Prognostic Implication of Persistent Human Papillomavirus Type 16 DNA Detection in Oral Rinses for Human Papillomavirus–Related Oropharyngeal Carcinoma | Dermatology | JAMA Oncology | JAMA Network
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Chaturvedi  AK, Engels  EA, Pfeiffer  RM,  et al.  Human papillomavirus and rising oropharyngeal cancer incidence in the United States.  J Clin Oncol. 2011;29(32):4294-4301.PubMedGoogle ScholarCrossref
Fakhry  C, Zhang  Q, Nguyen-Tan  PF,  et al.  Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma.  J Clin Oncol. 2014;32(30):3365-3373.PubMedGoogle ScholarCrossref
Ang  KK, Harris  J, Wheeler  R,  et al.  Human papillomavirus and survival of patients with oropharyngeal cancer.  N Engl J Med. 2010;363(1):24-35.PubMedGoogle ScholarCrossref
O’Sullivan  B, Huang  SH, Siu  LL,  et al.  Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis.  J Clin Oncol. 2013;31(5):543-550.PubMedGoogle ScholarCrossref
Lin  BM, Wang  H, D’Souza  G,  et al.  Long-term prognosis and risk factors among patients with HPV-associated oropharyngeal squamous cell carcinoma.  Cancer. 2013;119(19):3462-3471.PubMedGoogle Scholar
Fakhry  C, Westra  WH, Li  S,  et al.  Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial.  J Natl Cancer Inst. 2008;100(4):261-269.PubMedGoogle ScholarCrossref
Guo  T, Qualliotine  JR, Ha  PK,  et al.  Surgical salvage improves overall survival for patients with HPV-positive and HPV-negative recurrent locoregional and distant metastatic oropharyngeal cancer.  Cancer. 2015;121(12):1977-1984.PubMedGoogle ScholarCrossref
Vermorken  JB, Stöhlmacher-Williams  J, Davidenko  I,  et al; SPECTRUM investigators.  Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial.  Lancet Oncol. 2013;14(8):697-710.PubMedGoogle ScholarCrossref
Argiris  A, Li  S, Ghebremichael  M,  et al.  Prognostic significance of human papillomavirus in recurrent or metastatic head and neck cancer: an analysis of Eastern Cooperative Oncology Group trials.  Ann Oncol. 2014;25(7):1410-1416.PubMedGoogle ScholarCrossref
Smith  EM, Ritchie  JM, Summersgill  KF,  et al.  Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers.  Int J Cancer. 2004;108(5):766-772.PubMedGoogle ScholarCrossref
Ahn  SM, Chan  JY, Zhang  Z,  et al.  Saliva and plasma quantitative polymerase chain reaction-based detection and surveillance of human papillomavirus-related head and neck cancer.  JAMA Otolaryngol Head Neck Surg. 2014;140(9):846-854.PubMedGoogle ScholarCrossref
Agrawal  Y, Koch  WM, Xiao  W,  et al.  Oral human papillomavirus infection before and after treatment for human papillomavirus 16-positive and human papillomavirus 16-negative head and neck squamous cell carcinoma.  Clin Cancer Res. 2008;14(21):7143-7150.PubMedGoogle ScholarCrossref
D’Souza  G, Gross  ND, Pai  SI,  et al.  Oral human papillomavirus (HPV) infection in HPV-positive patients with oropharyngeal cancer and their partners.  J Clin Oncol. 2014;32(23):2408-2415.PubMedGoogle ScholarCrossref
Koslabova  E, Hamsikova  E, Salakova  M,  et al.  Markers of HPV infection and survival in patients with head and neck tumors.  Int J Cancer. 2013;133(8):1832-1839.PubMedGoogle ScholarCrossref
Chuang  AY, Chuang  TC, Chang  S,  et al.  Presence of HPV DNA in convalescent salivary rinses is an adverse prognostic marker in head and neck squamous cell carcinoma.  Oral Oncol. 2008;44(10):915-919.PubMedGoogle ScholarCrossref
D’Souza  G, Cullen  K, Bowie  J, Thorpe  R, Fakhry  C.  Differences in oral sexual behaviors by gender, age, and race explain observed differences in prevalence of oral human papillomavirus infection.  PLoS One. 2014;9(1):e86023.PubMedGoogle ScholarCrossref
Head and Neck Cancers. NCCN Clinical Practice Guidelines in Oncology 2015; Version 1.2015. Accessed May 27, 2015.
Broutian  TR, He  X, Gillison  ML.  Automated high throughput DNA isolation for detection of human papillomavirus in oral rinse samples.  J Clin Virol. 2011;50(4):270-275.PubMedGoogle ScholarCrossref
Koshiol  J, Rotunno  M, Gillison  ML,  et al.  Assessment of human papillomavirus in lung tumor tissue.  J Natl Cancer Inst. 2011;103(6):501-507.PubMedGoogle ScholarCrossref
Kaplan  EL, Meier  P.  Nonparametric estimation from incomplete observations.  J Am Stat Assoc.1958;53(282):457-481.Google ScholarCrossref
Gillison  ML, Zhang  Q, Jordan  R,  et al.  Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16-negative oropharyngeal cancer.  J Clin Oncol. 2012;30(17):2102-2111.PubMedGoogle ScholarCrossref
Anderson  KS, Gerber  J, D’Souza  G,  et al.  Biologic predictors of serologic responses to HPV in oropharyngeal cancer: the HOTSPOT study [published online June 18, 2015].  Oral Oncol. doi:10.1016/j.oraloncology.2015.05.007.Google Scholar
Herrero  R, Castellsagué  X, Pawlita  M,  et al; IARC Multicenter Oral Cancer Study Group.  Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study.  J Natl Cancer Inst. 2003;95(23):1772-1783.PubMedGoogle ScholarCrossref
Gillison  ML, Alemany  L, Snijders  PJ,  et al.  Human papillomavirus and diseases of the upper airway: head and neck cancer and respiratory papillomatosis.  Vaccine. 2012;30(suppl 5):F34-F54.PubMedGoogle ScholarCrossref
Gillison  ML, Broutian  T, Pickard  RK,  et al.  Prevalence of oral HPV infection in the United States, 2009-2010.  JAMA. 2012;307(7):693-703.PubMedGoogle ScholarCrossref
Chaturvedi  AK, Graubard  BI, Pickard  RK, Xiao  W, Gillison  ML.  High-risk oral human papillomavirus viral load in the US population, National Health and Nutrition Examination Survey 2009-2010.  J Infect Dis. 2014;210(3):441-447.Google ScholarCrossref
Original Investigation
October 2015

Prognostic Implication of Persistent Human Papillomavirus Type 16 DNA Detection in Oral Rinses for Human Papillomavirus–Related Oropharyngeal Carcinoma

Author Affiliations
  • 1Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 2Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
  • 3Tisch Cancer Institute, Head and Neck Oncology Center, Icahn School of Medicine at Mount Sinai Medical Center, New York, New York
  • 4Division of Surgery, Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston
  • 5Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 6Viral Oncology Program, Ohio State University Comprehensive Cancer Center, Columbus
  • 7Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 8Department of Otolaryngology–Head and Neck Surgery, Baylor College of Medicine, Houston, Texas
  • 9Department of Otolaryngology–Head and Neck Surgery, Oregon Health and Science University, Portland, Oregon
  • 10Department of Otolaryngology, Icahn School of Medicine at Mount Sinai Medical Center, New York, New York
  • 11Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 12 Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
  • 13Louisiana State University School of Medicine, New Orleans
JAMA Oncol. 2015;1(7):907-915. doi:10.1001/jamaoncol.2015.2524

Importance  Human papillomavirus–related oropharyngeal carcinoma (HPV-OPC) is increasing in incidence in the United States. Although HPV-OPC has favorable prognosis, 10% to 25% of HPV-OPCs recur. Detection of human papillomavirus (HPV) DNA in oral rinses is associated with HPV-OPC, but its potential as a prognostic biomarker is unclear.

Objective  To determine whether HPV DNA detection in oral rinses after treatment for HPV-OPC is associated with recurrence and survival.

Design, Setting, and Participants  Prospective cohort study of patients with incident HPV-OPC diagnosed from 2009 to 2013 at 4 academic tertiary referral cancer centers in the United States. Oral rinse samples were collected at diagnosis and after treatment (9, 12, 18, and 24 months after diagnosis), and evaluated for HPV DNA. Among an initial cohort of 157 participants with incident HPV-OPC treated with curative intent, 124 had 1 or more posttreatment oral rinses available and were included in this study.

Main Outcomes and Measures  Disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and the association of HPV DNA detection in oral rinses with survival was evaluated using Cox regression analysis.

Results  Oral HPV type 16 (HPV16) DNA was common at diagnosis (67 of 124 participants [54%]). In contrast, oral HPV16 DNA was detected in only 6 participants after treatment (5%), including 5 with HPV16 DNA also detected at diagnosis (persistent oral HPV16 DNA). Two-year DFS and OS were 92% (95% CI, 94%-100%) and 98% (95% CI, 93%-99%). Persistent oral HPV16 DNA was associated with worse DFS (hazard ratio, 29.7 [95% CI, 9.0-98.2]) and OS (hazard ratio, 23.5 [95% CI, 4.7-116.9]). All 5 participants with persistent oral HPV16 DNA developed recurrent disease, 3 with local disease involvement. In contrast, just 9 of 119 participants (8%) without persistent oral HPV16 DNA developed recurrent disease, only 1 (11%) with local disease involvement. Median (range) time from earliest posttreatment oral HPV16 DNA detection to recurrence was 7.0 (3.7-10.9) months.

Conclusions and Relevance  Human papillomavirus type 16 DNA in oral rinses is common at diagnosis but rare after treatment for HPV-OPC. Our data suggest that, although infrequent, persistent HPV16 DNA in posttreatment oral rinses is associated with poor prognosis and is a potential tool for long-term tumor surveillance, perhaps more so for local recurrence.