TOPO1 expression in primary and metastatic GI cancers.

643 Background: Irinotecan failed in Stage III colon cancer, but succeeds in Stage IV, to prolong survival. We propose that TOPO1 over-expression is a phenomenon of metastatic disease, and perhaps part of the epithelial-mesenchymal-transition (EMT) associated with metastatic phenotypes. Methods: 5029 colorectal (CRC), 3016 pancreatic, 848 gastric and 309 small bowel adenocarcinoma (SBA) patients were included in the study and tested centrally at a CLIA laboratory (Caris Life Sciences, Phoenix, AZ). A threshold of ≥ 2+ and ≥ 30% (intensity and percent staining) and TOPO1 (1D6) clone was utilized. TOPO1 was examined in primary and metastatic specimens. Two-tailed Fisher’s exact test was performed to test where proportions of positive results were different by subgroup (p ≤ 0.05). Results: See table below. Conclusions: The EMT associated with the transition from primary to invasive metastatic disease appears to include upregulation of TOPO1, in some GI cancers, including CRC, pancreatic and gastric cancer. The paradoxical failure of adjuvant irinotecan in stage III, the epithelial phase of the cancer, may be due to a smaller fraction of patient's whose cancers express this biomarker of response in that setting. A re-examination of irinotecan makes sense for a portion of stage III patients whose cancer expresses high levels of TOPO1 in the primary lesion. The recent superiority with regard to response rate and survival or FOLFOXIRI over FOLFOX alone in the stage IV setting raises renewed interest in whether patients with non-metastatic disease could derive a superior cure rate if suitably selected for FOLFOXIRI with a biomarker approach. At the same time, a large number of patients fail to express TOPO1 in the metastatic setting and perhaps should be spared irinotecan-based approaches including the use of FOLFOXIRI. [Table: see text]