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Clinical Trial
. 2012 Apr 15;18(8):2402-12.
doi: 10.1158/1078-0432.CCR-11-2956. Epub 2012 Feb 20.

Responsiveness of intrinsic subtypes to adjuvant anthracycline substitution in the NCIC.CTG MA.5 randomized trial

Maggie C U Cheang  1 , K David Voduc, Dongsheng Tu, Shan Jiang, Samuel Leung, Stephen K Chia, Lois E Shepherd, Mark N Levine, Kathleen I Pritchard, Sherri Davies, Inge J Stijleman, Carole Davis, Mark T W Ebbert, Joel S Parker, Matthew J Ellis, Philip S Bernard, Charles M Perou, Torsten O Nielsen
Affiliations
Clinical Trial

Responsiveness of intrinsic subtypes to adjuvant anthracycline substitution in the NCIC.CTG MA.5 randomized trial

Maggie C U Cheang et al. Clin Cancer Res. .

Abstract

Purpose: Recent studies suggest that intrinsic breast cancer subtypes may differ in their responsiveness to specific chemotherapy regimens. We examined this hypothesis on NCIC.CTG MA.5, a clinical trial randomizing premenopausal women with node-positive breast cancer to adjuvant CMF (cyclophosphamide-methotrexate-fluorouracil) versus CEF (cyclophosphamide-epirubicin-fluorouracil) chemotherapy.

Experimental design: Intrinsic subtype was determined for 476 tumors using the quantitative reverse transcriptase PCR PAM50 gene expression test. Luminal A, luminal B, HER2-enriched (HER2-E), and basal-like subtypes were correlated with relapse-free survival (RFS) and overall survival (OS), estimated using Kaplan-Meier plots and log-rank testing. Multivariable Cox regression analyses determined significance of interaction between treatment and intrinsic subtypes.

Results: Intrinsic subtypes were associated with RFS (P = 0.0005) and OS (P < 0.0001) on the combined cohort. The HER2-E showed the greatest benefit from CEF versus CMF, with absolute 5-year RFS and OS differences exceeding 20%, whereas there was a less than 2% difference for non-HER2-E tumors (interaction test P = 0.03 for RFS and 0.03 for OS). Within clinically defined Her2(+) tumors, 79% (72 of 91) were classified as the HER2-E subtype by gene expression and this subset was strongly associated with better response to CEF versus CMF (62% vs. 22%, P = 0.0006). There was no significant difference in benefit between CEF and CMF in basal-like tumors [n = 94; HR, 1.1; 95% confidence interval (CI), 0.6-2.1 for RFS and HR, 1.3; 95% CI, 0.7-2.5 for OS].

Conclusion: HER2-E strongly predicted anthracycline sensitivity. The chemotherapy-sensitive basal-like tumors showed no added benefit for CEF over CMF, suggesting that nonanthracycline regimens may be adequate in this subtype although further investigation is required.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest: J.S. Parker has ownership interest (including patents) and is coauthor of patent pending on PAM50 assay. M.J. Ellisand, P.S. Bernard, and T.O. Nielsen have ownership interest (including patents) at Bioclassifier LLC. T.O. Nielsen is the Consultant/Advisory Board member at Nanostring Technologies. No potential conflicts of interest were disclosed by the other authors.

Figures

Figure 1
Figure 1
RFS and OS by ROR-S risk of relapse score, stratified by adjuvant treatment arm (A and B, CMF; C and D, CEF).
Figure 2
Figure 2
Multivariable Cox regression analysis adjusted HR plots by PAM50 intrinsic subtype, adjusted for clinicopathologic variables.
Figure 3
Figure 3
Univariate RFS and OS Kaplan–Meier plots of treatment arms, CEF versus CMF, stratified by intrinsic subtypes (A–D, RFS; E– H, OS).
See this image and copyright information in PMC

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