Alterations in Homologous Recombination-Related Genes and Distinct Platinum Response in Metastatic Triple-Negative Breast Cancers: A Subgroup Analysis of the ProfiLER-01 Trial

Background: a specific subset of metastatic triple-negative breast cancers (mTNBC) is characterized by homologous recombination deficiency (HRD), leading to enhanced sensitivity to platinum-based chemotherapy. Apart from mutations in genes, the evaluation of other HRD-related alterations has been limited to date. As such, we analyzed data from mTNBC patients enrolled in the ProfiLER-01 study to determine the prevalence of alterations in homologous recombination-related (HRR) genes and their association with platinum sensitivity.

Methods: next-generation sequencing and promoter methylation of and were performed on tumors from patients with mTNBC, using a panel of 19 HRR genes. Tumors were separated into three groups based on their molecular status: mutations in , mutations in other HRR genes ( excluded) or promoter methylation and the absence of molecular alterations in HRR genes (groups A, B and C, respectively). Sensitivity to platinum-based chemotherapy was evaluated through the radiological response.

Results: mutations in were detected in seven (13.5%) patients, while alterations in other HRR genes or hypermethylation in or were reported in 16 (30.7%) patients; furthermore, no alteration was found in the majority of patients ( = 29; 55.8%). Among 27 patients who received platinum-based chemotherapy, the disease control rate was 80%, 55% and 18% (groups A, B and C, respectively; = 0.049). Regarding group B, patients with disease control exhibited mutations in , and the genes or methylation; Conclusion: mutations in HRR genes and epimutations in were associated with disease control through platinum-based chemotherapy. As such, apart from well-characterized alterations in , a more comprehensive evaluation of HRD should be considered in order to enlarge the selection of patients with mTNBC that could benefit from platinum-based chemotherapy.