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. 2012 Aug 15;18(16):4465-72.
doi: 10.1158/1078-0432.CCR-12-0286. Epub 2012 Jun 18.

A 50-gene intrinsic subtype classifier for prognosis and prediction of benefit from adjuvant tamoxifen

Stephen K Chia  1 , Vivien H Bramwell, Dongsheng Tu, Lois E Shepherd, Shan Jiang, Tammi Vickery, Elaine Mardis, Samuel Leung, Karen Ung, Kathleen I Pritchard, Joel S Parker, Philip S Bernard, Charles M Perou, Matthew J Ellis, Torsten O Nielsen
Affiliations

A 50-gene intrinsic subtype classifier for prognosis and prediction of benefit from adjuvant tamoxifen

Stephen K Chia et al. Clin Cancer Res. .

Abstract

Purpose: Gene expression profiling classifies breast cancer into intrinsic subtypes based on the biology of the underlying disease pathways. We have used material from a prospective randomized trial of tamoxifen versus placebo in premenopausal women with primary breast cancer (NCIC CTG MA.12) to evaluate the prognostic and predictive significance of intrinsic subtypes identified by both the PAM50 gene set and by immunohistochemistry.

Experimental design: Total RNA from 398 of 672 (59%) patients was available for intrinsic subtyping with a quantitative reverse transcriptase PCR (qRT-PCR) 50-gene predictor (PAM50) for luminal A, luminal B, HER-2-enriched, and basal-like subtypes. A tissue microarray was also constructed from 492 of 672 (73%) of the study population to assess a panel of six immunohistochemical IHC antibodies to define the same intrinsic subtypes.

Results: Classification into intrinsic subtypes by the PAM50 assay was prognostic for both disease-free survival (DFS; P = 0.0003) and overall survival (OS; P = 0.0002), whereas classification by the IHC panel was not. Luminal subtype by PAM50 was predictive of tamoxifen benefit [DFS: HR, 0.52; 95% confidence interval (CI), 0.32-0.86 vs. HR, 0.80; 95% CI, 0.50-1.29 for nonluminal subtypes], although the interaction test was not significant (P = 0.24), whereas neither subtyping by central immunohistochemistry nor by local estrogen receptor (ER) or progesterone receptor (PR) status were predictive. Risk of relapse (ROR) modeling with the PAM50 assay produced a continuous risk score in both node-negative and node-positive disease.

Conclusions: In the MA.12 study, intrinsic subtype classification by qRT-PCR with the PAM50 assay was superior to IHC profiling for both prognosis and prediction of benefit from adjuvant tamoxifen.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

J. Parker is an author of the patent (in part) for the PAM50 assay. P.S. Bernard, C.M. Perou, M.J. Ellis, and T.O. Nielsen have ownership interest (including patents) in Bioclassifier LLC. No potential conflict of interests were disclosed by other authors.

Figures

Figure 1
Figure 1
Prognosis based on PAM50 classifier for DFS (A) and OS (B).
Figure 2
Figure 2
Probability of disease event at 10 years based on the ROR-T model.
Figure 3
Figure 3
A, Kaplan–Meier curves for DFS among ER+ (local assessment) patients for tamoxifen versus placebo. B, Kaplan–Meier curves for DFS among luminal subtypes by immunohistochemistry for tamoxifen versus placebo. C, Kaplan–Meier curves for DFS among luminal subtypes by PAM50 for tamoxifen versus placebo.
See this image and copyright information in PMC

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