Abstract PD09-03: Impact of BRCA1/2 Mutation Status in TBCRC009: A multicenter phase II study of cisplatin or carboplatin for metastatic triple negative breast cancer.
Authors: Isakoff SJ , Goss PE , Mayer EL , Traina T , Carey LA , Krag KJ , Liu MC , Rugo H , Stearns V , Come S , Finkelstein D , Hartman A-R , Garber JE , Ryan PD , Winer EP , Ellisen LW 
Published: August 2014

Background: Triple negative breast cancer (TNBC) has a poor prognosis compared to other BC subtypes and lacks identified specific therapeutic targets. TNBC is frequent among BRCA1-associated breast cancer. Platinum chemotherapy has activity in TNBC, and several studies have suggested particular efficacy of platinum agents in BRCA-associated breast cancer. TBCRC009 is a multicenter single arm phase II study of single agent platinum in metastatic TNBC. Here we sought to evaluate the impact of BRCA1/2 mutation status on outcomes in this study population.

Methods: Eligible metastatic TNBC patients (pts) had measurable disease, available archival tumor, ≤ 1 prior metastatic therapy, and no prior platinum chemotherapy. Pts were assigned by physician choice (limited to equal enrollment in each arm) to cisplatin 75mg/m2 or carboplatin AUC=6 every 21 days with optional extension to 28 days after cycle 1. Co-primary endpoints were: 1) Response Rate (RR) and 2) whether tumor p63/p73 expression predicts response. Secondary endpoints included determination of BRCA1/2 mutation status and exploratory analysis of correlation of BRCA1/2 status with outcomes. Baseline blood samples from all pts were analyzed by Myriad Genetics using BRCAnalysis and BART testing. Results of this exploratory analysis are presented here.

Results: 86 TNBC pts enrolled between June 2007-Oct 2010. Results of primary endpoint 1 and patient characteristics were previously presented (ASCO 2011 Annual Meeting, J Clin Oncol 29: 2011 suppl; abstr 1025). In summary, median age=52 (30–78), 64% had ECOG PS=0, and 86% had adjuvant chemotherapy. Overall response rate (RR) was 30.2% (95% CI 20.8%–41.1%), including 4 CR (4.7%), 22 PR (25.6%). Among the 76 pts with BRCA1/2 status available, there were 11 (14.5%) BRCA1/2 carriers (9 BRCA1, 2 BRCA2) and 65 (85.5%) BRCA1/2 wild type (wt). Testing is ongoing for the remaining 10 pts. RR was 54.6% (5 PR, 1 CR) in BRCA1/2 carriers and 26.2% (14 PR, 3 CR) in BRCA1/2 wt (p = 0.0506). There was no significant difference in PFS between BRCA1/2 carriers (median PFS 99 days; 95% CI: 40–215) and BRCA1/2 wt (median PFS 86 days, 95% CI: 46–146). Interestingly, 6 pts (7%), including 5 BRCA1/2 wt and 1 BRCA unknown, remain without progression for 53, 41, 33, 27, 25, and 22 months as of June 2012. Of these 6 pts, 3 pts discontinued study drug due to toxicity and received no additional therapy and 3 pts had major responses and had consolidation therapy with surgery, chemotherapy, or radiation.

Conclusion: First or second line single agent platinum is effective in both BRCA1/2-associated and sporadic metastatic TNBC. In this exploratory analysis, we observed a higher RR in BRCA1/2 carriers than in BRCA wt patients, but we did not observe an improved PFS in this small cohort. We observed durable responses in 7% of pts which did not correlate with BRCA1/2 mutations. The lack of a clear relationship between the higher RR in patients with germline BRCA1/2 mutations and PFS is surprising and could be further elucidated by studies in a larger cohort, and our ongoing analyses of additional markers for platinum sensitivity.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD09-03.