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Current Guidelines Miss Relevant Germline Mutations in Prostate Cancer

Current Guidelines Miss Relevant Germline Mutations in Prostate Cancer

National Comprehensive Cancer Network (NCCN) genetic testing guidelines and Gleason scores do not predict which patients with prostate cancer will test positive for a pathogenic, likely pathogenic, or risk-allele (RA) gene variant, according to a study (abstract 5009) presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting.

The findings have important implications for targeted therapy trials, screening, chemoprevention, and surgical prevention of primary cancer recurrence, as well as the identification of relatives at risk for cancer who would benefit from screening and prevention interventions, said the authors, led by Piper L. W. Nicolosi, MD, of Invitae in San Francisco.

“Revisiting current guidelines will better serve this patient population and their families by providing greater access to germline genetic testing and therapeutic options,” noted the authors. “The number of genes represented with pathogenic/likely pathogenic/RA variants may indicate a role for broad multigene testing in patients with prostate cancer. Curated disease-specific gene panels may increase the rate of relevant findings compared to current recommendations of testing BRCA1/2 only.”

Patient blood and saliva was used to extract DNA. The research team employed a 14-gene prostate cancer risk–specific panel to detect germline mutation status in ATM, BRCA1, BRCA2, CHEK2, EPCAM, HOXB13, MLH1, MSH2, MSH6, NBN, PMS2, TP53, PALB2, and RAD51D. (PALB2 and RAD51D were added to the panel based on preliminary evidence of association with prostate cancer risk.)

The authors reported that other included genes were ordered from larger hereditary cancer panels. The researchers assessed the personal and family histories of patients with a positive variant to determine whether they met any current guidelines for genetic testing (NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, Colorectal).

Among 1,158 patients with a personal history of prostate cancer and for whom germline gene testing was conducted, 199 (17%) tested positive for at least one pathogenic, likely pathogenic, or RA variant, based on the Invitae Sherloc criteria. Most (65.5%) of the variants identified were in genes other than BRCA1/2, and 9% occurred in mismatch repair genes associated with Lynch syndrome, Nicolosi reported. Only 12 patients had cancer risk variants in more than 1 gene.

The most frequent risk variant loci were BRCA2 (27% of positive results for risk variants), CHEK2 (14.6%), MUTYH (9.4%), ATM (8.5%), BRCA1 (7.1%), and APC (5.2%).

“Current testing guidelines exclude a large proportion of individuals and families that would benefit from germline genetic testing: 126 (63%) patients with positive results were eligible for genetic testing based on all currently available testing guidelines, whereas 73 (37%) did not qualify,” Nicolosi reported. “Pathogenic/likely pathogenic/RA variants were identified in 15.4% of patients with a Gleason score of ≥ 7.”

Also presented at the meeting was a novel prostate cancer risk classifier that used a readily available genomic test combined with clinicopathologic variables to generate a simple-to-use classification system that was highly prognostic for distant metastases.

 
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