title: Prognostic Relevance of HPV Infection and p16 Overexpression in Squamous Cell Anal Cancer.
abstract: OBJECTIVE
  Human papillomavirus (HPV) DNA and p16 status have both been reported as prognostic factors in anal cancer, but the prognostic relevance of combined detection and particularly HPV-/p16+ and HPV+/p16- signatures is unknown. We evaluated combined HPV DNA and p16 status as a prognostic factor of treatment response in anal cancer.
  
  
  METHODS
  106 patients treated with radiochemotherapy (RCT+5-FU/MMC) with available paraffin-embedded tumor tissue specimens were evaluated regarding local control (LC) and overall survival (OS) at 5 years. In addition to HPV DNA/p16 status, the influence of age, gender, previous surgery, initial recurrence, T stage, N status, and tumor localization was analyzed.
  
  
  RESULTS
  63 patients were HPV+/p16+, 9 were HPV+/p16-, 11 were HPV-/p16+, and 23 were HPV-/p16-. In univariate analysis, LC was significantly better in patients with T1/2 stage, female gender, and HPV/p16 status. HPV+/p16+ was associated with significantly better LC (88.1%; 95% confidence interval [CI]: 78.89-97.31) compared with HPV-/p16+ (63.6%; 95% CI: 35.18-92.02; P=.021) and especially HPV-/p16- (55.8%; 95% CI: 33.46-78.14; P=.002) but not with HPV+/p16- (77.8%; 95% CI: 50.56-105.04; P=.270). OS was influenced by T stage and LC. HPV+/p16+ patients showed a trend toward better OS compared with HPV-/p16- patients (HPV+/p16+: 81.1%; 95% CI: 70.12-92.08 vs HPV-/p16-: 68.8%; 95%CI: 47.44-90.16; P=.138). On multivariate analysis, T3/4 stage and HPV/p16 status (HPV-/p16+, HPV-/p16- vs HPV+/p16+) predicted poorer LC (T3/4: 50.3% vs T1/2: 86.6%, hazard ratio [HR] 0.22; 95% CI: 0.09-0.53; P<.001; HPV+/p16+ vs HPV-/p16+: HR 4.73; 95% CI: 1.33-16.82; P=.016, and HPV+/p16+ vs HPV-/p16-: HR 6.40; 95% CI: 2.23-18.35; P<.001), whereas local relapse dramatically influenced OS.
  
  
  CONCLUSIONS
  Our data suggest that HPV/p16 signature determines prognosis. HPV+/p16+ patients had the best prognosis, and HPV-/p16+ and HPV-/p16- patients showed the worst outcome and therefore require therapy optimization, particularly given that LC is the most important factor for OS.
authors.affiliation: Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany. Electronic address: sabine.mai@umm.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Mai
authors.affiliation: Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Grit
authors.initials: G
authors.lastname: Welzel
authors.affiliation: Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Martine
authors.initials: M
authors.lastname: Ottstadt
authors.affiliation: Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Lohr
authors.affiliation: Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Sebastin
authors.initials: S
authors.lastname: Severa
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Elena-Sophie
authors.initials: ES
authors.lastname: Prigge
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wentzensen
authors.affiliation: Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Trunk
authors.affiliation: Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Wenz
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Magnus
authors.initials: M
authors.lastname: von Knebel-Doeberitz
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Reuschenbach
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000704:Analysis of Variance; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001005:Anus Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy / Q000821:virology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy / Q000821:virology*; D059248:Chemoradiotherapy / Q000379:methods; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004279:DNA, Viral / Q000032:analysis*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage; D009367:Neoplasm Staging; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000150:complications* / Q000401:mortality; D011379:Prognosis; D012189:Retrospective Studies; D012737:Sex Factors; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D016685:Mitomycin; D005472:Fluorouracil