Molecular characteristics of complete PTEN loss in metastatic colorectal cancer.

Abstract

389 Background: Loss of expression of phosphatase and tensin homolog (PTEN) is associated with activation of the PI3K/AKT pathway, and has been identified as a potential modulator of response to targeted therapies in metastatic colorectal cancer (mCRC). The association of PTEN loss with other molecular characteristics and outcomes has not been described for mCRC. Methods: Tumor from 229 mCRC patients (pts) were included for analysis of PTEN staining by IHC from whole-mounts, across two cohorts of unresectable mCRC or resectable liver-limited disease. PTEN loss was defined as complete loss of staining with preservation of expression of stromal components. Mutation status was defined using mass-spectroscopy or next-generation sequencing platforms. CpG island methylation (CIMP) status was determined using a previously defined 6-marker panel, with methylation of ≥3 markers denoting CIMP-High. Methylation findings where confirmed in 193 pts from the Cancer Genome Atlas (TCGA) database, using previously defined classifications. Results: The overall frequency of complete PTEN loss was 12% in the primary tumor and 15% when assayed from metastatic sites (P=NS). There was no difference in clinical characteristics in patients with PTEN-loss tumors. Complete PTEN loss and PIK3CA mutations were not mutually exclusive, with PIK3CA mutation rate of 24% and 14% in PTEN loss and intact, respectively (p=0.3). There was no association of PTEN loss with KRAS mutations (p=0.3), although there were non-significant trends toward higher rates of CIMP-High, BRAF mutations, and R-sided tumors (OR 3.2, 2.7, and 1.6, respectively; p<0.2), consistent with an association with the serrated adenoma pathway and epigenetic inactivation. In the TCGA, PTEN protein loss (defined by the lowest 12% of expression) was associated with increased AKT signaling (77% increase in pAKT/AKT, p<0.01) and a similar trend with CIMP-H tumors (OR 3.1, p=0.13). Conclusions: In patient samples, PTEN loss is independent of KRAS and PIK3CA mutations, associated with robust AKT pathway activation, and may be more prominent in tumors with hypermethylation and BRAF mutations.