Katherine L Pogue-Geile1, Nan Song1, Jong-Hyeon Jeong1, Patrick G Gavin1, Seong-Rim Kim1, Nicole L Blackmon1, Melanie Finnigan1, Priya Rastogi1, Louis Fehrenbacher1, Eleftherios P Mamounas1, Sandra M Swain1, D Lawrence Wickerham1, Charles E Geyer1, Joseph P Costantino1, Norman Wolmark1, Soonmyung Paik2. 1. Katherine L. Pogue-Geile, Nan Song, 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 Jr, Norman Wolmark, and Soonmyung Paik, National Surgical Adjuvant Breast and Bowel Project (now part of NRG Oncology); Jong-Hyeon Jeong and Joseph P. Costantino, NRG Oncology Statistics and Data Management Center; Jong-Hyeon Jeong and Joseph P. Costantino, Graduate School of Public Health, University of Pittsburgh; Priya Rastogi, University of Pittsburgh Cancer Institute; D. Lawrence Wickerham and Norman Wolmark, Allegheny Cancer Center, Allegheny General Hospital, Pittsburgh, PA; Louis Fehrenbacher, Kaiser-Permanente, Northern California, Vallejo, CA; Eleftherios P. Mamounas, UF Health Cancer Center, Orlando Health, Orlando, FL; Sandra M. Swain, Washington Cancer Institute, Medstar Washington Hospital Center, Washington, DC; Charles E. Geyer Jr, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, VA; and Soonmyung Paik, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea. 2. Katherine L. Pogue-Geile, Nan Song, 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 Jr, Norman Wolmark, and Soonmyung Paik, National Surgical Adjuvant Breast and Bowel Project (now part of NRG Oncology); Jong-Hyeon Jeong and Joseph P. Costantino, NRG Oncology Statistics and Data Management Center; Jong-Hyeon Jeong and Joseph P. Costantino, Graduate School of Public Health, University of Pittsburgh; Priya Rastogi, University of Pittsburgh Cancer Institute; D. Lawrence Wickerham and Norman Wolmark, Allegheny Cancer Center, Allegheny General Hospital, Pittsburgh, PA; Louis Fehrenbacher, Kaiser-Permanente, Northern California, Vallejo, CA; Eleftherios P. Mamounas, UF Health Cancer Center, Orlando Health, Orlando, FL; Sandra M. Swain, Washington Cancer Institute, Medstar Washington Hospital Center, Washington, DC; Charles E. Geyer Jr, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, VA; and Soonmyung Paik, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea. soon.paik@nsabp.org.
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.
PURPOSE: Considerable molecular heterogeneity exists among humanepidermal 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.
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