Genetic Risk of Prostate Cancer Underestimated; Testing Guidelines Miss Men With Elevated Prostate Cancer Risk

Neither guideline eligibility nor Gleason scores are reliable for predicting prostate cancer risk due to pathogenic germline variants, according to a study published Feb. 7 in JAMA Oncology. The authors say that expanding genetic testing guidelines will improve medical management of prostate cancer patients and their families.

“We propose that genetic testing guidelines should be simplified and expanded to include genetic testing of all men diagnosed with prostate cancer similar to guidelines for pancreatic and colorectal cancer,” say study coauthors led by Piper Nicolosi, Ph.D., from Invitae Corp. (San Francisco, Calif.), which also conducted the testing. “Simplification of testing guidelines would facilitate informed decision making for patients and their family members and provide the foundation for cascade testing of at-risk relatives before they develop cancer, initiating both surveillance and risk-reduction options.”

Inherited risk for prostate cancer is associated with aggressive disease and poorer outcomes and has implications for staging, screening, guiding treatment, genetic counseling, and cascade testing of family members. However, genetic testing guidelines are complex and inconsistent between organizations.

The present study evaluated the presence of pathologic variants in 3,607 men with a personal history of prostate cancer (mean age at diagnosis, 60 years) who underwent referral-based, germline testing between 2013 and 2018. Testing evaluated 14 genes on the Invitae curated prostate cancer panel (ATM, BRCA1, BRCA2, CHEK2, EPCAM, HOXB13, MLH1, MSH2, MSH6, NBN, PMS2, TP53, RAD51D, and PALB2) for 2,250 orders. For the remaining 38 percent of orders, analysis of other genes was ordered from larger hereditary cancer panels or through customized requests. The price of a panel was the same regardless of the genes tested, so variation was dependent on clinician preference.

The researchers found that 17.2 percent of men had a pathogenic germline variant, with the top 10 genes as a percentage of men tested being: BRCA2, (4.74 percent), CHEK2 (2.88 percent), ATM (2.03 percent), MUTYH (2.37 percent),  APC (1.28 percent), BRCA1 (1.25 percent), HOXB13 (1.12 percent), MSH2 (0.69 percent), TP53 (0.66 percent), and PALB2 (0.56 percent). Positive variants in mismatch repair genes (PMS2, MLH1, MSH2, MSH6) accounted for 1.74 percent of variants in the total population tested.

“The importance of BRCA1/2 and other DNA repair genes outlined in the NCCN guidelines represents a small subset of the findings that would benefit patients with prostate cancer,” write the authors. “Therapeutic implications of non-BRCA germline alterations remain unclear, but identification of positive variants in genes not included in the current guidelines have serious implications for treatment options, including clinical trials, particularly basket trials that examine specific genetic biomarkers regardless of tumor type.”

The researchers also note that there was a “considerable lag” between the initial diagnosis of prostate cancer and referral for germline genetic testing across almost all age groups, although age at testing was not associated with the risk of finding positive variants. Further, family history of breast, prostate, ovarian, colon, pancreatic, or other cancers did not correlate with positive variant detection. Gleason scores, which were available for 43 percent of patients, also were not associated with the presence of positive mutations.

There were significant differences in positive results seen by ancestry/ethnicity. The highest rates were found among Ashkenazi Jewish (22.7 percent) and white (17.8 percent) men. African Americans (10.1 percent) and Hispanics (6.4 percent) had significantly lower rates of positive variants.

Based on self-reported family histories, more than one-third of men (37 percent) with positive variants would not have been approved for genetic testing based on National Comprehensive Cancer Network recommendations. Additionally, only 43.8 percent of variants were detected in genes indicated for testing by the 2018 prostate cancer guidelines (BRCA1/2, ATM, PALB2, FANCA).

“Comparing the one-time cost of genetic testing to the high cost of treating catastrophic late-stage cancer in patients with a genetic risk that was not otherwise identified, as well as the benefit to family members from early screening, provides substantial justification for the simplification and expansion of current guidelines,” conclude the authors.

Takeaway: Disease-causing variants are more common in men with prostate cancer than previously thought. Additionally, current genetic testing recommendations miss more than one-third of men with prostate cancer who test positive for pathogenic variants, suggesting that broader genetic testing guidelines are needed.