Clinical impact of c-MET expression and mutational status in patients with colorectal cancer lung metastases.
OBJECTIVE
The c-MET tyrosine kinase is known to play a key role in tumour promotion in a variety of cancers. The prognostic significance of c-MET pathway alterations has previously been described in primary colorectal cancer (CRC). However, data on the expression and genetic mutational status of c-MET in CRC pulmonary metastases (PM) are lacking. We aimed to assess the clinical implications of alterations in the c-MET pathway in patients undergoing pulmonary metastasectomy.


METHODS
From April 2009 to November 2013, all patients with complete CRC lung metastasectomy were included in this study and prospectively followed up. Tissue samples of 51 PM and 33 paired primary CRCs were stained immunohistochemically for c-MET and phosphorylated signal transducer and activator of transcription 3 (pSTAT3). Genetic alterations of MET were detected using an exome panel on a next generation sequencing (NGS) platform. Serum hepatocyte growth factor (HGF) levels were measured in a patient subset (n = 10) before and after metastasectomy.


RESULTS
c-MET expression was significantly higher at the invasive front of metastases compared with central tumour areas (P = 0.020) and was associated with nuclear pSTAT3 expression (P = 0.042). pSTAT3 but not c-MET overexpression in PM was associated with time to tumour recurrence after metastasectomy (P = 0.036). Expression levels of neither c-MET nor pSTAT3 had an impact on time to lung-specific recurrence. However, patients with c-MET or pSTAT3 overexpression in PM had a significantly worse overall survival after metastasectomy (P = 0.023 and 0.008, respectively). Mutations in the MET gene were identified in 20 patients of our cohort by NGS, which failed to be of prognostic relevance. Serum HGF did not significantly differ between patients with PM and healthy controls.


CONCLUSIONS
To the best of our knowledge, this is the first structured evaluation of the c-MET axis in the context of pulmonary metastasectomy for CRC. Our results suggest that overexpression of c-MET/pSTAT3 is associated with an impaired prognosis following complete resection. Moreover, this work suggests that the value of c-MET tyrosine kinase inhibitors in the treatment of patients with CRC lung metastases should be assessed in clinical trials.
Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Vienna, Austria.
Thomas
T
Schweiger
Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.
Veronika
V
Starkl
Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Vienna, Austria.
Olaf
O
Glueck
Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Vienna, Austria.
Christoph
C
Glogner
Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Vienna, Austria.
Denise
D
Traxler
Department of General Surgery, Medical University of Vienna, Vienna, Austria.
Julia
J
Jedamzik
Core Facility Genomics, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Sandra
S
Liebmann-Reindl
Department of Pathology, Medical University of Vienna, Vienna, Austria.
Peter
P
Birner
Core Facility Genomics, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.
Berthold
B
Streubel
Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.
Walter
W
Klepetko
Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria konrad.hoetzenecker@meduniwien.ac.at.
Konrad
K
Hoetzenecker
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000473:pathology*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011446:Prospective Studies; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis / Q000235:genetics* / Q000378:metabolism
C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
Colorectal cancer; HGF; Metastasectomy; Pulmonary metastasis; STAT3; c-MET