Abstract P6-06-47: The association between EGFR and cMET expression and phosphorylation and its prognostic implication in patients with breast cancer
Authors: Chae YK , Qi Y , Sohn J , Chen H , Hortobagyi GN , Gonzalez-Angulo AM 
Published: August 2014

Background: It has been shown that EGFR, cMET and their cross-talk play an important role in the progression of breast cancer and development of resistance to different targeted therapies. cMET expression and phosphorylation is linked with poor survival outcome in breast cancer. Recently, EGFR and cMET dual blockade has been proposed as an attractive targeted therapy for breast cancer. However, little is known about the co-expression patterns of EGFR and cMET in human breast cancer and its prognostic significance. We hypothesized that co-expression or co-activation of EGFR and cMET is linked with adverse survival outcome.

Methods: We measured protein levels of EGFR, cMET and their phosphorylated proteins in 825 breast cancers using reverse phase protein array. Given unimodal distribution of proteins, median was selected as a cut-off after sensitivity analyses. Kaplan-Meier survival curves were used to estimate relapse-free (RFS) and overall survival (OS). Cox proportional hazards models were fit to determine associations of EGFR and cMET with outcomes after adjustment for other clinical characteristics such as age, tumor stage, nodal status, receptor subtype and histologic grade.

Results: Mean age was 58 years. There were 457 (55%) hormone receptor (HR) positive, 211 (26%) triple-negative (TN) and 148 (18%) HER2 positive tumors. HER2 subgroup showed higher EGFR expression and phosphorylation compared to HR and TN subtypes (p&lt;0.05).

High EGFR expression group was associated with higher phosho-cMET (pcMET) but not cMET compared to low expression group (ANOVA pcMET p&lt;0.001, MET p = 0.34). The same association was found with High phospho-EGFR (pEGFR) group at Try 992 and Tyr1068 (both p&lt;0.001). In HR subtype, similar association was observed between EGFR/pEGFRs and pcMET (all p&lt;0.01). High expression groups in either of two pEGFRs were linked with higher cMET as well (all p&lt;0.001). In TN subtype, High expression group in EGFR and pEGFR at Tyr992 but not at Tyr1068 was associated with higher pcMET (p&lt;0.00, p = 0.012, p = 0.4, respectively). Only high expression group in pEGFR at Tyr 992 was linked with higher expression of cMET (p = 0.02). In contrast, among HER2 subtype, high expression group in pEGFR at Tyr 1068 but not at Tyr992 was associated with higher cMET and pcMET (cMET p = 0.023, pcMET p&lt;0.001).

Four subgroups of patients defined by dichotomized EGFR (or pEGFR) and cMET (or pcMET) level demonstrated no significant differences in RFS and OS. In multivariate analyses, only cMET expression level was associated with adverse survival (RFS p = 0.06, OS p = 0.035) while levels of pcMET, EGFR, and pEGFRs did not show significant association with outcomes.

Conclusion: We report that EGFR and cMET are either frequently co-expressed or co-activated in human breast cancer. HER2 subtype showed higher EGFR expression and activation compared to other subtypes. cMET protein expression level was found to be an independent prognostic factor irrespective of the EGFR expression or phosphorylation status.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-47.