March 30, 2022

A prospective, multisite study conducted by Mayo Clinic physicians found that 1 in 6 patients with colorectal cancer (15.5%) had a germline predisposition for the disease, more than half of which would not have been detected following national guidelines. The study enrolled a cohort of 361 patients with a diagnosis of colorectal adenocarcinoma. This cohort was part of the larger Interrogating Cancer Etiology Using Proactive Genetic Testing (INTERCEPT) study that included 2,984 patients who had a new or active cancer diagnosis and were seen at Mayo Clinic Cancer Center sites in Arizona, Florida or Minnesota.

"Steps are being taken to ensure all patients are offered genomic sequencing to better understand the genes that led to the development of their cancer," said Niloy Jewel Samadder, M.D., a gastroenterologist at Mayo Clinic in Arizona. "This helps us know how to precisely target treatment and improve survival."

Colorectal cancer cohort

Of the 361 patients considered for the current study, 39.3% had rectal cancer. In the group of patients with colon cancer, 40.6% had right-sided colon cancer. Detailed family cancer history information was available for 178 patients, and 9% of those had a family history of colorectal cancer in a first-degree relative.

Colorectal cancer staging consisted of:

• 5.3% stage 1
• 19.9% stage 2
• 36.6% stage 3
• 38.2% stage 4

The median age at diagnosis was 57 years old and 43.5% were female. Nearly one-third of the patients had a body mass index (BMI) greater than 30 and 35% were ever smokers.

Analyzing germline predispositions

All patients received germline sequencing using a next-generation sequencing panel of 83 genes (84 genes as of July 2019) on the Invitae Multi-Cancer Panel at no cost. Full-gene sequencing, deletion and duplication analysis, and variant interpretation were performed at Invitae. Clinical, demographic, family history and pathologic information was collected from either medical records or electronic questionnaire. Those with pathogenic germline variants (PGVs) were invited for genetic counseling and cascade family variant testing at no cost for all blood relatives.

PGVs detected (positive results) based on the universal testing performed in this study were also compared with the indications outlined in guidelines by the National Comprehensive Cancer Network (NCCN), National Society of Genetic Counselors and American College of Medical Genetics. A PGV was considered incremental if it was detected in this study and would not have been detected based on these guidelines or if it was a gene outside of those recommended for sequencing in the guidelines.

PGVs and associated treatment modifications

Of the patients considered, 56 patients (15.5%) had a total of 62 PGVs detected. Five patients had more than one PGV. Of the patients with PGVs detected, 21 were considered high penetrance, 21 moderate penetrance and seven low penetrance. There were seven carriers associated with recessive syndromes.

The most common PGVs were in CHEK2 (1.9%), MSH2 (1.4%) and monoallelic MUTYH (1.4%). The rate of PGVs was higher in patients with rectal cancer than in those with colon cancer, and overall survival for those with PGVs and those without PGVs was similar. A molecular diagnosis of Lynch syndrome was confirmed in 11 patients, and 23 patients had a germline predisposition associated with homologous recombination deficiency (HRD).

"This may lead to novel targeted therapies based on the cancer's unique genetic basis," said Dr. Samadder. "This allows us to individualize care, target cancer screening to high-risk patients, and hopefully prevent cancer altogether in the next generation of the family."

Nearly 15% of patients who had a PGV had no family history of colorectal cancer, and the rate of PGVs in patients younger than 50 years old was 21.8% compared with 12.2% in those older than 50 years old. Logistic regression analysis showed that younger age at diagnosis was associated with increased likelihood of having a PGV.

Thirty-four patients had incremental PGVs that would not have been detected using indications suggested by national guidelines. This is 9.4% of the entire study cohort and 60.7% of the patients in which a PGV was detected. For nearly 10% of patients with a PGV, modifications were made in their treatment plans based on these findings.

This study demonstrates the strength of universal multigene panel testing in detecting more clinically actionable, hereditary predispositions. The discovery of PGV in patients with colorectal cancer has therapeutic implications for both patients and their families. Broader testing not only is feasible but can add valuable insights into developing individualized treatment plans.

For more information

Uson PLS, et al. Germline cancer susceptibility gene testing in unselected patients with colorectal adenocarcinoma: A multicenter prospective study. Clinical Gastroenterology and Hepatology. 2022;20:e508.

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