and infrequently require dose modification or treatment interruption. Lapatinib-associated DEs appear to differ clinically from those associated with EGFR TKIs in both frequency and severity. © 2008 Springer Science+Business Media, LLC.

Authors
Lacouture, ME; Laabs, SM; Koehler, M; Sweetman, RW; Preston, AJ; Leo, AD; Gomez, HL; Salazar, VM; Byrne, JA; Koch, KM; Blackwell, KL
MLA Citation
Lacouture, ME, Laabs, SM, Koehler, M, Sweetman, RW, Preston, AJ, Leo, AD, Gomez, HL, Salazar, VM, Byrne, JA, Koch, KM, and Blackwell, KL. "Analysis of dermatologic events in patients with cancer treated with lapatinib." Breast Cancer Research and Treatment 114.3 (2009): 485-493.
PMID
18600445
Source
scival
Published In
Breast Cancer Research and Treatment
Volume
114
Issue
3
Publish Date
2009
Start Page
485
End Page
493
DOI
10.1007/s10549-008-0020-7

Determination of utility scores for control of chemotherapy-induced nausea or vomiting - CALGB 309801

Utility scores for temporary health states are not well defined. We investigated two techniques to define utilities for chemotherapy-induced nausea and vomiting. Patients receiving cyclic chemotherapy evaluated various hypothetical health states, each assuming 2-year overall survival with 1 year of chemotherapy followed by 1 year of good health. Health states included perfect health, no nausea/vomiting, limited nausea, limited vomiting, limited nausea/vomiting, and continuous nausea/vomiting. Subjects scored each health state with a rating scale and a standard gamble, using perfect health and continuous nausea/vomiting as positive and negative anchors. In addition, continuous nausea/vomiting was compared with a standard gamble between perfect health and immediate death. The study included 96 evaluable subjects. With perfect health and continuous nausea/vomiting anchors, rating scale scores for intermediate health states ranged from 43-84 whereas standard gamble scores clustered at approximately 55. However, using a standard gamble between perfect health and death, continuous nausea/vomiting had a utility score of 53. The decrement in utility for severe nausea/vomiting can be well characterized, but utility scores for less extreme health states of nausea/vomiting are not as distinct. Although the rating scale suggests some differentiation, the standard gamble reveals clustering of intermediate health state scores. Evaluation of the effect of varying duration and intensity of nausea/vomiting on standard gamble utility scores will provide greater insight into the impact of such temporary health states on quality of life. © 2009 Elsevier Inc. All rights reserved.

Authors
Grunberg, SM; Weeks, J; Magnan, WF; Herndon, J; Naughton, ML; Blackwell, KL; Wood, ME; Christian, DL; Perry, MC; Dees, EC; Reed, E; Marshall, ME
MLA Citation
Grunberg, SM, Weeks, J, Magnan, WF, Herndon, J, Naughton, ML, Blackwell, KL, Wood, ME, Christian, DL, Perry, MC, Dees, EC, Reed, E, and Marshall, ME. "Determination of utility scores for control of chemotherapy-induced nausea or vomiting - CALGB 309801." Journal of Supportive Oncology 7.5 (2009): W17-W22.
Source
scival
Published In
The Journal of Supportive Oncology
Volume
7
Issue
5
Publish Date
2009
Start Page
W17
End Page
W22

Circulating tumor cells in HER-2 positive metastatic breast cancer patients treated with trastuzumab and chemotherapy

The detection of circulating tumor cells (CTCs) in peripheral blood may have important prognostic and predictive implications in breast cancer treatment. A limitation in this field has been the lack of a validated method of accurately measuring CTCs. While sensitivity has improved using RT-PCR, specificity remains a major challenge. The goal of this paper is to present a sensitive and specific methodology of detecting CTCs in women with HER-2-positive metastatic breast cancer, and to examine its role as a marker that tracks disease response during treatment with trastuzumab-containing regimens. The study included patients with HER-2-positive metastatic breast cancer enrolled on two different clinical protocols using a trastuzumab-containing regimen. Serial CTCs were measured at planned time points and clinical correlations were made. Immunomagnetic selection of circulating epithelial cells was used to address the specificity of tumor cell detection using cytokeratin 19 (CK19). In addition, the extracellular domain of the HER-2 protein (HER-2/ECD) was measured to determine if CTCs detected by CK19 accurately reflect tumor burden. The presence of CTCs at first restaging was associated with disease progression. We observed an association between CK19 and HER-2/ECD. The association of HER-2/ECD with clinical response followed a similar pattern to that seen with CK19. Finally, the absence of HER-2/ECD at best overall response and a change of HER-2/ECD from positive at baseline to negative at best overall response was associated with favorable treatment response. Our study supports the prognostic and predictive role of the detection of CTCs in treatment of HER-2-positive metastatic breast cancer patients. The association between CK19 and markers of disease burden is in line with the concept that CTCs may be a reliable measure of tumor cells in the peripheral blood of patients with metastatic breast cancer. The association of CTCs at first restaging with treatment failure indicates that CTCs may have a role as surrogate markers to monitor treatment response. © 2009 Wichtig Editore.

Authors
Nunes, RA; Li, X; Kang, SP; Burstein, H; Roberts, L; Carney, W; Blackwell, K; Ryan, P; Borges, V; Iglehart, JD; Friedman, P; Harris, LN
MLA Citation
Nunes, RA, Li, X, Kang, SP, Burstein, H, Roberts, L, Carney, W, Blackwell, K, Ryan, P, Borges, V, Iglehart, JD, Friedman, P, and Harris, LN. "Circulating tumor cells in HER-2 positive metastatic breast cancer patients treated with trastuzumab and chemotherapy." International Journal of Biological Markers 24.1 (2009): 1-10.
PMID
19404916
Source
scival
Published In
The International journal of biological markers
Volume
24
Issue
1
Publish Date
2009
Start Page
1
End Page
10

Are all aromatase inhibitors alike?

The anti-estrogen tamoxifen was the gold-standard adjuvant therapy for hormone-receptor-positive (HR+) early breast cancer for several decades, but has recently been displaced by the third-generation aromatase inhibitors (AIs). Three AIs are commercially available: letrozole, anastrozole and exemestane. All are more effective and at least as well tolerated as tamoxifen as adjuvant therapy for HR+ breast cancer in postmenopausal women. Despite the wealth of data comparing AIs with tamoxifen, it is unclear whether the three AIs are clinically equivalent, owing to the lack of head-to-head trials directly comparing them. Preclinical and small clinical studies suggest that letrozole is the most potent inhibitor of aromatase, reducing circulating estrogen levels to a greater degree than the other agents. However, whether this greater activity translates into superior clinical efficacy remains to be determined. In the absence of direct comparative data, cross-trial comparisons have been used to gain insights into any safety or efficacy differences. All three AIs have been compared directly with tamoxifen, and efficacy relative to tamoxifen has been compared across trials, although such analyses are complicated by differences in treatment schedules, patient populations and trial designs. Definitive conclusions cannot yet be drawn, but some important differences are coming to light, with upfront letrozole appearing particularly effective at preventing early distant metastasis, an event strongly associated with breast-cancer-related death. No safety differences between the AIs have yet been identified. This article explores the pharmacologic and clinical differences between the AIs, based on data from clinical and preclinical studies.

Authors
Blackwell, KL
MLA Citation
Blackwell, KL. "Are all aromatase inhibitors alike?." Breast Cancer Res Treat 112 Suppl 1 (December 2008): 35-43.
PMID
19101793
Source
pubmed
Published In
Breast Cancer Research and Treatment
Volume
112 Suppl 1
Publish Date
2008
Start Page
35
End Page
43
DOI
10.1007/s10549-008-0233-9

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

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

Aromatase inhibitors for breast cancer: proven efficacy across the spectrum of disease.

For more than 100 years, hormonal therapy has been known to be effective in the treatment of breast cancer. Initially, this therapy was dominated by the selective estrogen receptor antagonists such as tamoxifen. Aromatase inhibitors (AIs) are a distinct drug class with demonstrated activity in the treatment of hormone-sensitive breast cancer. All 3 third-generation AIs, exemestane, anastrozole, and letrozole, have been studied in multiple lines of therapy in advanced breast cancer and have demonstrated equivalence or superiority compared with tamoxifen. While initially developed as a treatment option for advanced disease, the AIs have also shown efficacy in the treatment of curable disease, including the neoadjuvant and adjuvant settings. In addition, the AIs demonstrate a tolerable side effect profile in comparison with tamoxifen, and this has led to their early incorporation as standard of care therapy. Given the proven efficacy of AIs across the spectrum of breast cancer, the remaining questions include definitive sequencing strategy, timing, and duration of use. Ongoing trials include head-to-head comparisons between the AIs in early-stage breast cancer; the results of these trials are eagerly anticipated and should further optimize the use of AIs.

Authors
Herold, CI; Blackwell, KL
MLA Citation
Herold, CI, and Blackwell, KL. "Aromatase inhibitors for breast cancer: proven efficacy across the spectrum of disease." Clin Breast Cancer 8.1 (February 2008): 50-64. (Review)
PMID
18501059
Source
pubmed
Published In
Clinical Breast Cancer
Volume
8
Issue
1
Publish Date
2008
Start Page
50
End Page
64
DOI
10.3816/CBC.2008.n.003

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

The significance of distant metastases in breast cancer.

Authors
Blackwell, KL
MLA Citation
Blackwell, KL. "The significance of distant metastases in breast cancer." Breast (Edinburgh, Scotland) 17 Suppl 1 (January 1, 2008).
Source
scopus
Published In
The Breast
Volume
17 Suppl 1
Publish Date
2008

The impact of adjuvant endocrine therapy on reducing the risk of distant metastases in hormone-responsive breast cancer.

SUMMARY: The primary goal of systemic adjuvant therapy for breast cancer is to control the risk of recurrence following surgery, thereby improving long-term survival. For many years, tamoxifen has served as the standard adjuvant endocrine therapy for postmenopausal women with hormone-sensitive breast cancer. The entry of the third-generation aromatase inhibitors (AIs) exemestane, anastrozole and letrozole as adjuvant therapy has introduced several different treatment options. Indirect comparisons suggest that appreciable differences may exist between the AIs in terms of early risk reduction, especially the risk for early distant metastases. Possible differences in efficacy may be related to differences in potency. Two ongoing trials directly comparing two AIs - the Femara versus Anastrozole Clinical Evaluation and MA.27 - may provide further information.

Authors
Herold, CI; Blackwell, KL
MLA Citation
Herold, CI, and Blackwell, KL. "The impact of adjuvant endocrine therapy on reducing the risk of distant metastases in hormone-responsive breast cancer." Breast 17 Suppl 1 (January 2008): S15-S24. (Review)
PMID
18279763
Source
pubmed
Published In
The Breast
Volume
17 Suppl 1
Publish Date
2008
Start Page
S15
End Page
S24
DOI
10.1016/S0960-9776(08)70004-3

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

A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer

Background: The efficacy and tolerability of the epidermal growth factor receptor/human epidermal growth factor receptor type 2 (HER2) tyrosine kinase inhibitor lapatinib in refractory metastatic breast cancer were assessed. Patients and methods: In a phase II, open-label study, patients with previously treated HER2-positive (n = 140) or HER2-negative (n = 89) metastatic breast cancer received once-daily oral lapatinib 1500 mg/day. Results: Most (76%) patients had received four or more lines of prior therapy. The response rate in the HER2-positive cohort was 4.3% by investigator assessment and 1.4% by independent assessment. Both assessments established that ∼6% of HER2-positive patients derived clinical benefit from lapatinib, being progression free for ≥6 months. No objective tumor responses occurred in the HER2-negative cohort. Independent review assessments of median time to progression and median progression-free survival were similar in the HER2-positive and HER2-negative cohorts (9.1 and 7.6 weeks, respectively). All responders exhibited HER2 overexpression (3+ by immunohistochemistry), and five of six responders were HER2 amplified by FISH. Lapatinib-related adverse events, including diarrhea (54%), rash (30%), and nausea (24%), were primarily mild to moderate in severity. Conclusions: Lapatinib monotherapy had modest clinical activity in HER2-positive metastatic breast cancer that progressed on prior trastuzumab regimens. No apparent clinical activity was observed in chemotherapy-refractory, HER2-negative disease. © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Authors
Burstein, HJ; Storniolo, AM; Franco, S; Forster, J; Stein, S; Rubin, S; Salazar, VM; Blackwell, KL
MLA Citation
Burstein, HJ, Storniolo, AM, Franco, S, Forster, J, Stein, S, Rubin, S, Salazar, VM, and Blackwell, KL. "A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer." Annals of Oncology 19.6 (2008): 1068-1074.
PMID
18283035
Source
scival
Published In
Annals of Oncology
Volume
19
Issue
6
Publish Date
2008
Start Page
1068
End Page
1074
DOI
10.1093/annonc/mdm601

Serum biomarker profiles and response to neoadjuvant chemotherapy for locally advanced breast cancer

Introduction: Neoadjuvant chemotherapy has become the standard of care for the diverse population of women diagnosed with locally advanced breast cancer. Serum biomarker levels are increasingly being investigated for their ability to predict therapy response and aid in the development of individualized treatment regimens. Multianalyte profiles may offer greater predictive power for neoadjuvant treatment response than the individual biomarkers currently in use.Methods: Serum samples were collected from 44 patients enrolled in a phase I-II, open-label study of liposomal doxorubicin and paclitaxel in combination with whole breast hyperthermia for the neoadjuvant treatment of locally advanced breast cancer (stage IIB or stage III). Samples were collected prior to each of four rounds of treatment and prior to definitive surgery. Samples were assayed by Luminex assay for 55 serum biomarkers, including cancer antigens, growth/angiogenic factors, apoptosis-related molecules, metastasis-related molecules, adhesion molecules, adipokines, cytokines, chemokines, hormones, and other proteins.Results: Biomarker levels were compared retrospectively with clinical and pathologic treatment responses. Univariate analysis of the data identified several groups of biomarkers that differed significantly among treatment outcome groups early in the course of neoadjuvant chemotherapy. Multivariate statistical analysis revealed multibiomarker panels that could differentiate between treatment response groups with high sensitivity and specificity.Conclusion: We demonstrate here that serum biomarker profiles may offer predictive power concerning treatment response and outcome in the neoadjuvant setting. The continued development of these findings will be of considerable clinical utility in the design of treatment regimens for individual breast cancer patients. © 2008 Nolen et al.; licensee BioMed Central Ltd.

Authors
Nolen, BM; Marks, JR; Ta'san, S; Rand, A; Luong, TM; Wang, Y; Blackwell, K; Lokshin, AE
MLA Citation
Nolen, BM, Marks, JR, Ta'san, S, Rand, A, Luong, TM, Wang, Y, Blackwell, K, and Lokshin, AE. "Serum biomarker profiles and response to neoadjuvant chemotherapy for locally advanced breast cancer." Breast Cancer Research 10.3 (2008).
PMID
18474099
Source
scival
Published In
Breast Cancer Research
Volume
10
Issue
3
Publish Date
2008
DOI
10.1186/bcr2096

Clinical efficacy of taxane-trastuzumab combination regimens for HER-2-positive metastatic breast cancer

The taxanes docetaxel (Taxotere®; Sanofi-Aventis U.S. LLC, Bridgewater, NJ) and paclitaxel (Taxol®; Bristol-Myers Squibb, Princeton, NJ) are highly active agents in metastatic breast cancer and may represent a safer alternative to anthracycline-based regimens when combined with the human epidermal growth factor receptor (HER)-2-targeted agent trastuzumab (Herceptin®; Genentech Inc., South San Francisco, CA). A number of preclinical and early clinical studies have evaluated the feasibility, duration, and appropriate dosing schedule(s) for taxane-trastuzumab combinations in HER-2-positive metastatic breast cancer. Preclinical studies of the taxanes in combination with trastuzumab demonstrate synergistic interactions of trastuzumab with docetaxel and additive interactions with paclitaxel. Even though not supported by head-to-head studies, clinical trial results indicate the response rates with docetaxel-trastuzumab combinations may be higher than those with paclitaxel-trastuzumab, although there is a lack of clear crosstrial differences in other clinical benefits. Weekly taxane-trastuzumab regimens have been shown to offer superior disease control. Results from two large, phase III trials that examined the addition of carboplatin to a taxane-trastuzumab doublet did not demonstrate a difference in survival with carboplatin. In one study, the addition of carboplatin to paclitaxel-trastuzumab therapy resulted in a higher response rate and longer progression-free survival time; in the second study, the docetaxel-trastuzumab and docetaxel-trastuzumab-carboplatin combinations were equally effective. Ongoing correlative studies of taxanes, as well as newer formulations such as nanoparticle albumin-bound paclitaxel, in combination with trastuzumab will inform clinical practice regarding the optimal agent, schedule, and use of these highly effective regimens. ©AlphaMed Press.

Authors
Bullock, K; Blackwell, K
MLA Citation
Bullock, K, and Blackwell, K. "Clinical efficacy of taxane-trastuzumab combination regimens for HER-2-positive metastatic breast cancer." Oncologist 13.5 (2008): 515-525.
PMID
18515736
Source
scival
Published In
The oncologist
Volume
13
Issue
5
Publish Date
2008
Start Page
515
End Page
525
DOI
10.1634/theoncologist.2007-0204

Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy

Purpose: Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor (EGFR) and human EGFR 2 (HER-2), demonstrated clinical activity in four of five IBC patients in phase I trials. We conducted a phase II trial to confirm the sensitivity of IBC to lapatinib, to determine whether response is HER-2 or EGFR dependent, and to elucidate a molecular signature predictive of lapatinib sensitivity. Patients and Methods: Our open-label multicenter phase II trial (EGF103009) assessed clinical activity and safety of lapatinib monotherapy in patients with recurrent or anthracycline-refractory IBC. Patients were assigned to cohorts A (HER-2-overexpressing [HER-2+]) or B(HER-2-/EGFR+) and fresh pretreatment tumor biopsies were collected. Results: Forty-five patients (30 in cohort A; 15 in cohort B) received lapatinib 1,500 mg once daily continuously. Clinical presentation and biomarker analyses demonstrated a tumor molecular signature consistent with IBC. Lapatinib was generally well tolerated, with primarily grade 1/2 skin and GI toxicities. Fifteen patients (50%) in cohort A had clinical responses to lapatinib in skin and/or measurable disease (according to Response Evaluation Criteria in Solid Tumors) compared with one patient in cohort B. Within cohort A, phosphorylated (p) HER-3 and lack of p53 expression predicted for response to lapatinib (P < .05). Tumors coexpressing pHER-2 and pHER-3 were more likely to respond to lapatinib (nine of 10 v four of 14; P = .0045). Prior trastuzumab therapy and loss of phosphate and tensin homolog 10 (PTEN) did not preclude response to lapatinib. Conclusion: Lapatinib is well tolerated with clinical activity in heavily pretreated HER-2+, but not EGFR+/HER-2-, IBC. In this study, coexpression of pHER-2 and pHER-3 in tumors seems to predict for a favorable response to lapatinib. These findings warrant further investigation of lapatinib monotherapy or combination therapy in HER-2+ IBC. © 2008 by American Society of Clinical Oncology.

Authors
Johnston, S; Trudeau, M; Kaufman, B; Boussen, H; Blackwell, K; LoRusso, P; Lombardi, DP; Ahmed, SB; Citrin, DL; DeSilvio, ML; Harris, J; Westlund, RE; Salazar, V; Zaks, TZ; Spector, NL
MLA Citation
Johnston, S, Trudeau, M, Kaufman, B, Boussen, H, Blackwell, K, LoRusso, P, Lombardi, DP, Ahmed, SB, Citrin, DL, DeSilvio, ML, Harris, J, Westlund, RE, Salazar, V, Zaks, TZ, and Spector, NL. "Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy." Journal of Clinical Oncology 26.7 (2008): 1066-1072.
PMID
18212337
Source
scival
Published In
Journal of Clinical Oncology
Volume
26
Issue
7
Publish Date
2008
Start Page
1066
End Page
1072
DOI
10.1200/JCO.2007.13.9949

The significance of distant metastases in breast cancer.

Authors
Blackwell, KL
MLA Citation
Blackwell, KL. "The significance of distant metastases in breast cancer." Breast (Edinburgh, Scotland) 17 Suppl 1 (2008): S1-S2.
PMID
18279762
Source
scival
Published In
The Breast
Volume
17 Suppl 1
Publish Date
2008
Start Page
S1
End Page
S2
DOI
10.1016/S0960-9776(08)70001-8

Editorial

Authors
Blackwell, KL
MLA Citation
Blackwell, KL. "Editorial." Breast 17.SUPPL.1 (2008): S1-S2.
Source
scival
Published In
The Breast
Volume
17
Issue
SUPPL.1
Publish Date
2008
Start Page
S1
End Page
S2
DOI
10.1016/S0960-9776(08)70001-8

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

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

Erythropoietin inhibits apoptosis in breast cancer cells via an Akt-dependent pathway without modulating in vivo chemosensitivity.

Evidence for erythropoietin signaling has been shown in several nonhematopoietic tissues, including many tumor types. Clinically, recombinant erythropoietin treatment of malignancy-related anemia has yet to be definitively associated with any modulation of chemotherapy or radiotherapy efficacy. Preclinically, recombinant erythropoietin has been shown to increase tumor oxygenation, but the direct effects of recombinant erythropoietin on tumor cells that express erythropoietin receptor are not yet fully characterized. This study examined the effects of exogenous recombinant erythropoietin on rodent mammary adenocarcinoma cells (R3230) in vitro and in vivo, and determined the effects of systemic recombinant erythropoietin on tumor growth delay in Taxol treatment. We showed that systemic recombinant erythropoietin treatment of rats bearing R3230 mammary carcinomas induced an increase in phospho-Akt levels within tumor cells. This was associated with a decrease in the frequency of apoptotic cells in tumors from recombinant erythropoietin-treated animals, but did not noticeably affect tumor growth rate. In vitro studies revealed that not only does recombinant erythropoietin induce Akt phosphorylation, but it also stimulates phosphorylation of p44/42 mitogen-activated protein kinases, Erk1 and Erk2. Activation of erythropoietin-mediated signaling in R3230 cells was associated with dose-dependent inhibition of apoptosis in response to Taxol treatment and serum starvation, an effect that was blocked by the addition of a phosphatidylinositol-3-kinase inhibitor. Despite its cytoprotective effects in vitro, recombinant erythropoietin did not significantly affect tumor growth delay in Taxol treatment. This study shows direct recombinant erythropoietin-mediated activation of specific intracellular signaling pathways in mammary adenocarcinoma cells in vivo and in vitro. Modulation of tumor apoptosis pathways by recombinant erythropoietin may have negative consequences by decreasing the chemosensitivity and radiosensitivity of erythropoietin receptor-positive breast tumors, although it did not have any obvious effects on growth with or without chemotherapy in this model.

Authors
Hardee, ME; Rabbani, ZN; Arcasoy, MO; Kirkpatrick, JP; Vujaskovic, Z; Dewhirst, MW; Blackwell, KL
MLA Citation
Hardee, ME, Rabbani, ZN, Arcasoy, MO, Kirkpatrick, JP, Vujaskovic, Z, Dewhirst, MW, and Blackwell, KL. "Erythropoietin inhibits apoptosis in breast cancer cells via an Akt-dependent pathway without modulating in vivo chemosensitivity." Mol Cancer Ther 5.2 (February 2006): 356-361.
PMID
16505109
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
5
Issue
2
Publish Date
2006
Start Page
356
End Page
361
DOI
10.1158/1535-7163.MCT-05-0196

The effect of darbepoetin alfa on growth, oxygenation and radioresponsiveness of a breast adenocarcinoma.

Tumor hypoxia is associated with poor clinical outcome in a variety of tumors, including cervical, head/neck and breast cancer. Administration of erythropoietic factors has been suggested as a means of improving tumor oxygenation (pO2). This study randomized rats to treatment with low-dose or high-dose darbepoetin alfa or a placebo to determine the effect of darbepoetin alfa on the pO2, growth and response to radiation therapy of R3230 mammary adenocarcinoma. Rats received 3 microg/kg (high dose) or 0.2 microg/kg (low dose) darbepoetin alfa or placebo for eight doses prior to either (1) pO2 measurement and pimonidazole staining or (2) irradiation or sham irradiation on post-transplant day 20. In the animals randomized to radiation treatment, placebo or darbepoetin alfa administration at a reduced dose was continued for 9 weeks or until the tumor diameter exceeded 15 mm (defined as failure for survival analysis). Treatment with high-dose and low-dose darbepoetin alfa produced hematocrits of 68 and 56% compared to 44 and 45% in their respective control groups (both P < 10(-5)). At 18 days post-transplant, tumor volume was not different for either darbepoetin alfa group compared to the placebo group. Tumor oxygenation, as measured by the fraction of pO2 measurement <10 mmHg and the intensity of pimonidazole staining, was significantly improved in the high-dose group (P = 0.046 and 0.03, respectively, compared with controls) but not in the low-dose group. Growth delay curves after irradiation did not differ significantly for high- or low-dose darbepoetin alfa compared to placebo. In this nonanemic animal model of mammary adenocarcinoma, darbepoetin alfa does not significantly alter tumor growth or radioresponsiveness, even though it improves oxygenation when administered at high doses.

Authors
Kirkpatrick, JP; Hardee, ME; Snyder, SA; Peltz, CM; Zhao, Y; Brizel, DM; Dewhirst, MW; Blackwell, KL
MLA Citation
Kirkpatrick, JP, Hardee, ME, Snyder, SA, Peltz, CM, Zhao, Y, Brizel, DM, Dewhirst, MW, and Blackwell, KL. "The effect of darbepoetin alfa on growth, oxygenation and radioresponsiveness of a breast adenocarcinoma." Radiat Res 165.2 (February 2006): 192-201.
PMID
16518899
Source
pubmed
Published In
Radiation Research
Volume
165
Issue
2
Publish Date
2006
Start Page
192
End Page
201

Erythropoietin biology in cancer.

Erythropoietin (Epo) has long been known to be the principal hematopoietic growth factor that regulates cellular proliferation and differentiation along the erythroid lineage. Recent studies have shown that Epo is a pleiotropic cytokine that is proangiogenic and exerts broad tissue-protective effects in diverse nonhematopoietic organs. Recombinant Epo (rEpo) has been widely used in the clinic to prevent or treat malignancy-associated anemia. A series of clinical trials have documented the efficacy of rEpo in reducing RBC transfusion requirements and improving quality of life in cancer patients, and a recent meta-analysis suggested a positive effect on survival. However, two randomized trials reported negative outcomes with rEpo, as patients in the rEpo arm fared worse than their placebo-treated counterparts with respect to progression-free survival. The expression of Epo receptor (EpoR) in cancer cells has raised the possibility that exogenous rEpo may exert direct effects on tumor cells associated with the potential for stimulation of proliferation, inhibition of apoptosis, or modulation of sensitivity to chemoradiation therapy. The presence of an autocrine-paracrine Epo-EpoR system in tumors and potential effects of Epo on tumor microenvironment and angiogenesis are consistent with a complex biology for Epo-EpoR signaling in cancer that requires further research. This review describes Epo and EpoR biology, focusing on the pleiotropic effects of Epo on nonhematopoietic tissues as well as the expression and function of EpoR in cancer cells.

Authors
Hardee, ME; Arcasoy, MO; Blackwell, KL; Kirkpatrick, JP; Dewhirst, MW
MLA Citation
Hardee, ME, Arcasoy, MO, Blackwell, KL, Kirkpatrick, JP, and Dewhirst, MW. "Erythropoietin biology in cancer." Clin Cancer Res 12.2 (January 15, 2006): 332-339. (Review)
PMID
16428469
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
2
Publish Date
2006
Start Page
332
End Page
339
DOI
10.1158/1078-0432.CCR-05-1771

Human recombinant erythropoietin (rEpo) has no effect on tumour growth or angiogenesis.

Tumour hypoxia has been shown to increase mutation rate, angiogenesis, and metastatic potential, and decrease response to conventional therapeutics. Improved tumour oxygenation should translate into increased treatment response. Exogenous recombinant erythropoietin (rEpo) has been recently shown to increase tumour oxygenation in a mammary carcinoma model. The mechanism of this action is not yet understood completely. The presence of Epo and its receptor (EpoR) have been demonstrated on several normal and neoplastic tissues, including blood vessels and various solid tumours. In addition, rEpo has been shown in two recent prospective, randomized clinical trials to negatively impact treatment outcome. In this study, we attempt to characterize the direct effects of rEpo on tumour growth and angiogenesis in two separate rodent carcinomas. The effect of rEpo on R3230 rat mammary adenocarcinomas, CT-26 mouse colon carcinomas, HCT-116 human colon carcinomas, and FaDu human head and neck tumours, all of which express EpoR, was examined. There were no differences in tumour growth or proliferation (measured by Ki-67) between placebo-treated and rEpo-treated tumours. In the mammary window chamber, vascular length density (VLD) measurements in serial images of both placebo-treated and Epo-treated rats revealed no difference in angiogenesis between the Epo-treated tumours and placebo-treated tumours at any time point. These experiments are important because they suggest that the recent clinical detriment seen with the use of Epo is not due to its tumour growth effects or angiogenesis. These studies also suggest that further preclinical studies need to examine rEpo's direct tumour effects in efforts to improve the therapeutic benefits of Epo in solid tumour patients.

Authors
Hardee, ME; Kirkpatrick, JP; Shan, S; Snyder, SA; Vujaskovic, Z; Rabbani, ZN; Dewhirst, MW; Blackwell, KL
MLA Citation
Hardee, ME, Kirkpatrick, JP, Shan, S, Snyder, SA, Vujaskovic, Z, Rabbani, ZN, Dewhirst, MW, and Blackwell, KL. "Human recombinant erythropoietin (rEpo) has no effect on tumour growth or angiogenesis." Br J Cancer 93.12 (December 12, 2005): 1350-1355.
PMID
16288305
Source
pubmed
Published In
British Journal of Cancer
Volume
93
Issue
12
Publish Date
2005
Start Page
1350
End Page
1355
DOI
10.1038/sj.bjc.6602846

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

Characterizing tumor changes during neoadjuvant treatment of locally advanced breast cancer patients (LABC) using dynamicenhanced magnetic resonance imaging (DE-MRI)

At Duke University Medical Center, selective LABC patients were treated on a protocol using neoadjuvant Myocet/Paclitaxel (ChT) and HT. With the purpose of generating perfusion/permeability parametric maps and to use gadolinium (Gd) enhancement curves to score and predict response to neoadjuvant treatment, a study was designed to acquire 3 sets of DE-MRI images along the 4 cycles of combined ChT and HT. A T1-weighted three-dimensional fast gradient echo technique was used over 30 minutes following bolus injection of Gd-based contrast agent. Perfusion/permeability maps were generated by fitting the signal intensity to a double exponential curve that generates washin (WiP) and washout (WoP), parameters that are associated with the tumors vascularity/permeability and cellularity. Based on the values of the WiP, the tumors were divided in lowWI (WiP < 100), mediumWI (100<WiP<200) and highWI (WiP > 200). During the HT treatments temperatures in the breast were measured invasively via a catheter inserted under CT guidance. Although minimum sampled temperatures give a crude indication of the temperature distribution, several thermal dose metrics were calculated for each of the HT fractions (e.g. T90, T50, T10). As expected, tumors that were more vascularized (i.e. higher WiP) heated less than tumors with low WiP, a degree on average. The adjuvant treatment also changed the shape and inhomogeneity of the perfusion/permeability maps, with dramatic changes after the first fraction in responders. The correlation between the thermal metrics and pathological response will be discussed, as well as possible correlation with other tumor physiology parameters. In conclusion, the Gd-enhancement analysis of DE-MRI images is able to generate information related to the tumor vascularity, permeability and cellularity that can correlate with the tumor's response to the neoadjuvant treatment in general, and to HT in particular. Work supported by a grant from the NCI CA42745.

Authors
Craciunescu, OI; Jones, EL; Blackwell, KL; Wong, TZ; Rosen, EL; Vujaskovic, Z; MacFall, JR; Liotcheva, V; Lora-Michels, M; Prosnitz, LR; Samulski, TV; Dewhirst, MW
MLA Citation
Craciunescu, OI, Jones, EL, Blackwell, KL, Wong, TZ, Rosen, EL, Vujaskovic, Z, MacFall, JR, Liotcheva, V, Lora-Michels, M, Prosnitz, LR, Samulski, TV, and Dewhirst, MW. "Characterizing tumor changes during neoadjuvant treatment of locally advanced breast cancer patients (LABC) using dynamicenhanced magnetic resonance imaging (DE-MRI)." Progress in Biomedical Optics and Imaging - Proceedings of SPIE 5698 (2005): 116-125.
Source
scival
Published In
Proceedings of SPIE
Volume
5698
Publish Date
2005
Start Page
116
End Page
125
DOI
10.1117/12.591173

Ectopic breast cancer: Rare, treatable, and potentially curable

Authors
Daniel, BR; Blackwell, K
MLA Citation
Daniel, BR, and Blackwell, K. "Ectopic breast cancer: Rare, treatable, and potentially curable." Community Oncology 2.2 (2005): 120-122.
Source
scival
Published In
Community Oncology
Volume
2
Issue
2
Publish Date
2005
Start Page
120
End Page
122

The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer

Effective treatment of estrogen receptor (ER)-positive breast cancers with tamoxifen is often curtailed by the development of drug resistance. Antiestrogen-resistant breast cancers often show increased expression of the epidermal growth factor receptor family members, ErbB1 and ErbB2. Tamoxifen activates the cyclin-dependent kinase inhibitor, p27 to mediate G1 arrest. ErbB2 or ErbB1 overexpression can abrogate tamoxifen sensitivity in breast cancer lines through both reduction in p27 levels and inhibition of its function. Here we show that the dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), can restore tamoxifen sensitivity in ER-positive, tamoxifen-resistant breast cancer models. Treatment of MCF-7pr, T-47D, and ZR-75 cells with lapatinib or tamoxifen alone caused an incomplete cell cycle arrest. Treatment with both drugs led to a more rapid and profound cell cycle arrest in all three lines. Mitogen-activated protein kinase and protein kinase B were inhibited by lapatinib. The two drugs together caused a greater reduction of cyclin D1 and a greater p27 increase and cyclin E-cdk2 inhibition than observed with either drug alone. In addition to inhibiting mitogenic signaling and cell cycle progression, lapatinib inhibited estrogen-stimulated ER transcriptional activity and cooperated with tamoxifen to further reduce ER-dependent transcription. Lapatinib in combination with tamoxifen effectively inhibited the growth of tamoxifen-resistant ErbB2 overexpressing MCF-7 mammary tumor xenografts. These data provide strong preclinical data to support clinical trials of ErbB1/ErbB2 inhibitors in combination with tamoxifen in the treatment of human breast cancer.

Authors
Chu, I; Blackwell, K; Chen, S; Slingerland, J
MLA Citation
Chu, I, Blackwell, K, Chen, S, and Slingerland, J. "The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer." Cancer Research 65.1 (2005): 18-25.
PMID
15665275
Source
scival
Published In
Cancer Research
Volume
65
Issue
1
Publish Date
2005
Start Page
18
End Page
25

The relationship between serum vascular endothelial growth factor, persistent disease, and survival at second-look laparotomy in ovarian cancer.

OBJECTIVE: To assess if the angiogenic factors vascular endothelial growth factor (VEGF) and D-dimer are predictive of persistent disease, early relapse, and survival in patients with ovarian cancer who achieve a complete clinical remission after first-line chemotherapy. METHODS: Serum levels of VEGF and D-dimer were assessed by ELISA in 62 patients who completed first-line chemotherapy and underwent second-look laparotomy at Duke University Medical Center. Cox Proportional Hazards Modeling was utilized to determine if VEGF and/or D-dimer levels could predict disease-free and overall survival. The Kaplan-Meier method was used to estimate median survival. The Wilcoxon test was used to determine if a significant difference existed in median VEGF and D-dimer levels between patients with positive and negative second-look operations. RESULTS: Forty (65%) of the 62 women who underwent second-look laparotomy had persistent disease. The median VEGF levels were 264 pg/ml (range 109-896 pg/ml) in the group with negative second looks compared to 390 pg/ml (range 99-1011 pg/ml) in those with positive second-looks (P = 0.1). High levels of VEGF were marginally associated with the presence of persistent (P = 0.10) and gross (P = 0.07) disease at the time of second look laparotomy. After adjusting for CA125, women with high VEGF serum levels had a worse overall survival (P = 0.004). CONCLUSIONS: This study suggests that serum VEGF may be a clinically important marker for persistent disease and is predictive of survival in ovarian cancer patients after first-line chemotherapy.

Authors
Alvarez Secord, A; Sayer, R; Snyder, SA; Broadwater, G; Rodriguez, GC; Berchuck, A; Blackwell, K
MLA Citation
Alvarez Secord, A, Sayer, R, Snyder, SA, Broadwater, G, Rodriguez, GC, Berchuck, A, and Blackwell, K. "The relationship between serum vascular endothelial growth factor, persistent disease, and survival at second-look laparotomy in ovarian cancer." Gynecol Oncol 94.1 (July 2004): 74-79.
PMID
15262122
Source
pubmed
Published In
Gynecologic Oncology
Volume
94
Issue
1
Publish Date
2004
Start Page
74
End Page
79
DOI
10.1016/j.ygyno.2004.03.043

HER-2 gene amplification correlates with higher levels of angiogenesis and lower levels of hypoxia in primary breast tumors.

PURPOSE: This study investigated the connection among HER-2 gene amplification, HER-2 protein expression, and markers of tumor angiogenesis and oxygenation in patients with operable, invasive breast tumors. EXPERIMENTAL DESIGN: From 1988 to 1995, 425 patients with metastatic breast cancer were enrolled in a study of high-dose chemotherapy with autologous transplant. Primary tumor blocks were obtained and evaluated using immunohistochemistry (IHC) staining of vessels with von Willebrand factor antibody. Mean microvessel densities (MVD) were determined by counting von Willebrand factor stained cells in three separate "vascular hot spots" using image analysis. Tumor samples were also stained for HER-2 by IHC, HER-2 gene amplification by fluorescence in situ hybridization, carbonic anhydrase 9 by IHC, and vascular endothelial growth factor (VEGF) by IHC. Plasma from 36 patients with primary tumor samples had VEGF (R&D Systems, MN) and d-dimer (American Diagnostica, Greenwich, CT) levels determined. RESULTS: There was a significant positive correlation between HER-2 gene amplification and both maximum and average MVD (Spearman coefficient = 0.51 and 0.50; P = 0.03 and 0.05, respectively). There was an inverse correlation with HER-2 gene amplification and expression of the tumor hypoxia marker CA-9 (chi(2) P = 0.02). The level of HER-2 gene amplification correlated with plasma d-dimer levels (Spearman coefficient = 0.43; P = 0.021). Interestingly, tumors with HER-2 by IHC had decreased amounts of VEGF staining (chi(2) = 5.81; P = 0.01). There was no correlation between HER-2 by IHC and MVD or d-dimer. Of all of the variables examined, only average (P = 0.0016) and maximum MVD (P = 0.0128) predicted disease-free survival (Cox univariate model). CONCLUSIONS: HER-2-amplified breast cancers have increased amounts of angiogenesis, decreased amounts of hypoxia, and increased markers of fibrin degradation. These findings have prognostic, predictive, and therapeutic implications in breast cancer treatment.

Authors
Blackwell, KL; Dewhirst, MW; Liotcheva, V; Snyder, S; Broadwater, G; Bentley, R; Lal, A; Riggins, G; Anderson, S; Vredenburgh, J; Proia, A; Harris, LN
MLA Citation
Blackwell, KL, Dewhirst, MW, Liotcheva, V, Snyder, S, Broadwater, G, Bentley, R, Lal, A, Riggins, G, Anderson, S, Vredenburgh, J, Proia, A, and Harris, LN. "HER-2 gene amplification correlates with higher levels of angiogenesis and lower levels of hypoxia in primary breast tumors." Clin Cancer Res 10.12 Pt 1 (June 15, 2004): 4083-4088.
PMID
15217943
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
10
Issue
12 Pt 1
Publish Date
2004
Start Page
4083
End Page
4088
DOI
10.1158/1078-0432.CCR-03-0695

Accuracy of MRI in the detection of residual breast cancer after neoadjuvant chemotherapy

Authors
Rosen, EL; Blackwell, KL; Baker, JA; Orel, SG
MLA Citation
Rosen, EL, Blackwell, KL, Baker, JA, and Orel, SG. "Accuracy of MRI in the detection of residual breast cancer after neoadjuvant chemotherapy." Breast Diseases 15.2 (2004): 140-142.
Source
scival
Published In
Breast Diseases: A Year Book Quarterly
Volume
15
Issue
2
Publish Date
2004
Start Page
140
End Page
142

Hypoxia and anemia: Factors in decreased sensitivity to radiation therapy and chemotherapy?

Hypoxia is a common feature of solid tumors that occurs across a wide variety of malignancies. Hypoxia and anemia (which contributes to tumor hypoxia) can lead to ionizing radiation and chemotherapy resistance by depriving tumor cells of the oxygen essential for the cytotoxic activities of these agents. Hypoxia may also reduce tumor sensitivity to radiation therapy and chemotherapy through one or more indirect mechanisms that include proteomic and genomic changes. These effects, in turn, can lead to increased invasiveness and metastatic potential, loss of apoptosis, and chaotic angiogenesis, thereby further increasing treatment resistance. Investigations of the prognostic significance of pretreatment tumor oxygenation status have shown that hypoxia (oxygen tension [pO2] value ≤10 mmHg) is associated with lower overall and disease-free survival, greater recurrence, and less locoregional control in head and neck carcinoma, cervical carcinoma, and soft-tissue sarcoma. In view of the deleterious effect of hypoxia on standard cancer treatment, a variety of hypoxia- and anemia-targeted therapies have been studied in an effort to improve therapeutic effectiveness and patient outcomes. Early evidence from experimental and clinical studies suggests the administration of recombinant human erythropoietin (rHuEPO) may enhance the effectiveness of radiation therapy and chemotherapy by increasing hemoglobin levels and ameliorating anemia in patients with disease- or treatment-related anemia. However, further research is needed in the area of hypoxia-related treatment resistance and its reversal.

Authors
Harrison, L; Blackwell, K
MLA Citation
Harrison, L, and Blackwell, K. "Hypoxia and anemia: Factors in decreased sensitivity to radiation therapy and chemotherapy?." Oncologist 9.SUPPL. 5 (2004): 31-40.
PMID
15591420
Source
scival
Published In
Oncologist
Volume
9
Issue
SUPPL. 5
Publish Date
2004
Start Page
31
End Page
40
DOI
10.1634/theoncologist.9-90005-31

Circulating D-dimer levels are better predictors of overall survival and disease progression than carcinoembryonic antigen levels in patients with metastatic colorectal carcinoma

BACKGROUND. Fibrin formation is required for tumor angiogenesis, metastasis, and invasion. D-dimer, a fibrin degradation product, is produced when crosslinked fibrin is degraded by plasmin. The current study prospectively examined D-dimer levels in patients with metastatic colorectal carcinoma treated in a Phase II randomized trial comparing bevacizumab (Avastin, Genentech, South San Francisco, CA) plus 5-fluorouracil/leucovorin (5-FU/LV) with 5-FU/LV alone. METHODS. At least one circulating D-dimer level was evaluable in 98 of the 104 previously untreated patients with metastatic colorectal carcinoma in the current trial. Plasma D-dimer levels were determined using a quantitative immunoassay kit at enrollment, before each treatment, and at the time of trial completion or disease progression. RESULTS. At trial enrollment, 86 of 104 patients (88%) had elevated D-dimer levels (> 20 ng/mL), and 86 of 102 patients (84%) had elevated carcinoembryonic antigen (CEA) levels (> 3 ng/mL). Baseline D-dimer levels were correlated with the following baseline characteristics: CEA (Pearson coefficient, 0.31; P = 0.002), albumin levels (Pearson coefficient, -0.32; P = 0.002), tumor burden (Pearson coefficient, 0.30; P = 0.003), and number of metastatic sites (Pearson coefficient, 0.21; P = 0.04). At the time of progression, plasma D-dimer levels reached a maximum postbaseline value in 51 of 61 patients (84%), whereas the CEA level was at its maximum postbaseline value in 39 of 55 patients (71%). Baseline D-dimer levels were a strong predictor of overall survival on univariate analysis (P = 0.008) and multivariate analysis (P = 0.03). Overall, treatment with bevacizumab (5 mg/kg) and baseline D-dimer levels were the only predictors of overall survival (P < 0.05). CONCLUSIONS. The current study indicates that fibrin remodeling is an important prognostic feature in metastatic colorectal carcinoma. D-dimer levels should be incorporated into prognostic models, and D-dimer may represent a useful biomarker for patients treated with antiangiogenic agents. © 2004 American Cancer Society.

Authors
Blackwell, K; Hurwitz, H; Liebérman, G; Novotny, W; Snyder, S; Dewhirst, M; Greenberg, C
MLA Citation
Blackwell, K, Hurwitz, H, Liebérman, G, Novotny, W, Snyder, S, Dewhirst, M, and Greenberg, C. "Circulating D-dimer levels are better predictors of overall survival and disease progression than carcinoembryonic antigen levels in patients with metastatic colorectal carcinoma." Cancer 101.1 (2004): 77-82.
PMID
15221991
Source
scival
Published In
Cancer
Volume
101
Issue
1
Publish Date
2004
Start Page
77
End Page
82
DOI
10.1002/cncr.20336

rHuEPO and improved treatment outcomes: Potential modes of action

Within the past decade, clinical trials have shown that the presence of anemia can diminish the physical status, functional abilities, and overall quality of life (QOL) of cancer patients and can negatively influence the outcome of their treatment. However, recent preclinical and clinical studies have also shown that increasing hemoglobin levels by administering recombinant human erythropoietin (rHuEPO, epoetin alfa) may ameliorate anemia and, in doing so, improve QOL and possibly result in better treatment outcomes following radiotherapy, chemotherapy, or a combination of these modalities. Several mechanisms by which rHuEPO may improve treatment outcome have been proposed, including correction of tumor hypoxia, increased sensitivity of tumor cells to radiotherapy and chemotherapy, correction of anemia and its associated symptoms (particularly fatigue), and immune-modulated effects of rHuEPO on tumor growth. Improvement of tumor oxygenation by rHuEPO could affect treatment outcome in two ways. First, correction of hypoxia results in the downregulation of hypoxia-inducible factor I (HIF-I), a key regulator of cellular adaptive responses to hypoxia (e.g., angiogenesis), including many pathways that are important for tumor growth and metastasis. Interruption of the HIF-1 pathway not only limits growth of the primary tumor but also reduces the potential for the development of more aggressive tumors and metastatic spread, which could ultimately improve treatment outcome. Second, within the tumor, it is the hypoxic cells that are resistant to oxygen-dependent radiotherapy and chemotherapy, and improvement in their oxygenation would increase their sensitivity to the cytotoxic effects of such treatment. Correction of anemia and its associated symptoms, particularly fatigue, can have a beneficial effect on patient QOL, and this in turn may translate into greater tolerance of radiotherapy and chemotherapy, allowing patients to receive full doses and on-schedule dosing, and thus have an increased likelihood of a therapeutic response. Lastly, results of a study using a murine model of multiple myeloma have indicated that rHuEPO may induce an immune-mediated antitumor effect. Therefore, additional research is warranted to further explore the biologic actions of rHuEPO and to determine their relevance to therapeutic outcome.

Authors
Blackwell, K; Gascón, P; Sigounas, G; Jolliffe, L
MLA Citation
Blackwell, K, Gascón, P, Sigounas, G, and Jolliffe, L. "rHuEPO and improved treatment outcomes: Potential modes of action." Oncologist 9.SUPPL. 5 (2004): 41-47.
PMID
15591421
Source
scival
Published In
Oncologist
Volume
9
Issue
SUPPL. 5
Publish Date
2004
Start Page
41
End Page
47
DOI
10.1634/theoncologist.9-90005-41

Accuracy of MRI in the detection of residual breast cancer after neoadjuvant chemotherapy.

OBJECTIVE: This study was undertaken to evaluate the ability of MRI to accurately show residual primary breast malignancy in women treated with neoadjuvant chemotherapy. MATERIALS AND METHODS: Twenty-one patients with locally advanced primary breast carcinoma underwent contrast-enhanced MRI before and after treatment with neoadjuvant anthracycline-based chemotherapy. For each patient, the maximum extent of the MRI abnormality was measured both before and after treatment. These measurements were subsequently compared with physical examination findings and histologic results to determine the ability of MRI to accurately reveal tumor extent after neoadjuvant chemotherapy. RESULTS: MRI after chemotherapy showed a correlation coefficient of 0.75 with histology, which was better than physical examination (r = 0.61). MRI underestimated the extent of residual tumor in two patients by more than 1 cm (including one false-negative examination), was within 1 cm in 12 of 21 patients, and overestimated tumor extent by more than 1 cm in seven of 21 patients. CONCLUSION: MRI can show residual malignancy after neoadjuvant chemotherapy better than physical examination, particularly in patients who have not had a complete clinical response to therapy.

Authors
Rosen, EL; Blackwell, KL; Baker, JA; Soo, MS; Bentley, RC; Yu, D; Samulski, TV; Dewhirst, MW
MLA Citation
Rosen, EL, Blackwell, KL, Baker, JA, Soo, MS, Bentley, RC, Yu, D, Samulski, TV, and Dewhirst, MW. "Accuracy of MRI in the detection of residual breast cancer after neoadjuvant chemotherapy." AJR Am J Roentgenol 181.5 (November 2003): 1275-1282.
PMID
14573420
Source
pubmed
Published In
AJR. American journal of roentgenology
Volume
181
Issue
5
Publish Date
2003
Start Page
1275
End Page
1282
DOI
10.2214/ajr.181.5.1811275

Human recombinant erythropoietin significantly improves tumor oxygenation independent of its effects on hemoglobin.

Tumor oxygenation is known to be an important predictive/prognostic marker in a variety of tumors, including cervix, head/neck, sarcoma, non-small cell of the lung, and breast. Tumor oxygenation is influenced by many interactions, including oxygen delivery (angiogenesis, permeability, and HgB) and consumption (metabolic and growth rates). This study randomized 30 nonanemic, female Fischer 344 rats into three treatment arms to examine the effects of recombinant human erythropoietin (EPO) on R3230 rodent mammary carcinoma oxygenation. The three treatment arms were: (a) placebo; (b) EPO after tumor implantation (2000 units/kg/SQdose, M/W/F for six doses); and (c) EPO before tumor implantation (2000 units/kg/SQdose, M/W/F for six doses). Tumors were implanted in the hindflank, and in vivo oxygenation was measured at day 22 after implantation using the Oxylite system (Oxford Optronix, Oxford, England). An average of 180 measurements/animal were performed. On day 22, median tumor volume was 399 mm(3) (range: 65-950 mm(3)), and no differences in tumor volume were seen between treatment arms. Mean hematocrit was equal between arms at therapy initiation but were significantly higher for both arms receiving EPO at day 22 (placebo versus Arm B versus Arm C; Wilcoxon P = 0.052). EPO-treated tumors had significantly less hypoxic measurements when compared with either the placebo or those receiving EPO before implantation. These data confirm that tumor oxygenation in nonanemic individuals may be improved through the administration of EPO, and this improvement appears to be independent of HgB effects.

Authors
Blackwell, KL; Kirkpatrick, JP; Snyder, SA; Broadwater, G; Farrell, F; Jolliffe, L; Brizel, DM; Dewhirst, MW
MLA Citation
Blackwell, KL, Kirkpatrick, JP, Snyder, SA, Broadwater, G, Farrell, F, Jolliffe, L, Brizel, DM, and Dewhirst, MW. "Human recombinant erythropoietin significantly improves tumor oxygenation independent of its effects on hemoglobin." Cancer Res 63.19 (October 1, 2003): 6162-6165.
PMID
14559797
Source
pubmed
Published In
Cancer Research
Volume
63
Issue
19
Publish Date
2003
Start Page
6162
End Page
6165

Ultrasound guided pO2 measurement of breast cancer reoxygenation after neoadjuvant chemotherapy and hyperthermia treatment.

The objective of this study was to determine whether neoadjuvant chemotherapy in combination with hyperthermia (HT) would improve oxygenation in locally advanced breast tumours. The study describes a new optimized ultrasound guided technique of pO2 measurement using Eppendorf polarographic oxygen probes in 18 stage IIB-III breast cancer patients. Prior to treatment, tumour hypoxia (median pO2<10 mmHg) was present in 11/18 patients (average median pO2=3.2 mmHg). Seven patients had well oxygenated tumours (median pO2 of 48.3 mmHg). Eight patients with hypoxic tumours prior to treatment had a significant improvement (p=0.0008) in tumour pO2 after treatment (pO2 increased to 19.2 mmHg). In three patients, tumours remained hypoxic (average median pO2=4.5 mmHg). The advantages of the ultrasound guided pO2 probe are in the accuracy of the Eppendorf electrode placement in tumour tissue, the ability to monitor electrode movement through the tumour tissue during the measurement and the ability to avoid electrode placement near or in large blood vessels by using colour Doppler imaging. The results of this preliminary study suggest that the combination of neoadjuvant chemotherapy and hyperthermia improves oxygenation in locally advanced breast tumours that are initially hypoxic.

Authors
Vujaskovic, Z; Rosen, EL; Blackwell, KL; Jones, EL; Brizel, DM; Prosnitz, LR; Samulski, TV; Dewhirst, MW
MLA Citation
Vujaskovic, Z, Rosen, EL, Blackwell, KL, Jones, EL, Brizel, DM, Prosnitz, LR, Samulski, TV, and Dewhirst, MW. "Ultrasound guided pO2 measurement of breast cancer reoxygenation after neoadjuvant chemotherapy and hyperthermia treatment." Int J Hyperthermia 19.5 (September 2003): 498-506.
PMID
12944165
Source
pubmed
Published In
International Journal of Hyperthermia (Informa)
Volume
19
Issue
5
Publish Date
2003
Start Page
498
End Page
506
DOI
10.1080/0265673031000121517

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

Head and neck: Editorial

Authors
Weber, RS; Abemayor, E; Adams, GL; Adelstein, DJ; Alavi, A; Alford, E; Al-Sarraf, M; Alvi, A; Ambinder, R; Amdur, R; Amedee, RG; Anand, VK; Andersen, P; Anderson, T; Ang, K-K; Antonelli, PJ; Ariyan, S; Aviv, JE; Ayala, A; Jong, RJBD; Backous, D; Bailey, BJ; Baker, S; Baloch, ZW; Barnes, EL; Barrera, J; Bastian, R; Batsakis, JG; Bauman, N; Becker, D; Beenken, S; Beitler, JJ; Berke, G; Blacklock, JB; Blackwell, K; Blitzer, A; Blom, E; Bolger, WE; Bone, RC; Boyd, J; Boyd, D; Boyle, J; Braakhuis, B et al.
MLA Citation
Weber, RS, Abemayor, E, Adams, GL, Adelstein, DJ, Alavi, A, Alford, E, Al-Sarraf, M, Alvi, A, Ambinder, R, Amdur, R, Amedee, RG, Anand, VK, Andersen, P, Anderson, T, Ang, K-K, Antonelli, PJ, Ariyan, S, Aviv, JE, Ayala, A, Jong, RJBD, Backous, D, Bailey, BJ, Baker, S, Baloch, ZW, Barnes, EL, Barrera, J, Bastian, R, Batsakis, JG, Bauman, N, Becker, D, Beenken, S, Beitler, JJ, Berke, G, Blacklock, JB, Blackwell, K, Blitzer, A, Blom, E, Bolger, WE, Bone, RC, Boyd, J, Boyd, D, Boyle, J, and Braakhuis, B et al. "Head and neck: Editorial." Head and Neck 23.12 (2001): 1021-1023.
Source
scival
Published In
Head & Neck: Journal for the Sciences & Specialties of the Head and Neck
Volume
23
Issue
12
Publish Date
2001
Start Page
1021
End Page
1023
DOI
10.1002/hed.1148

Tamoxifen inhibits angiogenesis in estrogen receptor-negative animal models.

Inhibition of tumor angiogenesis is a therapeutic strategy that can inhibit tumor growth and metastases. The aim of this study was to determine whether the estrogen receptor (ER) ligand drug tamoxifen has antiangiogenic effects. We used three different models of angiogenesis, including measurement of microvessel densities in murine tumors, ex vivo aortic ring assays, and corneal pocket assays. ER-negative fibrosarcoma tumors in tamoxifen-treated ovariectomized rats had significantly less vessel formation compared with untreated animals (median microvessel density, 53.6 versus 94.3 counts/per x 200 field; P = 0.002). Rat aortic rings treated with tamoxifen at several different concentrations demonstrated significantly less vascular sprouting than control rings (P = 0.0001). Corneal pocket assays performed in tamoxifen-treated rats compared with control and estrogen-treated rats demonstrated decreased vascular length (0.88 mm versus 1.26 mm versus 1.47 mm; P = 0.022) and vessel area (21% versus 34% versus 47%; P = 0.018). These three animal models all showed significant inhibition of angiogenesis by tamoxifen and suggest a possible contributory mechanism of ER-independent manipulation by tamoxifen in the treatment and prevention of breast cancer. These studies raise the question as to whether or not newer ER ligand drugs might possess even more potent antiangiogenic effects, which in turn could lead to the broadening of the clinical usefulness of these compounds in a number of diseases. More importantly, these studies suggest that the antiangiogenic effects of tamoxifen are due, in part, to ER-independent mechanisms.

Authors
Blackwell, KL; Haroon, ZA; Shan, S; Saito, W; Broadwater, G; Greenberg, CS; Dewhirst, MW
MLA Citation
Blackwell, KL, Haroon, ZA, Shan, S, Saito, W, Broadwater, G, Greenberg, CS, and Dewhirst, MW. "Tamoxifen inhibits angiogenesis in estrogen receptor-negative animal models." Clin Cancer Res 6.11 (November 2000): 4359-4364.
PMID
11106254
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
6
Issue
11
Publish Date
2000
Start Page
4359
End Page
4364

Plasma D-dimer levels in operable breast cancer patients correlate with clinical stage and axillary lymph node status.

PURPOSE: To investigate the relationship between preoperative plasma D-dimer levels and extent of tumor involvement in operable breast cancer patients. PATIENTS AND METHODS: A total of 140 preoperative plasma specimens were obtained from women scheduled to undergo diagnostic breast biopsies. Ninety-five patients in the initial group went on to undergo axillary lymph node dissection. Of the 140 patients from whom plasma samples were obtained, 102 were subsequently diagnosed with invasive breast carcinoma, nine were subsequently diagnosed with ductal carcinoma-in-situ, and 20 were subsequently diagnosed with benign breast disease. Plasma D-dimer levels were quantitated using a commercially available immunoassay kit (DIMERTEST; American Diagnostica, Greenwich, CT). The relationships between plasma D-dimer and other prognostic variables (tumor size, estrogen receptor, progesterone receptor, nuclear grade, histologic grade, lymphovascular invasion, and clinical stage grouping) were then examined using univariate and multivariate linear and logistic regression analyses. RESULTS: Median plasma D-dimer levels were significantly higher in patients with invasive carcinoma than those patients with either benign breast disease or carcinoma-in-situ (P =.0001). A significant relationship existed between the presence of elevated D-dimer (> 100 ng/mL) and involved axillary lymph nodes (chi(2) test; P =.001). Elevated D-dimer levels predicted positive lymph node involvement in both univariate regression (P =.0035) and multivariate linear regression (P =.012) models. In addition, elevated D-dimer levels predicted the presence of lymphovascular invasion in univariate logistic regression (P =. 0025) and multivariate logistic regression analysis (P =.0053). Quantitative D-dimer levels were highly correlated with clinical stage grouping (analysis of variance test; P =.002). CONCLUSION: Plasma D-dimer levels were markers of lymphovascular invasion, clinical stage, and lymph node involvement in operable breast cancer. This correlation suggests that detectable fibrin degradation, as measured by plasma D-dimer, is a clinically important marker for lymphovascular invasion and early tumor metastasis in operable breast cancer.

Authors
Blackwell, K; Haroon, Z; Broadwater, G; Berry, D; Harris, L; Iglehart, JD; Dewhirst, M; Greenberg, C
MLA Citation
Blackwell, K, Haroon, Z, Broadwater, G, Berry, D, Harris, L, Iglehart, JD, Dewhirst, M, and Greenberg, C. "Plasma D-dimer levels in operable breast cancer patients correlate with clinical stage and axillary lymph node status." J Clin Oncol 18.3 (February 2000): 600-608.
PMID
10653875
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
18
Issue
3
Publish Date
2000
Start Page
600
End Page
608
DOI
10.1200/JCO.2000.18.3.600

Combining prostate specific antigen with cancer and gland volume to predict more reliably pathological stage: The influence of prostate specific antigen cancer density

The serum prostate specific antigen (PSA) level was determined in 311 men with documented prostate cancer (stages T1cN0, T2N0 and T3N0) before bilateral pelvic lymphadenectomy and radical retropubic prostatectomy. The prostates were whole mounted, serially sectioned, and examined for cancer volume, capsular perforation, seminal vesicle invasion, lymph node involvement, Gleason grade, nuclear grade and nuclear deoxyribonucleic acid content. Median serum PSA level was significantly different between cancers that were organ confined, those that had capsular perforation or seminal vesicle invasion and those with positive lymph nodes (p <0.001). Median serum PSA level was also significantly different between tumors with Gleason scores of less than 6 and those with higher Gleason scores (p <0.001), and between tumors with greater than 30% of poorly differentiated cancer (Gleason primary grades 4 and 5) and those with 30% or less poorly differentiated cancer (p <0.001). Bivariate analysis revealed that the strongest correlations of serum PSA level were with cancer volume (r = 0.56), per cent of poorly differentiated cancer (r = 0.42), positive surgical margins (r = 0.39) and pathological stage (r = 0.38), for all p <0.001. Multivariate analysis showed that cancer volume was the major contributor to serum PSA level. The derivative, PSA-cancer density (serum PSA times cancer volume divided by prostate volume), accounted for the effects of prostate volume and cancer volume on serum PSA. PSA-cancer density showed a significant correlation with pathological stage (r = 0.56), Gleason score (r = 0.53) and per cent of poorly differentiated cancer (r = 0.49, for all p <0.001), and these correlations were significantly stronger than serum PSA level alone or PSA density (serum PSA divided by prostate volume; volume determined from tissue specimens) for all variables. These results indicate that preoperative serum PSA level has significant predictive value in determining tumor burden and pathological stage, and this predictive value is increased by accounting for cancer and gland volume with PSA-cancer density.

Authors
Blackwell, KL; Bostwick, DG; Myers, RP; Zincke, H; Oesterling, JE
MLA Citation
Blackwell, KL, Bostwick, DG, Myers, RP, Zincke, H, and Oesterling, JE. "Combining prostate specific antigen with cancer and gland volume to predict more reliably pathological stage: The influence of prostate specific antigen cancer density." Journal of Urology 151.6 (1994): 1565-1570.
PMID
7514689
Source
scival
Published In
Journal of Urology
Volume
151
Issue
6
Publish Date
1994
Start Page
1565
End Page
1570

A clinical experience in social medicine/cultural diversity.

Authors
Sandok, BA; Orford, RR; Blackwell, KL
MLA Citation
Sandok, BA, Orford, RR, and Blackwell, KL. "A clinical experience in social medicine/cultural diversity." Academic medicine : journal of the Association of American Medical Colleges 69.5 (1994): 410-411.
PMID
8086051
Source
scival
Published In
Academic medicine : journal of the Association of American Medical Colleges
Volume
69
Issue
5
Publish Date
1994
Start Page
410
End Page
411
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