BRCA Mutations in Prostate Cancer: What Do I Need to Know?
By: Neal Shore, MD, FACS; Sarah Nielsen, MS, LCGC | Posted on: 01 Apr 2021
As physicians, we appreciate the prevalence and burden of prostate cancer (PCa) on patients and their families. Germline (hereditary) and somatic (tumor) genetic testing (GT) enables personalized management for some PCa patients, including approved compendium therapeutics, opportunity for clinical trials, and testing of at-risk family members. The current likelihood of obtaining an actionable genomic finding has been ascertained. For example up to 17% of men with PCa, across all stages of disease, harbor a germline mutation.1 Correspondingly, 10% of primary tumors and 25% of metastases from prostate cancer harbor variants in genes in the DNA damage repair (DDR) pathway, including BRCA1 and BRCA2.2 BRCA2 is the most commonly altered gene in PCa, and numerous other homologous recombination repair (HRR) gene alterations (such as ATM and CHEK2) can be tested at the same time on a multigene panel.3
Somatic tumor evaluation is recommended for men with metastatic PCa, and can be considered for those with regional disease.4 Similarly, most germline GT recommendations have focused on men with metastatic disease, although growing evidence suggests that GT is indicated for most patients, including those with newly diagnosed and early-stage disease.3,5 Yet current testing guidelines are complex and may impede the routine implementation of GT. In fact, discrepancies exist between, and even within, societies regarding criteria for whom to test and how to implement results (fig. 1).3,6
The highest rates of germline mutations in PCa have been reported in metastatic disease (12% to 15%), with BRCA2 being the most commonly identified gene (4% to 6%).7–10 Accordingly, multiple guidelines and consensus statements advocate testing all men with metastatic (and advanced) disease for BRCA and other select DNA repair genes.4,6,11,12
The frequency of germline mutations in men with localized PCa is estimated to be 5% to 7%,1,13 although arguably this population has been understudied as treatment implications are not as well studied as they are for PARP inhibitor (PARPi) candidacy in metastatic disease. Guidelines for GT in this group of patients rely on histological features and family history, but criteria vary among guidelines.3 Ductal/intraductal histology is one such histological feature that has been shown to be particularly predictive of germline mutations, specifically DNA damage/homologous recombination repair (eg BRCA1/2, ATM) or mismatch repair (eg MLH1, Lynch syndrome) mutations.14,15 The converse is also true: men with certain DNA damage repair mutations are more likely to have ductal/intraductal histology and lymphovascular invasion.15
There is growing evidence that an “all-comers” approach for men with PCa uncovers a significant number of actionable mutations, one-third to one-half of which would have been missed by existing GT guidelines.1,10 These studies demonstrate an impressive 13% to 17% overall yield of germline mutations, with no statistical differences in the rate by Gleason score, stage, age or family history of cancer.1,5,10 The PROCLAIM registry, a U.S. guidelines efficacy study of community urology practices, is currently underway to evaluate potential underestimation of actionable GT findings. In addition to gaining a better understanding of the underlying genetics of all stages of PCa, an important benefit of broadening eligibility criteria for genomic profiling is to increase access to testing, especially for underrepresented and underserved populations. Genomic profiling registries have been initiated to 1) remove the barrier of cost, 2) increase patient and clinician access to actionable genetic information, and 3) improve genetics-driven matching of patients with precision therapy and/or clinical trials. Preliminary data from the DETECT registry show that the program is increasing access to testing in some populations, with more than double the percentage of Black patients tested through the program (16%) compared to a standard of care cohort (7%; unpublished data).1,5
Uncovering a BRCA1 or BRCA2 mutation has critical precision therapeutic implications for patients with metastatic disease. Two PARPis, rucaparib and olaparib, were U.S. Food and Drug Administration (FDA) approved in May 2020 for metastatic castration-resistant prostate cancer (mCRPC).16,17 These PARPis are approved for men with germline and/or somatic mutations in BRCA1/2, and olaparib also includes approval for mutations in 12 other HRR genes.16,17 PROFOUND is the first phase 3 trial to demonstrate the clinically significant benefit of HRR+ gene identification and the sequencing for olaparib after abiraterone acetate or enzalutamide for mCRPC patients. Importantly, germline and/or somatic testing can be utilized to identify patients with BRCA/HRR variants for PARPi therapy eligibility.
Of note, to only sequence tumor tissue or only germline testing does not always result in comprehensive genomic profiling. Therefore, to derive the most benefit for patients and their family members, germline and somatic testing can be used in a complementary fashion. Indeed, somatic testing alone will miss up to 8% of germline mutations, and germline testing alone could miss up to 50% of actionable HRR alterations (figs. 2 and 3).8,18 Therefore, up-front paired testing should be considered or reflex testing if the first test does not reveal any actionable variants.
The utility of GT and BRCA2 mutations in early-stage PCa is an active area of investigation. As BRCA2 carriers have a higher chance of developing high risk disease, a patient may decide to opt for surgery rather than active surveillance. Indeed, there is evidence that men with BRCA2 mutations have a higher risk of reclassification during active surveillance for early-stage PCa compared to noncarriers.19 Knowledge of BRCA status can inform additional cancer screening recommendations.6 For example men with BRCA2 mutations are at elevated risk for male breast cancer, and therefore are recommended to undergo clinical breast examinations beginning at age 35 years, with consideration of annual mammograms if gynecomastia is present. Consultation for pancreatic cancer screening can also be considered for those with a strong family history of pancreatic cancer. Due to melanoma risk, full-body skin examinations and minimizing UV exposure are recommended.6 Of significant importance is the potential to deploy predictive testing to identify at-risk male and female relatives who could benefit from earlier/increased surveillance and/or risk-reducing interventions. Women with BRCA mutations are at the highest risk for breast and ovarian cancer, and could opt for breast magnetic resonance imaging (MRI) screening or risk-reducing surgeries.6 Men with BRCA2 mutations who have not developed PCa have an elevated risk (up to 60% over their lifetime) and are recommended to begin prostate cancer screening by age 40 years.6,20
Studies have surveyed different types of PCa providers to better understand uptake of GT. A 2019 survey by the Canadian GenitoUrinary Research Consortium revealed that only 36% of community urologists, medical oncologists and radiation oncologists order GT for men with newly diagnosed metastatic PCa (fig. 4).21 Focusing on urologists, only 10% of respondents to a 2019–2020 survey reported performing GT in their practice.22
The above studies lend insight into practice variability in uptake of genomic testing, particularly underutilization in patients who meet testing guidelines, and serve as a call to action. Technology solutions, such as telehealth, online pre-test educational videos and smartphone apps, can be harnessed to address workflow and time constraint issues.23 These tools will help clinicians and patients realize the promise of precision medicine. Indeed, the promise of precision medicine lies in the ability to efficiently scale genetic testing and education.
- 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.
- Armenia J, Wankowicz SAM, Liu D et al: The long tail of oncogenic drivers in prostate cancer. Nat Genet 2018; 50: 645.
- Loeb S and Giri VN: Clinical implications of germline testing in newly diagnosed prostate cancer. Eur Urol Oncol 2021; 4: 1.
- National Comprehensive Cancer Network: NCCN guidelines: prostate cancer (version 1.2021). Available at https://www.nccn.org/professionals/557 physician_gls/pdf/prostate.pdf.
- Nielsen SM: Broad germline genetic testing criteria for prostate cancer yield actionable findings across all stages of disease. Presented at online annual meeting of American Society for Human Genetics, October 28, 2020. Available at https://view.publitas.com/invitae-6xkkz7rlqe79/invitae_ashg2020_nielsen/page/1.
- National Comprehensive Cancer Network: NCCN guidelines: genetic/familial high-risk assessment: breast, ovarian, and pancreatic (version 2.2021). Available at https://www.nccn.org/professionals/physician_560 gls/pdf/genetics_bop.pdf.
- 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: 443.
- Robinson D, Van Allen EM, Wu Y-M et al: Integrative clinical genomics of advanced prostate cancer. Cell 2015; 162: 454.
- Giri VN, Hegarty SE, Hyatt C et al: Germline genetic testing for inherited prostate cancer in practice: implications for genetic testing, precision therapy, and cascade testing. Prostate 2019; 79: 333.
- Samadder NJ, Riegert-Johnson D, Boardman L et al: Comparison of universal genetic testing vs guideline-directed targeted testing for patients with hereditary cancer syndrome. JAMA Oncol 2021; 7: 230.
- 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: 2798.
- Paller CJ, Antonarakis ES, Beer TM et al: Germline genetic testing in advanced prostate cancer; practices and barriers: survey results from the Germline Genetics Working Group of the Prostate Cancer Clinical Trials Consortium. Clin Genitourin Cancer 2019; 17: 275.
- Giri VN, Obeid E, Gross L et al: Inherited mutations in men undergoing multigene panel testing for prostate cancer: emerging implications for personalized prostate cancer genetic evaluation. JCO Precis Oncol 2017; doi:10.1200/po.16.00039.
- Schweizer MT, Antonarakis ES, Bismar TA et al: Genomic characterization of prostatic ductal adenocarcinoma identifies a high prevalence of DNA repair gene mutations. JCO Precis Oncol 2019; doi:10.1200/PO.18.00327.
- Isaacsson Velho P, Silberstein JL, Markowski MC et al: Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer. Prostate 2018; 78: 401.
- Abida W, Campbell D, Patnaik A et al: Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: analysis from the phase II TRITON2 study. Clin Cancer Res 2020; 26: 2487.
- de Bono J, Mateo J, Fizazi K et al: Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med 2020; 382: 2091.
- Lincoln SE, Nussbaum RL, Kurian AW et al: Yield and utility of germline testing following tumor sequencing in patients with cancer. JAMA Netw Open 2020; 3: e2019452.
- Carter HB, Helfand B, Mamawala M et al: Germline mutations in ATM and BRCA1/2 are associated with grade reclassification in men on active surveillance for prostate cancer. Eur Urol 2019; 75: 743.
- Nyberg T, Frost D, Barrowdale D et al: Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Eur Urol 2020; 77: 24.
- Hotte SJ, Finelli A, Chi KN et al: Real-world management of advanced prostate cancer: a description of management practices of community-based physicians and prostate cancer specialists. Can Urol Assoc J 2021; 15: E90.
- Loeb S, Byrne N, Walter D et al: Knowledge and practice regarding prostate cancer germline testing among urologists: gaps to address for optimal implementation. Cancer Treat Res Commun 2020; 25: 100212.
- Nazareth S, Nussbaum RL, Siglen E et al: Chatbots & artificial intelligence to scale genetic information delivery. J Genet Couns 2021; 30: 7.