Elsevier

Gynecologic Oncology

Volume 159, Issue 3, December 2020, Pages 887-898
Gynecologic Oncology

Invited Review
Clinical assays for assessment of homologous recombination DNA repair deficiency

https://doi.org/10.1016/j.ygyno.2020.09.029Get rights and content

Highlights

  • Homologous recombination DNA repair deficiency (HRD) is a functional defect in homologous recombination DNA repair.

  • Clinical tests for HRD detect “genomic scars” caused by HRD, which are permanent regardless of changes in HR function.

  • In trials of PARP inhibitors (PARPi), patients whose cancers have HRD by clinical tests may have more benefit from PARPi.

  • Clinical tests for HRD have limitations and discordance can occur between HRD test results and clinical responses to PARPi.

  • Genomic tests for HRD are potential biomarkers for PARPi and other DNA-damaging drugs, but more research is needed.

Abstract

Homologous recombination DNA repair deficiency (HRD) is a functional defect in homologous recombination DNA repair, arising from germline or somatic mutations in BRCA1/2 or other mechanisms. Cells with HRD are more sensitive to platinum and poly(ADP-ribose) polymerase inhibitors (PARPi). HRD generates permanent changes in the genome with specific, quantifiable patterns (“genomic scars”). Clinical tests for HRD, such as the Myriad genomic instability score and Foundation Medicine loss of heterozygosity test, aim to predict the presence of HRD based on genomic features. Clinical trials of PARPi in ovarian cancer have evaluated genetic mutations and HRD genomic assays as potential biomarkers of response. Patients with HRD due to BRCA1/2 mutations are more likely to respond to PARPi than those with wild-type (WT) BRCA1/2. In some clinical trials, patients with WT BRCA1/2 who were predicted to be HRD by a genomic test exhibited greater clinical benefit from PARPi than patients with WT BRCA1/2 and no evidence of HRD. HRD tests therefore hold promise as predictive biomarkers for PARPi and other DNA-damaging agents. However, HRD tests vary in terms of the specific genomic features they measure, and the methods used to determine thresholds defining patients with HRD. Also, HRD test results and PARPi responses can be discordant: for instance, tumors with reversion mutations that restore HR function still exhibit a “genomic scar” of HRD, and PARPi resistance mechanisms independent of HR can result in lack of PARPi response despite HRD. Emerging methods to predict HRD, including genomic and functional assays, may overcome some of these challenges. Evaluation of HRD in the clinical setting is an important tool that has potential to aid patient selection for PARPi and other DNA-damaging agents in ovarian cancer, but understanding the details of these tests and their limitations is critical to ensure their optimal clinical application.

Introduction

Poly(ADP-ribose) polymerase inhibitors (PARPi) and other targeted therapies directed at the DNA damage response pathway have transformed the care of ovarian cancer and other solid tumors. Assessment of the state of homologous recombination DNA repair (HRR) in tumor cells as a potential biomarker of response is an area of increasing clinical focus. The targets of PARPi are PARP1/2 enzymes, which promote DNA repair by binding to DNA breaks and recruiting DNA repair proteins [[1], [2], [3], [4]]. When PARP enzymes are inhibited by PARPi, DNA repair is impaired and PARP proteins are trapped on the DNA; unrepaired DNA damage accumulates, and DNA replication is blocked by PARP trapping at DNA replication forks, leading to cell death [[2], [3], [4]]. HRR is a key pathway that repairs DNA double-strand breaks, and cells with defects in HRR are particularly susceptible to the DNA damage and cell death induced by PARPi [[1], [2], [3], [4]]. Cellular mechanisms of HRR and assays for HRR function are reviewed in the accompanying article by Fuh et al. Cells with deleterious mutations in BRCA1 or BRCA2 (BRCA1/2) are highly sensitive to PARPi, because they cannot repair the DNA breaks and stalled replication forks induced by PARP inhibition [1]. The PARPi sensitivity of BRCA1/2-deficient cells is a classic example of “synthetic lethality,” the inability of a cell to tolerate the simultaneous loss of two critical functions, leading to cell death. Other mechanisms of HRR impairment beyond BRCA1/2 mutations can similarly confer PARPi sensitivity. However, identifying measures of dysfunctional HRR status that accurately predict clinical sensitivity to PARPi has been challenging [[5], [6], [7]].

Mechanistically, it is expected that PARPi will be most active in tumors with HRR deficiency (HRD), while tumors without HRD are unlikely to respond to PARPi. Identifying HRD in clinical specimens is critical to patient selection for PARPi. BRCA1/2 mutations and/or HRD status have been evaluated in clinical trials of PARPi [[7], [8], [9]] (Table 1, Table 2). However, identifying cancers with true HRD is not straightforward. Multiple genomic biomarkers have been evaluated to infer the presence of HRD [[5], [6], [7]]. Though promising, these biomarkers are imperfect predictors of responses to PARPi, with clinical benefit from PARPi observed in tumors both with and without HRD as measured by current clinical assays. In this review, we will examine genomic features associated with HRD, HRD tests in clinical trials of PARPi in ovarian cancer, and key challenges in the clinical use of HRD testing.

Section snippets

HRD is a functional state of cancer cells that alters the cancer genome and affects responses to platinum and PARPi

HRR is a DNA damage repair pathway responsible for accurately mending double-strand DNA breaks and inter-strand crosslinks. HRD is, put simply, the inability of a cell to perform HRR. HRD is a functional defect in the HRR process on a cellular level, where a cell with HRD is unable to repair DNA damage using HRR. HRD in cancer cells has many underlying causes (Table 3).

HRD results in a cascade of effects on the cancer cell's genome, due to the use of alternative DNA repair pathways with lower

Germline and somatic mutations as a measure of HRD status

Testing for germline and somatic mutations in BRCA1/2 and other HRD-related genes may be used to infer the presence of HRD (Fig. 1a). Heritable mutations in ovarian cancer risk genes are present in 13–15% of ovarian cancer patients [16,17] and germline genetic testing is recommended for all women with ovarian cancer, ideally with genetic counseling [9,18,19]. While germline mutations in BRCA1/2 are the most common, other genes can also increase risk, many of which are included in multigene

Clinical HRD assays utilizing patterns of genomic alteration

Given the challenges in assessing the presence of HRD using mutations in HRR genes, clinical assays have been developed that attempt to classify tumors' HRD status based on genomic metrics [[5], [6], [7],10]. “Genomic scars” of HRD consist of specific patterns of mutations and structural aberrations of chromosomes, including rearrangements, gains, and losses of DNA. Quantitative measures of HRD-associated chromosomal abnormalities were developed based on studies of patients with BRCA1/2

HRD assays in clinical trials of PARPi in ovarian cancer

Clinical trials of PARPi in ovarian cancer have evaluated several genomic HRD tests as predictive biomarkers of response. PARPi trials in breast, prostate, and pancreas cancer have also evaluated BRCA1/2 mutations, other HRR genes, and genomic HRD scores as biomarkers [23,24,[38], [39], [40], [41]]. Broadly, patients with evidence of HRD are more likely to obtain clinical benefit from PARPi. However, the precise details of how these tests were used varied among the trials, including the test

Challenges in clinical testing for HRD

Review of these clinical studies highlights several key points regarding HRD assays. The different assays measure different features: BRCA1/2 mutation testing (germline or somatic), percent genomic LOH assay, and the combined HRD (genomic instability) score incorporating LOH, LST, and TAI, are not equivalent assays. The clinical assays of HRD have not been directly compared in the clinical setting with regards to their accuracy in predicting PARPi activity. Although in most trials these tests

Mutational signatures and other emerging assays for evaluating HRD

Improved biomarkers are needed to predict HRD and the likelihood of PARPi activity more accurately. Recent studies have suggested new approaches to inferring HRD that require further clinical evaluation but hold promise for more precise assessment of HRD.

Mutational signatures reveal the impact of HRD and other processes on the genome by quantitating the number and types of mutations. A set of mutational signatures were generated from whole-exome sequencing of human tumors that describe distinct

Summary

HRR is a mechanism for repairing DNA double-strand breaks and inter-strand crosslinks; HRD is a functional defect of HRR in cells. HRD causes characteristic effects on the cancer cell genome, generating genomic patterns that can be detected by DNA sequencing assays. HRD also increases the susceptibility of cancer cells to platinum and PARPi. Patients with deleterious germline and somatic BRCA1/2 mutations clearly have increased benefit from PARPi compared to patients with WT BRCA1/2. Clinical

Declaration of Competing Interest

  • Dr. Stover has a patent 62/479,885 pending to Dana-Farber Cancer Institute, and a patent 62/565,470 pending to Dana-Farber Cancer Institute, outside the submitted work.

  • Dr. Fuh reports personal fees from Aravive, Myriad Genetics, Eisai, Immunogen, GSK, and a research grant and personal fees from MERCK, outside the submitted work.

  • Dr. Konstantinopoulos reports grants and personal fees from ASTRAZENECA, grants and personal fees from MERCK, grants and personal fees from PFIZER, grants and personal

Acknowledgements

We would like to thank Judy E. Garber, Brittany Bychkovsky, Melinda Telli, and the members of the DFCI gynecologic medical oncology group for helpful discussions.

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