Guidelines Recommend Widespread Genetic Testing for Metastatic Prostate Cancer, Associated Family History Risk

The first multidisciplinary, consensus-driven framework for genetic testing in prostate cancer was borne out of the 2019 Philadelphia Prostate Cancer Consensus Conference, leading to the creation of comprehensive guidelines regarding the evaluation, management, and implementation therein.¹

The guidelines strongly recommend germline and somatic testing for all men with metastatic prostate cancer. Additionally, men with nonmetastatic prostate cancer who are of Ashkenazi Jewish descent, have advanced T3a disease or higher, have intraductal or ductal pathology, or have a total Gleason score of 8 or higher should be considered for genetic testing to inform targeted treatment decisions, as well as clinical trial eligibility.

The consensus-driven framework also recommends that all men with a family history that could indicate an increased risk of hereditary prostate cancer or other cancers, such as breast, ovarian, pancreatic, and colon cancer, should receive reflex testing to determine whether active surveillance or screening is recommended.

“This implementation framework applies to oncologists, urologists, genetic counselors, and primary care providers engaged in the care of men with prostate cancer or at risk for the disease,” lead study author, Veda N. Giri, MD, director of the Cancer Risk Assessment & Clinical Cancer Genetics Program and the Men’s Genetic Risk Clinic at the Sidney Kimmel Cancer Center, stated in a press release.²

As part of the 2019 Philadelphia Prostate Cancer Consensus Conference, 97 participants from urology, medical oncology, radiation oncology, clinical genetics, genetic counseling, primary care, pathology, implementation science, population science, epidemiology, and basic science gathered to develop a genetic implementation framework in prostate cancer.

The conference, which was hosted by the Sidney Kimmel Cancer Center and the Department of Urology at Thomas Jefferson University, also included patient stakeholders and advocates, as well as members from national organizations, such as the National Comprehensive Cancer Network.

“Urologists who are on the front lines of the diagnosis of prostate cancer need to be familiar with these rapidly evolving genetic testing recommendations,” Leonard G. Gomella, MD, chair of the Department of Urology at Sidney Kimmel Cancer Center and co-chair of the conference, also stated in the press release.² “This includes the proper ordering of prostate cancer, gene panel testing, and the utilization of appropriate genetic counseling.”

Overarching topics of discussion included genetic contribution to prostate cancer risk and aggressiveness, germline mutations by prostate cancer clinical and molecular characteristics,

multigene testing, disparities in germline mutations in diverse patient populations, genetic testing capabilities and shortcomings, implementation of genetic counseling, and existing guidelines, among others.

The framework was driven by a series of questions that were voted on anonymously by a panel of 76 conference participants using a web-based polling platform. Each consensus was defined as strong (greater than 75% agreement), moderate (50% to 74% agreement), or lacking (less than 50% agreement).

Seven questions served as the basis for the recommended framework:

• Which men should be considered for germline prostate cancer genetic testing?
• Which panels should be considered, and which genes should be prioritized for testing?
• What prostate cancer-specific recommendations should be considered on the basis of genetic results?
• What is optimal informed consent for prostate cancer genetic testing?
• What collaborative strategies may facilitate prostate cancer genetic evaluation between health care and genetic providers?
• What post-test disclosure strategies are most appropriate on the basis of genetic results?
• What barriers must be addressed to enhance prostate cancer genetic testing?

The results indicated that patients should be able to make informed decisions regarding genetic testing. Moreover, genetic evaluations should be conducted by health care and genetics professionals in a multidisciplinary fashion.

Overall, the panel determined that screening for patients should begin at 40 years of age or 10 years prior to the age of the youngest prostate cancer diagnosis in a patient’s family among BRCA2 carriers.

In terms of family history, the criteria state that men with 1 brother or father or 2 or more male relatives who were diagnosed with prostate cancer at less than 60 years of age, died from prostate cancer, or had metastatic prostate cancer are recommended to receive testing. Additionally, men with a family history of 2 or more hereditary breast or ovarian cancers or Lynch spectrum cancers in any relatives on the same side of the family should be considered for genetic testing.

Although the role of genetic testing for African American men was a topic of discussion during the conference, a consensus was not met due to limited evidence in this space.

While comprehensive germline and somatic testing is recommended for all men with metastatic prostate cancer, BRCA1/2 mutations and genes associated with DNA mismatch repair deficiency (dMMR) should be prioritized. ATM mutations should also be considered. These mutations could also be the subject of reflex testing in men with nonmetastatic disease to inform active surveillance.

The mutations that should be prioritized for risk assessment in men with a family history of hereditary cancers include BRCA2 and HOXB13 with additional considerations for BRCA1, ATM and dMMR.

All patients who meet the recommendation criteria should undergo testing that captures the particular genes that put them at risk based on their family history.

Consensus for providing optimal informed consent showed that the recommended discussion points should include the purpose of genetic testing, the possibility of uncovering hereditary cancer syndromes, potential types of test results, the potential to uncover additional cancer risks, potential out-of-pocket cost to the patient, Genetic Information Nondiscrimination Act law and other laws that address genetic discrimination, and cascade testing and additional familial testing options. Additional points of discussion that should be considered are multigene panel options, data sharing and selling policies of genetic laboratories, and privacy regarding genetic testing.

Video options for pretest informed consent, as well as telehealth options for post-test result disclosure were recommended for men with prostate cancer. However, it was highly agreed upon that pathologic or likely pathogenic results, family history recommendations, and cascade testing options should be delivered by a genetic counselor.

“Models of genetic evaluation that incorporate technology to enhance access to genetic testing, such as telehealth or use of videos for pretest genetic education, were also endorsed, along with key elements of informed consent so men can make an informed decision for genetic testing,” said Giri.

The panel concluded that barriers of genetic education for providers, implementation of genetic testing in prostate cancer, and research priorities require additional guidance.

References:

1. Giri VN, Knudsen KE, Kelly WK, et al. Implementation of germline testing for prostate cancer: Philadelphia Prostate Cancer Consensus Conference 2019 [published online ahead of print June 9, 2020]. J Clin Oncol. doi:10.1200/JCO.20.00046
2. New Recommendations Offer Guidance for Clinicians & Patients on Implementing Genetic Testing for Prostate Cancer. Published June 9, 2020. https://bit.ly/2YuHHXU. Accessed June 10, 2020.