Homologous recombination repair deficiency (HRD): From biology to clinical exploitation

Abstract

Significant advances in cancer precision medicine over the last decade have led to a number of treatment options that have significantly improved patient outcomes. The underlying concept integrates detailed insights into disease mechanisms with clinical management where the understanding of specific vulnerabilities can be exploited for the development of drugs and therapies. One exciting aspect in this context is the rapidly evolving field of drugs that exploit defects in different DNA repair mechanisms. A recent major success is undoubtedly the high efficacy of checkpoint inhibition in tumors with high microsatellite instability (MSI-H). Another evolving area is centered around the concept of homologous recombination repair deficiency (HRD), which, similar to MSI-H cases, appears to occur across cancer types at different frequencies. The special issue “Homologous Recombination Repair Deficiency (HRD): from Biology to Clinical exploitation” highlights recent progress in the field and provides an overview on scientific and clinical developments. Over the last years, evidence that many cancer types exhibit defects within the homologous recombination repair (HRR) machinery has accumulated. HRR, a conservative mechanism predominantly acting in S and G2 phases of the cell cycle, restores the original DNA sequence at a site where double strand breaks occur. Impairment of this machinery, or HRD, which occurs at variable frequencies across cancer types, is caused by a loss of function in HRR mediators. Biologically, the impairment of the HRR pathway forces cells to utilize other mechanisms of DNA repair such as non-homologous end joining, which is comparably more error prone. Based on the concept of synthetic lethality, this biological phenomenon can be exploited therapeutically since a tumor exhibiting HRD is associated with a specific (“BRCAness”) phenotype characterized by sensitivity to platinum-based therapies and PARP-inhibition. The most common currently known causes of HRD are loss of function mutations in BRCA1, BRCA2, RAD51C, RAD51D, PALB2 and a few other genes as well as promoter hypermethylation of BRCA1. However, since the number of genes involved in HRR is high, their individual biological impact is diverse and interaction is complex, we are currently far from understanding the biological impact, let alone the clinical implications, of individual (germline or somatic, monovs biallelic) aberrations in many of the other HRR-coding genes. This scenario warrants further research efforts including tools, such as the one developed by Kolb and colleagues, that can be used to investigate HRD scenarios in preclinical models. It also poses a major challenge to the interpretation of clinical trial data where non BRCA1/2-HRR genes mutated at low frequencies and often identified by a tumor-sequencing only approach (which is unable to differentiate between somatic and germline events) are often lumped and analyzed in groups, which reflect only to a very limited extent the underlying biology and complexity of the network. The work by Hirsch et al. and George and Turnbull provides guidance on the interpretation and classification of mutations in individual HRR genes, which are nowadays often identified by large NGS gene panels (≥1 MB) used in precision oncology programs. In this context, it is important to keep in mind that clinical trials investigating the efficacy of PARP inhibitors adopted a variant classification system for response prediction that was originally developed for risk prediction of germline carriers and their relatives. This approach is also used in routine diagnostics when looking at variants in individual HRR genes Received: 20 January 2021 Accepted: 20 January 2021