title: IGF-1R expression is associated with HPV-negative status and adverse survival in head and neck squamous cell cancer.
abstract: Head and neck squamous cell carcinomas (HNSCC) are treated with surgery, radiotherapy and cisplatin-based chemotherapy, but survival from locally-advanced disease remains poor, particularly in patients whose tumors are negative for Human papillomavirus (HPV). Type 1 IGF receptor (IGF-1R) is known to promote tumorigenesis and resistance to cancer therapeutics. Here, we assessed IGF-1R immunohistochemistry on tissue microarrays containing 852 cores from 346 HNSCC patients with primary tumors in the oropharynx (n = 231), larynx (85), hypopharynx (28), oral cavity (2). Of these, 236 (68%) were HPV-negative, 110 (32%) positive. IGF-1R was detected in the cell membrane of 36% and cytoplasm of 92% of HNSCCs; in 64 cases with matched normal tonsillar epithelium, IGF-1R was overexpressed in the HNSCCs (P < 0.001). Overall survival (OS) and disease-specific survival (DSS) were reduced in patients whose tumors contained high membrane IGF-1R [OS: hazard ratio (HR) = 1.63, P = 0.006; DSS: HR = 1.63, P = 0.016], cytoplasmic IGF-1R (OS: HR = 1.58, P = 0.009; DSS: HR = 1.58, P = 0.024) and total IGF-1R (OS: HR = 2.02, P < 0.001; DSS: HR = 2.2, P < 0.001). High tumor IGF-1R showed significant association with high-tumor T-stage (P < 0.001) and HPV-negativity (P < 0.001), and was associated with shorter OS when considering patients with HPV-positive (P = 0.01) and negative (P = 0.006) tumors separately. IGF-1R was independently associated with survival in multivariate analysis including HPV, but not when lymphovascular invasion, perineural spread and T-stage were included. Of these factors, only IGF-1R can be manipulated; the association of IGF-1R with aggressive disease supports experimental incorporation of anti-IGF-1R agents into multimodality treatment programs for HPV-negative and high IGF-1R HPV-positive HNSCC.
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7LJ, UK, The Blenheim Head and Neck Unit, Churchill Hospital, Oxford OX3 7LE, UK, Present address: ENT Department, University Hospital Bristol, Bristol BS2 8EG, UK valentine.macaulay@oncology.ox.ac.uk otdale@doctors.org.uk.
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Dale
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7LJ, UK.
authors.forename: Tamara
authors.initials: T
authors.lastname: Aleksic
authors.affiliation: Department of Cellular Pathology, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Ketan A
authors.initials: KA
authors.lastname: Shah
authors.affiliation: Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford OX3 7LE, UK.
authors.forename: Cheng
authors.initials: C
authors.lastname: Han
authors.affiliation: Institute of Head and Neck Studies and Education (INHANSE), University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Hisham
authors.initials: H
authors.lastname: Mehanna
authors.affiliation: Institute of Head and Neck Studies and Education (INHANSE), University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Davy C M
authors.initials: DC
authors.lastname: Rapozo
authors.affiliation: Department of Cellular Pathology, Aintree University Hospitals NHS Foundation Trust, Liverpool L9 7AL, UK.
authors.forename: Jon D H
authors.initials: JD
authors.lastname: Sheard
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L3 9TA, UK and.
authors.forename: Paul
authors.initials: P
authors.lastname: Goodyear
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L3 9TA, UK and.
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Upile
authors.affiliation: School of Dental Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4BW, UK.
authors.forename: Max
authors.initials: M
authors.lastname: Robinson
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L3 9TA, UK and.
authors.forename: Terence M
authors.initials: TM
authors.lastname: Jones
authors.affiliation: The Blenheim Head and Neck Unit, Churchill Hospital, Oxford OX3 7LE, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Winter
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7LJ, UK, Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford OX3 7LE, UK, valentine.macaulay@oncology.ox.ac.uk.
authors.forename: Valentine M
authors.initials: VM
authors.lastname: Macaulay
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000401:mortality* / Q000821:virology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000401:mortality* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000150:complications*; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis*; D000077195:Squamous Cell Carcinoma of Head and Neck; D055815:Young Adult
chemical_list: D017526:Receptor, IGF Type 1