title: Functional Genomics Uncover the Biology behind the Responsiveness of Head and Neck Squamous Cell Cancer Patients to Cetuximab.
abstract: To identify the tumor portrait of the minority of head and neck squamous cell carcinoma (HNSCC) patients with recurrent-metastatic (RM) disease who upon treatment with platinum-based chemotherapy plus cetuximab present a long-lasting response.
  
  
  
  The gene expression of pretreatment samples from 40 HNSCC-RM patients, divided in two groups [14 long-progression-free survival (PFS) and 26 short-PFS (median = 19 and 3 months, respectively)], was associated with PFS and was challenged against a dataset from metastatic colon cancer patients treated with cetuximab. For biologic analysis, we performed functional and subtype association using gene set enrichment analysis, associated biology across all currently available HNSCC signatures, and inferred drug sensitivity using data from the Cancer Genomic Project.
  
  
  
  The identified genomic profile exhibited a significant predictive value that was essentially confirmed in the single publicly available dataset of cetuximab-treated patients. The main divergence between long- and short-PFS groups was based on developmental/differentiation status. The long-PFS patients are characterized by basal subtype traits such as strong EGFR signaling phenotype and hypoxic differentiation, further validated by the significantly higher association with the hypoxia metagene. The short-PFS patients presented a strong activation of RAS signaling confirmed in an in vitro model of two isogenic HNSCC cell lines sensitive or resistant to cetuximab. The predicted drug sensitivity for all four EGFR inhibitors was higher in long- versus short-PFS patients (P range: <0.0022-1e-07).
  
  
  
  Our data uncover the biology behind response to platinum-based chemotherapy plus cetuximab in RM-HNSCC cancer and may have translational implications improving treatment selection. Clin Cancer Res; 22(15); 3961-70. ©2016 AACRSee related commentary by Chau and Hammerman, p. 3710.
authors.affiliation: Head and Neck Cancer Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. loris.dececco@istitutotumori.mi.it silvana.canevari@istitutotumori.mi.it paolo.bossi@istitutotumori.mi.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bossi
authors.affiliation: Head and Neck Cancer Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Bergamini
authors.affiliation: Head and Neck Cancer Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Cantonal Hospital St Gallen, Department of Internal Medicine, Clinic for Medical Oncology, St Gallen, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Siano
authors.affiliation: Division of Medical Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Cossu Rocca
authors.affiliation: SC of Oncology, AOU Maggiore della Carità, Novara, Italy.
authors.forename: Andrea P
authors.initials: AP
authors.lastname: Sponghini
authors.affiliation: Head and Neck Cancer Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Favales
authors.affiliation: Functional Genomics and Bioinformatics, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Giannoccaro
authors.affiliation: Functional Genomics and Bioinformatics, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Marchesi
authors.affiliation: Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cortelazzi
authors.affiliation: Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Perrone
authors.affiliation: Laboratory of Experimental Molecular Pathology, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
authors.affiliation: Head and Neck Cancer Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Locati
authors.affiliation: Head and Neck Cancer Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Licitra
authors.affiliation: Functional Genomics and Bioinformatics, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. loris.dececco@istitutotumori.mi.it silvana.canevari@istitutotumori.mi.it paolo.bossi@istitutotumori.mi.it.
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.affiliation: Functional Genomics and Bioinformatics, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. loris.dececco@istitutotumori.mi.it silvana.canevari@istitutotumori.mi.it paolo.bossi@istitutotumori.mi.it.
authors.forename: Loris
authors.initials: L
authors.lastname: De Cecco
mesh_terms: D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D000068818:Cetuximab / Q000494:pharmacology / Q000627:therapeutic use*; D019295:Computational Biology / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D006258:Head and Neck Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010597:Pharmacogenetics / Q000379:methods; D011379:Prognosis; D012372:ROC Curve; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D000074322:Antineoplastic Agents, Immunological; D000068818:Cetuximab