Germline Testing in Prostate Cancer: Urologists Should Lead the Way
By: Daniel Triner, MD, PhD; Todd M. Morgan, MD | Posted on: 01 Sep 2022
Incorporation of germline testing into the management of patients with prostate cancer has brought about a new era. Mutations to genes involved in repairing DNA, such as through double-strand break repair (eg BRCA1, BRCA2, or ATM) or mismatch repair (eg MLH1, MSH2, PMS2, and MSH6) can all drive hereditary prostate cancer risk. Large cohort studies have shown that 5%–17% of patients with prostate cancer, depending on the cohort characteristics, will harbor a germline mutation.1 In a classic study, Pritchard and colleagues showed that approximately 12% of patients with metastatic prostate cancer have a relevant mutation in a DNA-repair gene, with BRCA2 mutations comprising nearly half of the mutations.2 This substantially impacted current guidelines, which recommend germline testing in any patient with metastatic or node-positive prostate cancer, those with very-high- and high-risk localized prostate cancer, and those with lower-risk prostate cancer who have a strong family history of cancer or Ashkenazi Jewish ancestry.3
There are several reasons why germline testing needs to be a key component of prostate cancer care. For one, pathogenic germline mutations have an important role in prognostication. For example, pathogenic germline mutations in BRCA2 are associated with a higher risk of developing metastatic disease and worse survival.4 Germline testing may also be useful for guiding prostate cancer therapy. In patients with metastatic castration-resistant prostate cancer and pathogenic alterations in BRCA1, BRCA2, or ATM, treatment with poly (ADP-ribose) polymerase (PARP) inhibitor therapy has been approved based on phase 3 trial data.5 Immune checkpoint inhibition is already approved for use in patients with metastatic solid tumors in the setting of mismatch repair gene mutations.
In addition to the prognostic and therapeutic importance of germline testing, there are important personal repercussions of germline testing. Identification of pathogenic germline variants can lead to high patient anxiety with regard to their diagnosis, life/disability insurance discrimination, and future financial considerations. In addition, there are critical considerations for screening/early detection in at-risk family members, with cascade testing a vital component of post-test genetic counseling.
Implementation of germline testing for men with prostate cancer requires appropriate pre-test genetic education, and multiple clinical models exist to guide implementation.6 One model includes referral of patients with indications for testing to certified genetic counselors for pre-test counseling (risks, benefits, limitations, possible results, and implications), germline testing, and patient/family followup based on results. However, as indications for genetic testing have expanded, there has been a concomitant nationwide shortage of genetic counselors, which has made this a significant barrier to genetic testing in many settings.7
Another model for germline testing involves the clinicians performing pre-test counseling and testing and waiting on test results to guide the need for referral to genetic counseling. Among medical oncologists, a growing number of providers are performing testing and counseling on their own. Provider-level germline testing has been implemented in patients with ovarian or breast cancer with a high level of patient satisfaction, and recent efforts have brought this approach into the prostate cancer clinic. In 2020, Scheinberg and colleagues published a study in which medical oncologists were provided with 1 hour of training in germline testing and counseling of men with metastatic prostate cancer.8 Pre-test genetic counseling was performed by the physician at the initial oncology appointment, and 98% of patients (63/66) agreed to germline testing. This was met with high patient and clinician satisfaction.8
To assess the viability of this approach in a multidisciplinary setting, we performed a prospective study of 275 patients with localized or metastatic prostate cancer, assessing both urologist- and medical oncologist-led pre-test genetic counseling.9 In both settings, there were high rates of germline testing, and 98% of patients reported being satisfied with the quality of pre-test counseling. This study lends support to a clinician-led genetic testing model, but also emphasizes the importance of educating patients prior to performing testing.
As an alternative to clinician-led pre-test counseling, video education may provide an effective medium for patient education. In fact, one study found that when given the choice between a brief pre-recorded video and in-person counseling, men with prostate cancer chose video-based pre-test education at a high rate with comparable use of germline testing.10 Additionally, COVID-19 has increased the nationwide utilization of telemedicine. This can be telephone- or Web-based (audio and/or visual) pre- and post-test counseling with provided visual aids. Telegenetics is an effective delivery model for genetic education that is already widely available and has been highly successful in breast and ovarian cancer.11
In summary, expanded indications for germline testing, particularly in clinically localized prostate cancer, necessitate increased access to testing. To alleviate this need, we propose updated clinic workflows to include physician-level pre-test counseling. We and others have shown that, with brief training, physicians can effectively provide pre-test counseling with positive outcomes and high utilization. This specific model may decrease the burden on genetic counselors to perform pre- and post-test counseling and streamline clinical care for patients. Moreover, we should work toward expansion of video and telegenetics, and development of more patient-facing educational material, which have all been shown to be effective. Prostate cancer providers must also remain aware of updated indications for germline testing. Undoubtedly, addressing gaps in implementation of germline testing will improve the care of prostate cancer patients and their families.
- Nicolosi P, Ledet E, Yang S, et al: Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines. JAMA Oncol. 2019;5:523-528.
- 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;38(24):2798-2811.
- Castro E, Goh C, Olmos D, et al: Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757.
- Mateo J, Carreira S, Sandhu S, et al: DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697-1708.
- Giri VN, Hyatt C and Gomella LG: Germline testing for men with prostate cancer: navigating an expanding new world of genetic evaluation for precision therapy and precision management. J Clin Oncol. 2019;37(17):1455-1459.
- Kurian AW, Griffith KA, Hamilton AS, et al: Genetic testing and counseling among patients with newly diagnosed breast cancer. JAMA. 2017;317(5):531-534.
- Scheinberg T, Goodwin A, Ip E, et al: Evaluation of a mainstream model of genetic testing for men with prostate cancer. JCO Oncol Pract. 2020;17(2): e204-e216.
- Abusamra SM, Solozano MA, Luke M, et al. Satisfaction with clinician-led germline genetic counseling in patients with prostate cancer. J Urol. 2022; doi: 10.1097/JU.0000000000002865.
- Russo J, McDougall C, Bowler N, et al: Pretest genetic education video versus genetic counseling for men considering prostate cancer germline testing: a patient-choice study to address urgent practice needs. JCO Precis Oncol. 2021;5:PO.21.00238.
- Schwartz MD, Valdimarsdottir HB, Peshkin BN, et al: Randomized noninferiority trial of telephone versus in-person genetic counseling for hereditary breast and ovarian cancer. J Clin Oncol. 2014;32(7):618-626.