Breast cancer prognosis in BRCA1/2 mutation carriers: A case control study.

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1554 Background: We evaluated the clinical impact of germ-line BRCA1/2 mutations and variants of unknown clinical significance (VUS) for BRCA1/2 in patients (pts) with early breast cancer (BC). Methods: Twenty-eight BRCA-positive (BRCA+) BC pts with germ-line BRCA1 /2 mutations and 16 VUS BC pts were selected from our database and matched (1:3) with 154 nonhereditary BC controls (sporadic controls, SC, defined by no associated personal history of breast cancer and no family history of breast and ovarian cancer or an uninformative BRCA mutation test) for stage, histologic subtype, age, and year of diagnosis. Clinical characteristics, recurrence (rec) pattern, disease free survival (DFS) and overall survival (OS) were analyzed. Results: Compared with VUS and SC, BRCA+ pts were less likely to express estrogen receptor (64% vs. 89% vs. 54% respectively p<.005) and progesterone receptor (64% vs. 86% vs. 59% respectively p<.005) but more likely to be triple negative (0 vs. 3.4% vs 47.4% respectively p<.005). Compared with VUS and SC, BRCA+ pts were more likely treated by radical mastectomy (37.5% vs. 26.4% vs. 59.3% % respectively p<.005). Pattern of rec was also different. Compared with VUS and SC, BRAC+ pts developed more second tumors (11% vs. 6.3% vs. 1.9% respectively p<.0001) but less local or distant rec (31% vs. 2.6 vs. 0% for local rec and 12% vs. 16% vs. 11% for distant rec respectively p<.0001). Controlateral BC was more frequent in VUS compared to the BRAC+ and SC pts (12% vs. 7% vs. 1% respectively, p<.0001). At a median follow up of 88 months, at univariate analysis, BRAC+ but not VUS pts had worse OS compared to SC (p=.006). No difference in DFS was observed for VUS or BRAC+ when compared to SC pts. After adjustment for age, stage, grade, nodal status, hormone receptors, adjuvant therapy and year of diagnosis, BRCA+ pts continued to have and increased risk of death compared to SC (HR 5.9, 95% CI 1.9-18.1, p<.002). Most of the deaths observed in BRAC+ pts were not cancer related. Conclusions: Despite decrease incidence of local or distant recs, BRAC+ pts seems to be more likely to die compared to SC. Development of second cancers and unknown effects of BRCA1/2 mutations on nonneoplastic diseases that cause death may account for this findings.