Abstract 2759: Transcriptional intra-tumoral heterogeneity of putative therapeutic targets in colorectal cancer peritoneal metastases

Abstract Background: The poor prognosis of peritoneal metastasis (PM) in colorectal cancer (CRC) is typically attributed to, and characterized by, resistance to systemic chemotherapy and immunotherapy. The evolutionarily conserved plasma-peritoneal barrier as well as reduced tumor tissue vascularity contributes to poorer responses to systemically administered antineoplastic therapy. Beyond these, we sought to understand transcriptomic variations of important therapeutic targets implicated in peritoneal organotropism and by extension, resistance to systemic regimens in CRC PM. Methodology: FFPE tissue samples from CRC patients were collected during oncological surgical resection of the synchronous PM (cytoreductive surgery CRS with or without hyperthermic intra-peritoneal chemotherapy HIPEC), or exploratory laparotomy for palliative surgery, with the majority of patients receiving systemic therapy prior to surgery. Samples were sequenced with whole transcriptomic sequencing. Paired and unpaired T-tests between PT and PM samples were undertaken with log2 (fragments per kilobase of exon per million mapped FPKM) gene expression values. Results: Fifty-six (22 primary tumor PT, 34 peritoneal metastases PM) samples from 35 patients, comprising 21 paired PT-PM samples, were included in this analysis. TEAD1 (unpaired T-test, p=0. 087; paired T-test, p=0. 041), FGFR1 (unpaired T-test, p=0. 003; paired T-test, p0. 001), PIK3CA (unpaired T-test, p=0. 034; paired T-test, p=0. 003), SMAD4 (unpaired T-test, p=0. 095; paired T-test, p=0. 010), and HAVCR2 (unpaired T-test, p=0. 009; paired T-test, p=0. 007) were found to be upregulated in the PM. Conversely, MET was found to be downregulated in PM samples (unpaired T-test, p=0. 004; paired T-test, p=0. 002). There were no significant differences in gene expression profiles of BRAF, RHOA, CD274, CTLA4, PDCD1 and TIGIT between PT-PM (all p0. 05). Conclusion: Through CRC PT-PM comparisons, we identify potential therapeutic targets implicated in transcoelomic metastasis and provide rationale for development of immunotherapeutic biology and drug discovery for CRC PM. These findings underscore an exigent need to develop intra-peritoneal therapeutic strategies to overcome resistance to systemic regimens. Citation Format: Joseph J. Zhao, Johnny CA Ong, Daryl Kai Ann Chia, Melissa Ching Ching Teo, Qiu Xuan Tan, Gillian Ng, Joey Wee-Shan Tan, Haoran Ma, Xuewen Ong, Su Ting Tay, Patrick Tan, Raghav Sundar. Transcriptional intra-tumoral heterogeneity of putative therapeutic targets in colorectal cancer peritoneal metastases abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2759.