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 health-care providers in facilitating prostate cancer genetic testing in a timely and responsible manner.
Key recommendations, which were published in the Journal of Clinical Oncology,1 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, in addition to other cancers, such as breast, ovarian, pancreatic, and colon, 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 BRCA2 carriers begin early prostate-specific antigen screening.
Background on Recommendations
The consensus recommendations come on the heels of two U.S. Food and Drug Administration (FDA) approvals for drugs that target metastatic prostate cancer in men who carry BRCA mutations or mutations in other DNA repair genes. Rucaparib and olaparib were recently granted FDA approval for treatment among men with specific genetic mutations due to clinical benefit, thus expanding precision medicine for prostate cancer. Therefore, the consensus 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. The panel 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 strategies for genetic evaluation for men with prostate cancer.
Furthermore, this is the first formal, multidisciplinary recommendation that men with metastatic prostate cancer should 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 and Clinical Cancer Genetics Program and the Men’s Genetic Risk Clinic at SKCC.
Veda N. Giri, MD
“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,” Dr. Giri said.
Germline mutations are found in between 12% and 17% of men with metastatic prostate cancer and 7% of men with early-stage disease. A patient’s genetic information may inform how health-care providers screen, diagnose, and treat prostate cancer, as well as enable them to enroll in a clinical trial, Dr. 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 recommendations2 in 2018 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. It is important to ensure that genetic testing for prostate cancer is implemented responsibly, according to Dr. Giri, who co-chaired the conference in 2017 and 2019.
“Urologists who are on the front lines of the diagnosis of prostate cancer need to be familiar with these rapidly evolving genetic testing recommendations. That includes the proper ordering of prostate cancer gene panel testing and the utilization of appropriate genetic counseling,” said Leonard G. Gomella, MD, Chair of the Department of Urology at Jefferson and a conference co-chair.
“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
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“Oncologists will also be increasingly ordering germline testing to determine whether their patients with metastatic prostate cancer may qualify for a PARP inhibitor, given the recent FDA approvals,” Dr. Giri said. “As it is not feasible for all men to be referred to genetic counseling, it is imperative for providers offering genetic testing to be aware of best practice recommendations so 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.”
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 toward understanding and mitigating prostate cancer risk,” said Karen E. Knudsen, MBA, PhD, Enterprise Director of SKCC, EVP of Oncology Services, and a conference co-chair.
Karen E. Knudsen, MBA, PhD
Key Recommendations
The consensus panel comprised 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 the National Comprehensive Cancer Network, and patient advocates. Criteria achieving a strong consensus among 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 suggestive of hereditary prostate cancer, such as men diagnosed with prostate cancer at a young age, who died of prostate cancer, or who had metastatic disease, were recommended for testing. Additional considerations for testing included a 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 a 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 items with all patients:
- 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. In addition, the implications for family members regarding genetic testing and hereditary cancer risk were key topics.
Future Considerations
The panel also examined practice, research, and policy gaps posing barriers to the 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 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 the purpose of genetic testing, understanding the types of results, test options, laws that address genetic discrimination, and hereditary cancer syndromes. Multiple educational resources regarding genetic testing were included in the consensus publication.
Additionally, the consensus panel identified areas in critical need of further research, including metastatic disease biology, genetics of prostate cancer in black men, and clinical outcomes by germline mutation status. They are currently planning working groups to address gaps and barriers to germline testing for prostate cancer.
DISCLOSURE: Dr. Giri holds stock or other ownership interests in Novopyxis. Dr. Gomella has served in a consulting or advisory role for Janssen Oncology, Astellas Pharma, Pfizer, Clovis Oncology, and Bayer and is associated with patents held by Thomas Jefferson University. Dr. Knudsen holds stock or other ownership interests in Pfizer and Genomic Health; has received honoraria from CellCentric and Sanofi; has served in a consulting or advisory role for CellCentric, Sanofi, Atrin Pharmaceuticals, and Context Therapeutics; has received research funding from Celgene; and has received reimbursement for travel, accommodations, or other expenses from Sanofi and Genentech.
REFERENCES
1. Giri VN, Knudsen KE, Kelly WK, et al: Implementation of germline testing for prostate cancer: Philadelphia Prostate Cancer Consensus Conference 2019. J Clin Oncol. June 9, 2020 (early release online).
2. Giri VN, Knudsen KE, Kelly WK, et al: Role of genetic testing for inherited prostate cancer risk: Philadelphia Prostate Cancer Consensus Conference 2017. J Clin Oncol 36:414-424, 2018.
