PHILADELPHIA — An international panel of experts led by researchers and thought-leaders at the Sidney Kimmel Cancer Center – Jefferson Health (SKCC) and the Department of Urology at Jefferson have published the first multidisciplinary, consensus-driven prostate cancer genetic implementation framework for the precision medicine era. The consensus framework is a unified approach to help guide a spectrum of healthcare providers in facilitating prostate cancer genetic testing in a timely and responsible manner.
Key recommendations, which were published on June 9, 2020 in the Journal of Clinical Oncology, include a strong endorsement to test all men with metastatic prostate cancer to inform precision medicine or clinical trial eligibility, as well as men with a family history suggesting hereditary prostate cancer as well as other cancers such as breast, ovarian, pancreatic, and colon cancers, to inform active surveillance or screening discussions. Recommended priority genes for testing include BRCA2, BRCA1, and DNA mismatch repair genes in metastatic prostate cancer, BRCA2 for active surveillance discussions, and BRCA2 and HOXB13 for early detection discussions. The panel also recommended that BRCA2 carriers should begin early PSA screening.
The Consensus recommendations come on the heels of two very important FDA approvals for drugs that target metastatic prostate cancer in men who carry BRCA mutations or mutations in other DNA repair genes. Two medications, rucaparib and olaparib, were granted FDA approval recently for treatment among men with specific genetic mutations due to clinical benefit, thus expanding precision medicine for prostate cancer. Therefore, the Conference results have significant impact for implementing germline testing and treatment decision-making for men with metastatic prostate cancer.
The panel also proposed novel genetic evaluation models linking urology and oncology practices with genetic counseling and suggested specific types of gene panel tests that might support traditional vs. alternative genetic evaluation models for men with prostate cancer. This is the first implementation guidance for genetic testing incorporating endorsements for types of gene panels and strategy for genetic evaluation for men with prostate cancer.
Furthermore, this is the first formal, multidisciplinary recommendation that men with metastatic prostate cancer undergo broad germline panel testing and that multiple clinical scenarios—including testing in men with earlier stage disease or for assessing prostate cancer risk—may benefit from reflex testing strategies, according to lead author Veda N. Giri, MD, Director of the Cancer Risk Assessment & Clinical Cancer Genetics Program and the Men’s Genetic Risk Clinic at SKCC.
“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,” Giri said.
Germline mutations are found in 12-17 percent of men with metastatic prostate cancer and 7 percent of men with early-stage disease. A patient’s genetic information may inform how healthcare providers screen, diagnose, and treat prostate cancer, as well as enable them to enroll in a clinical trial, Giri explained. “Therefore, 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.”
Philadelphia Prostate Cancer Consensus
The recommendations were the result of the Philadelphia Prostate Cancer Consensus Conference, which SKCC and the Jefferson Department of Urology hosted in October 2019. The conference was a follow-up to the inaugural Philadelphia Prostate Cancer Consensus Conference, which SKCC convened in 2017 to address the growing role of genetic testing for hereditary prostate cancer. The expert panel published the first set of comprehensive recommendations in 2018 (J Clin Oncol. 2018 Feb 1;36(4):414-424) to guide physicians about multigene testing for men and inform genetic consultation for prostate cancer risk.
Since then, genetic testing for prostate cancer has rapidly expanded to include an increasing subset of men. However, the field lacks clear recommendations about which men to test beyond those with metastatic disease, which genes to prioritize for testing, as well as guidelines for managing disease screening, surveillance, and treatment based on growing information on genetic results. Additionally, the expansion of genetic testing has outpaced the availability of genetic counseling—an important factor for patients in making an informed decision about whether to undergo genetic testing—and providers not formally trained in genetic counseling have been increasingly ordering genetic tests for their patients, according to Giri, who co-chaired the conference in 2017 and 2019, along with Leonard G. Gomella, MD, Chair of the Department of Urology, and Karen E. Knudsen, MBA, PhD, EVP of Oncology Services and Enterprise Director of SKCC.
It is important to ensure that genetic testing for prostate cancer is implemented responsibly, Giri explained. “Urologists who are on the front lines of the diagnosis of prostate cancer need to be familiar with these rapidly evolving genetic testing recommendations. This includes the proper ordering of prostate cancer gene panel testing and the utilization of appropriate genetic counseling,” Dr. Gomella, Chair of the Department of Urology at Jefferson and Conference Co-Chair said. “Oncologists will also be increasingly ordering germline testing to determine if their patients with metastatic prostate cancer may qualify for a PARP inhibitor, given the recent FDA approvals,” Giri said. “As it is not feasible that all men be referred to genetic counseling, it is imperative that providers offering genetic testing are aware of best practice recommendations so that they can help their patients make an informed decision. These recommendations will be helpful to urologists and oncologists when thinking of offering genetic testing to men with prostate cancer across the stage spectrum,” Giri explained.
The 2019 conference thus focused on addressing key gaps in implementation of genetic testing, including who should be considered for testing, which genes should be prioritized for testing, recommendations for patients based on the results of the genetic testing, and optimal ways to deliver genetic counseling.
“The Philadelphia Consensus Conference serves a critical role in synthesizing best available evidence into clinical recommendations, made possible through the depth and breadth of expertise represented at the meeting. The impact of the recommendations has been significant, and SKCC is thankful for all the consensus members. This is a major step forward toward understanding and mitigating prostate cancer risk,” Knudsen said.
The consensus panel was comprised of a multidisciplinary group of experts from across the United States, Europe, and Australia, representing fields such as urology, medical and radiation oncology, genetic counseling, epidemiology, implementation science, pathology, and primary care, as well as organizations including NCCN, and patient advocates. Criteria that achieved a strong consensus amongst the panel were designated as “recommend” and those with a moderate consensus were designated “consider” in the final framework.
Key recommendations that garnered strong consensus include:
- All men with metastatic prostate cancer should undergo comprehensive gene panel testing to help determine precision therapy or clinical trial eligibility.
- Men who have a family history that suggests hereditary prostate cancer such as men diagnosed with prostate cancer at a young age, who died from prostate cancer, or who had metastatic disease, or family history suggestive of other hereditary cancer syndromes such as hereditary breast and ovarian cancer or Lynch syndrome.
- The following genes were endorsed for testing:
- BRCA2, BRCA1, and DNA mismatch repair genes in men with metastatic prostate cancer.
- BRCA2 among men with nonmetastatic disease, particularly to inform active surveillance.
- BRCA2 and HOXB13 among men who do not have a diagnosis of prostate cancer but fit the family history criteria for prostate cancer screening
- Any additional genes based on personal or family history.
- Screening should begin at age 40 or 10 years prior to the age of the youngest prostate cancer diagnosis in the family among BRCA2 carriers.
- Recommendations from the consensus conference support recent FDA approvals for PARP inhibitors in metastatic prostate cancer, with testing endorsed for multiple DNA repair genes to inform PARP inhibitor candidacy.
- To ensure optimal pretest informed consent, providers should discuss the following with each patient:
- The purpose of genetic testing
- The possibility of uncovering hereditary cancer syndromes and additional cancer risks
- Potential costs to the patient
- Genetic discrimination laws
- Further testing among family members
Additional testing criteria, genes for testing, and use in clinical care for men with prostate cancer were also addressed by the consensus conference. Implications for family members regarding genetic testing and hereditary cancer risk were also key topics.
The panel also examined practice, research, and policy gaps posing barriers to implementation of prostate cancer genetic testing. Strong recommendations to help increase implementation include greater advocacy and public awareness for prostate cancer genetic testing, reimbursement for telehealth and telephone counseling, and the implementation of virtual tumor boards, molecular boards, or genetics boards to better disseminate expertise.
They also recommended that providers who are not formally trained in cancer genetics and genetic counseling be able to access genetic education materials on several priority topics, including purpose of genetic testing, understanding types of results, test options, laws that address genetic discrimination, and hereditary cancer syndromes that might be uncovered. Multiple educational resources regarding genetic testing were included in the consensus publication.
Additionally, the consensus panel identified areas in critical need of further research, which includes basic scientific research into metastatic disease biology, additional research into the genetics of prostate cancer in African American men, and clinical outcomes by germline mutation status, and they are currently planning working groups to address gaps and barriers to germline testing for prostate cancer.
Article Reference: Giri et al., “Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019,” Journal of Clinical Oncology, DOI: 10.1200/JCO.20.00046, 2020.
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