Abstract CT129: Association of the FCGR2A and FCGR3A genotypes with trastuzumab benefit in NSABP B-31

Background: The FCGR3A-158V and FCGR2A-131H alleles are referred to as favorable alleles with regards to trastuzumab response because the FCGR3A-V/V and FCGR2A-H/H genotypes have been associated with higher trastuzumab induced antibody-dependent cell-mediated cytotoxicity (ADCC) response in vitro. The objective of this study was to assess the interaction between these genotypes and the degree of benefit from trastuzumab in a phase III trial which demonstrated the benefit of adding trastuzumab to the standard adjuvant chemotherapy in the treatment of HER2-positive breast cancer (NSABP B-31). Methods: Genotypes for FCGR3A-158V/F and FCGR2A-131H/R alleles were determined in a representative cohort of NSABP clinical trial B-31 which included all available pre-treatment blood samples (N = 1251). Genotypes were determined by Typeplex chemistry and mass spectrometry on the Seqeunom platform. A custom nested PCR design was required to enable specific amplification of the FCGR3A gene due to the extensive homology between the FCGR3A and FCGR3B genes. Cox regression analyses were used to test for genotype-treatment interactions. Endpoint was disease free survival (DFS). Results: The genotyped cohort resembled the entire B-31 cohort based on clinical variables and the degree of benefit from trastuzumab. Results are summarized in the table. While there were trends for interaction between polymorphisms and trastuzumab for both genes, only FCGR3A-158 polymorphism reached statistical significance for interaction (p = 0.005). Conclusion: In NSABP B-31 there was a trend for benefit in the favorable genotypes of the FCGR2A-131 SNP, but only the favorable FCGR3A-158 genotypes showed a significant association with trastuzumab benefit with genotype-treatment interaction. However, polymorphism alone could not identify a subgroup with no benefit from trastuzumab, since even the patients with less favorable genotypes received significant benefit. Support: NCI U10-CA-12027, -69651, -37377, -69974. PA DOH disclaims responsibility for analysis, interpretations, or conclusions. Citation Format: Patrick G. Gavin, Nan Song, Nicole L. Johnson, Corey Lipchik, Seong-Rim Kim, Melanie Finnigan, Hanna Bandos, Jong-Hyeon Jeong, Joseph P. Costantino, Priya Rastogi, Edward H. Romond, Louis Fehrenbacher, Eleftherios P. Mamounas, Sandra M. Swain, D. Lawrence Wickerham, Charles E. Geyer, Jr., Norman Wolmark, Soonmyung Paik, Katherine L. Pogue-Geile. Association of the FCGR2A and FCGR3A genotypes wi