RAD51 Foci as a Biomarker Predictive of Platinum Chemotherapy Response in Ovarian Cancer

Compadre, Amanda J.; Biljon, Lillian N. van; Valentine, Mark C.; Llop‐Guevara, Alba; Graham, Emily; Fashemi, Bisiayo; Herencia-Ropero, Andrea; Kotnik, Emilee N.; Cooper, Isaac; Harrington, Shariska P.; Kuroki, Lindsay M.; McCourt, Carolyn K.; Hagemann, Andrea R.; Thaker, Premal H.; Mutch, David G.; Powell, Matthew A.; Sun, Lulu; Mosammaparast, Nima; Serra, Violeta; Zhao, Peinan; Khabele, Dineo; Mullen, Mary M.

doi:10.1158/1078-0432.ccr-22-3335

Cited by 26 publications

(13 citation statements)

References 52 publications

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“…For instance, Compadre et al. showed the feasibility and consistency of RAD51 IF across different sample types, such as cell lines, organoids, and FFPE samples ( 33 ). Pikkussari et al.…”

Section: Discussionmentioning

confidence: 99%

RAD51 as an immunohistochemistry-based marker of poly(ADP-ribose) polymerase inhibitor resistance in ovarian cancer

Kim,

Joung

et al. 2024

Front. Oncol.

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ObjectiveEffective functional biomarkers that can be readily used in clinical practice to predict poly(ADP-ribose) polymerase inhibitor (PARPi) sensitivity are lacking. With the widespread adoption of PARPi maintenance therapy in ovarian cancer, particularly in patients with BRCA mutation or HR deficiencies, accurately identifying de novo or acquired resistance to PARPi has become critical in clinical practice. We investigated RAD51 immunohistochemistry (IHC) as a functional biomarker for predicting PARPi sensitivity in ovarian cancer.MethodsOvarian cancer patients who had received PARPi and had archival tissue samples prior to PARPi exposure (“pre-PARPi”) and/or after progression on PARPi (“post-PARPi”) were selected. RAD51 IHC expression was semi-quantitatively evaluated using the H-score in geminin (a G2/S phase marker)- and γH2AX (a DNA damage marker)-positive tissues. A RAD51 H-score of 20 was used as the cutoff value.ResultsIn total, 72 samples from 56 patients were analyzed. The median RAD51 H-score was 20 (range: 0–90) overall, 10 (0–190) in pre-PARPi samples (n = 34), and 25 (1–170) in post-PARPi samples (n = 19). Among patients with BRCA mutations, RAD51-low patients had better progression-free survival (PFS) after PARPi treatment than RAD51-high patients (P = 0.029). No difference was found in PFS with respect to the genomic scar score (P = 0.930). Analysis of matched pre- and post-PARPi samples collected from 15 patients indicated an increase in the RAD51 H-score upon progression on PARPi, particularly among pre-PARPi low-RAD51-expressing patients.ConclusionRAD51 is a potential functional IHC biomarker of de novo and acquired PARPi resistance in BRCA-mutated ovarian cancer and can be used to fine-tune ovarian cancer treatment.

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“…For instance, Compadre et al. showed the feasibility and consistency of RAD51 IF across different sample types, such as cell lines, organoids, and FFPE samples ( 33 ). Pikkussari et al.…”

Section: Discussionmentioning

confidence: 99%

RAD51 as an immunohistochemistry-based marker of poly(ADP-ribose) polymerase inhibitor resistance in ovarian cancer

Kim,

Joung

et al. 2024

Front. Oncol.

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“…RNF24, encoding an integral membrane protein with a RING-type zinc finger, correlates with immune cell infiltration in various cancers, including OC [Yu et al, 2021]. RAD51, involved in homologous recombination and DNA repair, is crucial for platinum chemotherapy response and survival in ovarian cancer [Compadre et al, 2023], and defects in RAD51 trigger a STING-mediated innate immune response, emphasizing its role in genomic stability [Bhattacharya et al, 2017]. In the mesenchymal subtype, the transmembrane signaling enzyme PLCG2 is identified by MORE as a hub gene.…”

Section: More Insights For Hgsoc-tcga Datamentioning

confidence: 99%

MORE interpretable multi-omic regulatory networks to characterize phenotypes

Aguerralde-Martin,

Clemente-Císcar,

Lopez-Cárcel

et al. 2024

Preprint

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The emergence of omics has revolutionized how we study and understand biological systems, enabling breakthrough discoveries with profound implications for medicine, agriculture, biotechnology, and more. However, with the help of advanced computational tools and artificial intelligence, meaningful patterns and relationships can now be uncovered in omics data, offering a unique opportunity to gain a deeper understanding and contribute to new insights into the complex regulatory mechanisms of biological systems. In this context, we have developed MORE (Multi-Omics REgulation), a tool designed to identify relevant regulations of the gene expression for the biological system under study and subsequently construct the regulatory networks for the considered experimental conditions. The presented method not only allows the incorporation of prior biological information into network construction but also can infer relationships de novo in the absence of such information. Moreover, we effectively addressed multicollinearity issues inherent in such data types, ensuring precise and reliable inference of regulatory networks when performing GLM models. In our comparison to KiMONo, our tool exhibited superior evaluation metrics, including F1-score, R2, and computational efficiency. Finally, applying our tool to a real ovarian cancer dataset yielded intriguing and biologically meaningful results. Our developed methodology represents a versatile and powerful multi-omic regulatory network inference approach, demonstrating good performance and applicability to real-world biological datasets. It is freely available at https://github.com/ConesaLab/MORE.git.

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“…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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RAD51 Foci as a Biomarker Predictive of Platinum Chemotherapy Response in Ovarian Cancer

Cited by 26 publications

References 52 publications

RAD51 as an immunohistochemistry-based marker of poly(ADP-ribose) polymerase inhibitor resistance in ovarian cancer

RAD51 as an immunohistochemistry-based marker of poly(ADP-ribose) polymerase inhibitor resistance in ovarian cancer

MORE interpretable multi-omic regulatory networks to characterize phenotypes

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

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