Superior pathological complete response to neo-adjuvant chemotherapy in breast cancer amongst women with BRCA1/2 mutations.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #5104 Background: Germline mutations in BRCA1 and BRCA2 occur in ∼ 11% of Jewish Ashkenazi women with breast cancer. BRCA1 and BRCA2 proteins are key players in the repair mechanisms of double-strand DNA breaks induced by DNA-damaging agents such as anthracyclines. Hence, inactivating mutations in BRCA1/2 genes have been postulated to result in increased chemo-sensitivity in women with breast cancer who carry these germline mutations. Neo-adjuvant therapy provides the opportunity for a rough, in vivo assessment of this notion by assessing chemotherapy (CT) sensitivity via pathological complete response (pCR) rates, in breast cancer patients, both carriers and non-carriers of deleterious BRCA1 BRCA2 mutations. In particular, response in the axillary lymph nodes to neo-adjuvant therapy is significant, as it is a surrogate marker for long-term outcome. This study assessed the pCR amongst women with BRCA1/2 mutations compared to those who are BRCA1/2 mutation negative. Methods: Retrospective evaluation of response to neo-adjuvant CT amongst consecutive women diagnosed with breast cancer who had received neo-adjuvant CT and who have all undergone genetic testing at the Oncogenetics unit, Sheba Medical Centre to define their BRCA1 BRCA2 mutational status. pCR was defined as the absence of residual invasive carcinoma in the breast and axillary lymph nodes. Only women who received anthracycline based therapy were included. Women who had received concurrent trastuzumab in the neo-adjuvant setting were excluded. Statistical analysis included Fisher's exact test for categorical variables, and student t-test for continuous variables. Results: A total of 75 women were identified who had received neo-adjuvant chemotherapy and who had undergone genetic testing. Overall, 61 were BRCA non-carriers and 14 harbored BRCA1/2 mutations (5 BRCA1 mutation carriers and 9 BRCA2 mutation carriers). There were no statistically significant differences between the BRCA1/2 positive and BRCA1/2 negative groups with regard to mean age, grade 3 histology, hormone receptor status or HER2/neu over-expression, and clinical T and N staging. Seven women received anthracycline based CT and 68 received an anthracycline and taxane regimen. No statistically significant differences existed between the two groups with regards to chemotherapy treatment protocol. Amongst women with a BRCA1/2 mutation 50% had a pCR compared with only 21% in BRCA-negative women, p=0.035. Conclusions: Women with BRCA1/2 mutations demonstrated a higher pCR compared with women who were BRCA negative. Further studies that encompass more mutation carriers with a prospective design are needed to optimize choice of chemotherapy agents in BRCA1/2 positive breast cancer patients in order to exploit the putative biological mechanisms underlying the seemingly unique chemo-sensitivity in this subset of patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5104.