Homologous recombination deficiency (HRD) is a phenotype defined by cells’ inability to repair double-strand DNA breaks using the homologous recombination repair (HRR) pathway (1). When the HRR pathway is compromised, genomic alterations and instability can occur – contributing to cancerous tumor growth.
Table 1. Genes involved in the HRR pathway (2).
HRD has been associated with various cancer types, such as ovarian, prostate, breast, and pancreatic cancer, and is an important predictive biomarker for cancer patients. When a tumor exhibits HRD, the patient may be eligible for treatment with PARP inhibitors (PARPi) or platinum-based chemotherapy. HRD is also a positive prognostic marker for both progression-free and overall survival (3).
HRD status can provide predictive information on the patient’s expected benefit from PARPi treatment and inform strategies for optimal maintenance therapy. Blocking the PARP enzyme inhibits DNA single-strand break repair and cell replication can cause double-strand breaks. Because these breaks would typically be repaired via HRR, inhibiting that pathway through PARPi treatment of HRD-positive tumors can result in cancer cell death.
Different mechanisms are available to detect gene functionality loss in the HRR pathway. HRR genes can be sequenced to detect mutations or the HRD phenotype can be measured by a so-called “scar test” (see “Testing methods to detect HRD”). There is increasing evidence for the need to assess both the causal genes of the HRR pathway and genomic scarring to maximize detection of HRD-positive cancers (1). Testing methods limited to BRCA1 and BRCA2 or HRR gene panel testing might not be sufficient because HRD can be present without such mutations. Therefore, HRD “scar testing” can identify additional cancer patients who may benefit from PARPi treatment.
HRD has been associated with various cancer types; so far, clinical utility has been demonstrated with PARPi in ovarian (HRD, germline and somatic BRCA1/BRCA2), prostate (germline and somatic BRCA1/BRCA2, HRR genes), breast (germline BRCA1/BRCA2), and pancreatic cancer (germline BRCA1/ BRCA2). Beyond BRCA, HRR genes, and HRD, genomic signatures such as microsatellite instability may be associated with different ovarian cancer subtypes. Although these genomic alterations are rarer, it is valuable to assess the genome in a comprehensive manner because of not only these changes, but also the various types of alterations caused by HRD.
Both germline and somatic mutations are associated with HRD in cancer patients. In a 2020 study, researchers characterized the BRCA1/BRCA2 mutation spectrum in a consecutive series of ovarian carcinomas and observed a frequency of 19.3 percent deleterious, 13.3 percent germline, and 5.9 percent somatic variants (4). Germline and somatic BRCA mutation testing is a routine first-line clinical recommendation for highgrade serous carcinoma (HGSC) patients who should receive a PARP inhibitor (5). However, HRD tests do not distinguish between somatic and germline mutations; if a relevant mutation is detected, a genetic counselor should be consulted for germline testing to identify potential familial risk.
HRD status can be measured by “cause” through mutations in the HRR pathway (e.g., BRCA1 and BRCA2) and by the “effect” of the presence of genomic scars at a given threshold or functional assay. Patients with an HRD-positive tumor may be eligible for targeted PARPi treatments. In the case of ovarian cancer, a composite genomic instability score (GIS) versus a measurement of an individual scar (TAI, LST, or LOH) status may be a better predictor of outcomes for PARPi or platinum-based treatment than the individual components alone (6).
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References
CJ Lord, A Ashworth, “BRCAness revisited,” Nat Rev Cancer, 16, 110 (2016). PMID: 26775620.
PA Konstantinopoulos et al., “Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer,” Cancer Discov, 5, 1137 (2015). PMID: 26463832.
JA How et al., “Modification of homologous recombination deficiency score threshold and association with long-term survival in epithelial ovarian cancer,” Cancers (Basel), 13, 946 (2021). PMID: 33668244.
A Peixoto et al., “Tumor testing for somatic and germline BRCA1/BRCA2 variants in ovarian cancer patients in the context of strong founder effects,” Front Oncol, 10, 1318 (2020). PMID: 2850417.
RE Miller et al., “ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer,” Ann Oncol, 31, 1606 (2020). PMID: 33004253.
GB Mills et al., “Comparison of genomic instability (GI) scores for predicting PARP activity in ovarian cancer.” Presented at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 12–22, 2016; San Diego, California, USA. Poster #296.