DNA repair in prostate cancer is highlighted by several DNA repair pathways:
- Homologous recombination repair (HR): key genes include BRCA1 and BRCA2, associated with the King germline syndrome and treated with PARP inhibitors or platinum chemotherapy.
- Mismatch Repair (MMR): the key gene is MSH2, associated with Lynch syndrome and treated with anti-PD1/PD-L1 therapy.
But, Dr. Pritchard notes that not all DDR genes are the same. BRCA2 and MSH2 are highly prevalent as germline mutations, however, treated with different therapies: BRCA2 with PARP inhibitors or platinum chemotherapy, and MSH2 with anti-PD/PD-L1 therapy. Other genes with moderate prevalence as germline mutations include BRCA1, ATM, CHEK2, MSH6, and MLH1. PALB2 is also emerging and appears to have high prevalence in the germline setting.
Highlighting the guidelines, Dr. Pritchard notes that the 2019 NCCN Prostate Cancer guidelines suggest that all patients with advanced disease (i) should be considered for a metastatic biopsy, (ii) should be considered for tumor testing for MSI-high or dMMR, and (iii) should be considered for germline and tumor testing for HR DNA repair genes (BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, and CHEK2). The ISUP 2019 recommendations include (i) germline panel testing for DNA repair genes in patients with metastatic and high-risk localized disease, and (ii) somatic tumor DNA testing in all metastatic patients. Ideally, testing should be from the metastatic tissue, however, testing from the primary tumor is acceptable.
Dr. Pritchard notes that there are several issues with testing. For HR DDR testing, it is important to confirm bi-allelic inactivation, either by HR signature analysis (for BRCA1/2) or immunohistochemistry for ATM protein. Furthermore, there is the issue of variation in interpretation between commercial assays. For MMR DDR testing, there are issues with the accuracy of MSI and immunohistochemistry, as well as the fact these mutations are technically challenging to detect. Liquid biopsy is an emerging diagnostic utility, however this depends on the underlying disease burden. For instance, ctDNA mutations are much more likely to be detected in patients with a PSA >10 vs PSA <10.1 But, similar to other modalities of testing, there is poor congruence between commercial labs.
Dr. Pritchard summarized his talk by highlighting several key points:
- Germline and tumor next generation sequence testing of DNA repair genes are increasingly recommended to guide advanced prostate cancer treatment.
- Liquid biopsy of ctDNA testing is increasingly used in place of tissue testing and useful when patients are carefully selected with adequate disease burden.
- Sample, methods, and interpretation matter, as there is an increasing role for molecular pathologists.
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland
- Schweizer MT, Gulati R, Beightol M, et al. Clinical determinants of successful circulating tumor DNA analysis in prostate cancer. Prostate 2019 May;79(7):701-708.
Further Related Content: The State of the Art on Molecular Characterization of Advanced Prostate Cancer Presentation