AbstractCINSARC, 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.