Expanding genetic testing for prostate cancer could improve patient management

By Marilynn Larkin

NEW YORK (Reuters Health) - 15/2/2019

Expanding genetic testing beyond current guidelines could better stratify prostate cancer patients for the presence of pathogenic variants and improve their medical management, researchers say.

"Inherited pathological mutations in the genes of prostate cancer patients are more common than previously appreciated," Dr. Oliver Sartor of Tulane Medical School in New Orleans told Reuters Health by email. Common pathogenic variations in BRCA genes "represent only a minority of the genes implicated. A variety of other genes are important, as well."

"Current guidelines, which rely heavily on family history, are clearly inadequate to guide testing," he stressed. "Re-evaluation of guidelines is warranted to reflect currently understood realties."

Dr. Sartor and colleagues studied data on 3,607 men with a personal history of prostate cancer who underwent germline genetic testing between 2013-2018. The men had a mean age of 60 at diagnosis and 67 at testing.

As reported online February 7 in JAMA Oncology, 17.2% of men had positive germline variants; however, only 30.7% were variants in BRCA1/2, and only 43.8% of positive variants were detected in genes indicated for testing by the 2018 prostate cancer guidelines: BRCA1/2, ATM, PALB2, and FANCA.

Further, DNA mismatch repair variants with "substantial known therapeutic implications" were detected in 1.74% of variants tested.

Among patients with positive results, the top 10 genes were: BRCA2, 24.3%; CHEK2, 14.1%; ATM, 9.6%; MUTYH, 8.2%; BRCA1, 6.4%; HOXB13 (a gene associated only with prostate cancer risk), 4.5%; APC, 4.5%; MSH2, 3.4%; TP53, 3.3%; and PMS2, 2.7%

The highest rates of positive variants were found among men identified as Ashkenazi Jewish (22.7%) and white (17.8%). Compared with the other ethnic groups, African Americans (10.1%; odds ratio, 0.527) and Hispanics (6.4%; OR,0.325) had lower rates of positive variants.

An assessment of self-reported family histories revealed that 37% of men with positive variants would not have qualified (at the time of testing) for genetic testing per the National Comprehensive Cancer Network (NCCN) genetic/familial breast and ovarian guidelines for patients with prostate cancer.

Dr. Sartor said, "Genetic testing can help men understand their future risk of other cancers; can potentially help their families obtain additional testing that can help manage their future cancer risks; and at times, help to guide therapeutic prostate cancer decision making in a personalized manner."

The NCCN has multiple prostate cancer guidelines that "are not consistent with one another," he noted, and revisiting these guidelines is warranted.

"Raising awareness is important!" he concluded.

Dr. Alberto Martini, a urologist at the Icahn School of Medicine at Mount Sinai, told Reuters Health by email that the study "confirms previous results regarding the most common germline mutated genes in prostate cancer, and appropriately points out...some consistencies among the current guidelines."

"However, some aspects need to be dissected before talking about changing the guidelines," he said.

The fact that the study patients were referred for genetic testing points to the possibility of selection bias, he noted. "There was some concern either in the clinical or familial history that led the treating physician to order these tests. Thus, it is not unlikely that the actual frequencies of these mutations would be lower in the general population."

Before changing guidelines, he added, "one should be able to prove that the diagnostic modalities that are to be implemented can lead to an actual benefit to the population of interest. However, as of today, given the low percentages of patients who would be treated differently, it seems that the numbers don't justify the costs."

"Certainly, more research is needed," Dr. Martini concluded. "When newer therapeutic modalities are available to target more germline mutations, it will then be time to implement (new) guidelines."

Seven coauthors are employees of Invitae Corporation, a testing laboratory that provided the diagnostic test results used in the study. Dr. Sartor has received grants from the company.

SOURCE: http://bit.ly/2N8EYNV JAMA Oncol 2019.

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