# 17.6% of patients in a German cohort with exocrine pancreatic cancer were diagnosed with a genetic tumor syndrome—a case for universal genetic testing?

## TL;DR

About 18% of pancreatic cancer patients in Germany had a genetic tumor syndrome, suggesting the need for universal genetic testing.

## Contribution

The study shows that existing criteria miss some genetic variant carriers and supports universal genetic testing for pancreatic cancer patients.

## Key findings

- 17.6% of patients had a genetic tumor syndrome.
- 23.8% of pathogenic variant carriers would have been missed by current testing criteria.
- A meta-analysis found a 14% median yield of pathogenic germline variants in pancreatic cancer.

## Abstract

Yields for (likely) pathogenic germline variants (PGVs) in cancer predisposition genes (CPGs) in pancreatic cancer (PCA) cases range from 5% to 10% in initial literature to 15% to 20% in recent literature. PGVs can impact therapy recommendations and cancer surveillance for individuals and families.

We retrospectively evaluated prospective cancer predisposition testing in 125 patients with exocrine PCA from a single-center clinical genetics clinic (n = 41) and a multicenter precision oncology program (n = 84) within 64 genes, including 14 established PCA risk genes. Associations with clinical and somatic molecular parameters, as well as therapy recommendations, were assessed.

PGVs were identified in 21.6% of patients (n = 27/125) across 14 CPGs. A genetic tumor syndrome was diagnosed in 17.6% of patients (n = 22/125). Existing inclusion criteria for germline testing [European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN)] would have missed up to 23.8% of PGV carriers (n = 5/21). Age of onset was not associated with PGV yield. A meta-analysis of 10 other PCA cohorts showed a median PGV yield of 14.1%.

In a precision oncology program, 10.7% (n = 9/84) of PCA patients received treatment recommendations supported by PGVs. Genetic testing was carried out on relatives of 73.3% of PGV-positive patients (n = 11/15), with one family demonstrating PGV confirmation in 7 of 13 tested relatives.

These findings support ASCO and NCCN recommendations for germline testing in all PCA patients. We suggest offering large-panel genetic diagnostics early in clinical management, regardless of clinical parameters, with ongoing evaluation and adjustment of the gene panel.

•Across two German cohorts, 17.6% of pancreatic cancer patients were diagnosed with a genetic tumor risk syndrome.•Strict germline testing criteria would have missed up to 23.8% of pathogenic germline variant carriers.•Two-thirds of pathogenic germline variants informed treatment; 73% led to cascade testing, identifying 18 carriers.•A meta-analysis of 11 PCA cohorts shows pathogenic germline variants in ∼14%—higher than the previously estimated 10%.•Pathogenic germline variants in pancreatic cancer are under-recognized—universal testing and multidisciplinary care is needed.

Across two German cohorts, 17.6% of pancreatic cancer patients were diagnosed with a genetic tumor risk syndrome.

Strict germline testing criteria would have missed up to 23.8% of pathogenic germline variant carriers.

Two-thirds of pathogenic germline variants informed treatment; 73% led to cascade testing, identifying 18 carriers.

A meta-analysis of 11 PCA cohorts shows pathogenic germline variants in ∼14%—higher than the previously estimated 10%.

Pathogenic germline variants in pancreatic cancer are under-recognized—universal testing and multidisciplinary care is needed.