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

Katherine L. Pogue-Geile, Nan Song, Jong Hyeon Jeong, Patrick G. Gavin, Seong Rim Kim, Nicole L. Blackmon, Melanie Finnigan, Priya Rastogi, Louis Fehrenbacher, Eleftherios P. Mamounas, Sandra M. Swain, D. Lawrence Wickerham, Charles E. Geyer, Joseph P. Costantino, Norman Wolmark, Soonmyung Paik

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Purpose: Considerable molecular heterogeneity exists among human epidermal growth factor receptor 2 (HER2) -positive breast cancer regarding gene expression and mutation profiling. Evidence from preclinical, clinical neoadjuvant, and metastatic clinical trials suggested that 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 National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31. Patients and Methods: Expression data for 49 genes using the nCounter platform were used to generate PAM50 intrinsic subtypes for 1,578 archived tumor blocks from patients in the B-31 trial. Six 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 end point. Results: Seven hundred forty-one (47.0%) of 1,578 tumors were classified as HER2-enriched (HER2E) subtype, and 166 (24.7%) of 671 tumors had PIK3CA mutations. Hazard ratios (HRs) for trastuzumab in HER2E and other subtypes were 0.44 (95% CI, 0.34 to 0.58; P < .001) and 0.47 (95% CI, 0.35 to 0.62; P < .001), respectively (interaction P = .67). HRs for trastuzumab in PIK3CA wild-type and mutated tumors were 0.51 (95% CI, 0.37 to 0.71; P < .001) and 0.44 (95% CI, 0.24 to 0.82; P = .009), respectively (interaction P = .64). Conclusion: Unlike results seen in the metastatic and neoadjuvant clinical trials, PIK3CA and PAM50 intrinsic subtypes were not predictive biomarkers for adjuvant 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.

Original languageEnglish (US)
Pages (from-to)1340-1347
Number of pages8
JournalJournal of Clinical Oncology
Volume33
Issue number12
DOIs
StatePublished - Apr 20 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Pogue-Geile, K. L., Song, N., Jeong, J. H., Gavin, P. G., Kim, S. R., Blackmon, N. L., Finnigan, M., Rastogi, P., Fehrenbacher, L., Mamounas, E. P., Swain, S. M., Wickerham, D. L., Geyer, C. E., Costantino, J. P., Wolmark, N., & Paik, S. (2015). Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in the NSABP B-31 trial. Journal of Clinical Oncology, 33(12), 1340-1347. https://doi.org/10.1200/JCO.2014.56.2439