Genetic Mutations and Prostate Cancer: Screening Recommendations

David L. Graham, MD


March 14, 2018

Of late, discussion of the use of genetic testing in men with prostate cancer has been increasing. The article by Pritchard and colleagues[1] in the New England Journal of Medicine (NEJM) last year has been an impetus for these considerations. Those investigators found DNA repair mutations in 11.8% of men with metastatic disease. Mutations included BRCA1 and BRCA2, ATM, CHEK2, and others. At our institution, these findings have led to an increased number of men being tested; and I have little doubt that our experience is being reflected at many other institutions. The finding of a positive result on genetic testing in patients with prostate or other malignancies will often lead to a recommendation that family members be tested. As a consequence, our question then becomes: What should our testing recommendation be for those men without known prostate cancer but an abnormal finding on genetic testing?

The current recommendation for prostate cancer screening of the general population is that it not be performed. Although there continues to be disagreement with this recommendation in some quarters, it still stands. A significant basis for this recommendation was the fact that many cancers found by prostate-specific antigen (PSA) screening were of low risk for mortality (T2 disease with a Gleason score of 6 or less); and, as a result, many men were likely to undergo therapies with significant toxicities for a disease that would not affect their lives. A screening recommendation for men with proven genetic mutations associated with prostate cancer should therefore take into account the impact that these mutations have on the lethality of the cancers associated with them.

There are data suggesting an increased aggressiveness with some mutations associated with prostate cancer. A number of investigators have found that cancers with BRCA2 have an increased lethality. Tryggvadottir and colleagues[2] reported on Icelandic men with prostate cancer and the BRCA2 mutation. They found that those men had a significantly increased risk for higher stage and grade of disease. In addition, the men with BRCA2-associated prostate cancers had a cause-specific survival of only 2.1 years as compared with 12.4 years if the mutation was not present. The impact on cause-specific survival was also reported by Thorne and colleagues[3] in 2011, who found that the BRCA2 mutation was an independent predictor of cause-specific survival.[3] In 2014, Akbari and colleagues[4] reported on a series of 4187 prostate biopsies sequenced for BRCA2.[4] The mutation was found in 1.4% of biopsies with cancer as compared with 0.4% of controls. The hazard ratio of cause-specific survival when the mutation was present was 3.48.

There are also data in patients with Lynch syndrome regarding increased malignant risks of prostate cancer. Grindedal and colleagues[5] reported in 2009 that MMR carriers had a 30% cumulative risk for prostate cancer by age 70 years and that all of the cancers found were Gleason 8 or higher. Engel and colleagues[6] in 2012 and Barrow and colleagues[7] in 2013 both demonstrated that the risk for prostate cancer was increased with the MSH2 mutation but not with MLH1. The element of lethality was not delineated in these articles. Very few data exist regarding the clinical impact of the mutations described in the NEJM article.

The effect of a screening program for these men is being evaluated by investigators on the IMPACT trial. In this international trial, 791 men with BRCA1 and 731 men with BRCA2, along with matched controls, have undergone a PSA test on enrollment. If the PSA level was greater than 3, a biopsy was performed. If the PSA was less than 3, they underwent yearly PSA testing. The results of the initial screening round were reported in 2014 by Bancroft and colleagues.[8] On enrollment, 8% of men on the trial had a PSA greater than 3. Among those 199 men, 162 underwent biopsy, and cancer was found in 59 men. Although the positive predictive value for all cancers was not statistically different from controls, the positive predictive value for intermediate- or high-risk disease was significantly different in men with BRCA1 or BRCA2 compared with controls. Screening rounds continue, and prostate cancer-specific morbidity and mortality will be evaluated as an endpoint.

With these data in mind, some recommendations regarding screening can be considered. Many would suggest that men with a family history of prostate cancer with a significant lethal potential—that is to say, metastatic or a cause of death—should likely be screened more aggressively. In addition, the initial reported findings of the IMPACT trial would suggest that men with BRCA1 or BRCA2 mutations should be screened. Men with other genetic findings on screening and no family history should be counseled that we have no clear information whether they are more likely to get prostate cancer or whether it would be more likely to have a significant clinical impact on their lives.


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