(UroToday.com) The 2023 EAU annual meeting included a session on clinically meaningful questions in the management of advanced, hormone-sensitive prostate cancer, featuring a state-of-the-art presentation by Dr. Derya Tilki discussing germline testing in hormone-sensitive prostate cancer. Dr. Tilki started by highlighting what is now considered a landmark study in advanced prostate cancer: “Inherited DNA-repair gene mutations in men with metastatic prostate cancer.”1 Among 692 men with metastatic disease who were unselected for family history of cancer or age at diagnosis, germline DNA-repair gene mutations were identified in 11.8% of patients:
The NCCN guidelines provide comprehensive direction for when testing should be performed, namely for very high and high risk patients, but also in certain situations of intermediate, low, and very low risk patients, particularly if family history is positive:
The NCCN defines a positive family of prostate cancer as either:
- Brother or father or multiple family members who were diagnosed with prostate cancer (but not clinically localized Grade Group 1) at <60 years of age or who died from prostate cancer, OR
- >= 3 cancers on the same side of the family, especially diagnosed <= 50 years of age: bile duct, breast, colorectal, endometrial, gastric, kidney, melanoma, ovarian, pancreatic, prostate (but not clinically localized Grade Group 1), small bowel, or urothelial cancer
The 2019 Philadelphia Prostate Cancer Consensus Conference also provides several recommendations and considerations for testing:
More recently, the EAU guidelines now provide recommendations for germline testing:
- Consider germline testing in men with metastatic prostate cancer (Strength rating: Weak)
- Consider germline testing in men with high-risk prostate cancer who have a family member diagnosed with prostate cancer at <60 years of age (Strength rating: Weak)
- Consider germline testing in men with multiple family members diagnosed with prostate cancer at <60 years of age or a family member who died from prostate cancer (Strength rating: Weak)
- Consider germline testing in men with a family history of high-risk germline mutations or a family history of multiple cancer on the same side of the family (Strength rating: Weak)
Importantly, Dr. Tilki emphasized that we must consider the priority elements of informed consent for prostate cancer germline testing:2
With regards to what to use to test, there is variability in prostate cancer specific multigene panels. There are focused-guideline-based panels (5-6 genes), comprehensive cancer panels (~80 genes), and reflex panels (initial set of genes tested followed by broad gene testing). Panels include genes with strong, limited, and unknown risk of prostate cancer. Importantly, benefits of expanded testing have to be balanced with other considerations, such as higher rates of variants of uncertain significance. Dr. Tilki also noted that localized prostate tumors from germline BRCA2-mutation carriers have genomic features that are more similar to those present in CRPC tumors in men with sporadic disease. Thus, understanding the biology of germline mutations is crucial in the localized setting.
Dr. Tilki emphasized that why we germline test is to facilitate a need for precision medicine strategies:
- Who does not need active therapy? (spare toxicity)
- Who may suffer a relapse?
- Who should get surgery versus radiation?
- Who may benefit from more aggressive therapeutic approaches?
- Identification of family risk
- Optimal sequential use of standard therapies for each patient
- Who should receive more intensive therapy upfront?
- Personalizing therapy based on targetable alterations (ie. DDR, PI3K)
- Monitoring drug resistance and anticipating tumor progression
Dr. Tilki concluded her presentation discussing germ line testing in hormone-sensitive prostate cancer with the following take-home messages:
- Genetic testing for germline gene alterations in men with prostate cancer is now part of the standard of care and has been included in international guidelines
- Different guidelines recommend testing non-metastatic patients with higher risk disease
- Germline pathogenic variants in DNA repair genes have been reported in up to 12% of men with advanced or metastatic prostate cancer
- Men with BRCA2 pathogenic variants have been reported to have more aggressive prostate cancer, with younger age of onset, lymph node involvement, and distant metastases at diagnosis
- Germline genetic results can impact patient management and cascade testing
Presented by: Derya Tilki, MD, Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany
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 2023 European Association of Urology (EAU) 38th annual congress held in Milan, Italy between March 10-13, 2023
References:
- 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.
- Giri VN, Knudsen KE, Kelly WK et al. Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019. J Clin Oncol. 2020 Aug 20;38(24):2798-2811.