Genetic testing guidelines miss men at risk for aggressive prostate cancer - Healio

Current National Comprehensive Cancer Network guidelines and Gleason scores proved unreliable in stratifying men with prostate cancer based on the presence or absence of pathogenic germline variants, according to study results published in JAMA Oncology.

Simplifying and expanding testing guidelines for genetic mutations would improve management of these men, according to the researchers.

“Guidelines specifically addressing genetic testing for patients with prostate cancer were sparse until recently,” Piper Nicolosi, PhD, researcher in clinical genomics at Invitae Corp. in San Francisco, and colleagues wrote. “The purpose of this study was to evaluate the prevalence of germline mutations in a large, diverse cohort with prostate cancer with respect to current genetic testing guidelines and to bridge gaps in knowledge given the heterogeneity in both prostate cancer and germline testing recommendations.”

In the cross-sectional study, Nicolosi and colleagues reviewed data from 3,607 men (mean age at testing, 67 years; mean age at diagnosis, 60 years) with a history of prostate cancer who underwent germline testing between 2013 and 2018. Men were unselected for family history, disease stage and age at diagnosis.

Analysis for each man included two to 80 genes chosen at the discretion of the ordering clinician.

The incidence and distribution of positive (pathogenic, likely pathogenic and increased risk) germline variants and the proportion of men with prostate cancer who met NCCN guidelines for germline genetic testing served as the primary outcome measures.

The researchers found that among the men who underwent genetic testing, 620 (17.2%) had positive germline variants, only 30.7% of which were variants in BRCA1 or BRCA2. Further, only 291 of 674 (43.8%) positive variants were detected in genes indicated for testing by the 2018 prostate cancer guidelines.

Gleason scores, which were available for 43% of the men, did not demonstrate any correlation with the presence of positive mutations. Positive germline variants were found in 15.1% of the 148 men with Gleason scores of 6 or lower for a primary tumor, compared with 16.3% of the 1,391 men with Gleason scores of 7 or higher.

In the overall cohort, the top 10 genes with positive variants (expressed as proportion of men tested) were BRCA2 (4.74%); CHEK2 (2.88%); ATM (2.03%); MUTYH (2.37%); APC (1.28%); BRCA1 (1.25%); HOXB13 (1.12%); MSH2 (0.69%); TP53 (0.66%) and PALB2 (0.56%). The researchers identified DNA mismatch repair variants with significant known therapeutic implications (PMS2, MLH1, MSH2 and MSH6) in 1.74% of the total variants in the study population.

Among men with positive results, the top 10 genes were BRCA2 (24.3%); CHEK2 (14.1%); ATM (9.6%); MUTYH (8.2%); BRCA1 (6.4%); HOXB13 (4.5%); APC (4.5%); MSH2 (3.4%); TP53 (3.3%); and PMS2 (2.7%). Extended genetic testing detected several rare but significant pathogenic variants involved in hereditary cancer risk. Thirty patients had positive variants in HOXB13, a gene linked exclusively to prostate cancer risk.

An assessment of self-reported family histories showed 37% of men in the study with positive variants (n = 229) would not have qualified for genetic testing using the NCCN genetic/familiar breast and ovarian guidelines for patients with prostate cancer.

The researchers acknowledged limitations to their study, including underrepresentation of various ethnic groups, the reliance upon clinician reporting for Gleason data and family history, and the fact that the study was not population-based.

They noted that although these data show that NCCN guidelines and Gleason scores are not dependable for stratifying patients with prostate cancer for germline variants, the repercussions of expanded genetic testing must be considered.

“A persistent shortage of genetics professionals and coordination of follow-up when indicated are issues being addressed by multiple national organizations,” the researchers wrote. “The economic implications of genetic testing must also be considered. However, as costs continue to decrease, the benefits of a single germline genetic test become apparent when compared with the potentially dramatic cost of managing advanced prostate cancer.” – by Jennifer Byrne

Disclosures: Nicolosi reports employment with Invitae Corp., a testing laboratory that furnished the diagnostic test results used in this study. She also reports personal fees from Invitae outside the submitted work. Please see the study for all other authors’ relevant financial disclosures.

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