Measuring prevalence of oncogenic homologous recombination pathway mutations across 53,000 tumours

Measuring prevalence of oncogenic homologous recombination pathway mutations across 53,000 tumours

Results of a molecular profiling analysis to identify the frequency of Homologous Recombination Deficiencies (HRD) from approximately 53,000 tumours have been announced. The results demonstrated the utility of the company’s proprietary Caris Molecular Intelligence® Comprehensive Genomic Profiling Plus (CGP+) platform for use in personalised medicine and drug discovery and development. The study was presented at an oral abstract session at the 2017 American Society for Clinical Oncology (ASCO) Annual Meeting in Chicago.

Homologous recombination (HR) is an intracellular process to accurately repair double-stranded DNA breaks, which can cause cell death if not repaired by the cell. Deficiencies in HR can result in incomplete or incorrect recombination that may lead to tumourigenesis. Breast and ovarian cancers are known to have a high frequency of HRDs; the more well-known gene mutations, BRCA1/2, increase the risk of malignancy by this process. Drug developers try to exploit these mutations by further inhibiting deficient HR and causing cell death. Drugs that work by this process include PARP inhibitors, a class of drug recently approved based on their success in ovarian cancer.

The study’s objective was to investigate the prevalence of HR gene mutations in a wide variety of tumour types in order to identify other lineages that may be targeted with these new agents. More than 53,000 tumour samples from bladder, breast, ovarian, pancreas, prostate, colorectal, lung and many others cancer types were analysed by Caris Life Sciences. Caris Molecular Intelligence’s CGP+ approach assesses DNA, RNA and proteins to create a molecular profile of the tumour. This profile has utility in individualising a patient’s treatment regimen, as well as being a tool to improve drug discovery and development. This study evaluated the mutation prevalence of more than 15 HR genes in each of the tumour biopsy samples.

“Deficiencies in HR are a therapeutic target for breast and ovarian cancers, particularly patients with germline as well as somatic BRCA1/2 mutations,” said Arielle L. Heeke, MD, a clinical fellow at the Georgetown Lombardi Comprehensive Cancer Center and lead author of the study. “However, we know that other gene mutations play a role in HRD and that they can occur in other tumour types. Results of this study provide the evidence that many genetic mutations are involved in a wide range of tumour types. Caris’ tumour profiling platform enabled us to accurately identify the frequency of different mutations and which tumour types are most commonly impacted. These data hopefully will provide a pathway to development of additional agents to treat these cancers that have the potential to result in improved and more individualised treatment of our patients.”

The study determined that HR gene mutations were quite common, found in 13.0% of the 53,619 tumour samples evaluated. The study also determined that the mutations were found in a wide range of tumour lineages, the most common being ovarian (14.1%), bladder (9.7%), breast (8.0%), endometrial (7.4%), prostate (7.1%), and pancreas (6.5%). The most common HR gene mutations were PTEN (5.8%), BRCA2 (2.8%), BRCA1 (2.6%), ATM (1.2%) and PALB2 (0.5%). The authors concluded that the results suggest HRD is a common genetic abnormality amongst all cancers, and that determining a patient’s somatic genetic DNA repair landscape may assist clinicians in identifying individualised and beneficial treatment strategies.

“The substantial number of HRD-related mutations and the wide variety of tumour types in which they can be found require an accurate and sensitive platform to identify the mutations so that actionable approaches in both treatment design and drug discovery and development can be implemented,” said David Spetzler, MS, PhD, MBA, President and Chief Scientific Officer of Caris Life Sciences. “This study further validates the capabilities of our Comprehensive Genomic Profiling Plus platform in generating results of value to clinicians and drug developers.”

References

  1. Heeke AL, Lynce F, Baker T et al. Prevalence of homologous recombination deficiency among all tumor types.
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