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

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.

Advances in PARP Inhibitors for Prostate Cancer

“…Similarly, PARPi can be beneficial for patients with hereditary syndromes impairing DNA repair such as BRCA1 or BRCA2 [ 77 ]. Furthermore, whereas HRR gene mutations can induce prostate cancer by increased genomic instability, prostate cancers with these mutations have also been determined to be more aggressive, rapidly progressive and have a greater metastatic potential [ 78 ]. Hence, PARPi may be of particular benefit to this subgroup of prostate cancer patients.…”

Emerging Biomarker-Guided Therapies in Prostate Cancer

“…Despite this, there are challenges in obtaining testing for eligible individuals. Genetic testing for HRR genes can be costly, especially with NGS panels that include sequencing of multiple genes at once [ 82 ]. There are also limited resources for genetic counseling, which currently limits the availability of PARP inhibitor treatment worldwide [ 82 ].…”

“…The sample can be many years old from the original biopsy, with limited viable samples available for testing. However, new diagnostic tissue at diagnosis of metastatic disease can also be difficult to obtain, given the most common metastatic site is bone [ 82 ]. Furthermore, molecular analysis can be costly, and identifying heritable mutations should ideally be accompanied by genetic counseling, which limits the widespread utilization of biomarker-driven therapy worldwide.…”

“…This could result in missing an opportunity to treat 15–20% of patients who may have a somatic mutation but not a germline one. Blood samples from ctDNA also are less sensitive than tissue samples and, in some tumor sites, have a concordance of 80% with tissue samples [ 82 ]. A wide array of assays are utilized across laboratories, making standardization in terms of specificity and sensitivity difficult.…”

“…A wide array of assays are utilized across laboratories, making standardization in terms of specificity and sensitivity difficult. Furthermore, tumor sampling does not distinguish between germline or somatic mutations, which of course, can have important implications for at-risk relatives and genetic counseling [ 82 ]. All of the above highlight some of the difficulties with putting biomarker-driven treatment into clinical practice and the need for the development of improved access worldwide and cost-effective testing strategies.…”