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. 2015 Aug 29:13:282.
doi: 10.1186/s12967-015-0633-7.

Activation of MET pathway predicts poor outcome to cetuximab in patients with recurrent or metastatic head and neck cancer

Juan Madoz-Gúrpide  1 , Sandra Zazo  2 , Cristina Chamizo  3 , Victoria Casado  4 , Cristina Caramés  5 , Eduardo Gavín  6 , Ion Cristóbal  7 , Jesús García-Foncillas  8 , Federico Rojo  9   10
Affiliations

Activation of MET pathway predicts poor outcome to cetuximab in patients with recurrent or metastatic head and neck cancer

Juan Madoz-Gúrpide et al. J Transl Med. .

Abstract

Background: Activation of the MET oncogene promotes tumor growth, invasion and metastasis in several tumor types. Additionally, MET is activated as a compensatory pathway in the presence of EGFR blockade, thus resulting in a mechanism of resistance to EGFR inhibitors.

Methods: We have investigated the impact of HGF and MET expression, MET activation (phosphorylation), MET gene status, and MET-activating mutations on cetuximab sensitivity in recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) patients.

Results: A single-institution retrospective analysis was performed in 57 patients. MET overexpression was detected in 58% patients, MET amplification in 39% and MET activation (p-MET) in 30%. Amplification was associated with MET overexpression. Log-rank testing showed significantly worse outcomes in recurrent/metastatic, MET overexpressing patients for progression-free survival and overall survival. Activation of MET was correlated with worse PFS and OS. In multivariate logistic regression analysis, p-MET was an independent prognostic factor for PFS. HGF overexpression was observed in 58% patients and was associated with MET phosphorylation, suggesting a paracrine activation of the receptor.

Conclusions: HGF/MET pathway activation correlated with worse outcome in recurrent/metastatic HNSCC patients. When treated with a cetuximab-based regimen, these patients correlated with worse outcome. This supports a dual blocking strategy of HGF/MET and EGFR pathways for the treatment of patients with recurrent/metastatic HNSCC.

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Figures

Fig. 1
Fig. 1
MET (a), p-MET (b), and HGF (c) overexpression thresholds in the cohort of HNSCC patients. ROC curves were used to calculate the optimal biomarker thresholds based on the progression endpoint for each protein. These scores, in correspondence, defined protein overabundance. Full lines represent the ROC curves; in dot lines, the diagonal reference lines
Fig. 2
Fig. 2
HGF/MET pathway expression and activation in recurrent/metastatic HNSCC. a Representative pictures showing a range of EGFR, MET, p-MET, and HGF expression levels observed by IHC in human HNSCC. b MET identification in FFPE tissue samples by SISH. Left panel detail of a MET-amplified case (clusters of black dots are seen in the nuclei of tumoral cells, representing several copies of the MET locus; as opposed to just two red dots per cell, corresponding to the centromeric region on chromosome 7). Right panel non-amplified sample. c Protein expression levels and gene amplification in the complete series. Case numbers are ordered from test (#1–33) to controls (#34–57), and a dashed line has been drawn in between the two groups. The color intensity of the boxes is indicative of abundance level in each column, either protein level by IHC (EGRF, MET, p-MET, HGF) or gene amplification level by SISH (MET gene). Expression levels are indicated in a color gradient, from white (minimum) to red (maximum), with missing data in gray
Fig. 3
Fig. 3
Prognostic role of MET and p-MET in cetuximab-treated HNSCC patients. a Progression-free survival (PFS) for MET. b Overall survival (OS) for MET. c PFS for p-MET. d OS for p-MET. In light gray line, patients with MET overexpression; in black line, patients without MET overexpression
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