Prognostic and predictive impact of biologic classification by qRT-PCR with a 50-gene subtype predictor (PAM50) for adjuvant tamoxifen in premenopausal breast cancer: Results from the NCIC CTG MA.12 randomized trial.

Abstract

508 Background: Gene expression profiling has reclassified breast cancer into intrinsic subtypes based on the biology of the underlying disease pathways. We have utilized material from a prospective randomized trial of tamoxifen versus placebo in premenopausal women with primary breast cancer who have completed adjuvant chemotherapy (NCIC CTG MA.12) in order to evaluate the prognostic and predictive significance of intrinsic subtypes as classified by both the PAM50 gene set and an IHC panel of biomarkers. Methods: Total RNA from 399/672 (59%) patients were available for intrinsic subtyping with a 50 gene predictor (PAM50) by qRT-PCR for luminal A, luminal B, HER-2 enriched and basal like subtypes. A tissue microarray (TMA) was also constructed from 492/672 (72%) of the study population to assess a panel of six IHC antibodies (ER, PR, HER2, EGFR, CK 5/6 and Ki67), with established cut-offs, to define the same intrinsic subtypes. Results: There were no apparent differences in baseline characteristics between all patients randomized to the trial and patients with either PAM50 or IHC datasets. PAM50 by qRT- PCR classified 35% as luminal A, 21% luminal B, 18% HER2-enriched and 21% basal-like. Intrinsic subtypes as classified by the PAM50 assay was clearly prognostic for both RFS (p = 0.0003) and OS (p = 0.0002), whereas classification by the IHC panel was not (p = 0.63 and 0.11 for RFS and OS respectively). Luminal subtypes by PAM50 was predictive of tamoxifen benefit (RFS: HR 0.56; 95% CI 0.35-0.90 vs HR 0.80; 95% CI 0.49-1.30 for non-luminal subtypes), though the interaction test was not significant (p = 0.35), whereas neither subtyping by central IHC panel (HR 0.75; 95% CI 0.51-1.09) nor by local ER status was predictive of tamoxifen benefit. Risk of relapse (ROR) modeling with the PAM50 assay will be presented. Conclusions: In the MA.12 study, intrinsic biological classification by qRT-PCR with the PAM50 assay is superior to IHC profiling for both prognosis, and prediction of benefit from hormone therapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration University Genomics Bioclassifier LLC