Risk Prediction Tools Available for Germline BRCA1/2 Mutations Underperform in Prostate Cancer Patients - Beyond the Abstract

Robinson et al. were the first to report in 2015 that germline mutations in DNA damage repair (DDR) genes are more common in advanced prostate cancer than previously considered.1 Pritchard et al identified inheritable mutations in genes related to cancer-predisposition syndromes in 12% of metastatic prostate cancer patients, and a significant proportion of them did not have a previous family history of cancer to suspect the presence of these genetic variants.2

Various reports have later validated these observations,3,4 confirming BRCA2 as the most commonly DDR mutated gene across populations with a different genetic background. Importantly, all these studies found that a substantial proportion of carriers would have not qualified for genetic testing according to the clinical guidelines in use, as these only recommend screening for individuals with a robust family history of cancer that was absent in approximately 30% of patients found to harbor a mutation. This led to an update of the National Comprehensive Cancer Network (NCCN) guidelines that currently recommend genetic testing for all patients with metastatic or high-risk localized prostate cancer.5 However, most scientific societies outside the US have not been modified and still rely on personal and family history of cancer to optimize genetic testing.

The most effective approach to genetic testing in prostate cancer is a matter of debate. No doubt a universal testing strategy would identify more carriers, but is unlikely to be funded by many medical insurances and most publicly funded healthcare systems, at least with the evidence currently available. In consequence, most patients in Europe and many other regions in the world do not get genetic testing until being considered for treatment with a PARP inhibitor or platinum-based chemotherapy.6

In this work,7 we aimed to elucidate the proportion of prostate cancer patients with known BRCA1/BRCA2 mutations that would have qualified for germline testing according to two risk-calculation models widely used for the selection of candidates for germline testing. BRCAPRO and Manchester Score System (MSS) are two mathematical models that estimate the likelihood of a BRCA1/BRCA2 mutation based on personal and family history. We analyzed 42 and 58 families with BRCA1 and BRCA2 germline mutations. In all cases, the proband that initiated cascade testing was a female with a personal history of breast and/or ovarian cancer. In 23 families, we identified a carrier with prostate cancer (2 BRCA1, 21 BRCA2). Only 30% and 48% of these patients would have qualified for testing using BRCAPRO and MSS, respectively.

It is important to note, that a median of two breasts and/or ovarian cancer cases, per family, had occurred between the first prostate cancer identified in a carrier and the cancer case leading to germline testing. Since the delay in identifying men with prostate cancer as mutation carriers would often translate in reduced implementation of cancer prevention strategies in unaffected relatives at risk, we would recommend continuing testing all patients with high-risk or metastatic disease until further methods to optimize screening are developed

Written by: Elena Castro, MD, PhD, Medical Oncologist, Clinician Scientist at Spanish National Cancer Research Center, Madrid, Spain

1. Robinson D, Van Allen EM, Wu YM, et al: Integrative Clinical Genomics of Advanced Prostate Cancer. Cell 162:454, 2015
2. Pritchard CC, Mateo J, Walsh MF, et al: Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 375:443-53, 2016
3. Castro E, Romero-Laorden N, Del Pozo A, et al: PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol 37:490-503, 2019
4. 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. NCCN NCCN: Prostate Cancer (version 1.2019). 2019
6. Gillessen S, Attard G, Beer TM, et al: Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017. Eur Urol 73:178-211, 2018
7. Oliva L, Lozano R, Llacer C, et al: Risk Prediction Tools Available for Germline BRCA1/2 Mutations Underperform in Prostate Cancer Patients. Eur Urol Oncol, 2019

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Further Related Content:
Watch: Influence of BRCA-2 Mutations on the Natural History and Response to Therapy in Prostate Cancer- Elena Castro
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