The association between EGFR and cMET expression and phosphorylation and its prognostic implication in patients with breast cancer

Young Kwang Chae, Debora De Melo Gagliato, Sachin Gopalkrishna Pai, Benedito Carneiro, Nisha Mohindra, Francis Joseph Giles, Praveen Ramakrishnan-Geethakumari, Joohyuk Sohn, Shuying Liu, Huiqin Chen, Naoto Ueno, Gabriel Hortobagyi, Ana Maria Gonzalez-Angulo

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 pcMET 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.

Original languageEnglish (US)
Article numbere0152585
JournalPLoS One
Volume11
Issue number4
DOIs
StatePublished - Apr 1 2016

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Phosphorylation
breast neoplasms
phosphorylation
Association reactions
Breast Neoplasms
Survival
hormone receptors
Hormones
Protein Array Analysis
Proteins
proteins
Kaplan-Meier Estimate
Proportional Hazards Models
Analysis of Variance
relapse
Multivariate Analysis
Analysis of variance (ANOVA)
Tumors
Recurrence
Hazards

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Chae, Y. K., De Melo Gagliato, D., Pai, S. G., Carneiro, B., Mohindra, N., Giles, F. J., ... Gonzalez-Angulo, A. M. (2016). The association between EGFR and cMET expression and phosphorylation and its prognostic implication in patients with breast cancer. PLoS One, 11(4), [e0152585]. https://doi.org/10.1371/journal.pone.0152585

The association between EGFR and cMET expression and phosphorylation and its prognostic implication in patients with breast cancer. / Chae, Young Kwang; De Melo Gagliato, Debora; Pai, Sachin Gopalkrishna; Carneiro, Benedito; Mohindra, Nisha; Giles, Francis Joseph; Ramakrishnan-Geethakumari, Praveen; Sohn, Joohyuk; Liu, Shuying; Chen, Huiqin; Ueno, Naoto; Hortobagyi, Gabriel; Gonzalez-Angulo, Ana Maria.

In: PLoS One, Vol. 11, No. 4, e0152585, 01.04.2016.

Research output: Contribution to journalArticle

Chae, YK, De Melo Gagliato, D, Pai, SG, Carneiro, B, Mohindra, N, Giles, FJ, Ramakrishnan-Geethakumari, P, Sohn, J, Liu, S, Chen, H, Ueno, N, Hortobagyi, G & Gonzalez-Angulo, AM 2016, 'The association between EGFR and cMET expression and phosphorylation and its prognostic implication in patients with breast cancer', PLoS One, vol. 11, no. 4, e0152585. https://doi.org/10.1371/journal.pone.0152585
Chae, Young Kwang ; De Melo Gagliato, Debora ; Pai, Sachin Gopalkrishna ; Carneiro, Benedito ; Mohindra, Nisha ; Giles, Francis Joseph ; Ramakrishnan-Geethakumari, Praveen ; Sohn, Joohyuk ; Liu, Shuying ; Chen, Huiqin ; Ueno, Naoto ; Hortobagyi, Gabriel ; Gonzalez-Angulo, Ana Maria. / The association between EGFR and cMET expression and phosphorylation and its prognostic implication in patients with breast cancer. In: PLoS One. 2016 ; Vol. 11, No. 4.
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AU - Giles, Francis Joseph

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AU - Liu, Shuying

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N2 - 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 pcMET 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.

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