P4-09-09: Expression of c-MET and Phospho c-MET in Breast Cancers by Subtype and Its Impact on Survival Outcomes.
Authors: Raghav KP , Wang W , Liu S , Chavez-MacGregor M , Meng X , Hortobagyi GN , Mills GB , Meric-Bernstam F , Blumenschein GR , Gonzalez-Angulo AM 
Published: June 2012

Background

cMET is a tyrosine-kinase membrane receptor and its dysregulation is involved in tumor proliferation, survival, angiogenesis, and migration. High levels of cMET have been observed in various tumor types and correlate with adverse outcome. The purpose of this study was to evaluate levels of total cMET and phospho-cMET (p-cMET) in breast cancer and their impact on survival outcomes.

Materials and Methods: We measured quantitative expression of cMET and p-cMET in a cohort of 257 breast cancer primary tumor samples using reverse phase protein array. The level of cMET/p-cMET in each sample was expressed as a log-mean centered value after correction for protein loading with the use of the average expression levels of &gt; 50 proteins. The regression tree method and Martingale residual plots were applied to find the best cutoff point for high and low levels of each protein. Linear regression models were used to determine if mean expression was different among breast cancer subtypes. The Kaplan-Meier method was used to estimate relapse-free survival (RFS) and overall survival (OS) by cMET and p-cMET levels. Cox proportional hazards models were fit to determine the association of cMET and p-cMET levels with the risk of recurrence and death after adjustment for other patient and disease characteristics.

Results: Median age was 51, (range 23–85) years. There were 140 (54.5%) hormone receptor (ER/PR)-positive, 53 (20.6%) HER2−positive, and 64 (24.9%) triple-negative tumors. Using the selected cutoffs, a total of 181 (70.4%) and 123 (47.9%) patients had high expression of cMET and p-cMET, respectively.

There were no significant differences in the mean expression of cMET (P&lt;0.128) and p-cMET (P&lt;0.088) by breast cancer subtype. Dichotomized cMET and p-cMET expression was a significant prognostic factor of RFS (HR: 0.41, 95% CI: 0.23−0.75, P=0.004, and HR: 0.61, 95% CI:0.38−0.96, P=0.033, respectively) and OS (HR: 0.31, 95% CI:0.14−0.70, P=0.005, and HR: 0.52, 95% CI:0.29−0.93, P=0.025, respectively). Within breast cancer subtypes, high cMET expression was associated with worse RFS (P=0.02) and OS (P=0.01) in ER/PR-positive tumors, and high p-cMET expression was associated with worse RFS (P=0.03) and OS (P=0.03) for patients with HER2−positive breast cancer. Multivariable model after adjustment for patient and tumor characteristics showed that patients with tumors with high cMET levels had a significant higher risk of recurrence (HR 0.28; 95% CI, 0.36−0.80) and death (HR 0.24; 95% CI, 0.09−0.65). Similarly, patients with tumors with high p-cMET levels had a significant higher risk of recurrence (HR 0.53; 95% CI, 0.29−0.97).

Conclusion: In this cohort of patients, high expression of cMET and p-cMET was seen in all subtypes of breast cancer. High levels of cMET and p-cMET had a significant impact on breast cancers survival outcomes. cMET inhibition may a be promising novel target for therapy in breast cancer and deserves investigation.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-09.