Pharmacogenomics of cetuximab in metastatic colorectal carcinoma.

Cetuximab is a chimeric monoclonal antibody that has revolutionized the treatment of metastatic colorectal cancer. Knowledge of the mechanisms that underlie its effectiveness, as well as the primary and secondary resistance mechanisms, have led to important developments in the understanding of cetuximab biology. In light of knowledge gained from recent trials, the efficacy of cetuximab has been clearly demonstrated to depend upon RAS mutational status, moreover cetuximab should only be used in a subset of patients who may benefit. In this article, we critically review clinical and pharmacogenetic issues of cetuximab, focusing on the cost-effectiveness involved with the use of the drug.

[1]  F. Garrido,et al.  Preclinical modeling of EGFR-specific antibody resistance: oncogenic and immune-associated escape mechanisms , 2014, Oncogene.

[2]  C. Bokemeyer,et al.  Treatment outcome according to tumor RAS mutation status in OPUS study patients with metastatic colorectal cancer (mCRC) randomized to FOLFOX4 with/without cetuximab. , 2014 .

[3]  Sabine Tejpar,et al.  Hsa-miR-31-3p Expression Is Linked to Progression-free Survival in Patients with KRAS Wild-type Metastatic Colorectal Cancer Treated with Anti-EGFR Therapy , 2014, Clinical Cancer Research.

[4]  A. Bardelli,et al.  Blockade of EGFR and MEK Intercepts Heterogeneous Mechanisms of Acquired Resistance to Anti-EGFR Therapies in Colorectal Cancer , 2014, Science Translational Medicine.

[5]  H. Lenz,et al.  Prospective study of EGFR intron 1 (CA)n repeats variants as predictors of benefit from cetuximab and irinotecan in chemo-refractory metastatic colorectal cancer (mCRC) patients , 2014, The Pharmacogenomics Journal.

[6]  M. Ducreux,et al.  Targeted therapy in metastatic colorectal cancer -- an example of personalised medicine in action. , 2013, Cancer treatment reviews.

[7]  J. Tabernero,et al.  Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. , 2013, The New England journal of medicine.

[8]  Michael Scholz,et al.  Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). , 2013 .

[9]  U. Cortes,et al.  Epidermal growth factor receptor (EGFR) and KRAS mutations during chemotherapy plus anti-EGFR monoclonal antibody treatment in metastatic colorectal cancer , 2013, Cancer Chemotherapy and Pharmacology.

[10]  V. Velculescu,et al.  Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. , 2013, Cancer discovery.

[11]  A. Russo,et al.  Monoclonal antibodies in gastrointestinal cancers , 2013, Expert opinion on biological therapy.

[12]  L. Mazzucchelli,et al.  HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer patients , 2013, British Journal of Cancer.

[13]  R. Goldberg,et al.  Cost‐effectiveness of KRAS testing in metastatic colorectal cancer patients in the United States and Germany , 2012, International journal of cancer.

[14]  Enzo Medico,et al.  Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer , 2012, Nature.

[15]  Johannes G. Reiter,et al.  The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers , 2012, Nature.

[16]  H. Sorbye,et al.  Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  Daniel J. Freeman,et al.  Mechanisms mediating the negative interaction between oxaliplatin (Ox) and epidermal growth factor receptor (EGFR) inhibitors in patients (pts) with KRAS mutant (MT) colorectal cancer (CRC). , 2012 .

[18]  F. Bosch,et al.  Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer , 2012, Nature Medicine.

[19]  C. Dittrich,et al.  Clinical and Economic Aspects of KRAS Mutational Status as Predictor for Epidermal Growth Factor Receptor Inhibitor Therapy in Metastatic Colorectal Cancer Patients , 2012, Oncology.

[20]  S. Rüdiger,et al.  Pharmacogenetic predictors for EGFR-inhibitor-associated skin toxicity , 2011, The Pharmacogenomics Journal.

[21]  M. Caraglia,et al.  Predicting efficacy and toxicity in the era of targeted therapy: focus on anti-EGFR and anti-VEGF molecules. , 2011, Current drug metabolism.

[22]  P. Jänne,et al.  OP 85 Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab , 2011 .

[23]  P. Jänne,et al.  Activation of ERBB2 Signaling Causes Resistance to the EGFR-Directed Therapeutic Antibody Cetuximab , 2011, Science Translational Medicine.

[24]  C. Bokemeyer,et al.  Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[25]  D. Lambrechts,et al.  Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial , 2011, The Lancet.

[26]  Sabine Tejpar,et al.  KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. , 2011, The Lancet. Oncology.

[27]  P. Sondel,et al.  Clinical Cancer Therapy by NK Cells via Antibody-Dependent Cell-Mediated Cytotoxicity , 2011, Journal of biomedicine & biotechnology.

[28]  E. Van Cutsem,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. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  F. Ciardiello,et al.  An international consortium study in chemorefractory metastatic colorectal cancer (mCRC) patients (pts) to assess the impact of FCGR polymorphisms on cetuximab efficacy. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  D. Wheeler,et al.  Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab , 2011, Cancer biology & therapy.

[31]  Thomas Mittendorf,et al.  Cost-effectiveness of targeted therapy with cetuximab in patients with K-ras wild-type colorectal cancer presenting with initially unresectable metastases limited to the liver in a German setting. , 2011, Clinical therapeutics.

[32]  Seon-Young Kim,et al.  Novel Chemosensitive Single-Nucleotide Polymorphism Markers to Targeted Regimens in Metastatic Colorectal Cancer , 2011, Clinical Cancer Research.

[33]  B. Barber,et al.  Cost of illness in patients with metastatic colorectal cancer , 2011, Journal of medical economics.

[34]  C. Mathers,et al.  Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 , 2010, International journal of cancer.

[35]  Y. Motoo,et al.  Cost-Effectiveness Analysis of KRAS Testing and Cetuximab as Last-Line Therapy for Colorectal Cancer , 2010, Molecular Diagnosis & Therapy.

[36]  A. Bardelli,et al.  Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. , 2010, JAMA.

[37]  C. Punt,et al.  Correlation of FCGR3A and EGFR germline polymorphisms with the efficacy of cetuximab in KRAS wild-type metastatic colorectal cancer. , 2010, European journal of cancer.

[38]  Louis M. Weiner,et al.  Monoclonal antibodies: versatile platforms for cancer immunotherapy , 2010, Nature Reviews Immunology.

[39]  F. Lévi,et al.  Acquired KRAS mutations during progression of colorectal cancer metastases: possible implications for therapy and prognosis , 2010, Cancer Chemotherapy and Pharmacology.

[40]  V. Catalano,et al.  Genetic modulation of the Let-7 microRNA binding to KRAS 3′-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab–irinotecan , 2010, The Pharmacogenomics Journal.

[41]  T. Frebourg,et al.  Prognostic Value of Circulating Mutant DNA in Unresectable Metastatic Colorectal Cancer , 2010, Annals of surgery.

[42]  A. Russo,et al.  The Long and Winding Road to Useful Predictive Factors for Anti-EGFR Therapy in Metastatic Colorectal Carcinoma: The KRAS/BRAF Pathway , 2010, Oncology.

[43]  S. Tommasi,et al.  The Dark Side of the Moon: The PI3K/PTEN/AKT Pathway in Colorectal Carcinoma , 2010, Oncology.

[44]  K. Schaefer,et al.  Prevalence and Heterogeneity of KRAS, BRAF, and PIK3CA Mutations in Primary Colorectal Adenocarcinomas and Their Corresponding Metastases , 2010, Clinical Cancer Research.

[45]  J. Reid,et al.  Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[46]  E. Van Cutsem,et al.  Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. , 2009, The New England journal of medicine.

[47]  L. Mazzucchelli,et al.  Multi-Determinants Analysis of Molecular Alterations for Predicting Clinical Benefit to EGFR-Targeted Monoclonal Antibodies in Colorectal Cancer , 2009, PloS one.

[48]  F. De Vita,et al.  Anti‐epidermal growth factor receptor monoclonal antibodies in cancer therapy , 2009, Clinical and experimental immunology.

[49]  P. Gibbs,et al.  Prospective cost-effectiveness analysis of cetuximab in metastatic colorectal cancer: evaluation of National Cancer Institute of Canada Clinical Trials Group CO.17 trial. , 2009, Journal of the National Cancer Institute.

[50]  C. Grady,et al.  How much is life worth: cetuximab, non-small cell lung cancer, and the $440 billion question. , 2009, Journal of the National Cancer Institute.

[51]  V. Heinemann,et al.  Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. , 2009, Cancer treatment reviews.

[52]  S. Tommasi,et al.  KRAS mutations and sensitivity to anti-EGFR monoclonal antibodies in metastatic colorectal carcinoma: an open issue , 2009 .

[53]  Edd Fleming,et al.  The microeconomics of personalized medicine: today's challenge and tomorrow's promise , 2009, Nature Reviews Drug Discovery.

[54]  M. Ychou,et al.  Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  I. Floriani,et al.  High concordance of KRAS status between primary colorectal tumors and related metastatic sites: implications for clinical practice. , 2008, The oncologist.

[56]  H. Lenz,et al.  Polymorphisms in Cyclooxygenase-2 and Epidermal Growth Factor Receptor Are Associated with Progression-Free Survival Independent of K-ras in Metastatic Colorectal Cancer Patients Treated with Single-Agent Cetuximab , 2008, Clinical Cancer Research.

[57]  Y. Yin,et al.  PTEN: a new guardian of the genome , 2008, Oncogene.

[58]  P. Pandolfi.  P-TEN exciting years: from the cytosol to the nucleus and back to keep cancer at bay , 2008, Oncogene.

[59]  Daniel J. Freeman,et al.  Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[60]  V. Catalano,et al.  Pharmacogenetic profiling for cetuximab plus irinotecan therapy in patients with refractory advanced colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[61]  E. Van Cutsem,et al.  KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[62]  A. Lièvre,et al.  KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[63]  Dongsheng Tu,et al.  Cetuximab for the treatment of colorectal cancer. , 2007, The New England journal of medicine.

[64]  J. Abubaker,et al.  Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population , 2007, Oncogene.

[65]  G. Mills,et al.  Epidermal growth factor receptor (EGFR) ubiquitination as a mechanism of acquired resistance escaping treatment by the anti-EGFR monoclonal antibody cetuximab. , 2007, Cancer research.

[66]  S. Groshen,et al.  FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[67]  Manuel Hidalgo,et al.  Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[68]  F. Blanchard,et al.  Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy , 2007, British Journal of Cancer.

[69]  Silvia Benvenuti,et al.  Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. , 2007, Cancer research.

[70]  Ji Luo,et al.  The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism , 2006, Nature Reviews Genetics.

[71]  S. Groshen,et al.  Cyclin D1 and epidermal growth factor polymorphisms associated with survival in patients with advanced colorectal cancer treated with Cetuximab , 2006, Pharmacogenetics and genomics.

[72]  V. Adamo,et al.  Molecular detection of TP53, Ki-Ras and p16INK4A promoter methylation in plasma of patients with colorectal cancer and its association with prognosis. Results of a 3-year GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[73]  Siu-Fun Wong,et al.  Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. , 2005, Clinical therapeutics.

[74]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[75]  D. Sargent,et al.  Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[76]  D. Barford,et al.  Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF , 2004, Cell.

[77]  R. Perez-soler.  HER1/EGFR targeting: refining the strategy. , 2004, The oncologist.

[78]  G. Tortora,et al.  Antitumor Activity of ZD6474, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Human Cancer Cells with Acquired Resistance to Antiepidermal Growth Factor Receptor Therapy , 2004, Clinical Cancer Research.

[79]  J. Baselga,et al.  ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[80]  M. Stratton,et al.  Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. , 2002, Cancer research.

[81]  R. Labianca,et al.  Specific codon 13 K-ras mutations are predictive of clinical outcome in colorectal cancer patients, whereas codon 12 K-ras mutations are associated with mucinous histotype. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[82]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[83]  이석호,et al.  Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study , 2001, British Journal of Cancer.

[84]  D. Hicklin,et al.  Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. , 2001, Cancer research.

[85]  M. Leppert,et al.  Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival: a population-based study. , 2000, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[86]  K. Zänker,et al.  Modulation of Epidermal Growth Factor Receptor Gene Transcription by a Polymorphic Dinucleotide Repeat in Intron 1* , 1999, The Journal of Biological Chemistry.

[87]  A. Kinsella,et al.  K-ras gene mutations in adenomas and carcinomas of the colon. , 1992, Surgical oncology.

[88]  M. Kirstein,et al.  A systematic review of cost-effectiveness of monoclonal antibodies for metastatic colorectal cancer. , 2014, European journal of cancer.

[89]  yang-xin fu,et al.  Cetuximab-mediated tumor regression depends on innate and adaptive immune responses. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[90]  J. Feliu,et al.  Prognostic and predictive biomarkers for epidermal growth factor receptor-targeted therapy in colorectal cancer: beyond KRAS mutations. , 2013, Critical reviews in oncology/hematology.

[91]  M. Kahn,et al.  A let-7 microRNA-binding site polymorphism in 3'-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.