Abstract S3-05: Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in NSABP trial B-31

Abstract

Abstract Purpose: Considerable molecular heterogeneity exists among HER2-positive breast cancer regarding gene expression and mutation profiling. Evidence from preclinical, clinical neoadjuvant, and metastatic clinical trials suggested PIK3CA mutational status and PAM50 intrinsic subtype of a tumor were markers of response to anti-HER2 therapies. We evaluated the predictive value of these two biomarkers in the adjuvant setting using archived tumor blocks from NSABP trial B-31. Methods: Expression data for 49 genes using the nCounter platform was used to generate PAM50 intrinsic subtypes for 1,578 archived tumor blocks from B-31. Five PIK3CA hotspot mutations were examined by mass spectrometry of the primer extension products in a randomly selected subset (N=671). We examined the heterogeneity of trastuzumab treatment effect across different subsets defined by each marker using Cox regression and disease free survival as the endpoint. Results: 741/1578 (47.0%) tumors were classified as HER2E subtype; and 166/671 (24.7%) had PIK3CA mutations. Hazard ratios (HR) for trastuzumab in HER2E and other subtypes were 0.44 (95%CI: 0.34-0.58, p<0.001) and 0.47 (95% CI: 0.35-0.62, p<0.001), respectively (interaction p=0.67). HRs for trastuzumab in PIK3CA wild type and mutated were 0.51 (95%CI: 0.37-0.71, p<0.001) and 0.44 (95%CI: 0.24-0.82, p=0.009), respectively (interaction p=0.64). Conclusion: Unlike results seen in the metastatic and neoadjuvant clinical trials, PIK3CA and PAM50 intrinsic subtypes were not biomarkers for differential response to trastuzumab in NSABP B-31. These data suggest that results from the metastatic and neoadjuvant setting may not be always applicable to the adjuvant setting. Support: National Cancer Institute, Department of Health and Human Services, Public Health Service, Grants U10-CA-12027, U10-CA-69651, U10-CA-37377, and U10-CA-69974, and by a grant from the Pennsylvania State Department of Health. The latter Department specifically disclaims responsibility for any analysis, interpretations or conclusions. Citation Format: Soonmyung Paik, Katherine L Pogue-Geile, Nan Song, Patrick G Gavin, Seong-Rim Kim. Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in NSABP trial B-31 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S3-05.