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Inherited Mutations Increase Risk for Lethal Prostate Cancer

Xu, Jianfeng DrPH; Helfand, Brian MD, PhD

doi: 10.1097/01.COT.0000513033.19247.6a

A major challenge of prostate cancer screening is the relatively poor ability to predict a man's risk of developing aggressive prostate cancer. Furthermore, once diagnosed, it is difficult to differentiate one's prostate cancer prognosis. While the vast majority of prostate tumors are indolent and progress slowly, approximately 20 percent of prostate cancer patients will die of the disease, making it the second leading cause of death in American men. This inability to predict which men are at highest risk of dying from the disease contributes to overscreening, overbiopsy, and overtreatment of prostate cancer.

Recent genetic studies, however, provide evidence that inherited mutations in several DNA repair genes may help address this limitation. DNA repair genes are important to the process of carcinogenesis in that they identify and fix mutations that can lead to uncontrolled cell growth (cancer). When these DNA repair genes are mutated, tumors are likely to form. In a study of germline DNA samples from 692 patients with metastatic prostate cancer, investigators from the Stand Up To Cancer–Prostate Cancer Foundation (SU2C-PCF) International Prostate Cancer Dream Team found that 82 patients (11.8%) had inherited pathogenic mutations in 16 DNA repair genes (N Engl J Med 2016;375:443-53). In comparison, the frequencies of mutations in these genes were significantly lower in subjects from two publicly available consortia. The mutation frequency was 4.6 percent among 499 patients with localized prostate cancer in The Cancer Genome Atlas cohort, and even lower, at 2.7 percent, among 53,000 men without a known cancer diagnosis in the Exome Aggregation Consortium.

Although more studies are needed to better determine which of these 16 DNA repair genes are truly associated with risk for more aggressive prostate cancer (N Engl J Med 2016;375(18):1802-1803), this recent seminal study has provided strong evidence DNA repair genes play a critical role in prostate cancer. Furthermore, it demonstrated the frequency of these mutations in metastatic prostate cancer patients is much higher than previously thought, and the frequency of these mutations is likely even higher than in breast cancer patients.

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Importance of Screening

In another newly published study focusing on germline mutations of DNA repair genes for predicting lethal prostate cancer, investigators from NorthShore University HealthSystem, Johns Hopkins Hospital, and Huashan Hospital in China compared the frequencies of mutations in three well-established DNA repair genes (BRCA2, ATM, and BRCA1) among 313 prostate cancer patients who died of prostate cancer and 486 patients with localized prostate cancer (Eur Urol 2016; pii: S0302-2838(16)30885-5). This study offered several novel findings that may have important clinical implications in prostate cancer screening and care.

First, the study found that germline pathogenic mutations (mutations expected to compromise DNA repair capacity) in these three genes alone are significantly more common in lethal prostate cancer patients (6.07%) than in localized prostate cancer patients (1.23%). This was the first genetic study on a large cohort of lethal prostate cancer patients. Furthermore, the direct comparison of mutation frequencies between the two types of prostate cancer patients using the same genetic sequencing analysis provided convincing evidence that the difference was not due to sequencing technology.

Second, results from this study provided critical data to confirm the association of mutations of BRCA2 with the age of prostate-cancer-specific death. Importantly, for the first time, results also demonstrated a dose-response relationship between mutation carrier rate and age of death, as well as time to death. The mutation carrier rate is highest among lethal prostate cancer patients who died before 60 years old (10.00%) or who died within 5 years after a diagnosis of prostate cancer (12.26%), and it is lowest among patients who died of prostate cancer after 75 years old (2.97%) or died >10 years after diagnosis of prostate cancer (0.98%). The mutation frequency of patients with localized PCa was similar to those in the latter groups of lethal prostate cancer patients at 1.23 percent. These results suggest that not all lethal PCa patients have a similar genetic basis, and mutations in these three genes increase one's risk of developing the most lethal form of prostate cancer, dying younger and/or dying sooner after diagnosis.

Third, the ability of mutation status in these three DNA repair genes to predict prostate cancer survival was independent of the stage of prostate cancer at the time of diagnosis. Mutation carriers had poorer survival than non-carriers regardless of whether patients were diagnosed at a localized stage or after the disease had metastasized.

Finally, the study found that the mutation carrier rates were similar in patients with a negative family history (12/417, 2.9%) and a positive family history (8/252, 3.2%). More than 50 percent of mutation carriers in the study did not have a positive family history of prostate cancer. This result suggests genetic testing for mutations in these three genes should not be limited to patients with a positive family history, which is the current standard of care for genetic testing.

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Considering Genetic Testing

These two new studies, together with many other previously published studies (J Clin Oncol 2013;31:1748-57), may have important clinical impacts. Given the findings that having a mutation predicts lethality of prostate cancer at any stage of the disease and that patients can harbor DNA repair gene mutations regardless of family history, it is reasonable to suggest all men diagnosed with the disease should undergo genetic testing. Knowledge of a mutation can be a critical guiding factor in deciding whether to undergo surgery to remove the prostate, as those with low-grade disease and without a mutation may instead wish to engage in an Active Surveillance program (i.e., not undergo surgery unless the disease progresses). Knowledge of a mutation can also help determine which treatment (chemotherapy and rational therapy) is expected to be the most effective. Men with metastatic prostate cancer who have such mutations have been reported to have sustained responses to PARP inhibitors (N Engl J Med 2015;373(18):1697-708), and platinum-based chemotherapy (Eur Urol 2016;69(6):992-5). In addition, there is evidence to support that men who harbor mutations within these same genes may not respond as well to radiation (REF) (Eur Urol 2015;68(2):186-93).

Information conferred by germline mutations in these DNA repair genes is also useful for developing a personalized prostate cancer screening plan in asymptomatic men (e.g., whether, when and how often to undergo PSA testing). Since inherited DNA does not change throughout one's lifetime, obtaining a genetic test once can help guide prostate cancer screening throughout the entirety of a man's adult life.

For men with or without prostate cancer who are identified as harboring a cancer-related mutation, genetic counseling and testing of their relatives is important. For first-degree relatives of a mutation carrier, there is a 50 percent chance they also carry the mutation. These gene mutations are not only important for prostate cancer, but have been strongly implicated in other major cancers, including breast cancer, as well.

Currently, urologists and medical geneticists at NorthShore University HealthSystem are able to order genetic tests for these DNA repair genes, interpret results of genetic testing, and provide appropriate guidance and treatment as well as genetic counseling. Clinicians believe this model could be easily adapted at other institutions to optimize prostate cancer screening and care.

JIANFENG XU, DRPH, & BRIAN HELFAND, MD, PHD, are with the Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Ill.

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
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