Dr. Helfand first described the three components of genetic assessment, as he performs it: a family history, assessment of high-penetrance gene mutations, and a genetic risk score.
Family history is a well accepted risk factor for prostate cancer risk. As has long been appreciated, the number of affected relatives and their age at diagnosis significantly affects a man’s lifetime risk of developing prostate cancer.
However, there are many limitations to the use of family history. These include the relatively small proportion of individuals with a positive family history, the changing nature of family history through a patient’s life (ie. if a patient’s brother is diagnosed with prostate cancer today, the patient had a negative family history yesterday and a positive family history today), the fact that many men do not know their family history, and the limited scope of family history obtained (ie. omission of other meaningful cancers including breast, ovarian, pancreatic, colorectal, and endometrial cancers).
Second, he discussed the value of assessment of high penetrance genes. These are relatively low frequency mutations, affecting 2-5% of men with prostate cancer. They may fall into DNA repair genes (BRCA1, BRCA2, ATM), mismatch repair genes (MSH2, PALB2), and other genes (eg. HOXB13).
Third, he highlighted panels of single nucleotide polymorphisms which may explain up to 40% of hereditary prostate cancer risk. Assessment of a large number of these SNPs leads to the derivation of a genetic risk score which is an easily interpretable assessment of the risk of disease.
Interestingly, genetic risk scores provide much more predictive information about a man’s risk of prostate cancer than does family history.
Genetic risk assessment may provide benefit in each stage of the prostate cancer continuum. Beginning among patients with advanced disease, Dr. Helfand highlighted data demonstrating thatDNA repair and mismatch repair gene mutations were much more prevalent in this patient population.
Further, these mutations provided actionable information as patients with these defects may be particularly well suited for treatment with PARP inhibitors or platinum-based chemotherapeutic regimes.
Among men with localized disease, testing for DNA repair and mismatch repair gene mutations is again valuable in Dr. Helfand’s opinion. He highlighted data that patients with these defects are much more likely to have disease reclassification when on active surveillance.
Finally, in the context of prostate cancer screening, known genetic anomalies, particularly affection genetic risk scores or high-penetrance genes, may affect decisions on when to initiate screening and on screening intensity. This is because these mutations affect both the risk of prostate cancer and prostate cancer prognosis.
Presented by: Brian Helfand, MD, University of Chicago
Written by: Christopher J.D. Wallis, Urology Resident, University of Toronto @WallisCJD at the American Urological Association's 2019 Annual Meeting (AUA 2019), May 3 – 6, 2019 in Chicago, Illinois