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Efficacy of platinum-based chemotherapy in metastatic breast cancer and HRD biomarkers: utility of exome sequencing

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Title: Efficacy of platinum-based chemotherapy in metastatic breast cancer and HRD biomarkers: utility of exome sequencing
Authors: Loïck Galland, Elise Ballot, Hugo Mananet, Romain Boidot, Julie Lecuelle, Juliette Albuisson, Laurent Arnould, Isabelle Desmoulins, Didier Mayeur, Courèche Kaderbhai, Silvia Ilie, Audrey Hennequin, Anthony Bergeron, Valentin Derangère, François Ghiringhelli, Caroline Truntzer, Sylvain Ladoire
Source: npj Breast Cancer, Vol 8, Iss 1, Pp 1-12 (2022)
Publisher Information: Nature Portfolio, 2022.
Publication Year: 2022
Collection: LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Subject Terms: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
More Details: Abstract Metastatic breast cancer (MBC) is frequently managed by platinum-based chemotherapy during the disease course. The real benefit of these treatments is uncertain at advanced stages of the disease and in non-triple-negative subtypes. Since homologous recombination deficiency (HRD) could inform about tumor sensitivity to DNA-damaging agents, we aimed to determine biomarkers of genomic instability, and their link with platinum efficacy. In this single-center study, we report BRCA1/2 mutational status, HRD score and signature 3 levels, all obtained by tumor exome sequencing, in 86 patients with various subtypes of MBC and who received platinum-based chemotherapy. Overall response rate, disease control rate, PFS and PFS2/PFS1 ratio were evaluated to assess platinum-based chemotherapy efficacy. Among the 86 tumor samples analyzed, 7 harbored BRCA1/2 mutations. We found a subset of BRCA-proficient MBC with high HRD score or high S3 levels, comparable to BRCA-mutated tumors. However, these patients with high HRD score or high S3 tumor level do not seem to benefit more from platinum-based chemotherapy than the others, in terms of response rates and/or PFS, regardless of BC molecular subtype. By multivariate analysis, only the absence of liver metastases was independently associated with significantly better PFS on platinum-based chemotherapy. However, some of our exploratory analyses reveal that certain methods, when optimized, seem to associate with platinum benefit. Tumor exome sequencing methodology for quantifying HRD has to be approached systematically, and further validated and standardized prior to its clinical use. Further studies are warranted to confirm these results to guide platinum use in MBC.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2374-4677
Relation: https://doaj.org/toc/2374-4677
DOI: 10.1038/s41523-022-00395-0
Access URL: https://doaj.org/article/8c75168bd84843898eaa4679c7af4e30
Accession Number: edsdoj.8c75168bd84843898eaa4679c7af4e30
Database: Directory of Open Access Journals
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  Data: Abstract Metastatic breast cancer (MBC) is frequently managed by platinum-based chemotherapy during the disease course. The real benefit of these treatments is uncertain at advanced stages of the disease and in non-triple-negative subtypes. Since homologous recombination deficiency (HRD) could inform about tumor sensitivity to DNA-damaging agents, we aimed to determine biomarkers of genomic instability, and their link with platinum efficacy. In this single-center study, we report BRCA1/2 mutational status, HRD score and signature 3 levels, all obtained by tumor exome sequencing, in 86 patients with various subtypes of MBC and who received platinum-based chemotherapy. Overall response rate, disease control rate, PFS and PFS2/PFS1 ratio were evaluated to assess platinum-based chemotherapy efficacy. Among the 86 tumor samples analyzed, 7 harbored BRCA1/2 mutations. We found a subset of BRCA-proficient MBC with high HRD score or high S3 levels, comparable to BRCA-mutated tumors. However, these patients with high HRD score or high S3 tumor level do not seem to benefit more from platinum-based chemotherapy than the others, in terms of response rates and/or PFS, regardless of BC molecular subtype. By multivariate analysis, only the absence of liver metastases was independently associated with significantly better PFS on platinum-based chemotherapy. However, some of our exploratory analyses reveal that certain methods, when optimized, seem to associate with platinum benefit. Tumor exome sequencing methodology for quantifying HRD has to be approached systematically, and further validated and standardized prior to its clinical use. Further studies are warranted to confirm these results to guide platinum use in MBC.
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