Limited association between HRR gene alterations and HRD in molecular tumor board cancer samples: Who should be tested for HRD?

TL;DR

This study shows that HRD testing in cancer patients outside of clinical trials can reveal HRD in some cases without HRR gene mutations, suggesting broader use of HRD as a biomarker for PARP inhibitor treatment.

Contribution

First study to analyze HRD testing in the context of molecular tumor boards, revealing limited association between HRR gene alterations and HRD.

Findings

38.1% of BRCA1/2-mutated cancers had elevated HRD scores, but not all inactivating BRCA1/2 mutations correlated with HRD.

HRD was observed in 4.3% of cancers without HRR gene mutations, suggesting HRD may be an independent biomarker.

HRD testing should be included in comprehensive genomic profiling to guide PARP inhibitor treatment decisions.

Abstract

Alterations in Homologous Recombination Repair (HRR) Pathway genes have been found to be associated with HR‐Deficiency (HRD), which is an approved biomarker for PARP Inhibitor (PARPi) treatment. The aim of a Molecular Tumor Board (MTB) is to identify molecular alterations in cancer patients with advanced tumors that may suggest off‐label treatment options. So far, few studies have analyzed the presence of HRR gene mutations and their association with HRD outside of clinical studies. Currently, no data on HRD testing in the setting of a MTB have been published. For the present study, a cohort of 237 patients encompassing 24 different tumor entities was collected from the MTB of the Comprehensive Cancer Center Erlangen‐EMN. We show that an elevated Genomic Instability Score (GIS ≥42) can occur in samples with and without mutations in HRR‐related genes. Overall, 38.1% of cancer samples with BRCA1/2 mutations, 10.9% of tumors with alterations in HRR genes other than BRCA1/2, and 4.3% of cancer samples without HRR gene mutations harbored an elevated GIS. Notably, our data show that various inactivating BRCA1/2 mutations are not associated with an elevated GIS. Taken together, panCancer assessment of HRD in addition to BRCA1/2 and other HRR gene mutational analysis is recommended to guide decisions regarding PARPi treatment. Further studies are needed to establish thresholds for GIS in non‐ovarian cancer entities. Finally, HRD can be observed in 4.3% of BRCA1/2 and other HRR gene wildtype cancer samples, and may emerge as an independent biomarker for PARPi in the future.

What's new?

Currently, no published data on homologous recombination deficiency (HRD) testing in the setting of molecular tumor boards exist. This study in a cohort of 237 patients encompassing 24 different tumor entities assessed by a molecular tumor board shows that inactivating alterations of BRCA1/2 are not always associated with an elevated genomic instability score. Furthermore, HRD could be detected in various tumor entities harboring deleterious alterations in homologous recombination repair (HRR) genes other than BRCA1/2. HRD analysis should become part of comprehensive genomic profiling as it provides additional information for PARPi treatment recommendation in the setting of molecular tumor boards.

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