Association of topoisomerase-1 (Topo1) with the efficacy of chemotherapy in a randomized trial for advanced colorectal cancer patients (FOCUS)

Abstract

10009 Background: We have assessed potential predictive markers of the efficacy of irinotecan and oxaliplatin in advanced CRC patients randomized to fluorouracil (FU), FU+irinotecan (Ir) or FU+oxaliplatin (Ox). Methods: Pathology specimens were retrieved from 1281 patient in the FOCUS trial (ASCO 05 #3518). Normal and tumor DNA were extracted and tissue microarrays were made for immunohistochemistry (IHC). The following factors were assessed for effect on failure-free survival (FFS) with first-line therapy: IHC for MLH1, MSH2, P53, Topo1, ERCC1, MGMT, and COX2; DNA polymorphisms in GSTP1 (105Val), ABCB1 (C3435T), XRCC1 (Q399R), ERCC2 (K751Q), and UGT1A1*28. Results: Among 823 patients assessable for Topo1 IHC, we observed highly significant heterogeneity (interaction) of treatment effect in relation to Topo1 staining intensity (p=0.008, see table). 489 patients (59%) had moderate or high Topo1 expression; these patients derived highly significant benefit from 1st-line chemotherapy with either Ir or Ox. In contrast, the 334 (41%) patients with low Topo1 IHC expression showed no evidence of benefit from the addition of either Ir or Ox compared with FU alone (HR 1 and 0.9 respectively). When patients receiving FU alone are considered separately, low Topo1 expression was associated with significantly better FFS (HR 0.7 (0.6–0.9)). The other 11 molecular markers showed no significant interactions with treatment received (p values for interaction all > 0.1). Conclusions: We have identified a subgroup of 41% patients (with low Topo1 expression) for whom treatment outcome with FU alone is superior, but who appear to gain no benefit from the addition of Ir or Ox. We believe this to be the first demonstration in a large randomized trial of a genuinely predictive molecular marker. If verified in an independent dataset, this information could be used to select patients who can be safely treated with FU alone, or together with alternative additional agents. [Table: see text] No significant financial relationships to disclose.