Homologous Recombination Deficiency: Concepts, Definitions, and Assays

Stewart, Mark; Merino, Diana M.; Arend, Rebecca C.; Baden, Jonathan; Barbash, Olena; Beaubier, Nike; Collins, Grace; French, Tim; Ghahramani, Negar; Hinson, Patsy; Jelinic, Petar; Marton, Matthew J.; McGregor, Kimberly; Parsons, Jerod; Ramamurthy, Lakshman; Sausen, Mark; Sokol, Ethan S.; Stenzinger, Albrecht; Stires, Hillary; Timms, Kirsten M.; Turco, D; Wang, Iris; Williams, JW; Wong-Ho, Elaine; Allen, Jeff

doi:10.1093/oncolo/oyab053

Cited by 115 publications

(98 citation statements)

References 44 publications

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“…Finally, some assays compare tumor mutations to matched normal tissue, whereas others compare to a population allele frequency database; selection of the comparison database is important, especially given differences in distribution of variant allele frequency by race for different genes. 33,34…”

Section: Focused Update Recommendationsmentioning

confidence: 99%

Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update

Henry

Somerfield

Dayao

et al. 2022

JCO

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PURPOSE To update the ASCO biomarkers to guide systemic therapy for metastatic breast cancer (MBC) guideline. METHODS An Expert Panel conducted a systematic review to identify randomized clinical trials and prospective-retrospective studies from January 2015 to January 2022. RESULTS The search identified 19 studies informing the evidence base. RECOMMENDATIONS Candidates for a regimen with a phosphatidylinositol 3-kinase inhibitor and hormonal therapy should undergo testing for PIK3CA mutations using next-generation sequencing of tumor tissue or circulating tumor DNA (ctDNA) in plasma to determine eligibility for alpelisib plus fulvestrant. If no mutation is found in ctDNA, testing in tumor tissue, if available, should be used. Patients who are candidates for poly (ADP-ribose) polymerase (PARP) inhibitor therapy should undergo testing for germline BRCA1 and BRCA2 pathogenic or likely pathogenic mutations to determine eligibility for a PARP inhibitor. There is insufficient evidence for or against testing for a germline PALB2 pathogenic variant to determine eligibility for PARP inhibitor therapy in the metastatic setting. Candidates for immune checkpoint inhibitor therapy should undergo testing for expression of programmed cell death ligand-1 in the tumor and immune cells to determine eligibility for treatment with pembrolizumab plus chemotherapy. Candidates for an immune checkpoint inhibitor should also undergo testing for deficient mismatch repair/microsatellite instability-high to determine eligibility for dostarlimab-gxly or pembrolizumab, as well as testing for tumor mutational burden. Clinicians may test for NTRK fusions to determine eligibility for TRK inhibitors. There are insufficient data to recommend routine testing of tumors for ESR1 mutations, for homologous recombination deficiency, or for TROP2 expression to guide MBC therapy selection. There are insufficient data to recommend routine use of ctDNA or circulating tumor cells to monitor response to therapy among patients with MBC. Additional information can be found at www.asco.org/breast-cancer-guidelines .

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Section: Focused Update Recommendationsmentioning

confidence: 99%

Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update

Henry

Somerfield

Dayao

et al. 2022

JCO

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“…Targeting homologous recombination deficiency (HRD) has been revealed in the last few years as one of the most promising strategies for various types of tumor. Alteration in the homologous recombination system (HR) genes is prevalent across tumor types and can be mostly found in breast, ovarian, pancreatic and prostate cancer [ 1 , 2 ]. HRD secondary to pathogenic germline and somatic variants in HR-associated genes has been reported as a predictive biomarker to inform about tumor sensitivity to platinum-based regimens and poly-ADP ribose polymerase (PARP) inhibitors (PARPi) [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

The Homologous Recombination Deficiency Scar in Advanced Cancer: Agnostic Targeting of Damaged DNA Repair

Pacheco-Barcía

Muñoz

Castro

et al. 2022

Cancers

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BRCA1 and BRCA2 are the most recognized tumor-suppressor genes involved in double-strand DNA break repair through the homologous recombination (HR) system. Widely known for its role in hereditary cancer, HR deficiency (HRD) has turned out to be critical beyond breast and ovarian cancer: for prostate and pancreatic cancer also. The relevance for the identification of these patients exceeds diagnostic purposes, since results published from clinical trials with poly-ADP ribose polymerase (PARP) inhibitors (PARPi) have shown how this type of targeted therapy can modify the long-term evolution of patients with HRD. Somatic aberrations in other HRD pathway genes, but also indirect genomic instability as a sign of this DNA repair impairment (known as HRD scar), have been reported to be relevant events that lead to more frequently than expected HR loss of function in several tumor types, and should therefore be included in the current diagnostic and therapeutic algorithm. However, the optimal strategy to identify HRD and potential PARPi responders in cancer remains undefined. In this review, we summarize the role and prevalence of HRD across tumor types and the current treatment landscape to guide the agnostic targeting of damaged DNA repair. We also discuss the challenge of testing patients and provide a special insight for new strategies to select patients who benefit from PARPi due to HRD scarring.

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“…The search was performed on May 21, 2020. HRD was defined as having either deleterious or suspected deleterious BRCA1/2 mutations or having a genomic instability score ≥42 by the Myriad test (standard definition) with an alternative definition of HRD as having a genomic instability score ≥42 alone (Stewart et al, 2022). The genomic instability score is an algorithmic measurement of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions using DNA isolated from formalin-fixed paraffin-embedded tumor tissue specimens.…”

Section: Study Design and Search Strategymentioning

confidence: 99%

A comprehensive literature review and meta‐analysis of the prevalence of pan‐cancer BRCA mutations, homologous recombination repair gene mutations, and homologous recombination deficiencies

Shao

Wan

Lam

et al. 2022

Environ and Mol Mutagen

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There is significant improvement in the outcomes following treatment with PARP inhibitors among patients with certain tumors that have BRCA mutations (BRCAm), homologous recombination repair (HRR) gene mutations, or homologous recombination deficiency (HRD) positivity. We performed a literature review and meta-analysis to evaluate the prevalence of BRCA1/2m, HRR gene mutations, and HRD positivity across multiple cancers. There were 265 publications on BRCA1/2 mutation prevalence, 189 on HRR gene mutation prevalence, and 7 on HRD positivity prevalence.The prevalences of germline BRCA1m and BRCA2m were 7.8% and 5.7% for breast cancer, 13.5% and 6.6% for ovarian cancer, 0.5% and 3.5% for prostate cancer, and 1.1% and 4.1% for pancreatic cancer, respectively. The prevalences of somatic BRCA1m and BRCA2m were 3.4% and 2.7% for breast cancer, 4.7% and 2.9% for ovarian cancer, 5.7% and 3.2% for prostate cancer, and 1.2% and 2.9% for pancreatic cancer, respectively. We identified 189 studies with over 418,649 samples across 25 tumor types that examined mutations in one or more HRR genes other than BRCA1/2. The prevalence of mutations among HRR genes remained low (less than 1%), with ATM (5.2%), CHEK2 (1.6%), and PALB2 (0.9%) exhibiting the highest prevalence. Seven studies evaluated HRD positivity in breast, ovarian, and prostate cancer patients. The prevalence of HRD positivity was 56% overall (95% CI = 48%-64%).The understanding of biomarker prevalence across tumor types and standardization of biomarker assays could have important clinical implications.

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Homologous Recombination Deficiency: Concepts, Definitions, and Assays

Cited by 115 publications

References 44 publications

Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update

Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update

The Homologous Recombination Deficiency Scar in Advanced Cancer: Agnostic Targeting of Damaged DNA Repair

A comprehensive literature review and meta‐analysis of the prevalence of pan‐cancer BRCA mutations, homologous recombination repair gene mutations, and homologous recombination deficiencies

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