Abstract PD09-02: BRCA1 insufficiency is predictive of superior survival in patients with triple negative breast cancer treated with platinum based chemotherapy
Authors: Sharma P , Stecklein S , Kimler BF , Klemp JR , Khan QJ , Fabian CJ , Tawfik OW , Connor CS , McGinness MK , Mammen JMW , Jensen RA 
Published: August 2014

Abstract
Introduction: Triple negative breast cancer (TNBC) and BRCA1-associated breast cancers share many histopathologic and molecular features. BRCA1 plays a crucial role in HR-dependent DNA repair and BRCA1-deficient cells are particularly susceptible to the DNA damaging agents like platinums. Increasing evidence suggests that in addition to germline BRCA defects, other mechanisms (like epigenetic BRCA1 silencing) can lead to BRCA1 insufficiency in TNBC. However, the impact of BRCA1 insufficiency on the efficacy of DNA damaging agents in TNBC is not known.
Aim: To investigate the impact of BRCA1 insufficiency on relapse-free survival (RFS) and overall survival (OS) in patients with stage II-III TNBC treated with neoadjuvant platinum-based chemotherapy. BRCA1 insufficiency (BRCA1insuf) state was defined as presence of germline BRCA1/2 mutation or BRCA1 promoter methylation (PM) and/or low BRCA1 expression (lowest quartile).
Methods: Thirty patients with stage II/III TNBC received neoadjuvant chemotherapy (6 cycles of Carboplatin AUC 6, Docetaxel 75mg/m2 and Erlotinib 150 mg PO) on a phase II trial between 8/2007–6/2010. All but one patient underwent comprehensive BRCA analysis (Myriad Genetic Laboratories). Pre-treatment tumor specimens were used for evaluation of BRCA1 PM and expression. Genomic DNA was isolated from FFPE samples, bisulfite converted and then subjected to methylation-specific PCR (MSP). RNA was isolated, reverse transcribed to cDNA and assayed by quantitative real-time PCR (qRT-PCR) for determination of BRCA1 mRNA transcript levels. RFS and OS were estimated according to the Kaplan-Meier method and compared among groups with log-rank statistic. Cox proportional hazards models were fit to determine the association of BRCA1insuf with the risk of death after adjustment for other characteristics.
Results: Median age: 51yrs, African American: 20%, Median tumor size: 3.3 cm, LN positive: 40%. Six of 30 patients (20%) harbored germline BRCA mutation (4 BRCA1, 2 BRCA2). Baseline tumor specimen was available for 26/30 patients. BRCA1 MSP was successful in 92% and BRCA1 qRT-PCR was successful in 84% of specimens. BRCA1 PM and low BRCA1 expression was present in 30% and 15% of subjects, respectively. There was evidence of BRCA1insuf in 53% (16/30) of subjects. At a median time from diagnosis of 42 months (range, 23–59 months) there have been 9(30%) recurrences and 7(23%) deaths. On univariate analysis node negativity, lower stage and presence of BRCA1insuf were associated with better OS. At the median follow up, RFS is 81% for patients with BRCA1insuf versus 54% for patients without BRCA1insuf (p = 0.16); OS is 83% for patients with BRCA1insuf versus 46% for patients without BRCA1insuf (p = 0.021). After adjustment for clinical variables patients with BRCA1insuf had a significantly better OS compared to patients without BRCA1insuf (p = 0.036).
Conclusions: Germline BRCA testing plus tissue BRCA1 PM/expression can be used to identify a BRCA1insuf sub-population within TNBC demonstrating a favorable outcome with platinum treatment. This BRCA1insuf criteria can be easily used to select TNBC patients likely to benefit from DNA damaging agents like platinums and PARP inhibitors.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD09-02.