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

• Published in: Journal of personalized medicine Vol. 12; no. 10; p. 1595
• Main Authors: Bonnet, Elise, Haddad, Véronique, Quesada, Stanislas, Baffert, Kim-Arthur, Lardy-Cléaud, Audrey, Treilleux, Isabelle, Pissaloux, Daniel, Attignon, Valéry, Wang, Qing, Buisson, Adrien, Heudel, Pierre-Etienne, Bachelot, Thomas, Dufresne, Armelle, Eberst, Lauriane, Toussaint, Philippe, Bonadona, Valérie, Lasset, Christine, Viari, Alain, Sohier, Emilie, Paindavoine, Sandrine, Combaret, Valérie, Pérol, David, Ray-Coquard, Isabelle, Blay, Jean-Yves, Trédan, Olivier
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 27-09-2022; MDPI
• Subjects: BRCA1 protein; Breast cancer; Cancer therapies; Chemotherapy; Disease control; DNA methylation; Genes; Genetic counseling; Genetic engineering; Genomes; Homologous recombination; Homologous recombination repair; Life Sciences; Metastases; Metastasis; Mutation; Next-generation sequencing; Patients; Platinum; Precision medicine; Tumors; United States > US; Switzerland
• ISSN: 2075-4426; 2075-4426
• DOI: 10.3390/jpm12101595

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 BRCA1/2 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 BRCA1 and RAD51C 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 BRCA1/2, mutations in other HRR genes (BRCA1/2 excluded) or BRCA1/RAD51C 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 BRCA1/2 were detected in seven (13.5%) patients, while alterations in other HRR genes or hypermethylation in BRCA1 or RAD51C were reported in 16 (30.7%) patients; furthermore, no alteration was found in the majority of patients (n = 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; p = 0.049). Regarding group B, patients with disease control exhibited mutations in FANCL, FANCA and the RAD51D genes or RAD51C methylation; Conclusion: mutations in HRR genes and epimutations in RAD51C were associated with disease control through platinum-based chemotherapy. As such, apart from well-characterized alterations in BRCA1/2, 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.