2023 World Conference on Lung Cancer (Posters)-P1.21. Microsatellite Instability Defines a Subset of Lung Cancers with Smoking Exposure, High Tumor Mutational Burden and MLH1 Inactivation.<b></b>

P1.21. Microsatellite Instability Defines a Subset of Lung Cancers with Smoking Exposure, High Tumor Mutational Burden and MLH1 Inactivation. - PDF(Abstract)

Back to course

Pdf Summary

The study presented at WCLC 2023 investigated the clinicopathologic and molecular features of microsatellite instability (MSI) and mismatch repair (MMR) deficiency in lung carcinomas. The researchers analyzed MSI status in 5,171 patients with non-small cell lung cancer (NSCLC) and 315 patients with small cell lung cancer (SCLC) using next-generation sequencing data. They found that MSI-High (MSI-H) and MMR deficiency (MMR-D) were present in 0.41% of NSCLC patients and 1.9% of SCLC patients. All NSCLC patients with MSI-H were either former or current smokers.<br /><br />Compared to microsatellite stable (MSS) NSCLCs, the MSI-H/MMR-D tumors had a higher tumor mutational burden (TMB) and somatic biallelic alterations in MLH1, a gene involved in DNA mismatch repair. Pathogenic MLH1 alterations were accompanied by loss of MLH1 expression. Similar findings were observed in patients with MSI-H/MMR-D SCLC, where recurrent inactivating alterations in MLH1 were common.<br /><br />The researchers also found that histology with large cell neuroendocrine carcinoma was significantly enriched in MSI-H/MMR-D SCLC compared to MSS SCLC. One patient with MSI-H/MMR-D NSCLC had Lynch syndrome, a hereditary cancer syndrome, confirmed by the presence of a germline MSH2 alteration.<br /><br />In patients with advanced MSI-H/MMR-D lung cancers treated with immune-checkpoint inhibitors (ICIs), durable clinical benefit (DCB) was observed in some patients. In NSCLC, non-responders had mutations in STK11, KEAP1, and JAK1, while responders did not have these mutations.<br /><br />The study concludes that MSI-H/MMR-D occurs in a small subset of lung cancers associated with smoking history, high TMB, and recurrent somatic MLH1 inactivation. Although some patients with MSI-H/MMR-D lung cancers responded to ICI treatment, the range of responses suggests that clinical activity may be influenced by other genetic factors.

Asset Subtitle

Soo-Ryum Yang

Meta Tag

Speaker Soo-Ryum Yang

Topic Pathology & Biomarkers: Biomarkers for Immuno-oncology

Keywords

microsatellite instability

mismatch repair deficiency

lung carcinomas

non-small cell lung cancer

small cell lung cancer

next-generation sequencing

tumor mutational burden

MLH1 alterations

Lynch syndrome

immune-checkpoint inhibitors