The Prosigna gene expression assay and responsiveness to adjuvant cyclophosphamide-based chemotherapy in premenopausal high-risk patients with breast cancer

Abstract

BackgroundThe PAM50-based (Prosigna) risk of recurrence (ROR) score and intrinsic subtypes are prognostic for women with high-risk breast cancer. We investigate the predictive ability of Prosigna regarding the effectiveness of cyclophosphamide-based adjuvant chemotherapy in premenopausal patients with high-risk breast cancer.MethodsProsigna assays were performed on the NanoString platform in tumors from participants in Danish Breast Cancer Group (DBCG) 77B, a four-arm trial that randomized premenopausal women with high-risk early breast cancer to no systemic treatment, levamisole, oral cyclophosphamide (C) or cyclophosphamide, methotrexate and fluorouracil (CMF).ResultsIn total, this retrospective analysis included 460 women (40% of the 1146 randomized patients). The continuous Prosigna ROR score was prognostic in the no systemic treatment group (unadjusted P < 0.001 for disease-free survival (DFS), P = 0.001 for overall survival (OS)). No statistically significant interaction of continuous ROR score and treatment on DFS and OS was found. A highly significant association was observed between intrinsic subtypes and C/CMF treatment for DFS (Pinteraction = 0.003 unadjusted, P = 0.001 adjusted) and OS (Pinteraction = 0.04). In the adjusted analysis treatment with C/CMF was associated with a reduced risk of DFS events in patients with basal-like (hazard ratio (HR) 0.14; 95% CI 0.06; 0.32) and luminal B (HR 0.48; 95% CI 0.27; 0.84) subtypes but not in patients with Human epidermal growth factor receptor-enriched (HR 1.05; 95% CI 0.56; 1.95) or luminal A (HR 0.61; 95% CI 0.32; 1.16) subtypes.ConclusionThe Prosigna ROR score and intrinsic subtypes were prognostic in high-risk premenopausal patients with breast cancer, and intrinsic subtypes identify high-risk patients with or without major benefit from adjuvant C/CMF treatment.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1012-0) contains supplementary material, which is available to authorized users.

Summary of head‐to‐head comparisons of patient risk classifications by the 21‐gene Recurrence Score® (RS) assay and other genomic assays for early breast cancer

“…The prognostic value of ROR scores has been demonstrated in the transATAC and ABCSG08 studies, showing that the low ROR or Luminal A intrinsic subtype is associated with a very low 10 years distant recurrence . More recently, the Prosigna ROR score and intrinsic subtypes were shown to be prognostic in high‐risk premenopausal patients with early breast cancer, and intrinsic subtype was predictive for adjuvant C/CMF treatment in this study . No prospective data on Prosigna are available for predictive power for treatment benefit however.…”

“…4,8,16,19 More recently, the Prosigna ROR score and intrinsic subtypes were shown to be prognostic in high-risk premenopausal patients with early breast cancer, and intrinsic subtype was predictive for adjuvant C/CMF treatment in this study. 28 No prospective data on Prosigna are available for predictive power for treatment benefit however.…”

The Prosigna 50-gene profile and responsiveness to adjuvant anthracycline-based chemotherapy in high-risk breast cancer patients

“…While patients with a Her2-enriched subtype achieved the greatest benefit from allocation to CEF in this study, premenopausal patients with T3 or node positive breast cancer, and a Her2enriched subtype obtained no benefit from cyclophosphamidebased chemotherapy as compared to no chemotherapy in the DBCG 77B trial. 7 At that time, HER2 targeted therapy was not available for patients with HER2 overexpressing or amplified breast cancers, and with anti-HER2 therapy the effect of anthracyclines on the Her2-enriched subtype might be less clear. Patients with luminal breast cancer derived no significant benefit from substitution of methotrexate (in CMF) with epirubicin (in CEF), although the risk of permanent cessation of menses among premenopausal patients was higher in the CEF compared to the CMF group.…”

“…Lack of benefit from adjuvant CMF or cyclophosphamide was predicted by the Prosigna Risk Of Recurrence (ROR) score and by intrinsic subtypes in a recent retrospective analysis of the Danish Breast Cancer Group (DBCG) 77B trial that randomized premenopausal high-risk patients with early breast cancer to adjuvant chemotherapy vs. no chemotherapy. 7 A Basal-like subtype was associated with an 86% reduction in disease-free survival (DFS) event while no benefit was obtained by patients with an HER2-enriched subtype. Patients with a Luminal B subtype had a significant 52% reduction in DFS events while no significant benefit (39% improved DFS) was obtained by patients with a Luminal A subtype.…”

“…Patients with a Luminal B subtype had a significant 52% reduction in DFS events while no significant benefit (39% improved DFS) was obtained by patients with a Luminal A subtype. 7 Greater benefits were on average achieved by anthracycline containing regimens as compared to CMF-based adjuvant chemotherapy. 1,2 Anthracyclines are cardiotoxic and leukemogenic, but in the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis were not associated with an excess mortality caused by cardiac disease or leukemia.…”