Basel, Switzerland (UroToday.com) During the Molecular Biomarkers and Novel Imaging in Advanced Prostate Cancer session at the Advanced Prostate Cancer Consensus Conference (APCCC 2019), Dr. Rosalind Eeles discussed how patients should be selected for genetic counseling and testing. In her opinion, there are several important questions:
- What is the spectrum of genetic predisposition that we currently know?
- How should we use this? Who should be tested? Are there international discrepancies in the guidelines?
- How do we manage men who are at higher risk?
- What will the future look like?
Dr. Eeles notes that finding the full spectrum of genetic variants in advanced prostate cancer is not straightforward. Linkage/sequencing is effective for very rare variants and has a large effect size, next-generation sequencing is effective for rare/uncommon variants and has an intermediate effect size, and GWAS is effective for common variants but has a small effect size.
Excess familial risk is broken down into three groups:
- 60%: unexplained risk
- 33%: GWAS identified
- 7%: panel tested BRCA2, BRCA1, HOXB13, MMR, NBS1, CHEK2, ATM, PALB2, and possibly FANCA
Additional work in this space has recently been completed in men with African-American/African lineage, noting more than 80 new variants.
The OncoArray Groups (Prostate Cancer) PRACTICAL consortium includes 31 sites in the USA, 31 in Europe, two in Asia, two in Australia, and one in Africa, providing analysis of 98,500 samples assessing 170 SNPs.1 This led to a total of 27 new loci associated with aggressive and early onset (<55 years of age) disease (Gleason score >= 8; PSA >100, death from prostate cancer). In a study from the UK Genetic Prostate Cancer Study, 191 prostate cancer cases were assessed to elucidate the incidence of DNA repair gene mutations in men with a positive family history (3+ cases in the family of any age).2 There were 14 putative loss-of-function mutations in the 191 samples (7.3%) and these mutations were more frequently associated with nodal involvement, metastasis or T4 tumour stage (p = 0.00164). Furthermore, loss-of-function mutations in any of the studied genes conferred a relative risk of prostate cancer of 1.94 (95%CI 1.56-2.42).
Dr. Eeles concluded her talk by summarizing who should get genetic counseling/screening – in short, it depends on where you live and what you have:
- Men with prostate cancer and a family history of breast/ovarian cancer should get BRCA1/2 germline testing.
- Panel testing for men with young-onset of disease and family history of cancer and mCRPC should occur, but currently, this is typically only being done in the US and in private practice.
- Several areas where testing may eventually become mainstream.
- Testing at diagnosis, particularly for those on active surveillance and those in castration-resistant states.
- Testing for common variants to stratify populations and modify risk of those with a family history.
- Associated screening programs stratified by risk.
Presented by: Rosalind A. Eeles, PhD, The Institute of Cancer Research, London, United Kingdom
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
- Schumacher FR, Al Olama AA, Berndt SI, et al. Association analyses of more than 140,00 men identify 63 new prostate cancer susceptibility loci. Nat Genet 2018 Jul;50(7):928-936.
- Leongamornlert D, Saunders E, Dadaev T, et al. Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease. Br J Cancer 2014 Mar 18;110(6):1663-1672.