Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer

Telli, Melinda L.; Timms, Kirsten M.; Reid, Julia; Hennessy, Bryan T.; Mills, Gordon B.; Jensen, Kristin C.; Szállási, Zoltán; Barry, William T.; Winer, Eric P.; Tung, Nadine; Isakoff, Steven J.; Ryan, Paula D.; Greene-Colozzi, April; Gutin, Alexander; Sangale, Zaina; Iliev, Diana; Neff, Chris; Abkevich, Victor; Jones, Joshua T.; Lanchbury, Jerry S.; Hartman, Anne‐Renee; Garber, Judy E.; Ford, James M.; Silver, Daniel P.; Richardson, Andrea L.

doi:10.1158/1078-0432.ccr-15-2477

Cited by 756 publications

(702 citation statements)

References 32 publications

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“…These three genome-based scores (telomeric AI, LST and LOH) have been assessed as a combined homologous recombination deficiency (HRD) score (HRD Index) in various cohorts of breast cancer samples. The assay, developed using next generation sequencing, was collectively a more sensitive predictor of BRCA deficiency than individual parameters [92] and identified patients with increased benefit to neoadjuvant platinum based therapy [66,93]. Similar findings have been reported reflecting the burden of allelic imbalanced copy number alterations and response to platinum-based chemotherapy [70].…”

Section: Clinical Utility Of Mutation Signaturessupporting

confidence: 65%

“…Great interest has therefore been applied to develop 'biomarkers' of HR deficiency based on the pattern of somatic alterations identified in the tumour genome. These genome-based 'tools' utilise either aCGH or SNP array based genome data [64][65][66][67][68][69][70][71] or more recently whole genome sequencing data [91].…”

Section: Clinical Utility Of Mutation Signaturesmentioning

confidence: 99%

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Molecular signatures in breast cancer

Lal

Reed

Luca

et al. 2017

Methods

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The use of molecular signatures to add value to standard clinical and pathological parameters has impacted clinical practice in many cancer types, but perhaps most notably in the breast cancer field. This is, in part, due to the considerable complexity of the disease at the clinical, morphological and molecular levels. The adoption of molecular profiling of DNA, RNA and protein continues to reveal important differences in the intrinsic biology between molecular subtypes and has begun to impact the way patients are managed. Several bioinformatic tools have been developed using DNA or RNA-based signatures to stratify the disease into biologically and/or clinically meaningful subgroups. Here, we review the approaches that have been used to develop gene expression signatures into currently available diagnostic assays (e.g. OncotypeDX® and Mammaprint®), plus we describe the latest work on genome sequencing, the methodologies used in the discovery process of mutational signatures, and the potential of these signatures to impact the clinic.

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Section: Clinical Utility Of Mutation Signaturessupporting

confidence: 65%

Section: Clinical Utility Of Mutation Signaturesmentioning

confidence: 99%

Molecular signatures in breast cancer

Lal

Reed

Luca

et al. 2017

Methods

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“…Samples were assigned into high (!42) or low (<42) HRD score based on a threshold that was previously established in a separate discovery sample set and represents the 5th percentile of HRD scores in tumors with BRCA deficiency (14). Homologous DNA recombination deficiency was defined as either a high HRD score or mutation in BRCA1 or BRCA2 genes.…”

Section: Dna Extraction and Hrd Assaymentioning

confidence: 99%

“…Recently, a tumor DNA-based 3-biomarker HRD assay was developed that measures three distinct features of HR deficiency (14). These include a whole-genome loss of heterozygosity (LOH) profile score (15), a telomeric allelic imbalance score (TAI; ref.…”

Section: Introductionmentioning

confidence: 99%

“…17). All three scores are highly correlated with germline defects in BRCA1/2 and each, independently and in combination were shown to be associated with sensitivity to platinum agents (14)(15)(16)(17). The 3-biomarker HRD assay is now being evaluated in clinical studies that examine its ability to identify patients who are particularly sensitive to DNA-damaging agents.…”

Section: Introductionmentioning

confidence: 99%

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Intratumor Heterogeneity of Homologous Recombination Deficiency in Primary Breast Cancer

Wahlde

Timms

Chagpar

et al. 2017

Clinical Cancer Research

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Purpose: The 3-biomarker homologous recombination deficiency (HRD) assay measures the number of telomeric allelic imbalances, loss of heterozygosity, and large-scale state transitions in tumor DNA and combines these metrics into a single score that reflects DNA repair deficiency. The goal of this study is to assess the consistency of these HRD measures in different biopsies from distinct areas of the same cancer.Experimental Design: HRD scores, BRCA mutation status, and BRCA1 promoter methylation were assessed in 99 samples from 33 surgically resected, stage I-III breast cancers; each cancer was biopsied in three distinct areas. Homologous recombination repair (HR) deficiency was defined as either high HRD score (!42) or tumor BRCA mutation.Results: Eighty-one biopsies from 32 cancers were analyzed. Tumor BRCA status was available for all samples, HRD scores for 70, and BRCA1 methylation values for 76 samples. The BRCA1/2 mutation and promoter methylation status and HR category showed perfect concordance across all biopsies from the same cancer. All tumors with BRCA1/2 mutations or promoter methylation had high HRD scores, as did 17% (4/24) of the BRCA1/2 wild-type and nonmethylated tumors. The HRD scores were also highly consistent between different biopsies from the same tumor with an intraclass correlation coefficient of 0.977, indicating that only 2.3% of the variance is attributed to within-tumor biopsy-to-biopsy variation.Conclusions: These results indicate that within-tumor spatial heterogeneity for HRD metrics and the technical noise in the assay are small and do not influence HRD scores and HR status. Clin Cancer Res; 23(5);

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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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Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer

Cited by 756 publications

References 32 publications

Molecular signatures in breast cancer

Molecular signatures in breast cancer

Intratumor Heterogeneity of Homologous Recombination Deficiency in Primary Breast Cancer

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

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