Prognostic impact and the relevance of PTEN copy number alterations in patients with advanced colorectal cancer (CRC) receiving bevacizumab

Abstract

Loss of phosphatase and tensin homologue (PTEN) expression may be prognostic in colorectal cancer (CRC) and may have a correlation with vascular endothelial growth factor (VEGF) expression via hypoxia-inducible factor 1 (HIF-1) alpha, and the PI3K/mTOR pathways. We therefore have explored the prognostic association of PTEN loss and the potential that PTEN loss may be predictive of outcome with bevacizumab. Patients enrolled in the AGITG MAX trial, a randomized Phase III trial of capecitabine (C) +/− bevacizumab (B) (+/− mitomycin C [M]) with available tissues were analyzed for PTEN expression (loss vs. no loss) as assessed using a Taqman® copy number assay (CNA). Of the original 471 patients enrolled, tissues from 302 (64.1%) patients were analyzed. PTEN loss was observed in 38.7% of patients. There was no relationship between PTEN loss and KRAS or BRAF mutation. PTEN status was not prognostic for progression-free survival (PFS) or overall survival (OS) in multivariate analyses adjusting for other baseline factors; loss versus no loss PFS hazard ratio (HR) 0.9 (0.7–1.16), OS HR 1.04 (0.79–1.38). PTEN was not prognostic when assessed by KRAS and BRAF status. By using the comparison of C versus CB+CBM, PTEN status was not significantly predictive of the effectiveness of B for PFS or OS. PTEN status was not prognostic for survival in advanced colorectal cancer, irrespective of KRAS or BRAF status. PTEN status did not significantly predict different benefit with bevacizumb therapy.

KRAS mutation influences recurrence patterns in patients undergoing hepatic resection of colorectal metastases

“…PIK3CA (phosphoinositide‐3‐kinase, catalytic, alpha) mutations were found in a higher number of patients with lung metastases (20%) and brain metastases (23.9%) versus those with liver metastases (7.7%) . Patients with phosphatase and tensin homolog (PTEN) loss had less lung metastases . Higher levels of thymidylate synthase gene expression were noted in patients with pulmonary versus liver metastases .…”

Somatic gene copy number alterations in colorectal cancer: new quest for cancer drivers and biomarkers

“…The deletion of PTEN (10q) has been found without significant association with the outcome of CRC patients who received antivascular endothelial growth factor therapy, 121 although the PTEN gene is a well-established tumor suppressor. Instead, deletions on 10p15.3-p14 seem to associate with poor prognosis.…”

Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology

“…[91][92][93] Regarding response to EGFR-targeted therapies, several studies have shown an association with PTEN loss and lack of response to cetuximab and panitumumab. [94][95][96][97] However, other published studies failed to demonstrate a clear correlation between loss of PTEN expression and response to anti-EGFR therapy.…”