Homologous Recombination Deficiency as an Ovarian Cancer Biomarker in a Real-World Cohort

Denkert, Carsten; Romey, Marcel; Swedlund, Brad; Hattesohl, Akira; Teply-Szymanski, Julia; Kommoss, Stefan; Kaiser, Kristin; Staebler, Annette; Bois, Andreas du; Grass, Albert; Knappmeyer, Christiane; Heitz, Florian; Solimeno, Cara; Ebel, Thomas; Harter, Philipp; Marmé, Frederik; Jank, Paul; Gaiser, Timo; Neff, Chris; Wagner, Uwe; Timms, Kirsten M.; Rodepeter, Fiona

doi:10.1016/j.jmoldx.2022.09.004

Cited by 23 publications

(21 citation statements)

References 17 publications

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“…This observational study reports the largest real world evaluation of routine tumour testing for homologous recombination deficiency in women diagnosed with ovarian cancer (26). Over 12 months of testing, 895 women with newly diagnosed FIGO stage III/IV high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer in England, Wales and Northern Ireland were found to have a homologous recombination deficient tumour.…”

Section: Summary Of Main Resultsmentioning

confidence: 99%

“…As a result, non-high-grade serous carcinomas such as endometrioid (grade 2 or grade 3) and clear cell will have been tested. These subtypes account for approximately 10 to 15% of high-grade ovarian cancers and are rarely deficient in homologous recombination (26,29,30,31,32,33). Secondly, eligibility criteria did not mandate a response to first-line platinum-based chemotherapy prior to tumour testing.…”

Section: Results In the Context Of Published Literaturementioning

confidence: 99%

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Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: a multi-national observational study

Morgan

Barnes

Timms

et al. 2023

Int J Gynecol Cancer

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ObjectiveOlaparib plus bevacizumab maintenance therapy improves survival outcomes in women with newly diagnosed, advanced, high-grade ovarian cancer with a deficiency in homologous recombination. We report data from the first year of routine homologous recombination deficiency testing in the National Health Service (NHS) in England, Wales, and Northern Ireland between April 2021 and April 2022.MethodsThe Myriad myChoice companion diagnostic was used to test DNA extracted from formalin-fixed, paraffin-embedded tumor tissue in women with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Tumors with homologous recombination deficiency were those with aBRCA1/2mutation and/or a Genomic Instability Score (GIS) ≥42. Testing was coordinated by the NHS Genomic Laboratory Hub network.ResultsThe myChoice assay was performed on 2829 tumors. Of these, 2474 (87%) and 2178 (77%) successfully underwentBRCA1/2and GIS testing, respectively. All complete and partial assay failures occurred due to low tumor cellularity and/or low tumor DNA yield. 385 tumors (16%) contained aBRCA1/2mutation and 814 (37%) had a GIS ≥42. Tumors with a GIS ≥42 were more likely to beBRCA1/2wild-type (n=510) thanBRCA1/2 mutant (n=304). The distribution of GIS was bimodal, withBRCA1/2mutant tumors having a higher mean score thanBRCA1/2wild-type tumors (61 vs 33, respectively, χ2test p<0.0001).ConclusionThis is the largest real-world evaluation of homologous recombination deficiency testing in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is important to select tumor tissue with adequate tumor content and quality to reduce the risk of assay failure. The rapid uptake of testing across England, Wales, and Northern Ireland demonstrates the power of centralized NHS funding, center specialization, and the NHS Genomic Laboratory Hub network.

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Section: Summary Of Main Resultsmentioning

confidence: 99%

Section: Results In the Context Of Published Literaturementioning

confidence: 99%

Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: a multi-national observational study

Morgan

Barnes

Timms

et al. 2023

Int J Gynecol Cancer

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“…To assess genetic or genomic HRD, the Myriad myChoice HRD Plus CDx assay was performed at Philipps-Universität Marburg, as described in previous studies . Tumor DNA was isolated from FFPE samples and used for targeted multiplex polymerase chain reaction amplification and library construction.…”

Section: Methodsmentioning

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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“…PARPis bind to PARP1 at single-strand DNA breaks, avoiding effective repair and causing DNA-protein crosslinks to be processed into double-strand breaks (DSBs), which results in increased genomic instability and cellular death in BRCA1/2-mutant or other HRD-affected cells that are already defective in their DSB repair capacity. HRD has thus been identified as a possible prognostic biomarker for PARPi therapy in HGSOC, breast, pancreatic, and prostate malignancies based on these findings [ 18 , 19 , 20 , 21 ].…”

Section: Hrd In Ovarian Cancermentioning

confidence: 99%

Homologous Recombination Deficiency in Ovarian Cancer: from the Biological Rationale to Current Diagnostic Approaches

Mangogna

Munari

Pepe

et al. 2023

JPM

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The inability to efficiently repair DNA double-strand breaks using the homologous recombination repair pathway is defined as homologous recombination deficiency (HRD). This molecular phenotype represents a positive predictive biomarker for the clinical use of poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors and platinum-based chemotherapy in ovarian cancers. However, HRD is a complex genomic signature, and different methods of analysis have been developed to introduce HRD testing in the clinical setting. This review describes the technical aspects and challenges related to HRD testing in ovarian cancer and outlines the potential pitfalls and challenges that can be encountered in HRD diagnostics.

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Homologous Recombination Deficiency as an Ovarian Cancer Biomarker in a Real-World Cohort

Cited by 23 publications

References 17 publications

Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: a multi-national observational study

Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: a multi-national observational study

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

Homologous Recombination Deficiency in Ovarian Cancer: from the Biological Rationale to Current Diagnostic Approaches

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