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Gaps Seen in Prostate Cancer Gene Testing Criteria

Almost one-fifth of a large cohort of men with a personal history of prostate cancer tested positive for a pathogenic germline variant that likely caused their cancer, yet over one-third of them did not qualify for genetic testing based on current recommendations, a cross-sectional study has suggested.

In a cohort of 3,607 men previously diagnosed with prostate cancer, such variants were identified in 17.2% of the group overall, while 37% of those in whom a pathogenic variant was identified did not meet current guidelines for genetic testing as laid out by the National Comprehensive Cancer Network (NCCN), Oliver Sartor, MD, of Tulane Medical School in New Orleans, and colleagues reported.

“Inherited risk for prostate cancer is associated with aggressive disease and poorer outcomes, indicating a critical need for increased genetic screening to identify disease-causing variants that can pinpoint individuals at increased risk for metastatic castration-resistant prostate cancer,” the researchers wrote in JAMA Oncology.

“We propose that genetic testing guidelines … be simplified and expanded to include genetic testing of all men diagnosed with prostate cancer similar to guidelines for pancreatic and colorectal cancer,” the team concluded.

The study was designed to evaluate the prevalence of germline mutations in a diverse cohort of men with prostate cancer diagnosed at various disease stages. Participants had a mean age upon diagnosis of 60 and a mean age of 67 on genetic testing.

Family history, age at which the men were tested, ancestry or ethnicity, and Gleason score on diagnosis were also analyzed. Some 14 genes were included in the prostate cancer panel and blood and saliva samples upon which the sequencing and interpretation of variants detected were based; the age at testing was not associated with the risk of finding positive variants, the researchers noted.

The results analyzed by ancestry or ethnicity were also mixed, with the highest prevalence of germline variants identified in men of Ashkenazi Jewish descent at 22.7%, as well as among white men, at 17.8%. In contrast, the investigators did not find that a family history of other cancers, including breast and ovarian, correlated with the presence of a positive variant among those for whom family histories were available.

Nor was the Gleason score on diagnosis associated with the presence of a positive mutation among those for whom Gleason scores were known. As the investigators pointed out, current NCCN guidelines for prostate cancer rely heavily on Gleason scores to determine eligibility for genetic testing. Among the entire study cohort, the most common genes detected with a positive variant included BRCA1 (4.7%), followed by CHEK2 (2.8%), MUTYH (2.3%), and ATM (2.0%).

A similar pattern was seen among men who tested positive for a germline variant, the most common variants again being BRCA2 (24.2%), CHEK2 (14.1%), ATM (9.6%), and MUTYH (8.2%). The BRCA1 gene was also detected in 6.4% of men who were positive for a germline variant. On the other hand, only 30.7% of the positive variants identified in the overall cohort occurred in the BRCA1/2 genes and only 43.8% of them were found in genes indicated for genetic testing in recent guidelines.

Asked for his perspective, Daniel Spratt, MD, chief of the Genitourinary Radiotherapy Program at the University of Michigan in Ann Arbor, emphasized that the clinically relevant impact of identifying these germline variants in patients with localized prostate cancer has yet to be demonstrated.

Furthermore, roughly 90% of newly diagnosed prostate cancers are localized, which is overwhelmingly non-lethal, provided patients are treated with curative intent. “Thus, the bar for germline testing to help men with localized prostate cancers is very high,” Spratt emphasized.

This is not true for men who present with metastatic disease, however, as this group, although only a minority of newly diagnosed patients, is enriched for both germline variants as well as somatic mutations in DNA repair genes that may, in fact, sensitize them to either poly (ADP-ribose) polymerase (PARP) inhibitors or a platinum-based regimen — therapeutic strategies not yet supported in men with localized disease, Spratt noted.

He also questioned whether the men who participated in the study were, as the Sartor and co-authors said, an “unselected population,” as they all met NCCN guidelines for germline testing based on family history, stage of disease, and age of diagnosis. Thus, “this cohort was highly enriched for those who would have germline variants, and these positive rates may not apply to the general population,” Spratt said.

Still, he said he considered the paper to be important and that germline testing should be done for men who present with metastatic disease. He also congratulated the authors on “shedding light on the current limitations to national guidelines for genetic testing,” much as has been done by others for breast cancer.

“Clearly, more work is needed to understand who should be tested and whether testing will actually help improve a patient’s quality or quantity of life, as well as the impact on a patient’s family, especially given the expense of testing,” Spratt said, adding: “It is very hard to improve on the excellent outcomes many localized prostate cancer patients already achieve.”

Sartor reported grants from Invitae, which performed the genetic testing for the study, as well as relationships with Merck, AstraZeneca, Bayer, Bellicum, Bristol-Myers Squibb, Celgene, Dendreon, EMD Serono, Johnson & Johnson, OncoGenex, Pfizer, Sanofi-Aventis, Constellation, Endocyte, Advanced Accelerator Applications, Bavarian-Nordic, Endocyte, and Innocrin.