Cancer Treatment Today

Assays measuring homologous recombination deficiency (HRD) caused by a broader range of mechanisms than BRCA1/2 loss are the central focus. In addition to germline BRCA1/2 mutations, such tests identify somatic mutations in BRCA1/2 and other HRR-related genes and detect the presence of genomic scars indicative of HRD. Mechanistically, PARPi target the vulnerability that arises in tumor cells following breaks in DNA by inhibiting PARP-mediated DNA repair. However, backup mechanisms such as HR may salvage the integrity of tumor DNA and prevent the anti-tumor effects of PARPi. In cells with existing DNA repair defects, such as in the HR pathway, PARPi induces “synthetic lethality.”14 This makes HRD a valuable biomarker for identifying patients most likely to respond to PARPi therapy.

Recent Consensus Statement from ESMO supports this test. Consensus recommendations on the clinical utility of HRD tests
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In the first-line maintenance setting, germline and somatic BRCA mutation testing is routinely recommended identify HGSC patients who should receive a PARPi.
(Level of agreement = 100%; total agreement)
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In the first-line maintenance setting, it is reasonable to use a validated scar based HRD test to establish the magnitude of benefit conferred by PARPi use in BRCA wild-type HGSC.
(Level of agreement = 100%; total agreement)
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In the first-line maintenance setting, it is reasonable to use a validated scar based HRD test to identify the subgroup of BRCA wild-type patients who are least likely to benefit from PARPi therapy.
(Level of agreement = 100%; total agreement)
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In the platinum-sensitive relapse maintenance setting, it is reasonable to use BRCA mutation testing and validated scar based HRD tests to predict the likely magnitude of PARPi benefit for consideration of risks and benefits of maintenance therapy.
R.E. Miller et al, ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer. Ann Oncol VOLUME 31, ISSUE 12, P1606-1622, DECEMBER 01, 2020

Pellegrino B, Mateo J, Serra V, Balmaña J. Controversies in oncology: are genomic tests quantifying homologous recombination repair deficiency (HRD) useful for treatment decision making? ESMO Open. 2019;4(2):e000480.

Frey MK, Pothuri B. Homologous recombination deficiency (HRD) testing in ovarian cancer clinical practice: a review of the literature. Gynecol Oncol Res Pract. 2017;4:4.