title: Impact of human papilloma virus infection on the response of head and neck cancers to anti-epidermal growth factor receptor antibody therapy.
abstract: Infection with human papillomaviruses (HPVs) characterizes a distinct subset of head and neck squamous cell cancers (HNSCCs). HPV-positive HNSCC preferentially affect the oropharynx and tonsils. Localized HPV-positive HNSCCs have a favorable prognosis and treatment outcome. However, the impact of HPV in advanced or metastatic HNSCC remains to be defined. In particular, it is unclear whether HPV modulates the response to cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), which is a mainstay of treatment of advanced HNSCC. To this end, we have examined the sensitivity of HPV-positive and -negative HNSCC models to cetuximab and cytotoxic drugs in vitro and in vivo. In addition, we have stably expressed the HPV oncogenes E6 and E7 in cetuximab-sensitive cancer cell lines to specifically investigate their role in the antibody response. The endogenous HPV status or the expression of HPV oncogenes had no significant impact on cetuximab-mediated suppression of EGFR signaling and proliferation in vitro. Cetuximab effectively inhibited the growth of E6- and E7-expressing tumors grafted in NOD/SCID mice. In support, formalin-fixed, paraffin-embedded tumor samples from cetuximab-treated patients with recurrent or metastatic HNSCC were probed for p16(INK4a) expression, an established biomarker of HPV infection. Response rates (45.5% versus 45.5%) and median progression-free survival (97 versus 92 days) following cetuximab-based therapy were similar in patients with p16(INK4A)-positive and p16(INK4A)-negative tumors. In conclusion, HPV oncogenes do not modulate the anti-EGFR antibody response in HSNCC. Cetuximab treatment should be administered independently of HPV status.
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Pogorzelski
authors.affiliation: Institute of Pathology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Ting
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: T C
authors.initials: TC
authors.lastname: Gauler
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Breitenbuecher
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Vossebein
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Hoffarth
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Markowetz
authors.affiliation: Department of Otorhinolaryngology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Lang
authors.affiliation: Department of Otorhinolaryngology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Bergmann
authors.affiliation: Department of Otorhinolaryngology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Brandau
authors.affiliation: Department of Radiotherapy, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: J A
authors.initials: JA
authors.lastname: Jawad
authors.affiliation: Institute of Pathology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: K W
authors.initials: KW
authors.lastname: Schmid
authors.affiliation: 1] Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany [2] German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schuler
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kasper
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000821:virology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000821:virology; D052162:Human papillomavirus 16 / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism; D030361:Papillomavirus Infections / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000821:virology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab