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. 2022 Sep 27;12(10):1595.
doi: 10.3390/jpm12101595.

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  1 , Véronique Haddad  2 , Stanislas Quesada  1   3 , Kim-Arthur Baffert  1   4 , Audrey Lardy-Cléaud  5 , Isabelle Treilleux  2 , Daniel Pissaloux  2   6   7 , Valéry Attignon  2 , Qing Wang  2 , Adrien Buisson  2 , Pierre-Etienne Heudel  1 , Thomas Bachelot  1 , Armelle Dufresne  1 , Lauriane Eberst  8 , Philippe Toussaint  1 , Valérie Bonadona  9   10 , Christine Lasset  9   10 , Alain Viari  11 , Emilie Sohier  11 , Sandrine Paindavoine  2 , Valérie Combaret  2 , David Pérol  5 , Isabelle Ray-Coquard  1   12   13 , Jean-Yves Blay  1   12   13 , Olivier Trédan  1   10
Affiliations

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 et al. J Pers Med. .

Abstract

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.

Keywords: BRCA; DNA repair; HRR genes; TNBC; homologous recombination; platinum-based chemotherapy; triple-negative breast cancer.

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Conflict of interest statement

J.-Y.B.: received research support and honoraria from Astrazeneca, GSK, Novartis; P.-E.H. received grants and non-financial support from AstraZeneca, Roche, Novartis, Pfizer, personal fees from Mylan, personal fees and non-financial support from EISAI, outside the submitted work; I.R.-C.: received honoraria from AstraZeneca, Clovis, Tesaro and PharmaMar; Consulting/advisory board fees from AstraZeneca, Roche, Clovis, Tesaro, Genmab, PharmaMar, MSD and Pfizer, research funding from MSD and BMS, travel expenses from AstraZeneca, GSK and Roche; O.T.: received grants from Roche, MSD-Merck, BMS; personal fees from Roche, MSD-Merck, Novartis-Sandoz, Pfizer, Lilly, Astra-Zeneca, Daiichi Sankyo, Eisai, Pierre Fabre; D.P. (David Pérol): received honoraria from Astrazeneca, BMS, ELI-Lilly, IPSEN, Roche, Novartis, Pierre Fabre, MSD and Takeda, research funding from MSD Avenir, travel expenses from Astrazeneca; T.B.: received grants, advisory board fees and non-financial support from Novartis, AstraZeneca and Pfizer, advisory board fees and non-financial support from Roche, advisory board fees from SeattleGenetics. E.B., V.H., S.Q., K.-A.B., A.L.-C., Q.W., L.E., L.C., V.B., I.T., V.A., V.C., C.L., A.D., E.S., D.P. (Daniel Pissaloux), A.V., S.P., A.B. and P.T. declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Response to platinum-based therapy according to molecular status phenotype. Responses are given for each group taken separately (a), or by comparing patients with or without molecular alteration (groups A + B versus group C respectively) (b). * represents differences with statistical significance (p < 0.05).
Figure 2
Figure 2
Progression-free (a) and overall (b) survivals of patients challenged with platinum-based chemotherapy, according to molecular status.
Figure 3
Figure 3
Site of biopsy, molecular status and radiological response for each patient challenged with platinum-based chemotherapy. A black square indicates the presence of a given molecular alteration.
See this image and copyright information in PMC

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