BACKGROUND: The 2015 National Comprehensive Cancer Network guidelines recommend that genetic counseling and germline BRCA mutation testing be offered to women under age 60 with triple‐negative breast cancer (TNBC). As a result of the 2010 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for breast cancer, patients with breast cancers that are estrogen receptor (ER) or progesterone receptor (PR) low‐positive (1%‐9% on immunohistochemistry) are no longer strictly considered to have TNBC and may not be referred for genetic counseling. However, the incidence of BRCA mutation in patients with hormone receptor (HR) low‐positive breast cancers remains unknown, and current ASCO/CAP guidelines may result in undertesting for BRCA mutations.METHODS: A prospectively maintained research database of breast cancer patients evaluated at The University of Texas MD Anderson Cancer Center between 2004 and 2014 was reviewed; 314 patients were identified with HER2/neu–negative breast cancers expressing ER and PR <10% with known BRCA mutation status.RESULTS: Three hundred fourteen patients had breast cancers expressing ER and PR <10%; 238 (75.8%) had HR‐negative cancers (<1% ER and PR), and 76 (24.2%) had HR–low‐positive cancers (1%‐9% ER and/or PR). Among patients with HR‐negative tumors, 86 of 238 (36.1%) had a BRCA1/2 mutation, whereas in the HR–low‐positive group, 30 of 76 (39.5%) had a BRCA1/2 mutation. In multivariate analysis, HR status (<1% vs 1%‐9%) was not significantly associated with BRCA1/2 mutations.CONCLUSIONS: The incidence of BRCA1/2 mutations is similar in patients with HR–low‐positive breast cancer and patients with HR‐negative breast cancer. Genetic counseling and BRCA testing should be offered to patients under age 60 who have HR–low‐positive breast cancers. Cancer 2015;121:3435–43. © 2015 American Cancer Society.

The causes and consequences of abnormal biogenesis of extracellular vesicles (EVs) are not yet well understood in malignancies, including in breast cancers (BCs). Given the hormonal signaling dependence of estrogen receptor–positive (ER+) BC, we hypothesized that 17β-estradiol (estrogen) might influence EV production and microRNA (miRNA) loading. We report that physiological doses of 17β-estradiol promote EV secretion specifically from ER+ BC cells via inhibition of miR-149-5p, hindering its regulatory activity on SP1, a transcription factor that regulates the EV biogenesis factor nSMase2. Additionally, miR-149-5p downregulation promotes hnRNPA1 expression, responsible for the loading of let-7’s miRNAs into EVs. In multiple patient cohorts, we observed increased levels of let-7a-5p and let-7d-5p in EVs derived from the blood of premenopausal ER+ BC patients, and elevated EV levels in patients with high BMI, both conditions associated with higher levels of 17β-estradiol. In brief, we identified a unique estrogen-driven mechanism by which ER+ BC cells eliminate tumor suppressor miRNAs in EVs, with effects on modulating tumor-associated macrophages in the microenvironment.

Patients with hereditary mutations in BRCA1 or BRCA2 (gBRCA1/2) and breast cancer have distinct tumor biology, and encompass a predilection for brain metastasis (BM). We looked into baseline risk of BMs among gBRCA1/2 patients. Patients with gBRCA1/2, stage I-III invasive breast cancer seen between 2000–2017 with parenchymal BMs. Among gBRCA1 with distant breast cancer recurrence, 34 of 76 (44.7%) were diagnosed with brain metastases compared to 7 of 42 (16.7%) patients with gBRCA2. In the comparator group, 65 of 182 (35.7%) noncarrier triple-negative breast cancer (TNBC) and a distant recurrence experienced BM’s. In a competitive risk analysis using death as a competing factor, the cumulative incidence of BMs was similar between gBRCA1 and noncarrier TNBC patients. The time from primary breast cancer diagnosis to detection of BMs was similar between gBRCA1 and noncarrier TNBC patients (2.4 vs 2.2 years). Survival was poor after BMs (7.8 months for gBRCA1 patients vs. 6.2 months for TNBC noncarriers). Brain was a more common site of initial distant recurrence in gBRCA1 patients versus TNBC noncarriers (26.3% vs. 12.1%). Importantly, the presence of BMs, adversely impacted overall survival across groups (HR 1.68 (95% CI 1.12–2.53), hazard ratio for death if a patient had BMs at the time of initial breast cancer recurrence vs. not). In conclusion, breast cancer BMs is common and is similarly frequent among gBRCA1 and noncarrier patients with recurrent TNBC. Our study highlights the importance of improving the prevention and treatment of BMs in patients with TNBC, gBRCA1 carriers, and noncarriers.

Obese and overweight women have an increased risk of breast cancer and worse outcomes at the time of diagnosis. Women tend to gain weight after breast cancer diagnosis and during chemotherapy for early‐stage disease, which may in turn increase risk for worse outcomes. We examined if weight gained during adjuvant chemotherapy was associated with worse survival outcomes. We queried our database for data on patients who received adjuvant third‐generation chemotherapy for early‐stage breast cancer. Univariate and multivariate analyses by Cox regression were performed for survival outcomes across three categories according to BMI variation from start to end of chemotherapy: >0.5 kg/m² loss or gain and stable BMI (±0.5 kg/m²). We included 1998 patients in this study. Women over 50 years old and postmenopausal were more likely to lose weight during adjuvant chemotherapy, whereas women under 30 years old gained more weight (P < 0.001). At 1 year postchemotherapy, patients tended to return to their original weight (ρ = −0.3, P < 0.001). On multivariate analysis, BMI increase of >0.5 kg/m² compared to maintaining BMI was marginally associated with increased locoregional recurrence risk (HR: 2.53; 95% CI, 1.18–5.45; P = 0.017), adjusting for grade, stage, and radiation delivery. Weight variation during adjuvant chemotherapy for early‐stage breast cancer may occur as both weight gain and weight loss in a balanced manner. Furthermore, this variation seems to be transient in nature and does not appear to significantly influence recurrence rates and overall survival.

Although multigene panel testing is increasingly common in patients with cancer, the relationship between its use among breast cancer patients with non‐BRCA mutations or variants of uncertain significance (VUS) and disease management decisions has not been well described. This study evaluated the rate and predictive factors of CPM patients who underwent multigene panel testing. Three hundred and fourteen patients with breast cancer who underwent multigene panel testing between 2014 and 2017 were included in the analysis. Of the 314 patients, 70 elected CPM. Election of CPM by gene status was as follows: BRCA carriers (42.3%), non‐BRCA carriers (30.1%), and VUS (10.6%). CPM election rates did not differ between non‐BRCA carriers and BRCA carriers (P = 0.6205). Among non‐BRCA carriers, negative hormone receptor status was associated with CPM (P = 0.0115). For those with a VUS, hormone receptor status was not associated with CPM (P = 0.1879). Although the rate of CPM between BRCA carriers and non‐BRCA carriers was not significantly different, the predictors of CPM were different in each group. Our analyses shed the light on the increasing use of CPM among patients who are non‐BRCA carriers as well those with a VUS. Our study elucidates the differing predictive factors of CPM election among BRCA carriers, non‐BRCA carries, and those with a VUS. Our findings reveal the need for providers to be cognizant that non‐BRCA genes and VUS drive women to elect CPM despite the lack of data for contralateral breast cancer risk associated with these genes.