570PTHYMIDYLATE SYNTHASE OVER-EXPRESSION UNDERLIES THE OBSERVED LACK OF 5-FU THERAPY BENEFIT FOR MSI-H COLORECTAL CANCERS.
ABSTRACT Aim: 5-FU based treatment remains the standard of care for the adjuvant treatment of colorectal carcinoma (CRC), in combination with oxaliplatin and irinotecan. CRC is molecularly heterogenous disease and patients with microsatellite stable (MSS) CRC have been previously shown to benefit from 5-FU based therapies while patients with high microsatellite instability (MSI-H) CRC did not. We investigated the expression thymidylate synthase, the targeted enzyme for 5-FU and topoisomerase I (Topo1), the targeted enzyme for irinotecan, in molecularly defined cohort of CRC. Methods: 106 patients with CRC (86 MSS and 20 MSI-H) were molecularly profiled using multiplatform approach [Caris Life Sciences] including immunohsitochemistry, PCR microsatellite analysis and gene sequencing (NGS) . Results: TS over-expression (over the ≥1+ and ≥10% threshold, and frequently >2+ and >50%) was observed in all 20 MSI-H cases (100%). In contrast, MSS cases overexpressed TS in only 31/86 (36%) of the cases (p Conclusions: Two most common molecular subtypes of colorectal cancer exhibit different expression patterns of TS and Topo1; overexpression of TS may explain the observed lack of benefit of 5-FU based therapy in MSI-H CRC patients. Additional genetic and molecular biomarkers could provide guidance to alternative chemotherapy modalities. Disclosure: Z. Gatalica: Stock options Caris Life Sciences; D. Bryant: Stock options Caris Life Sciences All other authors have declared no conflicts of interest.