Carolyn Menendez

OBJECTIVE: The majority of tumor sequencing currently performed on cancer patients does not include a matched normal control, and in cases where germline testing is performed, it is usually run independently of tumor testing. The rates of concordance between variants identified via germline and tumor testing in this context are poorly understood. We compared tumor and germline sequencing results in patients with breast, ovarian, pancreatic, and prostate cancer who were found to harbor alterations in genes associated with homologous recombination deficiency (HRD) and increased hereditary cancer risk. We then evaluated the potential for a computational somatic-germline-zygosity (SGZ) modeling algorithm to predict germline status based on tumor-only comprehensive genomic profiling (CGP) results. METHODS: A retrospective chart review was performed using an academic cancer center's databases of somatic and germline sequencing tests, and concordance between tumor and germline results was assessed. SGZ modeling from tumor-only CGP was compared to germline results to assess this method's accuracy in determining germline mutation status. RESULTS: A total of 115 patients with 146 total alterations were identified. Concordance rates between somatic and germline alterations ranged from 0% to 85.7% depending on the gene and variant classification. After correcting for differences in variant classification and filtering practices, SGZ modeling was found to have 97.2% sensitivity and 90.3% specificity for the prediction of somatic versus germline origin. CONCLUSIONS: Mutations in HRD genes identified by tumor-only sequencing are frequently germline. Providers should be aware that technical differences related to assay design, variant filtering, and variant classification can contribute to discordance between tumor-only and germline sequencing test results. In addition, SGZ modeling had high predictive power to distinguish between mutations of somatic and germline origin without the need for a matched normal control, and could potentially be considered to inform clinical decision-making.

BACKGROUND: Multiple studies have demonstrated a link between obesity and breast cancer; however, the potential association between obesity and atypical high-risk breast lesions has not been well characterized. We sought to evaluate the characteristics and clinical outcomes of patients with breast atypia based on a woman's body mass index (BMI). METHODS: We retrospectively identified adult women diagnosed with atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and/or lobular carcinoma in situ (LCIS) at a single institution from 2008 to 2017. BMI groups were defined as a BMI 18.5 to < 30 or BMI ≥ 30 (obese). Adjusted logistic regression was used to estimate the association of BMI group with the odds of (1) upstage to cancer after atypia on needle biopsy, and (2) subsequent diagnosis of breast cancer. RESULTS: Breast atypia was identified in 503 patients (most advanced atypia: 74.8% ADH, 4.6% ALH, 20.7% LCIS), and 41% of these patients were classified as obese. After adjustment, BMI group was not associated with upstage to breast cancer at surgical excision following needle biopsy (p = 0.16) or development of a subsequent breast cancer (p = 0.08). For those upstaged to breast cancer at the time of surgical excision, or those who developed a subsequent malignancy, tumor subtype, grade and stage were not associated with BMI group (p > 0.05). CONCLUSION: In a large cohort of patients diagnosed with atypical breast histology, the risk of upstaging and/or subsequent progression to a breast malignancy was not associated with BMI. Factors other than obesity may influence breast cancer risk.

BACKGROUND: Controversy exists regarding the optimal sequence of chemotherapy among women with operable node-negative breast cancers with high-risk tumor biology. We evaluated national patterns of neoadjuvant chemotherapy (NACT) use among women with early-stage HER2+, triple-negative (TNBC), and high-risk hormone receptor-positive (HR+) invasive breast cancers. METHODS: Women ≥18 years with cT1-2/cN0 HER2+, TNBC, or high recurrence risk score (≥31) HR+ invasive breast cancers who received chemotherapy were identified in the National Cancer Database (2010-2016). Cochran-Armitage and logistic regression examined temporal trends and likelihood of undergoing NACT versus adjuvant chemotherapy based on patient age and molecular subtype. RESULTS: Overall, 96,622 patients met study criteria; 25% received NACT and 75% underwent surgery first, with comparable 5-year estimates of overall survival (0.90, 95% CI 0.892-0.905 vs 0.91, 95% CI 0.907-0.913). During the study period, utilization of NACT increased from 14% to 36% and varied according to molecular subtype (year*molecular subtype p < 0.001, p-corrected < 0.001). Women with HER2+ (OR 4.17, 95% CI 3.70-4.60, p < 0.001, p-corrected < 0.001) and TNBC (OR 3.81, 95% CI 3.38-4.31, p < 0.001, p-corrected < 0.001) were more likely to receive NACT over time, without a change in use among those with HR+ disease (OR 1.58, 95% CI 0.88-2.87, p = 0.13, p-corrected = 0.17). CONCLUSION: Among women with early-stage triple-negative and HER2+ breast cancers, utilization of NACT increased over time, a trend that correlates with previously reported improved rates of pCR and options post-neoadjuvant treatment with residual disease. Future research is needed to better understand multidisciplinary decisions for NACT and implications for breast cancer patients.