Tumor clock protein PER2 as a determinant of survival in patients (pts) receiving oxaliplatin-5-FU-leucovorin as first-line chemotherapy for metastatic colorectal cancer (MCC)

Abstract

11032 Background: The molecular circadian clock controls malignant proliferation and drug metabolism, with Period 2 (Per2) playing a central role (Nat Rev Cancer 2003, 3: 350; Ann Rev Pharm Toxicol 2007, 47:593). Per genes are down regulated in human breast, lung, gynecologic and blood malignancies. We investigate for the 1st time PER protein expressions in primary tumor (TUM) and in colonic mucosa (MUC) in MCC pts receiving FOLFOX2 or chronoFLO4 (EORTC 05963) (J Clin Oncol 2006, 24:3562) and correlate their expression to pt and tumor features and to clinical outcome. Methods: 13/25 centers (5 countries) collected paraffin-embedded TUM and MUC. PER1, PER2 and PER3 expression were assessed in two 2-mm carrots from each sample with tissue microarrays (TMA) using C-20, N-19 and Q-16 goat polyclonal primary antibodies (S. Cruz Biotechnology, USA). MUC was positive (+) if ≥1% cells expressed PER. The % labeled tumor cells (> 300 counted by 2 pathologists) were categorized as terciles. Results: 221 samples were retrieved (56% of corresponding pt accrual), with 180 adequate for TMA, representative of the trial population characteristics and outcome. The % TUM cells expressing PER1, PER2 and PER3 were significantly correlated (p<0.001). 21% of the pts shared lowest expression of all 3 PERs in TUM. PER2 was not detected in 26% of TUM vs 17% of MUC (p = 0.007). 19% of the pts with constitutive expression of PER2 in MUC had undetectable PER2 in TUM. No significant correlation was found between TUM PER1 or PER3 and pt outcome. The % tumor cells expressing PER2 predicted for PFS (Log Rank, p= 0.049). Furthermore, median overall survival ranged from 16.3 months (mo) (1st tercile, 0- 10% of PER2+ cells) to 18.1 mo (2nd tercile, 11–66%) and 22.6 mo (3rd tercile, 67–100%) (p = 0.038). Multivariate Cox analyses confirmed PER2 expression in primary tumor as an independent prognostic factor of survival (p= 0.036), jointly with performance status (p<0.001) and number of metastatic sites (p=0.007) Conclusions: Down regulation of core clock gene Per2 in tumors predicted for poor survival in chemo-naive pts with metastatic colorectal cancer. This is the first report of an association between clock gene down regulation and outcome in any cancer. No significant financial relationships to disclose.