Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer, Part 1: Technical Considerations

Abstract

High-grade serous ovarian cancer (HGSOC), the most frequent and lethal form of ovarian cancer, exhibits homologous recombination deficiency (HRD) in 50% of cases. In addition to mutations in BRCA1 and BRCA2, which are the best known thus far, defects can also be caused by diverse alterations to homologous recombination-related genes or epigenetic patterns. HRD leads to genomic instability (genomic scars) and is associated with PARP inhibitor (PARPi) sensitivity. HRD is currently assessed through BRCA1/2 analysis, which produces a genomic instability score (GIS). However, despite substantial clinical achievements, FDA-approved companion diagnostics (CDx) based on GISs have important limitations. Indeed, despite the use of GIS in clinical practice, the relevance of such assays remains controversial. Although international guidelines include companion diagnostics as part of HGSOC frontline management, they also underscore the need for more powerful and alternative approaches for assessing patient eligibility to PARP inhibitors. In these companion reviews, we review and present evidence to date regarding HRD definitions, achievements and limitations in HGSOC. Part 1 is dedicated to technical considerations and proposed perspectives that could lead to a more comprehensive and dynamic assessment of HR, while Part 2 provides a more integrated approach for clinicians.

Alterations in Homologous Recombination-Related Genes and Distinct Platinum Response in Metastatic Triple-Negative Breast Cancers: A Subgroup Analysis of the ProfiLER-01 Trial

“…Nevertheless, assessing the predictive value of initial biomarkers allowed us to decipher more robust ones (i.e., less sensitive to evolutionary fluctuations); furthermore, iterative biopsies with multiple molecular assays are not necessarily compatible with real-life practice. Thirdly, it is now well-known that HRD status may be assessed through diverse companion diagnostic assays; they nevertheless do not overlap perfectly [ 7 ]. The MyChoice ® assay has been shown to represent the current gold standard in ovarian cancer as a prerequisite to PARPi challenge [ 31 ].…”

“…At the molecular scale, a germline mutation in BRCA1 or BRCA2 ( gBRCA1/2 ) is found in 15–20% of patients with TNBC [ 5 , 6 ]. The disruption of BRCA1/2 genes leads to inefficient homologous recombination (HR) for double-strand break (DSB) processing, leading to the so-called homologous recombination deficiency (HRD) and subsequent specific features through genomic instability [ 7 ]. In the context of neoadjuvant chemotherapy, it has been shown that tumors with BRCA1/2 mutations exhibit an increased sensitivity to platinum salts [ 8 , 9 ].…”

“…In the metastatic setting, current guidelines from the European Society for Medical Oncology (ESMO) recommend platinum-based chemotherapies in the context of gBRCA1/2 -mutated TNBC [ 10 ]. Furthermore, in the context of gBRCA1/2, TNBCs exhibit higher sensitivity to Poly(ADP-ribose) polymerase inhibitors (PARPi) through synthetic lethality [ 7 ]. In recent years, several trials have shown the efficiency of PARPi’s in the context of gBRCA1/ 2, both in the metastatic and adjuvant settings [ 11 , 12 , 13 ].…”

“…In recent years, several trials have shown the efficiency of PARPi’s in the context of gBRCA1/ 2, both in the metastatic and adjuvant settings [ 11 , 12 , 13 ]. Apart from the well-characterized BRCA1/2 , several other causes leading to HRD have been described, such as the promoter hypermethylation of BRCA1 or RAD51C or mutations in HR-related (HRR) genes, which are grouped under the concept of “ BRCAness ”, which represent any molecular alteration out of BRCA1/2 that leads to an HRD phenotype [ 2 , 7 ]. In spite of their putative effect on HR function, it remains unclear if their presence in TNBC is associated with enhanced sensitivity to platinum-based chemotherapy.…”

Real-World Data on Newly Diagnosed BRCA-Mutated High-Grade Epithelial Ovarian Cancers: The French National Multicenter ESME Database

“…Apart from germline mutations, somatic mutations in BRCA1 or BRCA2 are found in an additional 4% and 3% of cases, respectively [ 7 ]. BRCA -mutated tumors have been reported to exhibit specific features, such as enhanced sensitivity to antineoplastic agents [ 8 ]. Nevertheless, BRCA1 and BRCA2 may have distinct impact on prognosis; several studies suggested that BRCA2 mutations are associated with a better prognosis than BRCA1 -mutated and non-mutated patients [ 9 , 10 ].…”