570P - Thymidylate synthase over-expression underlies the observed lack of 5-FU therapy benefit for MSI-H colorectal cancers

Date 29 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Colon Cancer
Rectal Cancer
Pathology/Molecular Biology
Translational Research
Presenter Zoran Gatalica
Citation Annals of Oncology (2014) 25 (suppl_4): iv167-iv209. 10.1093/annonc/mdu333
Authors Z. Gatalica1, S. Vranic2, G. Basu1, D. Bryant1, H. Lynch3
  • 1Molecular Diagnostics, Caris Life Sciences, 85040 - Phoenix/US
  • 2Pathology, Clinical Center, University of Sarajevo, 71000 - Sarajevo/BA
  • 3Preventive Medicine, Creighton University, 68178 - Omaha/US

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 < 0.001). Topo1 overexpression (≥2+ and ≥30%, threshold) was seen in 47% of MSS and 70% of the MSI-H cases, but the difference did not reach statistical significance (p = 0.15). In all CRC, 73% of the cases harbored multiple genetic alterations (≥2 gene mutations) and expressed additional biomarkers of drug response, which can be used to guide toward novel treatment modalities.

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.