AI Summary
This study examines real-world genetic testing outcomes of pan-cancer testing for mismatch repair deficiency, focusing on the identification of Lynch syndrome (LS) cases. MMR immunohistochemistry testing was found to be beneficial for all tumor types, not just for screening for LS. The study found that pan-cancer MMR testing can identify LS cases at a rate similar to universal CRC and EC screening programs, with LS cases most commonly identified in patients with dMMR brain and small intestinal cancers. The study highlights the importance of prioritizing MMR testing in certain tumor types and recommends multigene panel testing for patients with dMMR due to the frequency of finding pathogenic variants in non-LS genes. The challenge of subsequent uptake of genetic testing was also noted.
Abstract
Background
In 2017, the Food and Drug Administration approved pembrolizumab for treatment of any mismatch repair–deficient (dMMR) tumor making MMR immunohistochemistry (IHC) testing beneficial for all tumor types. For the first time, MMR IHC was not performed exclusively to screen for Lynch syndrome (LS).
Methods
In this study, all MMR IHC reports issued between 2017 and 2021 at an academic hospital were reviewed and completion of genetic testing was determined through chart review. Colorectal cancers (CRCs), endometrial cancers (ECs), and noncancerous lesions were excluded.
Results
Between 2017 and 2021, MMR IHC was completed in 1939 patients with a malignancy other than CRC or EC. Absent or weak staining for at least one MMR protein was detected in 115 (5.9%) patients and 59 (51%) of those completed germline genetic testing. Overall, the identification rate of LS in this cohort was 0.72%, which is similar to the rate in our previously reported CRC and EC universal screening cohort. A diagnosis of LS was most commonly made in patients with dMMR brain (18.75%) and small intestinal cancers (10.20%). Five additional patients were found to carry a pathogenic variant in a non-LS gene.
Conclusions
Pan-cancer MMR testing for pembrolizumab consideration can identify LS cases at a rate similar to universal CRC and EC screening programs. A persistent challenge is subsequent uptake of genetic testing. MMR testing should be prioritized in brain and small intestinal tumors, and multigene panel testing is recommended in patients with dMMR, as unexpected pathogenic variants in non-LS genes were found as frequently as LS gene variants.