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c-MET Overexpression in Colorectal Cancer: A Poor Prognostic Factor for Survival

  • Su Jin Lee
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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  • Jeeyun Lee
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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  • Se Hoon Park
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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  • Joon Oh Park
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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  • Ho Yeong Lim
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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  • Won Ki Kang
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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  • Young Suk Park
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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  • Seung Tae Kim
    Correspondence
    Address for correspondence: Seung Tae Kim, MD PhD, Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea. Fax: +82-2-3410-1754
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Open AccessPublished:March 02, 2018DOI:https://doi.org/10.1016/j.clcc.2018.02.013

      Abstract

      Introduction

      Increased mesenchymal-epithelial transition factor gene (c-MET) expression in several human malignancies is related to increased tumor progression and is a new potential drug target for several types of cancers. In the present study, we investigated the incidence of c-MET overexpression and its prognostic significance in patients with colorectal cancer (CRC).

      Patients and Methods

      We retrospectively reviewed the data from 255 stage IV CRC patients who had results from a c-MET immunohistochemical test at Samsung Medical Center. We explored the relationships between c-MET overexpression and clinicopathological features and survival.

      Results

      Primary tumor sites were 67 right-sided colon, 98 left-sided colon, and 90 rectum. Forty-two patients (16.7%) had poorly differentiated or mucinous carcinoma. Among the 255 patients, 39 (15.3%) exhibited c-MET overexpression. There was no significant difference in the prevalence of c-MET overexpression according to primary site, histologic differentiation, molecular markers, or metastatic sites. In a comparison of the tumor response to first-line chemotherapy according to the level of c-MET expression, we found no significant difference in either partial response or disease control rate. In the survival analysis, patients with c-MET overexpression had significantly shorter overall survival (39 vs. 27 months; P = .018) and progression-free survival (PFS) during bevacizumab treatment (10 vs. 7 months; P = .024).

      Conclusion

      c-MET overexpression, which was detected in 39 CRC patients (15.3%) irrespective of primary sites or molecular markers, indicated a poor survival prognosis and predicted shorter PFS during bevacizumab treatment in patients with CRC. Further studies are warranted to elucidate the value of c–MET-targeted therapy in CRC patients.

      Keywords

      Introduction

      Colorectal cancer (CRC) is the third most common malignancy around the world, with 1.2 million new patients diagnosed worldwide each year.
      • Torre L.A.
      • Bray F.
      • Siegel R.L.
      • et al.
      Global cancer statistics, 2012.
      In the past 2 decades, remarkable progress has been achieved in the treatment of metastatic CRC, especially since the introduction of an effective combination of chemotherapy regimens containing oxaliplatin, irinotecan, and molecular-targeted agents such as cetuximab and bevacizumab.
      • Douillard J.Y.
      • Oliner K.S.
      • Siena S.
      • et al.
      Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer.
      • Van Cutsem E.
      • Kohne C.H.
      • Lang I.
      • et al.
      Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status.
      • Van Cutsem E.
      • Kohne C.H.
      • Hitre E.
      • et al.
      Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.
      • Saltz L.B.
      • Clarke S.
      • Diaz-Rubio E.
      • et al.
      Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study.
      • Hurwitz H.
      • Fehrenbacher L.
      • Novotny W.
      • et al.
      Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.
      Today, the median overall survival (OS) for CRC patients in phase III trials as well as in large observational series is approximately 30 months, more than double that of 20 years ago.
      • Van Cutsem E.
      • Cervantes A.
      • Adam R.
      • et al.
      ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.
      The MET, also known as the N-methyl-N'-nitroso-guanidine human osteosarcoma transforming gene, is a proto-oncogene encoding a receptor tyrosine kinase, mesenchymal-epithelial transition factor gene (c-MET), for hepatocyte growth factor (HGF).
      • Sattler M.
      • Salgia R.
      c-Met and hepatocyte growth factor: potential as novel targets in cancer therapy.
      • Bladt F.
      • Riethmacher D.
      • Isenmann S.
      • et al.
      Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud.
      c-MET is the only known high-affinity receptor for HGF and is widely expressed in cells of epithelial–endothelial origin, including liver cells, fibroblasts, hematopoietic cells, and keratinocytes.
      • Naran S.
      • Zhang X.
      • Hughes S.J.
      Inhibition of HGF/MET as therapy for malignancy.
      The binding of active HGF to c-MET leads to receptor dimerization/multimerization, multiple tyrosine residue phosphorylation in the intracellular region, and downstream signaling for motility, proliferation, survival, and morphogenesis.
      • Rosario M.
      • Birchmeier W.
      How to make tubes: signaling by the Met receptor tyrosine kinase.
      • Zhang Y.W.
      • Vande Woude G.F.
      HGF/SF-met signaling in the control of branching morphogenesis and invasion.
      The deregulation and activation of c-MET can result in unregulated cell growth and differentiation, thus contributing to malignant transformation.
      • Trusolino L.
      • Bertotti A.
      • Comoglio P.M.
      MET signalling: principles and functions in development, organ regeneration and cancer.
      c-MET overexpression or enhanced activation relative to normal tissues has been noted in many types of human cancer, including gastric, colorectal, pancreatic, lung, head and neck, ovarian, renal, prostate, and breast.
      • Rosario M.
      • Birchmeier W.
      How to make tubes: signaling by the Met receptor tyrosine kinase.
      • Nakopoulou L.
      • Gakiopoulou H.
      • Keramopoulos A.
      • et al.
      c-Met tyrosine kinase receptor expression is associated with abnormal beta-catenin expression and favourable prognostic factors in invasive breast carcinoma.
      As a prognostic biomarker in CRC, c-MET has been examined in several studies, but the results are not confirmative. Targeted agents of c-MET are being evaluated in ongoing trials.
      Therefore, we undertook this study to report the incidence and clinicopathologic characteristics of CRC with and without c-MET overexpression. Moreover, we investigated the value of c-MET overexpression in predicting progression-free survival (PFS) and OS.

      Patients and Methods

       Patients

      We retrospectively reviewed the medical records of patients with metastatic CRC who had c-MET immunohistochemical staining results at Samsung Medical Center between May 2014 and December 2016. All standard chemotherapeutic regimens, including 5FU, leucovorin and oxaliplatin or 5FU, leucovorin and irinotecan with or without bevacizumab or cetuximab, were given at the physician's discretion or the patient's preference.
      Each patient's medical record included information about: age; sex; primary site; histologic type; tumor, node, metastases stage; Kirsten rat sarcoma 2 viral oncogene homolog (KRAS)/v-raf murine sarcoma viral oncogene homolog B1/neuroblastoma RAS viral oncogene homolog mutation results; microsatellite instability; extent of metastasis; and treatment details about surgical resection and chemotherapy.

       Immunohistochemistry of c-MET

      Hematoxylin and eosin stained slides were reviewed, and representative formalin-fixed, paraffin-embedded archival blocks were selected for each case. c-MET immunohistochemistry (IHC) was performed using the rabbit monoclonal primary antibody CONFIRM anti-total MET (SP44) (Ventana Medical Systems, Tucson, AZ) with a Ventana BenchMark XT automated slide processing system according to the manufacturer's protocol. All stained specimens were independently reviewed by a pathologist without previous knowledge of clinical information. For c-MET, we applied a recently developed scoring system for gastric cancer.
      • Ha S.Y.
      • Lee J.
      • Kang S.Y.
      • et al.
      MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas.
      c-MET overexpression was defined as 2+ or 3+ according to membranous and cytoplasmic interpretation and only 3+ according to membranous interpretation.

       Statistical Analyses

      To analyze the relationship between clinicopathologic characteristics and c-MET overexpression, we used Pearson χ2 test and Fisher exact test. PFS and OS were determined using the Kaplan–Meier method, and survival curves were compared using log rank test. OS was measured from the first date of diagnosis with stage IV CRC. The Cox proportional hazard model was used to evaluate the associations between clinicopathologic factors and survival. All tests were 2-sided, and P values < .05 were considered to be statistically significant. Statistical analysis was performed using SPSS software version 24 (IBM Corp, Armonk, NY)..

      Results

       Patient Characteristics

      A total of 255 patients were included in this analysis. The clinical characteristics of the patients are summarized in Table 1. The median age of the patients was 54 (range, 17-85) years, and the male to female ratio was 1.32. Primary tumor sites were 67 right-sided colon, 98 left-sided colon, and 90 rectum. Forty-two patients (16.7%) had poorly differentiated or mucinous carcinoma. The KRAS mutation was detected in 47.8% of patients.
      Table 1Patient Characteristics
      VariableValue
      Sex
       Male145 (56.9)
       Female110 (43.1)
      Age, Years
       Median (range)54 (17-85)
      Primary Tumor Site
       Right-sided67 (26.3)
       Left-sided98 (38.4)
       Rectum90 (35.3)
      Tumor Differentiation (n = 252)
       Well or moderately differentiated210 (83.3)
       Poorly differentiated or mucinous42 (16.7)
      Molecular Profile
       KRAS mutant (n = 247)118 (47.8)
       NRAS mutant (n = 30)1 (3.3)
       BRAF mutant (n = 201)7 (2.7)
       MSI high (n = 189)8 (4.2)
      Initial Stage
       I or II18 (7.1)
       III72 (28.2)
       IV165 (64.7)
      Primary Site Resection
       Yes198 (77.6)
      Metastatic Site
       Liver133 (52.2)
       Lung78 (30.6)
       Lymph node63 (24.7)
       Peritoneal seeding57 (22.4)
       Ovary19 (7.5)
      First-Line Treatment (n = 219)
       Fluoropyrimidine only3 (1.4)
       Oxaliplatin-based84 (38.4)
       Irinotecan-based130 (59.4)
       Bevacizumab combination98 (44.7)
       Cetuximab combination43 (19.6)
      Data are presented as n (%) except where otherwise stated.
      Abbreviations: MSI = microsatellite instability.
      Most patients (64.7%) were initially diagnosed with stage IV CRC. Common metastatic sites were liver (52.2%), lung (30.6%), lymph node (24.7%), peritoneal seeding (22.4%), and ovary (7.5%).

       Correlation Between c-MET Overexpression and Clinicopathologic Variables

      Among the 255 patients, only 39 (15.3%) exhibited c-MET overexpression in tumor tissues. Those patients exhibited no specific characteristics (Table 2). Patients with c-MET overexpression had a tendency toward left-sided tumors (82.1% in c-MET overexpression vs. 72.2% in c-MET non-overexpression; P = .177) and KRAS-mutant tumors (57.9% vs. 46.2%; P = .183), but those correlations were not statistically significant. The tumor response rate did not differ with c-MET overexpression (Table 3).
      Table 2Differences in c-MET Expression According to Clinicopathologic Characteristics
      c-MET IHCP
      Positive (n = 39)Negative (n = 216)Total (n = 255)
      Sex.264
       Male19 (48.7)126 (58.3)145 (56.9)
       Female20 (51.3)90 (41.7)110 (43.1)
      Primary Site.177
       Right-sided7 (17.9)60 (27.8)67 (26.3)
       Left-sided20 (51.3)78 (36.1)98 (38.4)
       Rectum12 (30.8)78 (36.1)90 (35.3)
      Histologic Differentiation.610
       W/D or M/D31 (79.5)179 (82.9)210 (82.4)
       P/D or mucinous8 (20.5)37 (17.1)45 (17.6)
      Molecular Marker
       MSI high (n = 189)2 (6.7)6 (3.8)8 (4.2).615
       KRAS mutant (n = 246)22 (57.9)96 (46.2)118 (48.0).183
       BRAF mutant (N = 189)1 (3.4)6 (3.8)7 (3.7)>.999
      Initial Stage.170
       1 to 310 (25.6)80 (37.0)90 (35.3)
       429 (74.4)136 (63.0)165 (64.7)
      Metastatic Site
       Liver22 (56.4)111 (51.4)133 (52.2).563
       Lung10 (25.6)68 (31.5)78 (30.6).466
       Peritoneum11 (28.2)46 (21.3)57 (22.4).341
       Lymph node8 (20.5)55 (25.5)63 (24.7).509
      Data are presented as n (%) except where otherwise stated.
      Abbreviations: IHC = immunohistochemistry; M/D = moderately differentiated; MSI = microsatellite instability; P/D = poorly differentiated; W/D = well differentiated.
      Table 3Differences in Response to First-Line Chemotherapy According to c-MET Expression in Immunohistochemistry
      c-MET+ (n = 35)c-MET (n = 184)P
      Complete Response01 (0.5)
      Partial Response15 (42.9)94 (51.1)
      Stable Disease13 (37.1)61 (33.2)
      Progressive Disease4 (11.4)14 (7.6)
      Nonevaluable3 (8.6)14 (7.6)
      Response Rate15 (46.9)95 (55.9).348
      Disease Control Rate28 (87.5)156 (91.8).496
      Data are presented as n (%) except where otherwise stated.

       The Significance of c-MET Overexpression for Survival

      The median OS time from the first date of stage IV CRC was significantly shorter in patients with c-MET overexpression (median OS: 27 vs. 39 months; P = .018; Figure 1A). For PFS after first-line chemotherapy, there was no significant difference between patients with c-MET overexpression and those without (median PFS: 10 vs. 11 months; P = .359; Figure 1B).
      Figure thumbnail gr1
      Figure 1(A) Kaplan–Meier Curve of Overall Survival for Colorectal Cancer (CRC) Patients According to Mesenchymal-Epithelial Transition Factor Gene (c-MET) Overexpression (P = .018); (B) Kaplan–Meier Curve of Progression-Free Survival (PFS) (P = .359); (C) Kaplan–Meier Curve of PFS in Patients Treated With Bevacizumab (P = .024); and (D) With Cetuximab (P = .981)
      Because the first-line chemotherapy used various combinations, we performed subgroup analysis according to bevacizumab or cetuximab treatment. In patients who were treated with the bevacizumab-containing regimen (n = 90), c-MET overexpression predicted shorter PFS (7 vs. 10 months; P = .024; Figure 1C). In patients who were treated with the cetuximab-containing regimen (n = 42), c-MET overexpression did not predict PFS (8 vs. 9 months; P = .981; Figure 1D).

      Discussion

      The role of c-MET signaling has not been fully elucidated in CRC. c-MET is aberrantly activated in many human cancers through diverse mechanisms, including point mutations, gene amplification, transcriptional upregulation, and ligand autocrine loops.
      • Mo H.N.
      • Liu P.
      Targeting MET in cancer therapy.
      In some non–small-cell lung cancers (NSCLCs), c-MET pathways are thought to be the primary driving mechanisms, particularly MET exon 14 alterations and MET gene amplification.
      • Drilon A.
      • Cappuzzo F.
      • Ou S.I.
      • et al.
      Targeting MET in lung cancer: will expectations finally be MET?.
      • Paik P.K.
      • Drilon A.
      • Fan P.D.
      • et al.
      Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping.
      MET mutations are exceeding rare in CRC, so c-MET is mainly activated by receptor overexpression or genomic upregulation.
      • Mo H.N.
      • Liu P.
      Targeting MET in cancer therapy.
      In this study, we analyzed the expression of c-MET in CRC patients and investigated the value of c-MET overexpression in predicting treatment response and prognosis for CRC patients. Among 255 patients, 39 (15.3%) had c-MET overexpression in tumor tissues. We found no significant correlations between the prevalence of c-MET overexpression and primary tumor site, histologic type, or molecular aberrations. c-MET overexpression was correlated with shorter OS, and in patients treated with bevacizumab, c-MET overexpression was a predictive biomarker for shorter PFS.
      Mesenchymal-epithelial transition factor gene overexpression has been reported to vary from 10% to 75% in CRC.
      • Zeng Z.S.
      • Weiser M.R.
      • Kuntz E.
      • et al.
      c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases.
      • Inno A.
      • Di Salvatore M.
      • Cenci T.
      • et al.
      Is there a role for IGF1R and c-MET pathways in resistance to cetuximab in metastatic colorectal cancer?.
      • Liu Y.
      • Li Q.
      • Zhu L.
      Expression of the hepatocyte growth factor and c-Met in colon cancer: correlation with clinicopathological features and overall survival.
      • Qian L.Y.
      • Li P.
      • Li X.R.
      • et al.
      Multivariate analysis of molecular indicators for postoperative liver metastasis in colorectal cancer cases.
      • Garouniatis A.
      • Zizi-Sermpetzoglou A.
      • Rizos S.
      • et al.
      FAK, CD44v6, c-Met and EGFR in colorectal cancer parameters: tumour progression, metastasis, patient survival and receptor crosstalk.
      • Al-Maghrabi J.
      • Emam E.
      • Gomaa W.
      • et al.
      c-MET immunostaining in colorectal carcinoma is associated with local disease recurrence.
      • Gao H.
      • Guan M.
      • Sun Z.
      • et al.
      High c-Met expression is a negative prognostic marker for colorectal cancer: a meta-analysis.
      Several studies have reported significant overexpression of c-MET mRNA and protein in CRC tumors compared with adjacent normal colon mucosa.
      • Zeng Z.S.
      • Weiser M.R.
      • Kuntz E.
      • et al.
      c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases.
      c-MET overexpression is considered to be related to advanced stage and distant metastases and to predict a poor prognosis.
      • Inno A.
      • Di Salvatore M.
      • Cenci T.
      • et al.
      Is there a role for IGF1R and c-MET pathways in resistance to cetuximab in metastatic colorectal cancer?.
      • Liu Y.
      • Li Q.
      • Zhu L.
      Expression of the hepatocyte growth factor and c-Met in colon cancer: correlation with clinicopathological features and overall survival.
      • Garouniatis A.
      • Zizi-Sermpetzoglou A.
      • Rizos S.
      • et al.
      FAK, CD44v6, c-Met and EGFR in colorectal cancer parameters: tumour progression, metastasis, patient survival and receptor crosstalk.
      Although some studies have suggested that c-MET could not predict the prognosis of CRC,
      • Qian L.Y.
      • Li P.
      • Li X.R.
      • et al.
      Multivariate analysis of molecular indicators for postoperative liver metastasis in colorectal cancer cases.
      a recent meta-analysis indicated a remarkable association between c-MET overexpression and poor OS in CRC patients,
      • Gao H.
      • Guan M.
      • Sun Z.
      • et al.
      High c-Met expression is a negative prognostic marker for colorectal cancer: a meta-analysis.
      which is compatible with our results.
      Crosstalk between the c-MET pathway and other receptor tyrosine kinases has been studied intensely because of its potential importance in understanding the mechanisms of resistance to targeted therapies.
      • Safaie Qamsari E.
      • Safaei Ghaderi S.
      • Zarei B.
      • et al.
      The c-Met receptor: implication for targeted therapies in colorectal cancer.
      Vascular endothelial growth factor (VEGF) and the vascular epidermal growth factor receptor (VEGFR) pathway is one example.
      • Ding S.
      • Merkulova-Rainon T.
      • Han Z.C.
      • et al.
      HGF receptor up-regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro.
      • Zhang J.
      • Jiang X.
      • Jiang Y.
      • et al.
      Recent advances in the development of dual VEGFR and c-Met small molecule inhibitors as anticancer drugs.
      The c-MET pathway activates signaling cascades, including v-src sarcoma viral oncogene homolog/focal adhesion kinase, signal transducer and activator of transcription 3, phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene homolog, and rat sarcoma oncogene homolog, that contribute to angiogenesis directly by stimulating endothelial cells or indirectly by increasing the expression of VEGF and decreasing the expression of thrombospondin 1.
      • Zhang Y.W.
      • Su Y.
      • Volpert O.V.
      • et al.
      Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation.
      Moreover, a patient-derived tumor explant model showed that hypoxia, which results from VEGF pathway inhibitors, induces c-MET expression, which in turn leads to resistance to VEGF inhibition.
      • Song E.K.
      • Tai W.M.
      • Messersmith W.A.
      • et al.
      Potent antitumor activity of cabozantinib, a c-MET and VEGFR2 inhibitor, in a colorectal cancer patient-derived tumor explant model.
      Another recent study suggested that the c-MET pathway mediates VEGFR inhibitor resistance and vascular remodeling in NSCLC.
      • Cascone T.
      • Xu L.
      • Lin H.Y.
      • et al.
      The HGF/c-MET pathway is a driver and biomarker of VEGFR-inhibitor resistance and vascular remodeling in non–small-cell lung cancer.
      Those findings could explain the underlying mechanism of our result that c-MET overexpression predicted shorter PFS during bevacizumab treatment. Inno et al previously suggested that c-MET overexpression might have a role in resistance to anti-EGFR therapy,
      • Inno A.
      • Di Salvatore M.
      • Cenci T.
      • et al.
      Is there a role for IGF1R and c-MET pathways in resistance to cetuximab in metastatic colorectal cancer?.
      but we could not corroborate that finding in our study. The discrepancy in the findings results from differences in the definition of c-MET expression, heterogeneous patient populations, and the small number of cases included in the cetuximab treatment group (n = 42).
      Because there is no standard scoring system for the IHC of c-MET, we applied a recent scoring system.
      • Ha S.Y.
      • Lee J.
      • Kang S.Y.
      • et al.
      MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas.
      We previously reported that MET gene expression levels correlated with protein overexpression, with high concordance between c-MET IHC and NanoString-based multigene assays, including MET.
      • Kim S.T.
      • Do I.G.
      • Lee J.
      • et al.
      The NanoString-based multigene assay as a novel platform to screen EGFR, HER2, and MET in patients with advanced gastric cancer.
      Therefore, our method of c-MET IHC is a reasonable assay for c-MET overexpression.
      This study has some limitations, including its retrospective nature and heterogeneous patient population. However, we applied a reasonable IHC method to evaluate c-MET overexpression and included a relatively large number of metastatic CRC patients.

      Conclusion

      Mesenchymal–epithelial transition factor gene overexpression, which was detected in 15.3% of CRC patients irrespective of primary sites or molecular markers, indicated a poor survival prognosis and predicted shorter PFS during bevacizumab treatment. Further studies are warranted to elucidate the value of c-MET targeted therapy in CRC patients and determine whether a combination of targeted therapies to overcome receptor crosstalk and resistance could maximize treatment efficacy.

       Clinical Practice Points

      • Mesenchymal–epithelial transition factor gene overexpression or enhanced activation has been noted in many types of human cancers, but its prognostic effect remains uncertain in CRC.
      • In this retrospective study, we found that 15.3% had c-MET overexpression and it was not related with other clinicopathologic characteristics.
      • In survival analysis, c-MET overexpression was a poor prognostic factor for survival and predicted shorter PFS in patients who had first-line bevacizumab chemotherapy. Crosstalk between the c-MET pathway and VEGF pathway might be the underlying mechanism of this finding.
      • Future research is needed to evaluate c-MET targeted therapy including combination therapy to overcome receptor crosstalk.

      Disclosure

      The authors have stated that they have no conflicts of interest.

      Supplemental Data

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