Association of PTEN loss and local recurrence in stage II-III colon cancer.

Abstract

399 Background: Activation of the PI3K/Akt signaling pathway by PIK3CA mutations has been associated with increased risk for local recurrence (LR) in rectal cancer patients (pts). We hypothesized that loss of expression of PTEN, a tumor suppressor gene and negative regulator of the PI3K/Akt pathway, may also be associated with increased rates of LR in colon cancer. Methods: We studied 156 pts with stage II-III colon cancer resected from 1/1990 to 12/2002, including pathology review, PTEN immunohistochemistry, microsatellite instability (MSI) status, 18q loss of heterozygosity (LOH) status and clinical follow-up. PTEN expression with a CLIA-compliant protocol (DAKO antibody) was determined in a tissue microarray with four cores from each tumor and with non-neoplastic mucosa. PTEN loss was defined as complete absence of expression in malignant epithelium with preserved expression of adjoining non-neoplastic tissue serving as a positive control. LR was defined as anastomotic or pericolic peritoneal disease. Results: 83 M and 73 F pts with median age of 63 were included, with median follow-up of 7.6 yrs. PTEN loss was identified in 26 (16.7%) pts. There were no significant differences in age, sex, T stage, N stage, tumor differentiation, tumor site, lymphovascular invasion (LVI), mucinous component, MSI status or 18q LOH between the PTEN-lost and PTEN-intact groups. The overall survival, relapse-free survival, and distant metastases rate were similar. However, PTEN loss was associated with higher rates of LR (15.4% vs. 4.6%, p = 0.041), and the time to LR was shorter for pts with PTEN loss in their tumor than in PTEN-intact pts (HR 3.3, p = 0.049 by log-rank). LR was associated with LVI, R-sided tumor, 18qLOH, and PTEN loss in univariate analysis. In a multivariate analysis, PTEN loss was associated with a 10.6 fold increased risk of LR (95% CI: 1.7-64.8, p = 0.011). Conclusions: PTEN loss is associated with a higher rate of and shorter time to LR after resection of colon cancer. This result is consistent with a prior report on the role of PI3K pathway in LR of rectal cancer and suggests that PTEN alteration is a prognostic indicator and that the PI3K/Akt pathway is a potential therapeutic target for these pts. No significant financial relationships to disclose.