Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers

Summary

Background

Germline variant evaluation in precision oncology opens new paths towards the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers.

Patients and Methods

Matched tumor and control genome/exome and RNA sequencing was performed for 1,485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the NCT/DKTK MASTER trial, a German multicenter, prospective observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies.

Results

Ten percent of patients (n=157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another five percent of patients (n=75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, 11/40), and more specific in wild-type GISTS (50%, n=10/20), leiomyosarcomas (21%, n=19/89), and hepatopancreaticobiliary cancers (16%, n=16/97). Forty-five percent of PGVs (n=100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n=10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation.

Conclusions

Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.