Homologous recombination deficiency: New biomarkers in innovative treatments
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memo (2020) 13:357–358 https://doi.org/10.1007/s12254-020-00660-7
Homologous recombination deficiency: New biomarkers in innovative treatments Christian F. Singer
© Springer-Verlag GmbH Austria, part of Springer Nature 2020
Homologous recombination (HR) is a key DNA repair mechanism that is essential for maintaining genome stability. It is characterized by its high fidelity and efficiency, and represents the pivotal repair mechanism for DNA double-strand breaks. Although known for years, its potential role as a therapeutic target has only recently been elucidated: malignant breast and ovarian tumors with mutations in the breast cancer susceptibility genes BRCA1 and BRCA2, two genes that are quintessential members of the homologous recombination repair (HRR) pathway, have been demonstrated to be particularly sensitive to polyADP ribose polymerase inhibitors (PARPi), such as talazoparib and olaparib. In addition, BRCA-associated HR deficiency (HRD) renders tumors particularly sensitive to platinum-based chemotherapy. After the initial approval of PARP inhibitors in advanced ovarian cancer in 2014, their therapeutic indications now span a wide range from BRCAassociated solid tumors from prostate to pancreatic cancers. BRCA testing has thus expanded from a purely predictive to a therapeutic assay. There is, however, mounting evidence suggesting that tumors might benefit from PARPi even in the absence of functional BRCA mutations. Alterations in several other HR-associated genes have been associated with HR deficiency, but the identification of patients with wild-type BRCA1/2 who nonetheless will benefit from PARP inhibition remains a significant challenge. Assays measuring HRD which is caused by a broader range of mechanisms than BRCA1/2 loss are now becoming increasingly popular for their ability to idenC. F. Singer, MD, MPH () Department of Obstetrics and Gynecology, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria [email protected]
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tify an additional subset of PARPi-sensitive. These tests identify both somatic and germline mutations in BRCA1/2 and in other HRR-related genes, and detect the presence of genomic alterations indicative of HRD. The so-called genomic “scars” are characterized by telomer–allelic imbalances, large scale transitions and loss of heterocytosity, and—when scored according to a specific algorithm—summarize the total burden of genomic burden in a particular tumor, and describe tumors that are potentially responsive to PARP inhibition. Several HRD assays have been developed and are now also clinically validated in patients with breast and ovarian cancer, and are now increasingly used in other solid tumors, as well. Recent approvals for the two PARP inhibitors niraparib and olaparib encompass patients with HRD-positive ovarian cancer in addition to those in whom germline or somatic BRCA mutations have been diagnosed. In May 2020, the FDA (US Food and Drug Administration) also approved olaparib for patients with metastatic castration-resistant prosta
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