Open Collections

UBC Faculty Research and Publications

Prognostic and predictive investigation of PAM50 intrinsic subtypes in the NCIC CTG MA.21 phase III chemotherapy trial Liu, Shuzhen; Chapman, Judy-Anne W.; Burnell, Margot J.; Levine, Mark N.; Pritchard, Kathleen I.; Whelan, Timothy J.; Rugo, Hope S.; Albain, Kathy S.; Perez, Edith A.; Virk, Shakeel; Barry, Garrett; Gao, Dongxia; O’Brien, Patti; Shepherd, Lois E.; Nielsen, Torsten; Gelmon, Karen A.

Abstract

Purpose: 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. Methods: NCIC CTG MA.21 randomized 2104 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 paraffinembedded 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. Results: 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); basallike=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) were predictive of taxane benefit (EC/T vs. CEF; p=0.05). Conclusion: 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.

Item Metadata

Title
Prognostic and predictive investigation of PAM50 intrinsic subtypes in the NCIC CTG MA.21 phase III chemotherapy trial
Creator
Liu, Shuzhen; Chapman, Judy-Anne W.; Burnell, Margot J.; Levine, Mark N.; Pritchard, Kathleen I.; Whelan, Timothy J.; Rugo, Hope S.; Albain, Kathy S.; Perez, Edith A.; Virk, Shakeel; Barry, Garrett; Gao, Dongxia; O’Brien, Patti; Shepherd, Lois E.; Nielsen, Torsten; Gelmon, Karen A.
Contributor
Vancouver Coastal Health Authority. Research Institute; BC Cancer Agency
Publisher
Breast Cancer Research and Treatment
Date Issued
2015-01
Description
Purpose: 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. Methods: NCIC CTG MA.21 randomized 2104 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 paraffinembedded 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. Results: 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); basallike=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) were predictive of taxane benefit (EC/T vs. CEF; p=0.05). Conclusion: 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.
Subject
PAM50 classification; breast cancer; clinical trial; predictive effect; survival analysis
Genre
Article; Postprint
Type
Text
Language
eng
Date Available
2021-06-24
Provider
Vancouver : University of British Columbia Library
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
DOI
10.14288/1.0398526
URI
http://hdl.handle.net/2429/78792
Affiliation
Medicine, Faculty of; Non UBC; Pathology and Laboratory Medicine, Department of
Citation
Liu S, Chapman JA, Burnell MJ, Levine MN, Pritchard KI, Whelan TJ, Rugo HS, Albain KS, Perez EA, Virk S, Barry G, Gao D, O'Brien P, Shepherd LE, Nielsen TO, Gelmon KA. Prognostic and predictive investigation of PAM50 intrinsic subtypes in the NCIC CTG MA.21 phase III chemotherapy trial. Breast Cancer Res Treat. 2015 Jan;149(2):439-48
Publisher DOI
10.1007/s10549-014-3259-1
Peer Review Status
Reviewed
Scholarly Level
Faculty; Researcher; Undergraduate
Rights URI
http://creativecommons.org/licenses/by-nc-nd/4.0/
Aggregated Source Repository
DSpace

Item Media

Item Citations and Data

Rights

Attribution-NonCommercial-NoDerivatives 4.0 International