Journal of Personalized Medicine (Sep 2022)

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

  • Elise Bonnet,
  • Véronique Haddad,
  • Stanislas Quesada,
  • Kim-Arthur Baffert,
  • Audrey Lardy-Cléaud,
  • Isabelle Treilleux,
  • Daniel Pissaloux,
  • Valéry Attignon,
  • Qing Wang,
  • Adrien Buisson,
  • Pierre-Etienne Heudel,
  • Thomas Bachelot,
  • Armelle Dufresne,
  • Lauriane Eberst,
  • Philippe Toussaint,
  • Valérie Bonadona,
  • Christine Lasset,
  • Alain Viari,
  • Emilie Sohier,
  • Sandrine Paindavoine,
  • Valérie Combaret,
  • David Pérol,
  • Isabelle Ray-Coquard,
  • Jean-Yves Blay,
  • Olivier Trédan

DOI
https://doi.org/10.3390/jpm12101595
Journal volume & issue
Vol. 12, no. 10
p. 1595

Abstract

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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.

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