KRAS Mutation as a Potential Prognostic Biomarker of Biliary Tract Cancers

BACKGROUND The aim of this study was to identify the unique molecular characteristics of biliary tract cancer (BTC) for the development of novel molecular-targeted therapies. MATERIALS AND METHODS We performed mutational analysis of KRAS, BRAF, PIK3CA, and FBXW7 and immunohistochemical analysis of EGFR and TP53 in 63 Japanese patients with BTC and retrospectively evaluated the association between the molecular characteristics and clinicopathological features of BTC. RESULTS KRAS mutations were identified in 9 (14%) of the 63 BTC patients; no mutations were detected within the analyzed regions of BRAF, PIK3CA, and FBXW7. EGFR overexpression was observed in 5 (8%) of the 63 tumors, while TP53 overexpression was observed in 48% (30/63) of the patients. Overall survival of patients with KRAS mutation was significantly shorter than that of patients with the wild-type KRAS gene (P = 0.005). By multivariate analysis incorporating molecular and clinicopathological features, KRAS mutations and lymph node metastasis were identified to be independently associated with shorter overall survival (KRAS, P = 0.004; lymph node metastasis, P = 0.015). CONCLUSIONS Our data suggest that KRAS mutation is a poor prognosis predictive biomarker for the survival in BTC patients.

[1]  D. Geynisman,et al.  Toward personalized treatment of advanced biliary tract cancers. , 2012, Discovery medicine.

[2]  J. L. Tang,et al.  PIK3CA exon 20 mutations as a potential biomarker for resistance to anti-EGFR monoclonal antibodies in KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[3]  Razelle Kurzrock,et al.  PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  A. Zullo,et al.  Chemotherapy for the Biliary Tract Cancers: Moving Toward Improved Survival Time , 2012, Journal of Gastrointestinal Cancer.

[5]  T. Cenci,et al.  Is there a role for IGF1R and c-MET pathways in resistance to cetuximab in metastatic colorectal cancer? , 2011, Clinical colorectal cancer.

[6]  J. M. Xie,et al.  KRAS and PIK3CA but not BRAF genes are frequently mutated in Chinese cholangiocarcinoma patients. , 2011, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[7]  M. Tzardi,et al.  Impact of KRAS, BRAF, PIK3CA Mutations, PTEN, AREG, EREG Expression and Skin Rash in ≥2nd Line Cetuximab-Based Therapy of Colorectal Cancer Patients , 2011, PloS one.

[8]  Razelle Kurzrock,et al.  PIK3CA Mutations in Patients with Advanced Cancers Treated with PI3K/AKT/mTOR Axis Inhibitors , 2011, Molecular Cancer Therapeutics.

[9]  L. Macconaill,et al.  Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma , 2011, BMC Cancer.

[10]  Xiao-dong Zhu,et al.  Predictive and prognostic value of KRAS mutations in metastatic colorectal cancer patients treated with cetuximab: a meta-analysis of 22 studies. , 2010, European journal of cancer.

[11]  Sabine Tejpar,et al.  Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. , 2010, The Lancet. Oncology.

[12]  A. Zhu,et al.  Genetics of biliary tract cancers and emerging targeted therapies. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  A. Bardelli,et al.  Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  A. Bardelli,et al.  Targeting EGFR/HER2 pathways enhances the antiproliferative effect of gemcitabine in biliary tract and gallbladder carcinomas , 2010, BMC Cancer.

[15]  J. Meyerhardt,et al.  Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer , 2009, British Journal of Cancer.

[16]  Francesca Molinari,et al.  PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. , 2009, Cancer research.

[17]  M. Olschewski,et al.  EGFR and HER2 expression in advanced biliary tract cancer. , 2008, World journal of gastroenterology.

[18]  T. Takada,et al.  Biliary tract cancer treatment: 5,584 results from the Biliary Tract Cancer Statistics Registry from 1998 to 2004 in Japan. , 2009, Journal of hepato-biliary-pancreatic surgery.

[19]  F. Siannis,et al.  Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. , 2008, The Lancet. Oncology.

[20]  S. Reed,et al.  FBXW7/hCDC4 is a general tumor suppressor in human cancer. , 2007, Cancer research.

[21]  M. Makuuchi,et al.  Report of the 17th Nationwide Follow‐up Survey of Primary Liver Cancer in Japan † , 2007, Hepatology research : the official journal of the Japan Society of Hepatology.

[22]  T. Goya,et al.  A Simple and Sensitive Method for Detecting Major Mutations Within the Tyrosine Kinase Domain of the Epidermal Growth Factor Receptor Gene in Non–small-cell Lung Carcinoma , 2006, Diagnostic molecular pathology : the American journal of surgical pathology, part B.

[23]  K. McGlynn,et al.  A Comparison of Trends in the Incidence of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma in the United States , 2006, Cancer Epidemiology Biomarkers & Prevention.

[24]  C. la Vecchia,et al.  Gallbladder cancer worldwide: Geographical distribution and risk factors , 2006, International journal of cancer.

[25]  H. Fujii,et al.  Amplification and overexpression of c‐erbB‐2, epidermal growth factor receptor, and c‐met in biliary tract cancers , 2005, The Journal of pathology.

[26]  L. Schwartz,et al.  Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  I. Ellis,et al.  Best Practice No 176 , 2004, Journal of Clinical Pathology.

[28]  F. Sommerer,et al.  Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma , 2003, Gut.

[29]  A. Rashid,et al.  K-ras mutation, p53 overexpression, and microsatellite instability in biliary tract cancers: a population-based study in China. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[30]  W. H. Kim,et al.  Genetic alterations in gallbladder adenoma, dysplasia and carcinoma. , 2001, Cancer letters.

[31]  M. Gnant,et al.  TP53 mutation and p53 overexpression for prediction of response to neoadjuvant treatment in breast cancer patients. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[32]  T. Itoi,et al.  Histological and genetic changes in malignant transformation of gallbladder adenoma. , 1999, Annals of oncology : official journal of the European Society for Medical Oncology.

[33]  L. Sobin,et al.  TNM Classification of Malignant Tumours , 1987, UICC International Union Against Cancer.