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Prostate Cancer Patients With Germline Variants Were Often Not Covered by Testing Guidelines

NEW YORK (GenomeWeb) – Nearly 20 percent of men with prostate cancer harbor a germline variant that places them at increased risk of developing the disease, according to a new study, but a third of them were not eligible for genetic testing according to guidelines in place at the time.

Men with germline mutations in genes like BRCA1 or BRCA2 tend to develop prostate cancer at a younger age and have an increased risk of more aggressive disease. In their study, researchers from Invitae — which makes a prostate cancer genetic risk test, as do other firms like Ambry Genetics and Myriad Genetics — and Tulane University examined how often men with prostate cancer had germline variants that increased their risk of disease and whether these men had met guidelines for germline genetic testing.

As they reported today in JAMA Oncology, the researchers found that 37 percent of men with positive results did not meet the National Comprehensive Cancer Network guidelines for germline testing that were in place when the study took place. The guidelines have since been updated, though.

"This research shows the genetic risks associated with prostate cancer have been underestimated and provides support for expanding testing to include an increased number of prostate cancer patients," senior author Oliver Sartor, medical director of the Tulane Cancer Center, said in a statement. "Expanding the use of genetic testing in prostate cancer patients can inform treatment strategies and potentially suggest treatment with targeted therapies or clinical trials."

The researchers conducted a cross-sectional study of 3,607 men diagnosed with prostate cancer who had been referred for germline genetic testing. The number of genes analyzed varied based on what the ordering clinician selected, ranging from two to 80 genes.

Overall, 17.2 percent of the men had pathogenic, likely pathogenic, or increased-risk allele variants. The researchers noted that individuals of Ashkenazi Jewish ancestry had the highest rate of positive results, while African-American or Hispanic individuals had lower rates, though they were underrepresented in the study population.

Nearly a quarter of these positive results were due to mutations in BRCA2. The next most commonly affected genes were CHEK2, ATM, and MUTYH, though the researchers noted there was a long tail of genes in which they found low numbers of alterations. A HOXB13 variant linked to prostate cancer risk was present in 4.5 percent of patients.

The researchers compared their findings to results from a 2016 New England Journal of Medicine study of almost 700 men with metastatic prostate cancer and noted that their results were largely similar. For instance, the Invitae and Tulane team reported that a BRCA1 or BRAC2 mutation was found in 5.99 percent of men, similar to the 6.22 percent reported in the NEJM paper, even though their patient populations differed.

Additionally, the researchers calculated that 37 percent of the men with positive results in their study would not have met the guidelines for germline testing that were in place at the time. Those guidelines, the researchers noted, relied on family history for making testing decisions.

NCCN, though, has updated its genetic/familial breast and ovarian cancer guidelines, which also cover prostate cancer patients. For those patients, they now rely more on Gleason scores to determine the appropriateness of germline testing.

Because their dataset was missing staging data for a number of samples, the researchers said, they were unable to analyze their findings in light of this recommendation shift. They said, though, that they found no correlation between Gleason score and whether they uncovered a positive variant.

Meanwhile, other, prostate cancer-specific NCCN guidelines suggest germline testing of BRCA1, BRCA2, ATM, PALB2, and FANCA genes in prostate cancer patients with metastatic disease, regional, high-risk or very-high-risk disease and in lower-risk prostate cancer patients with strong family history.

The researchers argued that testing guidelines should be simplified and altered to encompass all men diagnosed with prostate cancer.