Abstract
EGFR and cMET cross-talk is involved in breast cancer (BC) progression and resistance to different targeted therapies, however little is known about the co-expression patterns of EGFR and cMET or its prognostic significance in BC. Protein levels of EGFR, cMET and their phosphorylated proteins were measured in 825 BC samples using reverse phase protein array (RPPA). Given unimodal distribution of proteins, the 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 utilized to determine associations between EGFR and cMET with outcomes. Mean age was 58 years with 457 (55%) hormone receptor (HR) positive, 211 (26%) triple-negative (TN) and 148 (18%) HER2 positive tumors (HER2+). HER2+ was associated with higher EGFR expression and phosphorylation, compared to HR and TN (p<0.05). High EGFR expression was associated with higher phosphorylated-cMET (p-cMET) but not cMET (ANOVA p-cMET p < 0.001; cMET p = 0.34). The same association was found with high phosphorylated-EGFR (p-EGFR) group at Tyr992 and Tyr1068 (both p < 0.001). High expressions in either of two p-EGFRs were linked with higher cMET as well (all p<0.001). For the TN subtype, high expression in EGFR and p-EGFR at Tyr992 but not at Tyr1068 was associated with higher p-cMET (p<0.00, p = 0.012, p = 0.4 respectively). Only high expression in p-EGFR at Tyr992 was linked with higher expression of cMET (p = 0.02). In contrast, among HER2 subtype, high expression in p-EGFR at Tyr1068 but not at Tyr992 was associated with higher cMET and p-cMET (cMET p = 0.023;p-cMET p<0.001). Four subgroups of patients defined by dichotomized EGFR/p-EGFR and cMET/p-cMET level demonstrated no significant differences in survival. In multivariate analyses, neither cMET nor EGFR expression/activation was found to be an independent prognostic factor in survival outcome.
Highlights
Breast cancer is the most common invasive cancer and the second leading cause of cancer death in women worldwide[1]
EGFR expression correlated with p-cMET in hormone receptor (HR) + and TN subgroups, but not in the HER2+ subgroup
We found that EGFR and cMET are frequently co-expressed and/or co-activated in human breast cancer (BC) and this pattern varied according to BC subtypes
Summary
Breast cancer is the most common invasive cancer and the second leading cause of cancer death in women worldwide[1]. Proliferative intracellular downstream pathways are activated, such as the Ras-Erk/MAPK and the PI3K-Akt cascades, and promote invasive growth and apoptosis inhibition[4]. The role of HGF/SF and MET in cancer has been brought to light by several studies. Transcriptional deregulation constitutes one the most important mechanisms to disease modulation. Other alterations such as genomic amplification, activating point mutations, inadequate degradation and receptor crosstalk may contribute[6]. Aberrations in the cMET pathway are thought to play a role in the progression and invasive growth of several malignancies such as lung, kidney, head and neck, breast, and colorectal cancers[7,8,9,10]
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