- At the present time, genetic evaluation guidelines for prostate cancer primarily focus on BRCA1 and BRCA2 testing. The overall risk of prostate cancer has been reported up to 3.8-fold for men who carry BRCA1 mutations and up to 8.6-fold for men who carry BRCA2 mutations. BRCA2 mutations are also associated with more aggressive prostate cancer features.
- Current guidelines do not include early-onset prostate cancer or metastatic disease as stand-alone criteria for genetic testing, which may limit insurance coverage of testing. However, increasingly affordable out-of-pocket payment options have allowed more men to undergo genetic testing.
- A national consensus conference is scheduled in Philadelphia in March 2017 to develop comprehensive genetic evaluation guidelines relevant to prostate cancer risk, which will have an impact for men and their families regarding cancer risk and management.
Prostate cancer is a recognized component of the hereditary breast and ovarian cancer (HBOC) syndrome tumor spectrum, where inherited susceptibility is accounted for by mutations in BRCA1 and BRCA2.1-8 Familial clustering of breast and prostate cancers has also been previously reported, further supporting the potential inherited link of subsets of prostate cancer with breast cancer.9 The overall risk of prostate cancer has been reported up to 3.8-fold for men who carry BRCA1 mutations and up to 8.6-fold, depending on the study, for men who carry BRCA2 mutations.10 Mutations in BRCA2, in particular, have been associated with more aggressive clinicopathologic characteristics of prostate cancer and worse outcomes (increased risk of recurrence and poorer survival).11-15
Furthermore, BRCA2 mutations have been associated with early-onset prostate cancer (age at diagnosis 55 years or younger).16,17 Thus, genetic testing for BRCA1/2 mutations may provide some men with prostate cancer risk estimates, as well as their risk for developing aggressive disease. Genetic testing can be used to inform screening and may increasingly inform tailored approaches to disease management. In addition, men who carry a BRCA mutation may be at risk for other cancers in the BRCA-spectrum, such as male breast cancer, pancreatic cancer, and melanoma.18 Women who carry a BRCA mutation are also at risk for breast and ovarian cancers.18 Therefore, genetic evaluation of men for consideration of BRCA1/2 genetic testing is important to inform cancer risk assessment, screening, and emerging treatments. Oncologists must be aware of the need for full intake of family cancer history to identify specific subsets of men with prostate cancer who may warrant genetic evaluation.
Germline BRCA mutations are increasingly being reported in metastatic, castrate-resistant prostate cancer.19-22 Several studies involving tumor sequencing or germline DNA sequencing of patients with metastatic prostate cancer have reported rates of germline BRCA2 mutations of 5% to 6%.19-22 Tumor sequencing is increasingly being performed in oncology to identify mutational targets for treatment.23 In this process, germline mutations may be suspected if the tumor reveals mutations that are known cancer-predisposing mutations or if the family or personal cancer history are suspicious for inherited predisposition.23 Furthermore, if the tumor mutation is of a high variant allele fraction, this also increases suspicion that the variant is inherited.23 Therefore, the metastatic disease setting, particularly with castration resistance, is another developing area for inherited genetic evaluation.
Genetic Consultation for Prostate Cancer
There is now a growing need to develop strategies to identify men with prostate cancer for referral to genetic counseling. Genetic counseling is a cornerstone of genetic consultation, and the field of genetic evaluation for inherited prostate cancer is evolving.24 The purpose of genetic counseling is to provide individuals with personalized assessment of cancer risk based on their personal and/or family cancer history, provide education of cancer inheritance patterns, and discuss the options, benefits, risks, and limitations of genetic testing in order to make an informed decision about genetic testing. Additional aspects discussed include genetic discrimination laws and reproductive implications, particularly for recessive conditions. Genetic counselors and advanced genetics nurses have training and education in medical genetics and counseling to help educate patients and their families on the genetic component of disease and understand the implications of genetic testing. Despite the fact that guidelines exist for BRCA1/2 testing for prostate cancer, there may still be out-of-pocket cost depending on the insurance plan. If insurance denies coverage for genetic testing, out-of-pocket payments can range from under $500 to more than $2,000depending on the laboratory. If there is concern that insurance will not cover genetic testing, there may be options to proceed with genetic testing through commercial laboratories that offer more affordable testing, usual out-of-pocket cost under $500, though this could still pose a financial burden to some patients. These financial considerations also need to be discussed with patients prior to proceeding with genetic testing.
Current Genetic Testing Guidelines for Prostate Cancer
At the present time, genetic evaluation guidelines for prostate cancer primarily focus on BRCA1 and BRCA2 testing.18 The current National Comprehensive Cancer Network (NCCN) guideline (Genetic/Familial High-Risk Assessment: Breast and Ovarian [Version 2.2017]) states that a male warrants genetic counseling and to consider genetic testing if he has prostate cancer of Gleason score 7 or higher and one of the following: (1) at least one close blood relative with ovarian cancer or breast cancer at age 50 or younger, or (2) at least two relatives with breast, ovarian, or prostate cancers (Gleason 7 or higher) at any age. The NCCN states that unaffected men may also consider genetic evaluation if their family history meets the same criteria, although testing of an affected relative is preferred, if possible. Therefore, oncologic referrals must consider broad family cancer history inclusive of cancers in the hereditary breast and ovarian cancer tumor spectrum such as cancers of the breast, ovary, or pancreas. One challenge is that men may not know the Gleason score of their male relatives with prostate cancer, which may limit eligibility for insurance coverage of genetic testing.
Management Based on BRCA Mutation Status
For men without prostate cancer who carry a BRCA mutation, current NCCN guidelines recommend that prostate cancer screening begin at age 45 for BRCA2 carriers and that BRCA1 carriers also consider screening at age 45.18 Because of the additional risk for male breast cancer in men who carry a BRCA mutation, the NCCN recommends breast self-exam training and a yearly clinical breast exam starting at age 35.18BRCA mutation status in men can provide useful information for male and female relatives when considering their own genetic counseling and genetic testing. Thus, female relatives can gain cancer risk information and personalized screening recommendations for breast and ovarian cancers, and both men and women can gain information regarding risks for pancreatic cancer and melanoma and discuss the current issues and options of screening of these cancers.
Targeted treatment for metastatic castrate-resistant prostate cancer using PARP inhibition is now being reported.21,25 Improved response rates with olaparib have been reported among men with metastatic disease with DNA repair mutations including BRCA2 mutations.21,25. As this field grows, genetic testing for BRCA mutations will also be expected to increase when considering targeted therapy options for metastatic, castrate-resistant prostate cancer, as exemplified in other cancers.26
Referral Implications for Oncologists
Genetic evaluation for inherited prostate cancer is now a growing field, and there is a critical need to develop comprehensive approaches for referral, evaluation, and management (Fig. 1). At Sidney Kimmel Cancer Center of Thomas Jefferson University, we have developed the first Genitourinary (GU) Genetics Clinic, which comprehensively evaluates men with or at-risk for prostate cancer in a multidisciplinary setting.24 The GU Genetics Clinic began in late 2014 and is part of the GU Oncology Multidisciplinary Center. It provides genetic counseling to men with all stages of prostate cancer referred based upon their personal medical history, prostate cancer features, family cancer history, and emerging tumor sequencing to provide genetic testing options and personalized cancer screening and treatment based upon test results. Men evaluated in the GU Oncology Multidisciplinary Clinic have a unique opportunity to engage in genetic evaluation while they are seen by specialists for their prostate cancer treatment.
The GU Genetics Clinic also evaluates patients with prostate cancer referred by other urologic providers such as urologists, radiation oncologists, and medical oncologists. Furthermore, men have the option to enroll on the Genetic Evaluation of Men (GEM) study—a prospective multigene panel testing study for inherited prostate cancer. Development of referral criteria for genetic counseling has entailed committed engagement between medical oncology, urology, clinical cancer genetics, and radiation oncology for identification and referral of patients with prostate cancer for genetic evaluation.
Oncologists must develop strategies to capture comprehensive family cancer history to identify men to refer for genetic evaluation. Family history must include instances of not only of prostate cancer, but also melanoma and breast, pancreatic, and ovarian cancers. Family history of additional cancers may be considered in the future to a greater extent as the spectrum of inherited prostate cancer is better defined from ongoing studies. Furthermore, referral of younger men with early-onset prostate cancer, particularly those diagnosed at or before age 55, to undergo genetic counseling is important, as it will help them make informed decisions about genetic testing. As more studies are emerging describing germline BRCA mutations from tumor sequencing, more men with metastatic prostate cancer are being referred for genetic evaluation, Although current guidelines do not include early-onset prostate cancer or metastatic disease as stand-alone criteria, out-of-pocket payment options have allowed access for a greater number of men to undergo genetic testing, which may not be covered by insurance. A national consensus conference is scheduled in Philadelphia in March 2017 to develop comprehensive genetic evaluation guidelines relevant to prostate cancer risk, which will have an impact for men and their families regarding cancer risk and management.
About the Authors: Dr. Giri is the Director of the Cancer Risk Assessment and Clinical Cancer Genetics Program in the Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University. Ms. Hyatt is a licensed, certified genetic counselor in the Cancer Risk Assessment and Clinical Cancer Genetics Program of Sidney Kimmel Cancer Center, Thomas Jefferson University. Dr. Kelly is the Director of the Division of Solid Tumor Oncology in the Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University.