TY - JOUR
T1 - Prognostic and predictive investigation of PAM50 intrinsic subtypes in the NCIC CTG MA.21 phase III chemotherapy trial
AU - Liu, Shuzhen
AU - Chapman, Judy Anne W.
AU - Burnell, Margot J.
AU - Levine, Mark N.
AU - Pritchard, Kathleen I.
AU - Whelan, Timothy J.
AU - Rugo, Hope S.
AU - Albain, Kathy S.
AU - Perez, Edith A.
AU - Virk, Shakeel
AU - Barry, Garrett
AU - Gao, Dongxia
AU - O’Brien, Patti
AU - Shepherd, Lois E.
AU - Nielsen, Torsten O.
AU - Gelmon, Karen A.
N1 - Funding Information:
This study was funded by a grant from the Susan G Komen Foundation and supported by provision of reagents from NanoString Technologies. The NCIC CTG MA.21 trial was funded by the Canadian Cancer Society, through a Program Grant from the Canadian Cancer Research Institute to NCIC CTG, Pfizer, Bristol-Myers Squibb, Amgen, Janssen Ortho, Ortho Biotech, and the US NCI. We thank Dr. David Huntsman for providing facility support at the BC Cancer Agency’s Center for Translational and Applied Genomics; and Sherman Lau at the Genetic Pathology Evaluation Centre and Dr. Sean Ferree at the NanoString Technologies for assisting in primary data generation.
Funding Information:
K. I. Pritchard has remuneration and consultant/advisory role at Sanofi-Aventis, AstraZeneca, Pfizer, Roche, Amgen, Novartis, GlaxoSmithKline, Boehringer Ingelheim, Genomic Health, and Eisai. H. S. Rugo has funding from Plexxikon, Macrogenics, OBI, Eisai, Pfizer, Novartis, Lilly, GSK, Genentech, Celsion, Nektar, and Merck. K. S. Albain has consultant/advisory role at BioTheranostics, Genentech, Roche, Pfizer Novartis, and Novartis. T.O. Nielsen has ownership at Bioclassifier LLC, consultant/advisory role and funding from NanoString Technologies. No potential conflicts of interests were disclosed by other authors.
Publisher Copyright:
© 2015, Springer Science+Business Media New York.
PY - 2015/1
Y1 - 2015/1
N2 - PAM50-defined breast cancer intrinsic subtypes and risk-of-relapse (ROR) scores are prognostic and predictive of endocrine therapy and some chemotherapy. We investigated the prognostic and predictive effect of PAM50 classifications by chemotherapy type. NCIC CTG MA.21 randomized 2,104 patients to doxorubicin, cyclophosphamide, and paclitaxel (AC/T); dose-intense cyclophosphamide, epirubicin, and flurouracil (CEF); or dose-dense, dose-intense epirubicin, cyclophosphamide, and paclitaxel (EC/T). Patients were ≤60 years, with node-positive or high-risk node-negative disease, with median 8-year follow-up. Intrinsic subtypes and ROR were determined from RNA extracted from formalin-fixed paraffin-embedded sections by the NanoString PAM50 test. Univariate effects on relapse-free survival (RFS) were assessed with stratified log-rank test; multivariate analyses utilized stratified Cox regression. Among 1094 cases completing PAM50 intrinsic subtyping, 27 % were classified as luminal A, 23 % luminal B, 18 % HER2E, and 32 % basal-like. CEF and EC/T were superior to AC/T (p = 0.01). Higher continuous ROR was multivariately associated with worse RFS (p = 0.03), although categorical ROR was neither prognostic nor predictive. Intrinsic subtypes had a significant multivariate prognostic effect on RFS (p = 0.002). Compared with luminal A, hazard ratios were luminal B = 1.48 (95 % CI 0.92–2.37); HER2E = 2.68 (95 % CI 1.60–4.48); and basal-like = 1.97 (95 % CI 1.10–3.53). Intrinsic subtypes were not predictive of treatment benefit (AC/T vs. EC/T + CEF); however, subgroup analysis indicated subtypes (non-luminal vs. luminal) was predictive of taxane benefit (EC/T vs. CEF; p = 0.05). Both NanoString PAM50 subtypes and continuous ROR had significant prognostic effects on RFS for breast cancer patients treated with CEF, EC/T, and AC/T. Non-luminal tumors differentially responded to EC/T (with taxane) over CEF.
AB - PAM50-defined breast cancer intrinsic subtypes and risk-of-relapse (ROR) scores are prognostic and predictive of endocrine therapy and some chemotherapy. We investigated the prognostic and predictive effect of PAM50 classifications by chemotherapy type. NCIC CTG MA.21 randomized 2,104 patients to doxorubicin, cyclophosphamide, and paclitaxel (AC/T); dose-intense cyclophosphamide, epirubicin, and flurouracil (CEF); or dose-dense, dose-intense epirubicin, cyclophosphamide, and paclitaxel (EC/T). Patients were ≤60 years, with node-positive or high-risk node-negative disease, with median 8-year follow-up. Intrinsic subtypes and ROR were determined from RNA extracted from formalin-fixed paraffin-embedded sections by the NanoString PAM50 test. Univariate effects on relapse-free survival (RFS) were assessed with stratified log-rank test; multivariate analyses utilized stratified Cox regression. Among 1094 cases completing PAM50 intrinsic subtyping, 27 % were classified as luminal A, 23 % luminal B, 18 % HER2E, and 32 % basal-like. CEF and EC/T were superior to AC/T (p = 0.01). Higher continuous ROR was multivariately associated with worse RFS (p = 0.03), although categorical ROR was neither prognostic nor predictive. Intrinsic subtypes had a significant multivariate prognostic effect on RFS (p = 0.002). Compared with luminal A, hazard ratios were luminal B = 1.48 (95 % CI 0.92–2.37); HER2E = 2.68 (95 % CI 1.60–4.48); and basal-like = 1.97 (95 % CI 1.10–3.53). Intrinsic subtypes were not predictive of treatment benefit (AC/T vs. EC/T + CEF); however, subgroup analysis indicated subtypes (non-luminal vs. luminal) was predictive of taxane benefit (EC/T vs. CEF; p = 0.05). Both NanoString PAM50 subtypes and continuous ROR had significant prognostic effects on RFS for breast cancer patients treated with CEF, EC/T, and AC/T. Non-luminal tumors differentially responded to EC/T (with taxane) over CEF.
KW - Breast cancer
KW - Clinical trial
KW - PAM50 classification
KW - Predictive effect
KW - Survival analysis
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U2 - 10.1007/s10549-014-3259-1
DO - 10.1007/s10549-014-3259-1
M3 - Article
C2 - 25552364
AN - SCOPUS:84925532936
SN - 0167-6806
VL - 149
SP - 439
EP - 448
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 2
ER -