The Role of Homologous Recombination Deficiency (HRD) in Renal Cell Carcinoma (RCC): Biology, Biomarkers, and Therapeutic Opportunities.

Abstract

Renal Cell Carcinoma (RCC) is a common malignancy, often diagnosed incidentally. In recent years, the prognosis of metastatic disease has been improved due to the development of immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) as first-line treatments. However, when progression occurs, the therapeutic options are limited. Understanding crucial biological pathways could lead to a greater understanding of the natural history of the disease, which could help to overcome the mechanism of resistance and to develop new treatments. The clinical significance of homologous recombination deficiency (HRD) in RCC remains to be investigated. To improve the knowledge about this topic, we conducted a narrative review to summarize the current evidence on HRD-related variations and signatures in RCC, together with their prognostic and predictive implications. Preliminary evidence indicates that canonical HRD variants (BRCA1/2) are infrequent in RCC, while broader DNA damage response (DDR) alterations like BAP1, PBRM1, ATM, and SETD2 are more prevalent. Elevated HRD genomic scores in clear-cell RCC correlate with a worse prognosis and an immunologically exhausted microenvironment. From a therapeutic point of view, PARP inhibitor monotherapy has exhibited initial efficacy in small cohorts with high levels of DDR mutation, yet remains investigational for RCC.