Tumor Biol. (2015) 36:515–520 DOI 10.1007/s13277-014-2659-5
REVIEW
High c-Met expression is a negative prognostic marker for colorectal cancer: a meta-analysis HeLi Gao & Mei Guan & Zhao Sun & ChunMei Bai
Received: 8 July 2014 / Accepted: 18 September 2014 / Published online: 31 January 2015 # International Society of Oncology and BioMarkers (ISOBM) 2015
Abstract Recent studies have shown that c-Met is an important signal in the development of colorectal cancer, but the prognostic value of c-Met remains unclear. We aimed to analyze the prognostic effect of c-Met in colorectal cancer through a systematic review and meta-analysis. Through database searches, we identified six articles describing how cMet status affects colorectal cancer prognosis. A metaanalysis was performed to investigate the relationship between the hazard ratio and survival. The available outcome data from six articles were examined. A meta-analysis of the HR and the 95 % confidence interval (CI) indicated a significantly poor overall survival and disease-free survival in patients with high expression levels of c-Met. The subgroup analysis showed that the prognostic effect of the c-Met level was similar in different methods and was not associated with disease stages. High c-Met expression levels could predict a poor prognosis in colorectal cancer patients. The c-Met status could be used to evaluate the prognosis in clinical patients.
Keywords c-Met . Colorectal cancer . Prognosis . Meta-analysis
HeLi Gao and Mei Guan are equal contributors. H. Gao : M. Guan : Z. Sun : C. Bai (*) Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People’s Republic of China e-mail: [email protected]
Introduction Colorectal cancer (CRC) is the third most common malignancy around the world, and 1.2 million new patients are diagnosed worldwide each year. Although the diagnosis and treatment of CRC has improved, approximately 20 % of CRC patients have distant metastases at the time of diagnosis, and the 5-year survival rate for advanced stage disease is less than 12 % [1, 2]. Studies in recent years have found many clinical and pathological factors that are related to the prognosis of CRC, and various biomarkers have been used to explore treatment alternatives and improve the prediction accuracy of prognosis in patients with CRC [3]. c-Met, a tyrosine kinase receptor for hepatocyte growth factor (HGF), plays an important role in embryo development and physical regulation through multiple signaling pathways, among which including PI3K-AKT and MAPK [4]. Overexpression of c-Met has been detected in many malignant tumors, including breast cancer, lung cancer, and CRC [5]. In CRC, c-Met has been considered to be related with advanced stage and distant metastases, and overexpression of c-Met predicts a poor prognosis [6, 7]. Some studies suggested that c-Met could not predict the prognosis of colorectal cancer [8]. Due to the large number of studies which have focused on the association between the c-Met expression level and the prognosis of CRC, we aimed to clarify the relationship between cMet positive status and the prognosis of CRC by performing a meta-analysis of recently published articles.
H. Gao e-mail: [email protected]
Methods
M. Guan e-mail: [email protected]
Search strategy
Z. Sun e-mail: [email protected]
We searched PubMed, Cochrane Library, and Web of Science electronic databases for articles published between January
516
Tumor Biol. (2015) 36:515–520
most complete study was included in the meta-analysis. The exclusion criteria were as follows: (1) studies about the relationship between the co-expression of c-Met and other factors and CRC prognosis and (2) studies with no hazard ratios (HR) or 95 % confidence intervals (CI) data and without a KaplanMeier curve to calculate these data.
Records idenfied through searching databases (n=460)
Remove duplicates (n=460)
Data extraction Screening of abstract (n=87)
the
Full-text arcles assessed for eligibility (n=13)
Records excluded (n=74)
Each article was reviewed independently by two authors. If there was a different opinion, the articles will be discussed with a third author. The included articles were assessed according to “The Newcastle-Ottawa Scale for assessing the quality of nonrandomised studies in meta-analyses” [9]. The general data collected from each study were first author’s name, study country, publication year, patient ages, gender and number, disease stage, methodology of c-Met analysis, and HR with 95 % CI, which were used to measure the effective value. If the data were not given directly, the available data were obtained from Kaplan-Meier curves (using Engauge Digitizer version 4.1) and the HR and 95 % CI were calculated using the methods reported by Tierney et al. [10].
Full-text arcles excluded (n=7) 3 arcles excluded because of data unavailability; 4 arcles excluded because of co-expression with other signals
Studies included in the qualitave synthesis (n=6)
Studies included in the qualitave synthesis (meta-analysis)(n=6)
Fig. 1 PRISMA flow chart of the selection process for identifying eligible studies
1992 and December 25, 2013. The search strategy used the keywords “c-Met” or “met,” and “colon neoplasm [Mesh]” or “rectal neoplasm” or “colorectal neoplasm.” The language of the studies was limited to English. The reference lists of the selected articles were searched to ensure that no studies were overlooked. Selection criteria The meta-analysis included studies that met the following standards: (1) all the patients were diagnosed with CRC by histopathology; (2) the study reported the c-Met expression level in CRC patients and their prognoses, including the overall survival (OS) or disease-free survival (DFS); (3) the results were part of an original analysis; and (4) if the same patient population was used in several publications, only the
Statistical analysis The expression of c-Met was considered “high” or “low” according to the cutoff values used in each study. The endpoints were DFS and OS, and the association between c-Met and the clinical outcomes was evaluated using the hazard ratio of low/normal c-Met expression level patients over high c-Met level patients and the 95 % confidence interval. Multivariate Cox proportional hazards models were used. When we utilized the hazard ratio of low/normal vs high level of c-Met expression, the HR>1 and 95 % CI that did not overlap with 1 implied a good prognosis for the patient with a high level, while the HR0.05, I2
REVIEW
High c-Met expression is a negative prognostic marker for colorectal cancer: a meta-analysis HeLi Gao & Mei Guan & Zhao Sun & ChunMei Bai
Received: 8 July 2014 / Accepted: 18 September 2014 / Published online: 31 January 2015 # International Society of Oncology and BioMarkers (ISOBM) 2015
Abstract Recent studies have shown that c-Met is an important signal in the development of colorectal cancer, but the prognostic value of c-Met remains unclear. We aimed to analyze the prognostic effect of c-Met in colorectal cancer through a systematic review and meta-analysis. Through database searches, we identified six articles describing how cMet status affects colorectal cancer prognosis. A metaanalysis was performed to investigate the relationship between the hazard ratio and survival. The available outcome data from six articles were examined. A meta-analysis of the HR and the 95 % confidence interval (CI) indicated a significantly poor overall survival and disease-free survival in patients with high expression levels of c-Met. The subgroup analysis showed that the prognostic effect of the c-Met level was similar in different methods and was not associated with disease stages. High c-Met expression levels could predict a poor prognosis in colorectal cancer patients. The c-Met status could be used to evaluate the prognosis in clinical patients.
Keywords c-Met . Colorectal cancer . Prognosis . Meta-analysis
HeLi Gao and Mei Guan are equal contributors. H. Gao : M. Guan : Z. Sun : C. Bai (*) Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People’s Republic of China e-mail: [email protected]
Introduction Colorectal cancer (CRC) is the third most common malignancy around the world, and 1.2 million new patients are diagnosed worldwide each year. Although the diagnosis and treatment of CRC has improved, approximately 20 % of CRC patients have distant metastases at the time of diagnosis, and the 5-year survival rate for advanced stage disease is less than 12 % [1, 2]. Studies in recent years have found many clinical and pathological factors that are related to the prognosis of CRC, and various biomarkers have been used to explore treatment alternatives and improve the prediction accuracy of prognosis in patients with CRC [3]. c-Met, a tyrosine kinase receptor for hepatocyte growth factor (HGF), plays an important role in embryo development and physical regulation through multiple signaling pathways, among which including PI3K-AKT and MAPK [4]. Overexpression of c-Met has been detected in many malignant tumors, including breast cancer, lung cancer, and CRC [5]. In CRC, c-Met has been considered to be related with advanced stage and distant metastases, and overexpression of c-Met predicts a poor prognosis [6, 7]. Some studies suggested that c-Met could not predict the prognosis of colorectal cancer [8]. Due to the large number of studies which have focused on the association between the c-Met expression level and the prognosis of CRC, we aimed to clarify the relationship between cMet positive status and the prognosis of CRC by performing a meta-analysis of recently published articles.
H. Gao e-mail: [email protected]
Methods
M. Guan e-mail: [email protected]
Search strategy
Z. Sun e-mail: [email protected]
We searched PubMed, Cochrane Library, and Web of Science electronic databases for articles published between January
516
Tumor Biol. (2015) 36:515–520
most complete study was included in the meta-analysis. The exclusion criteria were as follows: (1) studies about the relationship between the co-expression of c-Met and other factors and CRC prognosis and (2) studies with no hazard ratios (HR) or 95 % confidence intervals (CI) data and without a KaplanMeier curve to calculate these data.
Records idenfied through searching databases (n=460)
Remove duplicates (n=460)
Data extraction Screening of abstract (n=87)
the
Full-text arcles assessed for eligibility (n=13)
Records excluded (n=74)
Each article was reviewed independently by two authors. If there was a different opinion, the articles will be discussed with a third author. The included articles were assessed according to “The Newcastle-Ottawa Scale for assessing the quality of nonrandomised studies in meta-analyses” [9]. The general data collected from each study were first author’s name, study country, publication year, patient ages, gender and number, disease stage, methodology of c-Met analysis, and HR with 95 % CI, which were used to measure the effective value. If the data were not given directly, the available data were obtained from Kaplan-Meier curves (using Engauge Digitizer version 4.1) and the HR and 95 % CI were calculated using the methods reported by Tierney et al. [10].
Full-text arcles excluded (n=7) 3 arcles excluded because of data unavailability; 4 arcles excluded because of co-expression with other signals
Studies included in the qualitave synthesis (n=6)
Studies included in the qualitave synthesis (meta-analysis)(n=6)
Fig. 1 PRISMA flow chart of the selection process for identifying eligible studies
1992 and December 25, 2013. The search strategy used the keywords “c-Met” or “met,” and “colon neoplasm [Mesh]” or “rectal neoplasm” or “colorectal neoplasm.” The language of the studies was limited to English. The reference lists of the selected articles were searched to ensure that no studies were overlooked. Selection criteria The meta-analysis included studies that met the following standards: (1) all the patients were diagnosed with CRC by histopathology; (2) the study reported the c-Met expression level in CRC patients and their prognoses, including the overall survival (OS) or disease-free survival (DFS); (3) the results were part of an original analysis; and (4) if the same patient population was used in several publications, only the
Statistical analysis The expression of c-Met was considered “high” or “low” according to the cutoff values used in each study. The endpoints were DFS and OS, and the association between c-Met and the clinical outcomes was evaluated using the hazard ratio of low/normal c-Met expression level patients over high c-Met level patients and the 95 % confidence interval. Multivariate Cox proportional hazards models were used. When we utilized the hazard ratio of low/normal vs high level of c-Met expression, the HR>1 and 95 % CI that did not overlap with 1 implied a good prognosis for the patient with a high level, while the HR0.05, I2
