Coupling tumor genomics, whole transcriptome sequencing, and patient outcomes to define the tumor microenvironment in receptor tyrosine amplified gastrointestinal cancers: Analysis from 24,598 cases.

Abstract

427 Background: The tumor microenvironment (TME) is increasingly appreciated as a modulator of response to standard chemotherapy and biologic agents. Prior studies have suggested that receptor tyrosine kinase amplifications (RTKamp) in ERBB2 , EGFR , MET , and FGFR2 may be associated with an immunosuppressive TME. As RTKs are among the most common oncologic targets, we sought to map TME features to tumor genomics across RTKamp and RTK non-amplified GI cancers. Methods: Tempus Lens was used to identify 24,598 patients with gastroesophageal adenocarcinoma, colorectal carcinoma, or cholangiocarcinoma and xT and xR testing. Squamous cell histology, MSI-H, and known MMR deficiency were excluded. Patients were classified as RTKamp if they had a ERBB2 , MET , EGFR , or FGFR2 copy number ≥8. Wilcoxon rank sum, Fisher’s exact, and Pearson’s Chi-squared tests were used to compare groups. Somatic alterations were examined, along with RNA expression data for relevant receptor genes, and biomarkers including PD-L1 and tumor mutational burden (TMB). Immune cell proportions were estimated using quanTIseq. Real-world overall survival (rwOS) was measured as time from first-line therapy start to death or censoring and was analyzed using the Kaplan-Meier method and log-rank tests. Results: A total of 2,088 patients with RTKamp and 22,510 patients with RTKnon-amp were identified. TP53 , MYC , MTAP , and CCNE1 alterations were enriched among RTKamp (p < 0.001). KRAS , APC , PIK3CA , PTEN and BRAF alterations were enriched among RTKnon-amp (p < 0.001). ERBB2 was the most commonly amplified RTK (58% of RTKamp), followed by EGFR (25%), MET (13%) and FGFR2 (8%). RTKamps were more commonly PD-L1 positive (61% vs 45%, p < 0.001), though no difference in TMB was seen. RTKamps showed higher expression of immunosuppressive IDO1 , and MET amplifications had higher HAVCR2 ( TIM-3 ) expression. MET , EGFR , and ERBB2 RTKamps also showed significantly different LAG3 expression. Although absolute differences were small, statistically significant enrichment among RTKnon-amps was seen in B-cells, macrophages, T regulatory cells, and NK cells (p < 0.001), but not CD8 T-cells (p = 0.8). Increasing RTK amp level was associated with lower NK cell percentage across RTKs. Across all cancer types, RTKamp was associated with shorter median rwOS (16.3 vs 20.8 months, p = 0.001), though this was reversed for gastroesophageal patients (13.6 vs 11.0 months, p = 0.009). MET amplification exhibited the shortest median rwOS (7.7 months). Conclusions: In our study cohort, RTKamps were seen in approximately 10% of all samples and aligned with known tumor specific prevalences. RTK amplifications were enriched for MYC and CCNE1 genomic alterations, and associated with modified expression of immunosuppressive regulatory genes IDO1 , TIM-3 , and LAG3 .