title: Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer.
abstract: BACKGROUND.EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition.METHODS.Patients with operable stage II-IVa HNSCC were randomized to 7-21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size.RESULTS.From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms (P= 0.0014); however, no effect was seen with dasatinib alone (P= 0.24). High baseline pMAPK expression was associated with response to erlotinib (P= 0.03). High baseline pSTAT3 was associated with resistance to dasatinib (P= 0.099).CONCLUSIONS.Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts.TRIAL REGISTRATION.NCT00779389.FUNDING.National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma.
authors.affiliation: Department of Medicine and.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Bauman
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Umamaheswar
authors.initials: U
authors.lastname: Duvvuri
authors.affiliation: Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Gooding
authors.affiliation: Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Tanya J
authors.initials: TJ
authors.lastname: Rath
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Oregon Health Sciences University, Portland, Oregon, USA.
authors.forename: Neil D
authors.initials: ND
authors.lastname: Gross
authors.affiliation: Department of Otolaryngology and.
authors.forename: John
authors.initials: J
authors.lastname: Song
authors.affiliation: Division of Medical Oncology University of Colorado, Denver, Colorado, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.affiliation: Department of Otolaryngology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Wendell G
authors.initials: WG
authors.lastname: Yarbrough
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Faye M
authors.initials: FM
authors.lastname: Johnson
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Simion
authors.initials: S
authors.lastname: Chiosea
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Malabika
authors.initials: M
authors.lastname: Sen
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Kass
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Jonas T
authors.initials: JT
authors.lastname: Johnson
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Seungwon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of Colorado, Denver, Colorado, USA.
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
authors.affiliation: Department of Medicine, University of Colorado, Denver, Colorado, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Ellison
authors.affiliation: Department of Medicine and.
authors.forename: John T
authors.initials: JT
authors.lastname: Flaherty
authors.affiliation: Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D004311:Double-Blind Method; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D014408:Biomarkers, Tumor; D010919:Placebos; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D019061:src-Family Kinases