PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline- and taxane-based chemotherapy: correlative analysis of C9741 (Alliance)

Abstract

PAM50 intrinsic breast cancer subtypes are prognostic independent of standard clinicopathologic factors. CALGB 9741 demonstrated improved recurrence-free (RFS) and overall survival (OS) with 2-weekly dose-dense (DD) versus 3-weekly therapy. A significant interaction between intrinsic subtypes and DD-therapy benefit was hypothesized. Suitable tumor samples were available from 1,471 (73%) of 2,005 subjects. Multiplexed gene-expression profiling generated the PAM50 subtype call, proliferation score, and risk of recurrence score (ROR-PT) for the evaluable subset of 1,311 treated patients. The interaction between DD-therapy benefit and intrinsic subtype was tested in a Cox proportional hazards model using two-sided alpha = 0.05. Additional multivariable Cox models evaluated the proliferation and ROR-PT scores as continuous measures with selected clinical covariates. Improved outcomes for DD therapy in the evaluable subset mirrored results from the complete data set (RFS; hazard ratio = 1.20; 95% confidence interval = 0.99-1.44) with 12.3-year median follow-up. Intrinsic subtypes were prognostic of RFS (P < 0.0001) irrespective of treatment assignment. No subtype-specific treatment effect on RFS was identified (interaction P = 0.44). Proliferation and ROR-PT scores were prognostic for RFS (both P < 0.0001), but no association with treatment benefit was seen (P = 0.14 and 0.59, respectively). Results were similar for OS. The prognostic value of PAM50 intrinsic subtype was greater than estrogen receptor/HER2 immunohistochemistry classification. PAM50 gene signatures were highly prognostic but did not predict for improved outcomes with DD anthracycline- and taxane-based therapy. Clinical validation studies will assess the ability of PAM50 and other gene signatures to stratify patients and individualize treatment based on expected risks of distant recurrence.

Figure 1

(a) Kaplan–Meier plot of RFS in C9741 patients classified by PAM50 intrinsic subtype: basal-like, HER2-E, LumA, and LumB. (b) Kaplan–Meier plot of OS in C9741 patients classified by PAM50 intrinsic subtype: basal-like, HER2-E, LumA, and LumB. OS, overall survival; RFS, recurrence-free survival.

Figure 2

Forest plot displaying hazard ratios (HR) and 95% confidence intervals (CI) for RFS with DD therapy in patient subgroups from C9741 defined by tumor characteristics (number of positive nodes and tumor size), PAM50 assay (intrinsic subtype, proliferation score, and ROR-PT score), and immunohistochemistry (ER/HER2, Ki67, CK5/6, and EGFR). CK, cytokeratin; DD, dose dense; EGFR, epidermal growth factor receptor; ER, estrogen receptor; IHC, immunohistochemistry; N, number of subjects; RFS, recurrence-free survival; ROR-PT, risk of recurrence score.

Figure 3

(a) Scatterplot of proliferation and ROR-PT scores labeled by intrinsic subtype: basal-like (red), HER2-E (pink), LumA (dark blue), and LumB (light blue). Cutpoints that divide each score into tertiles are shown in gray. (b) Kaplan–Meier plot and 5-year RFS estimates for the low, intermediate (inter.), and high subgroups of proliferation (prolif.) scores. (c) Kaplan–Meier plot and 5-year RFS estimates for the low, intermediate, and high subgroups of ROR-PT scores. CI, confidence interval; RFS, recurrence-free survival; ROR-PT, risk of recurrence score.