The CINSARC signature predicts the clinical outcome in patients with Luminal B breast cancer

Anthony Goncalves,Daniel Birnbaum,Pascal Finetti,François Bertucci

doi:10.1038/s41523-021-00256-2

Abstract

CINSARC, a multigene expression signature originally developed in sarcomas, was shown to have prognostic impact in various cancers. We tested the prognostic value for disease-free survival (DFS) of CINSARC in a series of 6035 early-stage invasive primary breast cancers. CINSARC had independent prognostic value in the Luminal B subtype and not in the other subtypes. In Luminal B patients receiving adjuvant endocrine therapy but no chemotherapy, CINSARC identified patients with different 5-year DFS (90% [95%CI 86–95] in low-risk vs. 79% [95%CI 75–84] in high-risk, p = 1.04E−02). Luminal B CINSARC high-risk tumors were predicted to be less sensitive to endocrine therapy and CDK4/6 inhibitors, but more vulnerable to homologous recombination targeting and immunotherapy. We concluded that CINSARC adds prognostic information to that of clinicopathological features in Luminal B breast cancers, which might improve patients’ stratification and better orient adjuvant treatment. Moreover, it identifies potential therapeutic avenues in this aggressive molecular subtype.

Highlights

During the last decades, significant progresses have been achieved in early breast cancer management, most notably through the routine use of post-operative systemic treatment including adjuvant cytotoxic chemotherapy and endocrine therapy[1,2]
We found that CINSARC had independent prognostic value in the Luminal B subtype but not in the other subtypes, notably in patients treated with adjuvant endocrine therapy without chemotherapy, identifying a subset of luminal B breast cancer in which therapeutic de-escalation might be possible
We analyzed our database of 8930 patients with early breast cancer, including 6,035 treated with primary surgery and with available disease-free survival (DFS) data (Supplementary Table 1)

Summary

INTRODUCTION

Significant progresses have been achieved in early breast cancer management, most notably through the routine use of post-operative systemic treatment including adjuvant cytotoxic chemotherapy and endocrine therapy[1,2]. Various prognostic signatures have been established and made commercially available to help identify these patients, and are increasingly used in the clinic[4,5] These signatures distinguish patients with low-, intermediate-, and high-risk of unfavorable outcome, the latter being recommended for adjuvant chemotherapy. Aberrant expression of CINSARC proteins was suggested to favor higher migration and invasion abilities[8,9] All of these features are associated with increased tumor aggressiveness and may explain the potential of this signature to prognosticate the recurrence of cancer across multiple malignancies. We found that CINSARC had independent prognostic value in the Luminal B subtype but not in the other subtypes, notably in patients treated with adjuvant endocrine therapy without chemotherapy, identifying a subset of luminal B breast cancer in which therapeutic de-escalation might be possible. We identified in CINSARC high-risk patients an enrichment in gene signatures associated with response to PARP inhibitors and immunotherapy, providing potential clues to treat these poor-prognosis patients

RESULTS

DISCUSSION

Goncalves et al 6

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