Abstract 128P
Background
MSLN overexpression ranges from 40-45% in CRC and is associated with aggressive clinicopathological features and worse survival. We analyzed the association of MSLN expression based on RNA sequencing with molecular features, tumor microenvironment, enrichment of cancer related pathways, and overall survival(OS) in CRC.
Methods
14,892 CRC samples were tested by NGS, WES, WTS (Caris Life Sciences, Phoenix, AZ). Tumors with MSLN-high(H) and MSLN-low(L) expression were classified by top and bottom quartile, respectively. Pathway enrichment was calculated through Gene Set Enrichment Analysis (GSEA). Chi-square and Mann-Whitney U tests with p-values adjusted for multiple comparisons (q<0.05) were used. Real world OS was extracted from insurance claims and calculated using Kaplan-Meier estimates from treatment start to last contact.
Results
MSLN-H tumors had enrichment of inflammatory, IFN-γ, IL2/STAT5, IFN-α responses, IL6/JAK/STAT3, TNFα and TGFβ signaling pathways (NES: 1.3-1.4, all FDR < 0.25). MSLN-H tumors had higher expression of immune-related genes TNF, TIGIT, VTCN1, IL1A, IL1B, CD274, PDCD1, PDCD1LG2, CTLA4, LAG3, HAVCR2, FOXP3 (FC: 1.1-1.8), but lower expression of IL12A (FC: 1.1) (all q<0.05). MSLN-H tumors had higher IHC-PD-L1 positivity (4.4% vs 2.0%, q<0.05). Median MSLN expression was not associated with post-5-FU-chemotherapy OS (MSLN- > Median vs -< Median: 37.0 vs 40.9 m, HR: 0.93, 95% CI 0.86 – 1.0, p=0.09) but numericaly improved OS post-Nivolumab (MSLN- > Median (n=37) vs -< Median (n=30): 13.0 vs 4.6 m; HR: 1.7, 95% CI 0.95 – 3.1, p=0.06). Quartile MSLN expression was associated with worse post-5-FU-chemotherapy OS (MSLN- top 25% vs - bottom 25%: 33.3 vs 40.5 m, HR: 0.87, 95% CI 0.77 – 0.97, p=0.01) but improved OS post-Nivolumab (MSLN-top 25% (n=19) vs - bottom 25% (n=11): 12.2 vs 3.9 m; HR: 4.8, 95% CI 1.5 – 14.9, p=0.003).
Conclusions
CRC patients with MSLN-H expression treated with chemotherapy have inferior prognosis compared to MSLN-L CRC. However, OS for MSLN-H MSS CRC patients who received immunotherapy was significantly improved compared to the latter. Our results support further investigation of MSLN as a predictive biomarker for immunotherapy in future prospective studies in MSS CRC patients.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
M. Malla: Financial Interests, Personal, Advisory Board: Natera, Exelixis, AstraZeneca. S.K. Deshmukh, S. Wu, J. Xiu, A. Farrell, D. Spetzler: Financial Interests, Personal and Institutional, Stocks/Shares: Caris. All other authors have declared no conflicts of interest.