June 16, 2022
A prospective, multisite study conducted by Mayo Clinic physicians found that 1 in 6 patients with pancreatic cancer (15.2%) had a genetic predisposition to developing the deadly disease. Study results were published in Clinical and Translational Gastroenterology in 2021. For these patients with a genetic susceptibility to pancreatic cancer, the researchers noted a moderate improvement in survival. Genetic testing should be offered to all patients with pancreatic cancer to aid in treatment selection, prognostication and familial cancer risk counseling.
The study enrolled a cohort of 250 patients with a diagnosis of pancreatic 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.
"Next-generation sequencing is important to help patients and their care providers 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 target treatment, improve survival and appropriately inform a patient's at-risk family members."
Pancreatic cancer cohort
Of the 250 patients considered for the study, 66.8% had a pancreatic tumor with primary location in the head, followed by 17.6% in the pancreatic body and 15.6% in the pancreatic tail. Detailed family cancer history information was available for 124 patients, and 13.7% of those patients had a family history of pancreatic cancer in a first-degree relative.
Pancreatic cancer staging consisted of:
- 14.4% with stage 1 cancer
- 20% with stage 2 cancer
- 24.8% with stage 3 cancer
- 40.8% with stage 4 cancer
The median age at diagnosis was 66.5 years old, and 56% of the patients were male. More than 85% of the patients had a body mass index (BMI) lower than 30, and 56% of all the patients were never smokers.
Analysis of genetic predispositions
All patients received germline genetic testing 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 pathological information was collected from either medical records or electronic questionnaires. 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 and Genomics. 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 not indicated for sequencing in the guidelines.
PGVs, family history and clinical outcomes
Of the 250 patients, 38 patients (15.2%) had a total of 40 PGVs detected. Two patients had more than one PGV. Of the patients with PGVs detected, 17 were considered high penetrance genes, 14 were moderate penetrance genes and four were low penetrance genes. There were also three carriers of genes associated with recessive syndromes.
The most common PGVs were in BRCA2 (22.5%), ATM (17.5%) and CHEK2 (10%). A molecular diagnosis of Lynch syndrome was also confirmed in one patient. Overall, 26 patients had a germline predisposition associated with the homologous recombination repair (HRR) pathway that is the target of several novel cancer therapies. Twelve patients (31.5% of those with PGVs) had incremental PGVs that would not have been detected using indications for genetic evaluation and testing suggested by national guidelines.
The median overall survival of patients with PGVs was 16.8 months compared with 16.5 months in those without PGVs. A similar trend was seen when comparing patients with PGVs in the HRR pathway to those without.
"Uncovering genetic predispositions using universal testing can save lives," said Dr. Samadder. "We can individualize care, use targeted therapies and hopefully prevent cancer altogether in the next generation of the family."
Having a family history of cancer in a first-degree relative was the only significant predictor of PGV. Nationally, only 5% to 10% of pancreatic cancer cases occur in patients with a family history of the disease, making this a rare indication for genetics evaluation.
The discovery of PGVs in patients with pancreatic cancer has therapeutic implications for both patients and their families. Broader testing not only is feasible but also can add valuable insights into developing individualized treatment plans.
For more information
Uson PLS Jr, et al. Clinical impact of pathogenic germline variants in pancreatic cancer: Results from a multicenter, prospective, universal genetic testing study. Clinical and Translational Gastroenterology. 2021;12:e00414.
Refer a patient to Mayo Clinic.