Predictive Biomarkers and Personalized Medicine Contrasted Outcomes to Ge fi tinib on Tumoral IGF 1 R Expression in Head and Neck Cancer Patients Receiving Postoperative Chemoradiation ( GORTEC Trial 2004-02 )

Purpose: Intermediate/high-risk operated patients with head and neck cancer may benefit from the addition of EGF receptor (EGFR) inhibitor gefitinib to chemoradiation. This study was designed to assess improved outcomes and identify predictive biomarkers. Experimental Design: Patients provided informed consent for tumor biomarker analyses and, when eligible, were further enrolled in the therapeutic CARISSA multicenter randomized phase II trial of postoperative irradiation with cisplatin þ gefitinib (GORTEC 2004-02-NCT00169221). Results: Seventy-nine patients were included in the biomarker study, whereas 27 did not meet prerequisites for randomization between gefitinib and placebo. Two-year disease-free survival (DFS) rate was 65.0% and did not differ between randomized patients treatedwith gefitinib or placebo (P1⁄4 0.85). The similarity of DFS curves between nonrandomized patients (n1⁄4 27), randomized patients without gefitinib (n 1⁄4 27), and randomized patients receiving gefitinib (n 1⁄4 25), and similar histoclinical parameter distributions for all groups, allowed us to conduct statistical analyses on the entire population. On multivariate analysis, elevated expression of PAK1 by Western blotting, CD31 and membranous insulin-like growth factor 1 receptor (IGF1R) both by immunohistochemistry was significantly associated with shorter DFS. There was a significant interaction between IGF1R and gefitinib. Gefitinib abolished the prognostic discriminative power of high IGF1R expression; patients with elevated IGF1R expression benefited from gefitinib whereas those with low IGF1R fared worse. Conclusion: Gefitinib treatment affords no significant clinical benefit on DFS in an unselected population of patients with head and neck cancer. Our results point to the potential advantage of personalizing treatment for gefitinib based on tumoral IGF1R expression. This should foster confirmatory analyses in trials involving EGFR-targeting agents. Clin Cancer Res; 18(18); 5123–33. 2012 AACR.

[1]  K Kian Ang,et al.  The epidermal growth factor receptor mediates radioresistance. , 2003, International journal of radiation oncology, biology, physics.

[2]  F. Huang,et al.  Correlation between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer , 2012, Clinical Cancer Research.

[3]  P. Lara,et al.  IGF-1R expression predicts clinical outcome in patients with locally advanced oral squamous cell carcinoma. , 2011, Oral oncology.

[4]  K. Soo,et al.  Gefitinib, cisplatin, and concurrent radiotherapy for locally advanced head and neck cancer: EGFR FISH, protein expression, and mutational status are not predictive biomarkers. , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[5]  G Milano,et al.  Sequence-dependent effects of ZD1839 (‘Iressa’) in combination with cytotoxic treatment in human head and neck cancer , 2002, British Journal of Cancer.

[6]  W. Sauerbrei,et al.  REporting recommendations for tumor MARKer prognostic studies (REMARK) , 2005, Nature Clinical Practice Oncology.

[7]  J. Crowley,et al.  Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  Bei-bei Yang,et al.  Anti-epidermal growth factor receptor therapy for advanced head and neck squamous cell carcinoma: a meta-analysis , 2012, European Journal of Clinical Pharmacology.

[9]  Sarat Chandarlapaty,et al.  AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. , 2011, Cancer cell.

[10]  Xiaojiang Xu,et al.  Proteomic Signatures of Epidermal Growth Factor Receptor and Survival Signal Pathways Correspond to Gefitinib Sensitivity in Head and Neck Cancer , 2009, Clinical Cancer Research.

[11]  C. J. Barnes,et al.  Suppression of epidermal growth factor receptor, mitogen-activated protein kinase, and Pak1 pathways and invasiveness of human cutaneous squamous cancer cells by the tyrosine kinase inhibitor ZD1839 (Iressa). , 2003 .

[12]  Olufunmilayo I. Olopade,et al.  Epidermal growth factor receptor inhibitor gefitinib added to chemoradiotherapy in locally advanced head and neck cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  Hung-Ming Wang,et al.  Gefitinib plus cisplatin and radiotherapy in previously untreated head and neck squamous cell carcinoma: a phase II, randomized, double-blind, placebo-controlled study. , 2011, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[14]  R. Nicholson,et al.  Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. , 2004, Endocrine-related cancer.

[15]  H. Lenz,et al.  Germline Polymorphisms in Genes Involved in the IGF1 Pathway Predict Efficacy of Cetuximab in Wild-type KRAS mCRC Patients , 2010, Clinical Cancer Research.

[16]  N. Magné,et al.  Pharmacological background of EGFR targeting. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[17]  J. Siegfried,et al.  Dual Blockade of EGFR and c-Met Abrogates Redundant Signaling and Proliferation in Head and Neck Carcinoma Cells , 2011, Clinical Cancer Research.

[18]  G. Giaccone,et al.  Biomarkers of response to epidermal growth factor receptor inhibitors in Non-Small-Cell Lung Cancer Working Group: standardization for use in the clinical trial setting. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  E. Vokes,et al.  Induction chemotherapy and concurrent chemoradiotherapy for locoregionally advanced head and neck cancer: a multi-institutional phase II trial investigating three radiotherapy dose levels. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[20]  G. Calais,et al.  Compliance and toxicity profiles of the CARISSA trial of postoperative cisplatin-based chemoradiation ± gefitinib in head and neck cancer. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  N. Rosen,et al.  Induction of cutaneous squamous cell carcinomas by RAF inhibitors: cause for concern? , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  J. Siegfried,et al.  Src Family Kinases Mediate Epidermal Growth Factor Receptor Ligand Cleavage, Proliferation, and Invasion of Head and Neck Cancer Cells , 2004, Cancer Research.

[23]  Tetsuo Akimoto,et al.  Relationship between cyclin D1 expression and poor radioresponse of murine carcinomas. , 2002, International journal of radiation oncology, biology, physics.

[24]  J. Dancey,et al.  Phase I trial of gefitinib in combination with radiation or chemoradiation for patients with locally advanced squamous cell head and neck cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  F Demard,et al.  Characterization, quantification, and potential clinical value of the epidermal growth factor receptor in head and neck squamous cell carcinomas , 1991, Head & neck.

[26]  Anurag K. Singh,et al.  Molecular and clinical responses in a pilot study of gefitinib with paclitaxel and radiation in locally advanced head-and-neck cancer. , 2010, International journal of radiation oncology, biology, physics.

[27]  P. Bunn,et al.  Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non–small cell lung carcinoma , 2007, Molecular Cancer Therapeutics.

[28]  Ruth Katz,et al.  Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. , 2002, Cancer research.

[29]  A. Jimeno,et al.  KRAS mutations and sensitivity to epidermal growth factor receptor inhibitors in colorectal cancer: practical application of patient selection. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  C. J. Barnes,et al.  Insulin-like Growth Factor Receptor as a Therapeutic Target in Head and Neck Cancer , 2007, Clinical Cancer Research.

[31]  G Milano,et al.  Influence of epidermal growth factor receptor (EGFR), p53 and intrinsic MAP kinase pathway status of tumour cells on the antiproliferative effect of ZD1839 (‘Iressa’) , 2002, British Journal of Cancer.

[32]  J. Hainsworth,et al.  Neoadjuvant chemotherapy/gefitinib followed by concurrent chemotherapy/radiation therapy/gefitinib for patients with locally advanced squamous carcinoma of the head and neck , 2009, Cancer.

[33]  György Kéri,et al.  Cellular targets of gefitinib. , 2005, Cancer research.

[34]  Gordon B Mills,et al.  mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. , 2006, Cancer research.

[35]  Shu-Chun Lin,et al.  The frequent co-expression of the oncogenes PIK3CA and PAK1 in oral carcinomas. , 2011, Oral oncology.

[36]  Jeffrey Field,et al.  Pak protein kinases and their role in cancer , 2009, Cancer and Metastasis Reviews.

[37]  Christopher U. Jones,et al.  Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. , 2006, The New England journal of medicine.

[38]  Jacques Bernier,et al.  Adjuvant therapy in patients with resected poor-risk head and neck cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  J. Grandis,et al.  Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. , 1993, Cancer research.

[40]  Amine Sadok,et al.  Modulation of cellular redox state underlies antagonism between oxaliplatin and cetuximab in human colorectal cancer cell lines , 2009, British journal of pharmacology.

[41]  M. Namer,et al.  Epidermal growth factor receptor assay: Validation of a single point method and application to breast cancer , 2005, Breast Cancer Research and Treatment.

[42]  Xiaosong Zhang,et al.  Dual EGFR and mTOR targeting in squamous cell carcinoma models, and development of early markers of efficacy , 2007, British Journal of Cancer.

[43]  K. Ang,et al.  Integrating radiotherapy with epidermal growth factor receptor antagonists and other molecular therapeutics for the treatment of head and neck cancer. , 2007, International journal of radiation oncology, biology, physics.

[44]  R. Nahta,et al.  Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling , 2007, Molecular Cancer Therapeutics.

[45]  F. Penault-Llorca,et al.  Correlative analyses between EGFR pathways and stroma-tumor profiles in head and neck cancer patients (HNSCC) on postoperative radiotherapy plus cisplatin (PORTc) plus or minus gefitinib (GORTEC-GETTEC CARISSA trial): Implications for sensitivity to gefitinib. , 2010 .

[46]  F Demard,et al.  Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. , 1993, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[47]  J. Stockman.  Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer , 2012 .

[48]  Laetitia Padovani,et al.  Response of endothelial cells to a dual tyrosine kinase receptor inhibition combined with irradiation , 2005, Molecular Cancer Therapeutics.

[49]  P. Giraud,et al.  Epidermal Growth Factor Receptor Protein Detection in Head and Neck Cancer Patients: A Many-Faceted Picture , 2012, Clinical Cancer Research.