Prevalence of BRCA1 and BRCA2 mutations in Jewish women with triple negative breast cancer

22002 Background: Approximately 10% of Ashkenazi Jewish (AJ) women with breast cancer (BC) carry one of three mutations in BRCA1 or BRCA2 (BRCA1 185delAG or 5382insC, BRCA2 6174delT). There is an association between BRCA1 mutations and ‘triple negative’ (TripNeg) phenotype (estrogen receptor (ER) and progesterone receptor (PR) negative, HER2 non- overexpressing). TripNeg is not over-represented in BRCA2-BC. We sought to determine the predictive value of the TripNeg phenotype for the presence of any BRCA mutation in a cohort of Jewish women ascertained without respect to family history (FH). Methods: DNA samples were collected between 8/2000 and 6/2004 from 495 Jewish women with BC(median age at diagnosis 57 years) treated at a single institution. Medical records were reviewed and samples annotated with limited clinical information. Patients were considered to be ER or PR negative if fewer than 10% of cells stained by IHC, and HER2 negative if they were 0–1+ by IHC or 2+ with FISH < 2.0. Samples were genotyped for AJ founder mutations. Results: 389 (78.6%) of patients were ER+, 280 (56.6%) were PR+, and 96 (19.4%) were ER-/PR-. Most patients (n=388, 78.4%) were HER2-. TripNeg phenotype was observed in 65 (13.1%). Founder mutations were detected in 52 samples (10.5%, BRCA1 in 5.5% (n=27), BRCA2 in 5.1% (n=25)). Compared to women without mutations (mut neg), BRCA1 mutation carriers (but not BRCA2 carriers) were younger at diagnosis (P <0.001) and more likely to have a family history of breast cancer (P = 0.004). BRCA1 carriers were more likely than mut neg women to be ER-/PR- (74% vs 16%, P < 0.001) and TripNeg (70.4% vs 9.8%, P<0.001). The positive predictive value (PPV) of TripNeg for a BRCA1 mutation was 29% overall, 48% in women diagnosed < 50 yrs, and 14% in women diagnosed ≥50. Although 24% of BRCA2-BC were TripNeg, BRCA2 carriers were not significantly more likely than non-carriers to be ER-/PR- or TripNeg. TripNeg phenotype was significantly associated with detecting a mutation in either BRCA1 or BRCA2, but only 25/52 (48%) mutation-associated cancers were TripNeg. Conclusion: TripNeg phenotype predicts for BRCA1 mutation, but many women with mutations do not have TripNeg disease. Overemphasis on TripNeg to select for genetic testing may lead to under-recognition of hereditary breast cancer. No significant financial relationships to disclose.