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. 2024 Apr 1;7(4):e247811.
doi: 10.1001/jamanetworkopen.2024.7811.

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

Sara Torres-Esquius  1 , Alba Llop-Guevara  2   3 , Sara Gutiérrez-Enríquez  1 , Marcel Romey  4 , Àlex Teulé  5 , Gemma Llort  6 , Ana Herrero  7 , Pilar Sánchez-Henarejos  8 , Anna Vallmajó  9 , Santiago González-Santiago  10 , Isabel Chirivella  11 , Juana Maria Cano  12 , Begoña Graña  13 , Sara Simonetti  14 , Isabela Díaz de Corcuera  15 , Teresa Ramon Y Cajal  16 , Judit Sanz  17 , Sara Serrano  18 , Andrea Otero  19 , Cristina Churruca  20 , Ana Beatriz Sánchez-Heras  21 , Sonia Servitja  22 , Carmen Guillén-Ponce  23 , Joan Brunet  24   25 , Carsten Denkert  4 , Violeta Serra  2 , Judith Balmaña  1   26
Affiliations

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

Sara Torres-Esquius et al. JAMA Netw Open. .

Abstract

Importance: RAD51C 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.

Objective: To characterize the clinical and tumor characteristics of germline RAD51C/D PV carriers, including the evaluation of HRD status.

Design, setting, and participants: This 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 measures: Clinical 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.

Results: A 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>T (9 of 56 [16.1%]) in RAD51C and c.694C>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 relevance: In 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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Llop-Guevara reported having a patent for WO2019122411A1 pending. Mr Romey reported receiving nonfinancial support from Myriad Genetics outside the submitted work. Dr Churruca reported serving in a consulting or advisory Role for GSK; receiving travel, accommodations, and expenses from MSD; and providing expert testimony for PharmaMar outside the submitted work. Dr Guillén-Ponce reported receiving nonfinancial support from AstraZeneca, Roche, and GE Healthcare; personal fees from Boston; and performing clinical trials for QED Therapeutics, Boston, AstraZeneca, Erytech, IPSEN, Panbela Therapeutics, and Oncosil Medical outside the submitted work. Dr Denkert reported receiving grants from BMBF/European Commission during the conduct of the study; grants from Myriad; and personal fees from AstraZeneca and DaiichiSankyo outside the submitted work. Dr Serra reported receiving grants from AstraZeneca; personal fees from AstraZeneca and GSK outside the submitted work; and having a patent for WO2019122411A1 pending. Dr Balmaña reported receiving personal fees from AstraZeneca outside the submitted work; and having a patent for WO2019122411A1 pending. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Functional and Genomic Homologous Recombination Deficiency (HRD)
A, Summary of clinical and molecular features for the 45 breast cancer (BC) or ovarian cancer (OC) tumors analyzed. Waterfall with the RAD51 scores (bars) and yH2AX scores (dots) for each sample. The table indicates the type of each tumor, gene mutated, gene-specific loss of heterozygosity (gsLOH) status, genomic instability score (GIS), and age at diagnosis. B, Functional HRD by RAD51 in hereditary cancers. The RAD51 scores of 141 tumor samples from patients with BC or OC with germline pathogenic variants in RAD51C, RAD51D, BRCA1, BRCA2, or PALB2 are shown. C, Genomic HRD by genomic instability. The GIS of 28 tumor samples from patients with BC or OC with germline pathogenic variants in RAD51C or RAD51D are shown. The gsLOH status in RAD51C/D is also shown. D, Correlation between RAD51 and GIS, showing a 91% concordance. Each dot represents 1 tumor per patient, the horizontal black lines indicate the mean of each group, and the horizontal dotted lines indicate the predefined threshold of the RAD51 test (10%) or GIS (42) to discriminate HRD vs homologous recombination proficiency (HRP) status. Gray shaded areas in panel D represent concordant HRD or HRP status by both tests. Het indicates heterozygous; HRR, homologous recombination repair; NA, not available; NE, not evaluable; and TNBC, triple-negative breast cancer.
Figure 2.
Figure 2.. Distribution of Functional Homologous Recombination Deficiency (HRD) Across Tumor Subtypes
RAD51 scores in estrogen receptor (ER)–positive breast cancer (BC), ER-negative BC, and high-grade ovarian cancer (HGOC) samples and gene-specific loss of heterozygosity (gsLOH) status. The horizontal black lines indicate mean values. HRP indicates homologous recombination proficiency.
See this image and copyright information in PMC

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