Genetic testing for homologous recombination repair (HRR) in metastatic castration-resistant prostate cancer (mCRPC): challenges and solutions.

Rodney J Scott,Wafaa El Metnawy,Ravindran Kanesvaran,Pavel S Borisov,Anurag Mehta,Gabriel S Macedo

doi:10.18632/oncotarget.28015

Abstract

Patients with metastatic castration-resistant prostate cancer (mCRPC) have an average survival of only 13 months. Identification of novel predictive and actionable biomarkers in the homologous recombination repair (HRR) pathway in up to a quarter of patients with mCRPC has led to the approval of targeted therapies like poly-ADP ribose polymerase inhibitors (PARPi), with the potential to improve survival outcomes. The approval of PARPi has led to guideline bodies such as the National Comprehensive Cancer Network (NCCN) to actively recommend germline and or somatic HRR gene panel testing to identify patients who will benefit from PARPi. However, there are several challenges as genetic testing is still at an early stage especially in low- and middle-income countries, with cost and availability being major impediments. In addition, there are issues such as choice of optimal tissue for genetic testing, archival, storage, retrieval of tissue blocks, interpretation and classification of variants in the HRR pathway, and the need for pretest and post-test genetic counseling. This review provides insights into the HRR gene mutations prevalent in mCRPC and the challenges for a more widespread gene testing to identify actionable germline pathogenic variants and somatic mutations in the HRR pathway, and proposes a clinical algorithm to enhance the efficiency of the gene testing process.

Highlights

Metastatic castration-resistant prostate cancer is a latestage disease with an average survival of ≤13 months [1]
On most occasions, the tissue available for genetic testing is from archival samples, which poses multiple challenges
Testing for the three predominant genes (BRCA1/2 and ataxia-telangiectasia mutated (ATM)) as an initial step and proceeding by an elimination method can improve the efficiency of genetic testing in metastatic castration-resistant prostate cancer (mCRPC) in countries with limitations on genetic testing resources

Summary

INTRODUCTION

Metastatic castration-resistant prostate cancer (mCRPC) is a latestage disease with an average survival of ≤13 months [1]. Somatic testing with target genes (initiated with BRCA1/2 and ATM and followed by other genes) can be used as an initial screening test to provide personalized precision medicine to patients This decreases the amount of time and resources spent on blood-based germline testing followed by tumor testing to identify a somatic mutation, in the absence of germline mutations. Olaparib is a treatment option (category 1 recommendation) for patients with mCRPC and a pathogenic mutation (germline and/somatic) in a HRR gene (BRCA1/2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L), who have been treated with androgen-receptor directed therapy. In clinical settings, it may not always be possible to perform a re-biopsy, and determination of tumor content may be a challenge before proceeding for NGS-based HRR gene testing In such cases, archived samples are often

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CONCLUSIONS