麻豆传媒

ORLANDO -- Many patients with BRCA mutations that carry a high risk of hereditary breast and ovarian cancer (HBOC) or with Lynch syndrome are not only unaware of their genetic status, but would not qualify for genetic screening under current guidelines, according to Mayo Clinic researchers.

More than half of patients (52%) were newly diagnosed with HBOC and Lynch syndrome based on the results of this exome sequencing study, "meaning they were not aware of their genetic condition prior to their participating in the trial," reported Niloy Jewel Samadder, MD, of the Mayo Clinic in Phoenix, Arizona, during a press briefing at the American Association for Cancer Research annual meeting.

Importantly, 39.2% of these carriers did not meet National Comprehensive Cancer Network (NCCN) guidelines for genetic screening, including 56.2% of those with Lynch syndrome and 32% of those with HBOC.

Why didn't they meet NCCN criteria? Samadder said that 63.3% had no personal history of cancer, while 60.5% had an insufficient number of relatives with cancer, and 58.6% had a cancer type that was not related to their genetic syndrome.

He pointed out that patients with BRCA mutations have up to an 80% lifetime risk of developing breast cancer, as well as an increased risk of developing melanoma and ovarian, pancreatic, and prostate cancers. Patients with Lynch syndrome have substantially increased lifetime risks of developing colorectal and endometrial cancers, as well as additional increased risks of upper gastrointestinal, urinary tract, skin, and other cancers.

"Both of these conditions have a strong correlation with cancer risk," Samadder said. "There is no disagreement that you have a high risk of breast, ovarian, colorectal, or uterine cancer, and there are clear screening guidelines recommended by the NCCN and major professional societies in terms of breast imaging in patients with BRCA1 and BRCA2, considering prophylactic mastectomy or oophorectomy, timing of colonoscopy, and hysterectomy and oophorectomy in patients with Lynch syndrome. And usually, most of those screening pathways start between 20 and 25 years of age."

"So, by not diagnosing those patients, you leave them at high risk of developing multiple cancers and denying them the possibility of screening and either preventing or detecting a very curable early cancer," he added.

A 'Concerning Finding'

"An interesting and concerning finding is that NCCN criteria seems to work less well in those in underrepresented minority populations," Samadder noted.

He and his colleagues found that NCCN criteria would have missed 49% of underrepresented minorities with HBOC and Lynch syndrome, compared with 32% of white patients.

He suggested those criteria were created with primarily European populations studied in terms of personal and family cancer history, "and that may lead to a systemic bias in the way these guidelines proposed genetic evaluation and testing in other populations."

Finally, Samadder said that 34% of patients who met the NCCN criteria had not received clinical evaluation or testing, suggesting that NCCN guidelines are being underutilized in clinical practice.

"Our results emphasize the need for increased access to genomic screening for CDC Tier 1 genetic conditions, and the potential use of exome sequencing in large populations," he said.

NCCN criteria were created during a period when genetic testing was costly and aimed at identifying those with the greatest chances of being a mutation carrier in the absence of population-wide whole-exome sequencing, Samadder noted.

However, the cost of exome sequencing "is rapidly decreasing" and studies show that testing for HBOC and Lynch syndrome in the general population is cost effective once it gets down to about $500, "which exome sequencing is approaching," he said. This suggests that it should be possible for exome sequencing to be implemented "en masse."

For this study, Samadder and colleagues used data from the , in which whole-exome sequencing was done on saliva samples provided by 44,306 patients at Mayo Clinic sites in Arizona, Florida, and Minnesota.

They evaluated samples for pathogenic mutations in BRCA1 and BRCA2 (denoting HBOC), and MLH1, MSH2, MSH6, PMS2, and EPCAM, denoting Lynch syndrome. They found that 550 individuals (1.2%) had these genetic conditions (387 with HBOC and 163 with Lynch syndrome), which are considered to be CDC Tier 1 genetic conditions that have "significant potential for positive impact on public health based on available evidence-based guidelines and recommendations," .

Among the HBOC and Lynch syndrome groups, median age was 57, 63% were women, and 89% to 95% were white. Common comorbidities included hypertension and ever smoking.

When stratified by gene variants, the largest group of patients unaware of their genetic condition were those with a PMS2 mutation (81.6%).

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