Sensitivity to first-line chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers

M. Kriege1, C. Seynaeve1, H. Meijers-Heijboer2, J.M. Collée2, M.B.E. Menke-Pluymers3, C.C.M. Bartels3, A. van den Ouweland2, M. Hooning1, C.T.M. Brekelmans1, J.G.M. Klijn1
Department of Medical Oncology1, Clinical Genetics2 and Surgical Oncology3, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam

Background: Pre-clinical as well as retrospective, neo-adjuvant studies suggested that BRCA1- and BRCA2-associated breast cancer patients have an increased sensitivity to chemotherapeutic agents causing double-strands DNA breaks, such as anthracyclins and platinum. We assessed the response to first-line chemotherapy for metastatic breast cancer in BRCA1 and BRCA2-associated patients, respectively, compared to sporadic patients.

Methods: For this retrospective cohort study we selected 93 BRCA1- and 28 BRCA2-associated patients diagnosed with metastatic breast cancer before 2007, January 1 and treated with chemotherapy for metastatic breast cancer. Objective response, progression-free (PFS) and overall survival (OS) after start of first-line chemotherapy were compared with those of 121 sporadic breast cancer patients, matched for year of birth, age at diagnosis of primary breast cancer and year of detection of metastatic disease (within 5-years categories). Multivariate analyses were adjusted for estrogen receptor (ER)-status and adjuvant chemotherapy.

Results: Mean age at diagnosis of primary breast cancer was 40.6 years (range 22-65 years) and of metastatic breast cancer 44.6 years (range 25-69 years). First line chemotherapy of the 242 BRCA1-, BRCA2-asssociated and sporadic patients consisted of anthracyclin-based regimens (n=147), CMF(-like) (n=68), taxane-based regimens (n=21) and other regimens (n=6). As compared to sporadic patients, BRCA2-associated patients had higher objective response rate (89% vs. 50%; p=0.001), a longer PFS (hazard ratio multivariate (HRmult) 0.64; 95% confidence interval (CI) 0.41-0.99) and a prolonged OS (HRmult 0.53; 95% CI 0.34-0.85). For BRCA1-associated patients a non-significant trend for a higher objective response (66% vs. 50%; p=0.07) and a longer PFS (HRmult 0.79; 95% CI 0.57-1.08) was observed. OS was not significantly different between BRCA1-associated and sporadic metastatic breast cancer patients (HRmult 0.87; 95% CI 0.63-1.19).

Conclusion: Chemotherapy for metastatic breast cancer is more effective in BRCA2-associated patients in comparison with sporadic breast cancer patients. In BRCA1-associated metastatic breast cancer patients, a trend for a higher sensitivity to chemotherapy was observed. These findings are of importance as this ultimately may have implications for clinical practice.