A RAD51 functional assay as a candidate test for homologous recombination deficiency in ovarian cancer

Blanc‐Durand, Félix; Yaniz‐Galende, Elisa; Llop‐Guevara, Alba; Genestie, Catherine; Serra, Violeta; Herencia-Ropero, Andrea; Klein, Christophe; Berton, Dominique; Lortholary, Alain; Dohollou, N.; Desauw, Christophe; Fabbro, Michel; Malaurie, E.; Bonichon-Lamaichhane, Nathalie; Dubot, Coraline; Kurtz, Jean Emmanuel; Rauglaudre, Gaëtan De; Raban, Nadia; Chevalier-Place, Annick; Ferron, Gwénaël; Kaminsky, Marie‐Christine; Kramer, Claire J H; Rouleau, Étienne; Leary, Alexandra

doi:10.1016/j.ygyno.2023.01.026

Cited by 14 publications

(14 citation statements)

References 27 publications

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“…In addition, BRCA1 counteracts 53BP1 s inhibition of HR, while BRCA2 plays a role in the loading of RAD51 onto resected DNA ends [96,97]. Mutations in these genes have been associated with an increased risk of developing cancer, particularly breast and ovarian cancers [98].…”

Section: Implications Of the Dsbr On Tumorigenesis And Its Alteration...mentioning

confidence: 99%

Recent Research Advances in Double-Strand Break and Mismatch Repair Defects in Prostate Cancer and Potential Clinical Applications

Jaworski

Brzoszczyk

Szylberg

2023

Cells

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Prostate cancer remains a leading cause of cancer-related death in men worldwide. Recent research advances have emphasized the critical roles of mismatch repair (MMR) and double-strand break (DSB) in prostate cancer development and progression. Here, we provide a comprehensive review of the molecular mechanisms underlying DSB and MMR defects in prostate cancer, as well as their clinical implications. Furthermore, we discuss the promising therapeutic potential of immune checkpoint inhibitors and PARP inhibitors in targeting these defects, particularly in the context of personalized medicine and further perspectives. Recent clinical trials have demonstrated the efficacy of these novel treatments, including Food and Drugs Association (FDA) drug approvals, offering hope for improved patient outcomes. Overall, this review emphasizes the importance of understanding the interplay between MMR and DSB defects in prostate cancer to develop innovative and effective therapeutic strategies for patients.

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Section: Implications Of the Dsbr On Tumorigenesis And Its Alteration...mentioning

confidence: 99%

Recent Research Advances in Double-Strand Break and Mismatch Repair Defects in Prostate Cancer and Potential Clinical Applications

Jaworski

Brzoszczyk

Szylberg

2023

Cells

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“…12 Regarding functional assays of HRD, studies have shown that the RAD51 assay can effectively identify tumors with HRD that are sensitive to platinum and PARP inhibitors, albeit this functional assay has not yet been validated for treatment selection. [13][14][15][16][17][18][19][20] The prevalence of genomic HRD in tumors of RAD51C/D PV carriers has mainly been investigated within large cohorts of pan-cancer HRD analysis. 21 In a small sample, Li et al 22 showed that 7 of 9 cases of RAD51C-associated breast cancer (77.8%) harbored genomic HRD based on a high genomic instability score (GIS) and concomitant gsLOH.…”

Section: Introductionmentioning

confidence: 99%

“…Selection of patients for treatment with a poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitor is currently based on germline BRCA1/2 ( BRCA1 , OMIM 113705; BRCA2 , OMIM 600185) mutation status for breast cancer or platinum sensitivity, BRCA1/2 alteration, or genomic HRD for ovarian cancer . Regarding functional assays of HRD, studies have shown that the RAD51 assay can effectively identify tumors with HRD that are sensitive to platinum and PARP inhibitors, albeit this functional assay has not yet been validated for treatment selection …”

Section: Introductionmentioning

confidence: 99%

Prevalence of Homologous Recombination Deficiency Among Patients With Germline RAD51C/D Breast or Ovarian Cancer

Torres-Esquius,

Llop-Guevara,

Gutiérrez-Enríquez

et al. 2024

JAMA Netw Open

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ImportanceRAD51C and RAD51D are involved in DNA repair by homologous recombination. Germline pathogenic variants (PVs) in these genes are associated with an increased risk of ovarian and breast cancer. Understanding the homologous recombination deficiency (HRD) status of tumors from patients with germline PVs in RAD51C/D could guide therapeutic decision-making and improve survival.ObjectiveTo characterize the clinical and tumor characteristics of germline RAD51C/D PV carriers, including the evaluation of HRD status.Design, Setting, and ParticipantsThis retrospective cohort study included 91 index patients plus 90 relatives carrying germline RAD51C/D PV (n = 181) in Spanish hospitals from January 1, 2014, to December 31, 2021. Genomic and functional HRD biomarkers were assessed in untreated breast and ovarian tumor samples (n = 45) from June 2022 to February 2023.Main Outcomes and MeasuresClinical and pathologic characteristics were assessed using descriptive statistics. Genomic HRD by genomic instability scores, functional HRD by RAD51, and gene-specific loss of heterozygosity were analyzed. Associations between HRD status and tumor subtype, age at diagnosis, and gene-specific loss of heterozygosity in RAD51C/D were investigated using logistic regression or the t test.ResultsA total of 9507 index patients were reviewed, and 91 patients (1.0%) were found to carry a PV in RAD51C/D; 90 family members with a germline PV in RAD51C/D were also included. A total of 157 of carriers (86.7%) were women and 181 (55.8%) had received a diagnosis of cancer, mainly breast cancer or ovarian cancer. The most prevalent PVs were c.1026+5_1026+7del (11 of 56 [19.6%]) and c.709C&gt;T (9 of 56 [16.1%]) in RAD51C and c.694C&gt;T (20 of 35 [57.1%]) in RAD51D. In untreated breast cancer and ovarian cancer, the prevalence of functional and genomic HRD was 55.2% (16 of 29) and 61.1% (11 of 18) for RAD51C, respectively, and 66.7% (6 of 9) and 90.0% (9 of 10) for RAD51D. The concordance between HRD biomarkers was 91%. Tumors with the same PV displayed contrasting HRD status, and age at diagnosis did not correlate with the occurrence of HRD. All breast cancers retaining the wild-type allele were estrogen receptor positive and lacked HRD.Conclusions and RelevanceIn this cohort study of germline RAD51C/D breast cancer and ovarian cancer, less than 70% of tumors displayed functional HRD, and half of those that did not display HRD were explained by retention of the wild-type allele, which was more frequent among estrogen receptor–positive breast cancers. Understanding which tumors are associated with RAD51C/D and HRD is key to identify patients who can benefit from targeted therapies, such as PARP (poly [adenosine diphosphate–ribose] polymerase) inhibitors.

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“…Similarly, Blanc-Durand and colleagues developed an assay to study HR in a chemotherapy treatment context. Their study found that HR deficiency, identified through a RAD51 functional assay, was associated with higher response rates to neoadjuvant platinum chemotherapy and longer progression-free survival in OC [ 173 ]. Another study by Acland et al aimed to identify molecular features specific to chemoresistance in OC using carboplatin-resistant OVCAR5 and CaOV3 cell line models.…”

Section: Introductionmentioning

confidence: 99%

Novel frontiers in urogenital cancers: from molecular bases to preclinical models to tailor personalized treatments in ovarian and prostate cancer patients

De Lazzari,

Opattova,

Arena

2024

J Exp Clin Cancer Res

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Over the last few decades, the incidence of urogenital cancers has exhibited diverse trends influenced by screening programs and geographical variations. Among women, there has been a consistent or even increased occurrence of endometrial and ovarian cancers; conversely, prostate cancer remains one of the most diagnosed malignancies, with a rise in reported cases, partly due to enhanced and improved screening efforts.Simultaneously, the landscape of cancer therapeutics has undergone a remarkable evolution, encompassing the introduction of targeted therapies and significant advancements in traditional chemotherapy. Modern targeted treatments aim to selectively address the molecular aberrations driving cancer, minimizing adverse effects on normal cells. However, traditional chemotherapy retains its crucial role, offering a broad-spectrum approach that, despite its wider range of side effects, remains indispensable in the treatment of various cancers, often working synergistically with targeted therapies to enhance overall efficacy.For urogenital cancers, especially ovarian and prostate cancers, DNA damage response inhibitors, such as PARP inhibitors, have emerged as promising therapeutic avenues. In BRCA-mutated ovarian cancer, PARP inhibitors like olaparib and niraparib have demonstrated efficacy, leading to their approval for specific indications. Similarly, patients with DNA damage response mutations have shown sensitivity to these agents in prostate cancer, heralding a new frontier in disease management. Furthermore, the progression of ovarian and prostate cancer is intricately linked to hormonal regulation. Ovarian cancer development has also been associated with prolonged exposure to estrogen, while testosterone and its metabolite dihydrotestosterone, can fuel the growth of prostate cancer cells. Thus, understanding the interplay between hormones, DNA damage and repair mechanisms can hold promise for exploring novel targeted therapies for ovarian and prostate tumors.In addition, it is of primary importance the use of preclinical models that mirror as close as possible the biological and genetic features of patients’ tumors in order to effectively translate novel therapeutic findings “from the bench to the bedside”.In summary, the complex landscape of urogenital cancers underscores the need for innovative approaches. Targeted therapy tailored to DNA repair mechanisms and hormone regulation might offer promising avenues for improving the management and outcomes for patients affected by ovarian and prostate cancers.

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A RAD51 functional assay as a candidate test for homologous recombination deficiency in ovarian cancer

Cited by 14 publications

References 27 publications

Recent Research Advances in Double-Strand Break and Mismatch Repair Defects in Prostate Cancer and Potential Clinical Applications

Recent Research Advances in Double-Strand Break and Mismatch Repair Defects in Prostate Cancer and Potential Clinical Applications

Prevalence of Homologous Recombination Deficiency Among Patients With Germline RAD51C/D Breast or Ovarian Cancer

Novel frontiers in urogenital cancers: from molecular bases to preclinical models to tailor personalized treatments in ovarian and prostate cancer patients

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