(UroToday.com) The Advanced Prostate Cancer Consensus Conference 2021 virtual meeting session discussing PARP inhibitors and beyond included a presentation by Dr. Dana Rathkopf regarding who needs germline testing and what should be tested. There are several groups of patients that need germline testing, according to Dr. Rathkopf:
- According to the NCCN, AUA/ASTRO/SUO, ESMO, and EAU guidelines, all men with metastatic prostate cancer
- According to the new 2021 NCCN guidelines, all men with very high-risk and high-risk localized prostate cancer, with a consideration among men with intermediate risk prostate cancer and intraductal/cribriform histology
- Patients with a family or personal history of cancer:
- BRCA1/2 associated: ovarian, breast, pancreas
- Lynch syndrome associated: colorectal, endometrial, upper tract urothelial carcinoma, and gastric carcinoma
- HOXB13 associated: prostate cancer
- Ashkenazi ancestry and/or family history of known germline variants (per the NCCN 2021 guidelines: BRCA1/2, ATM, PALB2, CHEK2, MLH1, MSH2/6, PMS2, EPCAM)
- Tumor-only sequencing positive for cancer predisposition genes (3-12% are associated with actionable germline mutations)
Based on data from the Swedish Family-Cancer database, prostate cancer has the highest familial risk at 20%, compared to 14% for breast cancer, and 13% for colorectal carcinoma. Familial concordance of prostate cancer is associated with both incidence and survival, and high-risk increases with number of affected family members and decreases with advancing age. High penetrance genetic variants are rare, often in coding DNA, and are associated with high-risk disease, whereas low penetrance genetic variants are associated with single nucleotide polymorphisms, often in non-coding DNA, and associated with low-risk disease.
In early data from Robinson et al. , an integrated analysis of somatic and germline in mCRPC identified ~23% of patients with DDR aberrations (8% germline). Furthermore, ~13% of mCRPC patients had a loss of BRCA2 (5.7% germline), and 90% of BRCA2 loss were biallelic due to somatic mutations, LOH, and homozygous deletions. Subsequent data from Pritchard et al.  showed that DDR germline mutations were present in 11.8% of metastatic prostate cancer, 4.6% of localized prostate cancer, and 2% in the general population. Mutation frequencies did not differ according to family history of prostate cancer or age at diagnosis:
Lynch syndrome also increases the risk of prostate cancer. Data presented by Dr. Pritchard at APCCC 2019 showed that among patients with MSH2 mutation, the cumulative risk of prostate cancer incidence stratified by age was:
- 50 years of age: 0.8%
- 60 years of age: 6.3%
- 70 years of age: 15.9%
- 75 years of age: 23.8%
HOXB13 G84E is involved in regulation of androgen receptor target genes involved in prostate cancer growth. Although HOXB13 G84E is rare, it is important secondary to a strong familial component and association with early-onset disease. Furthermore, in a population-based assessment, HOXB13 G84E carriers had a 33% lifetime risk of developing prostate cancer; unfortunately, there is no current therapeutic intervention targeting this mutation in prostate cancer.
The 2019 Philadelphia Prostate Cancer Consensus Conference provides guidance for what gene panels should be tested, stratified by who is being germline tested (based on disease state):
Importantly, the prevalence of germline mutations is variable across ancestral groups with particularly high-rates of mutations among Ashkenazi Jewish men :
Options for germline testing vary widely, with the following options:
- Focused multi-gene panels (5-6 genes): guideline-based, relevant to individual patient care and clinical history
- Prostate cancer specific multi-gene panels (~10-15 genes): includes DDR and other genes associated with prostate cancer risk and treatment
- Comprehensive panels (~80 genes): designed to gain additional genetic knowledge including trial options
- Reflex testing: additional testing in a step-wise manner based on personal and family history
Somatic (tumor) testing is not a surrogate for germline testing, as highlighted in the following table comparing these two options:
Dr. Rathkopf notes that genetic counselors are the gold standard, however with limitations such as availability, accessibility, and insurance coverage. Counseling considerations are as follows:
- Pre-testing counseling: evaluating a patient’s needs/concerns, obtaining a history, discussing possible outcomes and interventions including potential impact on family members, documenting consent, and providing available information on cost and privacy
- Point of care model: a non-genetic provider does a pre-test consent/order the genetic counselor provides the results
- Electronic genetic education model: non-inferior electronic results supports consideration of individualized counseling for positive results only
Dr. Rathkopf concluded her presentation of who needs germline testing and what should be tested with the following take-home messages:
- Who should be tested?
- There is universal agreement on metastatic prostate cancer
- Other considerations include: history of cancer/variants and tumor features
- What should be tested?
- Multiple germline testing options are available and should be selected based on risk management for the patient and family, and potential impact on prognosis and treatment
- For metastatic prostate cancer, multigene testing is recommended with at least the following per the NCCN guidelines: BRCA1/2, ATM, PALB2, CHEK2, MLH1, MSH2/6, PMS2 and consider HOXB13
- Provider education and ensuring patient understanding is critical both pre- and post-testing
Presented by: Dana Rathkopf, MD, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 Advanced Prostate Cancer Consensus Conference, Saturday, October 9, 2021.
- Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-1228.
- Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453.
- Berro T, Barrett E, Al Dubayan SH. Clinical Multigene Testing for Prostate Cancer. Urol Clin North Am. 2021;48(3):297-309.