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

Bonnet, Elise; Haddad, Véronique; Quesada, Stanislas; Baffert, Kim-Arthur; Lardy-Cléaud, Audrey; Treilleux, Isabelle; Pissaloux, Daniel; Attignon, Valéry; Wang, Qing; Buisson, Adrien; Heudel, Pierre-Étienne; 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

doi:10.3390/jpm12101595

Cited by 5 publications

(6 citation statements)

References 32 publications

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“…A theoretical interest for DNA damaging chemotherapy drugs in the treatment of HR defective cancers arise from the reduced ability of these cancers to repair defects induced by these drugs. Consistent with this assumption, in the sub-set of patients with HR defects in the Profiler-01 trial who received cisplatin, Disease Control Rate (DCR) was 80% in patients with BRCA1 or BRCA2 mutations, 55% in patients with other DDR gene mutations or BRCA1 or RAD51C promoter methylations and 18% in patients without alterations (47). Patients with mutations in FANCL, FANCA and RAD51D and methylation in RAD51C were those among whom platinum treatment led to control of the disease.…”

Section: Platinum and Other Chemotherapy Regimens In Breast Cancers W...mentioning

confidence: 77%

Homologous Recombination Defects and Mutations in DNA Damage Response (DDR) Genes BesidesBRCA1andBRCA2as Breast Cancer Biomarkers for PARP Inhibitors and Other DDR Targeting Therapies

Voutsadakis

Stravodimou

2023

Anticancer Res

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Homologous recombination repair (HRR) is the cellular mechanism for error-free repair of double strand DNA (dsDNA) breaks. Cancer cells with mutations in both alleles of genes encoding for proteins involved in HRR, such as BRCA1 and BRCA2, have defects in the repair process. As a result, these cells repair dsDNA breaks with alternative mechanisms, such as non-homologous end joining. In breast cancers with germline mutations in BRCA1 and BRCA2 genes, HRR defects result in sensitivity to PARP inhibitors, drugs that interfere with the function of PARP enzyme and promote trapping of the enzyme on DNA and stalling of the process of repairing single strand breaks. HRR defects also lead to sensitivity to DNA damaging chemotherapy due to the inability of cells to repair chemotherapy induced DNA lesions. Besides germline mutations in BRCA1 and BRCA2, somatic mutations in these genes or germline and somatic mutations or other genetic and epigenetic alterations of other genes involved in homologous recombination (HR) may produce HRR defects leading to sensitivity to PARP inhibitors. However, studies are less conclusive, a fact that may relate to the common lack of bi-allelic loss of function in these cases, as opposed to cancers with germline BRCA1 or BRCA2 defects that usually acquire bi-allelic loss of function. In addition, there is heterogeneity between the different HRR genes and the severity of the resulting HRR defects, as measured by HR defect assays. This review article examines the landscape of HRR gene mutations in breast cancer and the possible therapeutic implications of HRR defects other than germline BRCA1 and BRCA2 mutations for targeted therapies. Identification of a wider range of breast cancers with HRR defects may expand the subset of patients that derive benefit from PARP inhibitors and other DDR-targeting drugs in the clinic.

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Section: Platinum and Other Chemotherapy Regimens In Breast Cancers W...mentioning

confidence: 77%

Homologous Recombination Defects and Mutations in DNA Damage Response (DDR) Genes BesidesBRCA1andBRCA2as Breast Cancer Biomarkers for PARP Inhibitors and Other DDR Targeting Therapies

Voutsadakis

Stravodimou

2023

Anticancer Res

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“…DNA methylation in triple-negative breast cancers affects many cellular responses, including the response to endoplasmic reticulum stress [38]. In addition, the methylation of homologous recombination gene promoters such as BRCA1 and RAD51C lead to homologous recombination-deficient breast cancer development in sporadic cases [39].…”

Section: Discussionmentioning

confidence: 99%

EMT Features in Claudin-Low versus Claudin-Non-Suppressed Breast Cancers and the Role of Epigenetic Modifications

Voutsadakis

2023

CIMB

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Background: Breast cancers are heterogeneous and are classified according to the expression of ER, PR and HER2 receptors to distinct groups with prognostic and therapeutic implications. Within the triple-negative group, with no expression of these three receptors, molecular heterogeneity exists but is currently not exploited in the clinic. The claudin-low phenotype is present in a subset of triple-negative breast cancers and constitutes together with basal-like cancers the most extensive groups within triple-negative breast cancers. Suppression of epithelial cell adhesion molecules in claudin-low cancers is also a hallmark of Epithelial Mesenchymal Transition (EMT). Methods: The groups of claudin-low and claudin-non-suppressed breast cancers from the extensive publicly available genomic cohorts of the METABRIC study were examined to delineate and compare their molecular landscape. Genetic and epigenetic alterations of key factors involved in EMT and potentially associated with the pathogenesis of the claudin-low phenotype were analyzed in the two groups. Results: Claudin-low cancers displayed up-regulation of several core transcription factors of EMT at the mRNA level, compared with claudin-non-suppressed breast cancers. Global promoter DNA methylation was increased in both groups of triple-negative cancers and in claudin-low ER-positive cancers compared with the rest of ER-positive cancers. Histone modifier enzymes, including methyltransferases, demethylases, acetyltransferases and deacetylases displayed amplifications more frequently in claudin-non-suppressed triple-negative cancers than in claudin-low counterparts and the expression of some of these enzymes differed significantly between the two groups. Conclusion: Claudin-low and claudin-non-suppressed triple-negative breast cancers differ in their landscape of EMT core regulators and epigenetic regulators. These differences may be explored as targets for therapeutic interventions specific to the two groups of triple-negative breast cancers.

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“…The everolimus, pazopanib and lapatinib cohorts are closed to enrolment and under analysis. Although there is a randomisation for comparative analysis, a potential limitation in the including patients with gastro-oesophageal cancers [7], patients with alterations in homologous recombination-related genes and distinct platinum response in metastatic triple-negative breast cancers [8], patients with primary brain tumours [9], refractory gynaecological cancers [10], metastatic sarcomas [11] and paediatric tumours [12].…”

Section: Mostmentioning

confidence: 99%

The French multicentric molecular analysis platforms and personalized medicine trials MOST, MOST Plus and MEGAMOST

Verlingue,

Desevre,

Polito

et al. 2024

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Background and purpose: In this manuscript we describe the academic French multicentric molecular analysis platforms including PROFILER, promoted by Centre Léon Berard, and the multicentric personalized medicine trials MOST, MOST Plus and MEGAMOST. Patients/material and methods: MOST, MOST Plus and MEGAMOST comprise 14 cohorts with different targeted agents and immunotherapies. Results and interpretation: PROFILER has recruited 5,991 patients in 10 years, MOST and MOST Plus 875 patients since 2014 and MEGAMOST 172 patients since 2020, and are still ongoing. We provide a description of the local, national and international implications of these initiatives, and we review the results of the sorafenib and olaparib cohorts.

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

Cited by 5 publications

References 32 publications

Homologous Recombination Defects and Mutations in DNA Damage Response (DDR) Genes BesidesBRCA1andBRCA2as Breast Cancer Biomarkers for PARP Inhibitors and Other DDR Targeting Therapies

Homologous Recombination Defects and Mutations in DNA Damage Response (DDR) Genes BesidesBRCA1andBRCA2as Breast Cancer Biomarkers for PARP Inhibitors and Other DDR Targeting Therapies

EMT Features in Claudin-Low versus Claudin-Non-Suppressed Breast Cancers and the Role of Epigenetic Modifications

The French multicentric molecular analysis platforms and personalized medicine trials MOST, MOST Plus and MEGAMOST

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