Carole Fakhry

Improved Survival of Patients With Human Papillomavirus–Positive Head and Neck Squamous Cell Carcinoma in a Prospective Clinical Trial

BACKGROUND The improved prognosis for patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) relative to HPV-negative HNSCC observed in retrospective analyses remains to be confirmed in a prospective clinical trial. METHODS We prospectively evaluated the association of tumor HPV status with therapeutic response and survival among 96 patients with stage III or IV HNSCC of the oropharynx or larynx who participated in an Eastern Cooperative Oncology Group (ECOG) phase II trial and who received two cycles of induction chemotherapy with intravenous paclitaxel and carboplatin followed by concomitant weekly intravenous paclitaxel and standard fractionation radiation therapy. The presence or absence of HPV oncogenic types in tumors was determined by multiplex polymerase chain reaction (PCR) and in situ hybridization. Two-year overall and progression-free survival for HPV-positive and HPV-negative patients were estimated by Kaplan-Meier analysis. The relative hazard of mortality and progression for HPV-positive vs HPV-negative patients after adjustment for age, ECOG performance status, stage, and other covariables was estimated by use of a multivariable Cox proportional hazards model. All statistical tests were two-sided. RESULTS Genomic DNA of oncogenic HPV types 16, 33, or 35 was located within tumor cell nuclei of 40% (95% confidence interval [CI] = 30% to 50%) of patients with HNSCC of the oropharynx or larynx by in situ hybridization and PCR. Compared with patients with HPV-negative tumors, patients with HPV-positive tumors had higher response rates after induction chemotherapy (82% vs 55%, difference = 27%, 95% CI = 9.3% to 44.7%, P = .01) and after chemoradiation treatment (84% vs 57%, difference = 27%, 95% CI = 9.7% to 44.3%, P = .007). After a median follow-up of 39.1 months, patients with HPV-positive tumors had improved overall survival (2-year overall survival = 95% [95% CI = 87% to 100%] vs 62% [95% CI = 49% to 74%], difference = 33%, 95% CI = 18.6% to 47.4%, P = .005, log-rank test) and, after adjustment for age, tumor stage, and ECOG performance status, lower risks of progression (hazard ratio [HR] = 0.27, 95% CI = 0.10 to 0.75), and death from any cause (HR = 0.36, 95% CI = 0.15 to 0.85) than those with HPV-negative tumors. CONCLUSION For patients with HNSCC of the oropharynx, tumor HPV status is strongly associated with therapeutic response and survival.

Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1

The mutational profile of head and neck cancer is complex and may pose challenges to the development of targeted therapies. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.

Clinical Implications of Human Papillomavirus in Head and Neck Cancers

Human papillomavirus (HPV) is now recognized to play a role in the pathogenesis of a subset of head and neck squamous cell carcinomas (HNSCCs), particularly those that arise from the lingual and palatine tonsils within the oropharynx. High-risk HPV16 is identified in the overwhelming majority of HPV-positive tumors, which have molecular-genetic alterations indicative of viral oncogene function. Measures of HPV exposure, including sexual behaviors, seropositivity to HPV16, and oral, high-risk HPV infection, are associated with increased risk for oropharyngeal cancer. HPV infection may be altering the demographics of HNSCC patients, as these patients tend to be younger, nonsmokers, and nondrinkers. There is sufficient evidence to conclude that a diagnosis of HPV-positive HNSCC has significant prognostic implications; these patients have at least half the risk of death from HNSCC when compared with the HPV-negative patient. The HPV etiology of these tumors may have future clinical implications for the diagnosis, therapy, screening, and prevention of HNSCC.

Epidemiology of Human Papillomavirus–Positive Head and Neck Squamous Cell Carcinoma

Human papillomavirus (HPV) is now established as the principal cause of an increase in incidence of a subset of head and neck squamous cell cancers (HNCs) in numerous geographic regions around the world. Further study of the epidemiology of HPV-positive HNC will be critical to the development and implementation of public health interventions to reverse these global incidence trends. Here, recent data are reviewed to provide insight into several topics, including incidence trends and projections for HPV-positive HNC; the worldwide HPV-attributable fraction; sex disparities in cancer risk; the epidemiology of oral HPV infection; the latency period between infection and cancer; the potential impact of prophylactic HPV vaccination; and prospects for secondary prevention through screening for oral HPV infection or seroreactivity to viral antigens. The identification of a single necessary cause for any cancer provides a rare and perhaps extraordinary opportunity for cancer prevention.

Human Papillomavirus and Overall Survival After Progression of Oropharyngeal Squamous Cell Carcinoma

PURPOSE Risk of cancer progression is reduced for patients with human papillomavirus (HPV) -positive oropharynx cancer (OPC) relative to HPV-negative OPC, but it is unknown whether risk of death after progression is similarly reduced. PATIENTS AND METHODS Patients with stage III-IV OPC enrolled onto Radiation Therapy Oncology Group trials 0129 or RTOG 0522 who had known tumor p16 status plus local, regional, and/or distant progression after receiving platinum-based chemoradiotherapy were eligible for a retrospective analysis of the association between tumor p16 status and overall survival (OS) after disease progression. Rates were estimated by Kaplan-Meier method and compared by log-rank; hazard ratios (HRs) were estimated by Cox models. Tests and models were stratified by treatment protocol. RESULTS A total of 181 patients with p16-positive (n = 105) or p16-negative (n = 76) OPC were included in the analysis. Patterns of failure and median time to progression (8.2 v 7.3 months; P = .67) were similar for patients with p16-positive and p16-negative tumors. After a median follow-up period of 4.0 years after disease progression, patients with p16-positive OPC had significantly improved survival rates compared with p16-negative patients (2-year OS, 54.6% v 27.6%; median, 2.6 v 0.8 years; P < .001). p16-positive tumor status (HR, 0.48; 95% CI, 0.31 to 0.74) and receipt of salvage surgery (HR, 0.48; 95% CI; 0.27 to 0.84) reduced risk of death after disease progression whereas distant versus locoregional progression (HR, 1.99; 95% CI, 1.28 to 3.09) increased risk, after adjustment for tumor stage and cigarette pack-years at enrollment. CONCLUSION Tumor HPV status is a strong and independent predictor of OS after disease progression and should be a stratification factor for clinical trials for patients with recurrent or metastatic OPC.

Six-month natural history of oral versus cervical human papillomavirus infection

Human papillomavirus (HPV) infection is etiologically associated with a subset of oral cancers, and yet, the natural history of oral HPV infection remains unexplored. The feasibility of studying oral HPV natural history was evaluated by collecting oral rinse samples on 2 occasions at a 6‐month interval from 136 HIV‐positive and 63 HIV‐negative participants. Cervical vaginal lavage samples were concurrently collected for comparison. HPV genomic DNA was detected in oral and cervical samples by consensus primer PCR and type‐specified for 37 HPV types. The six‐month cumulative prevalence of oral HPV infection was significantly less than for cervical infection (p < 0.0001). HIV‐positive women were more likely than HIV‐negative women to have an oral (33 vs. 15%, p = 0.016) or cervical (78 vs. 51%, p < 0.001) infection detected. Oral HPV infections detected at baseline were as likely as cervical infections to persist to 6 months among HIV‐negative (60% vs. 51%, p = 0.70) and HIV‐positive (55% vs. 63%, p = 0.27) women. Factors that independently elevated odds for oral HPV persistence differed from cervical infection and included current smoking (OR = 8, 95% CI = 1.3–53), age above 44 years (OR = 20, 95% CI = 4.1–83), CD4 < 500 (OR = 6, 95% CI = 1.1–26), use of HAART therapy (OR = 12, 95% CI = 1.0–156), and time on HAART therapy (trend p = 0.04). The rate of oral HPV infections newly detected at follow‐up was significantly lower than cervical infection among HIV‐positive (p < 0.001) and HIV‐negative women (p < 0.001). Our study not only demonstrates that it is feasible to study the natural history of oral HPV infection with oral rinse sampling, but also indicates that oral and cervical HPV natural history may differ.

The clinical impact of HPV tumor status upon head and neck squamous cell carcinomas

Human papillomavirus (HPV) is etiologically responsible for a distinct subset of head and neck squamous cell cancers (HNSCCs). HPV-positive HNSCCs (HPV-HNSCCs) most commonly arise from the oropharynx and are responsible for the increasing incidence of oropharyngeal SCC (OSCC) in the United States (US) and abroad. HPV-positive OSCC (HPV-OSCC) has a unique demographic and risk factor profile and tumor biology. HPV-OSCC patients tend to be white, younger, and have a higher cumulative exposure to sexual behaviors as compared with HPV-negative OSCC patients. HPV-positive tumor status also significantly improves survival, and is indeed the single strongest prognostic factor for OSCC. The mechanisms that underlie the improved prognosis conferred by HPV-positive disease are unknown. The purpose of this review is to describe the clinical impact of HPV status in HNSCC, particularly in OSCC, both in terms of the unique clinic-demographic profile and prognostic implications.

Associations between oral HPV16 infection and cytopathology: evaluation of an oropharyngeal "pap-test equivalent" in high-risk populations.

Human papillomavirus (HPV) is responsible for the rising incidence of oropharyngeal squamous cell cancers (OSCC) in the United States, and yet, no screening strategies have been evaluated. Secondary prevention by means of HPV detection and cervical cytology has led to a decline in cervical cancer incidence in the United States. Here, we explored an analogous strategy by evaluating associations between HPV16 infection, cytopathology, and histopathology in two populations at elevated risk for OSCCs. In the first, a cross-sectional study population (PAP1), cytology specimens were collected by means of brush biopsy from patients presenting with oropharyngeal abnormalities. In the second (PAP2), a nested case–control study, bilateral tonsillar cytology samples were collected at 12-month intervals from HIV-infected individuals. The presence of cytopathologic abnormality in HPV16-positive tonsil brush biopsies (cases) was compared with HPV16-negative samples (controls) matched on age and gender. HPV16 was detected in samples by consensus primer PCR and/or type-specific PCR. Univariate logistic regression was used to evaluate associations. In PAP1, HPV16 alone (OR: 6.1, 95% CI: 1.6–22.7) or in combination with abnormal cytology (OR: 20, 95% CI: 4.2–95.4) was associated with OSCC. In PAP2, 4.7% (72 of 1,524) of tonsillar cytology specimens from HIV-infected individuals without oropharyngeal abnormalities were HPV16 positive. Tonsillar HPV16 infection was not associated with atypical squamous cells of unknown significance (ASCUS), the only cytologic abnormality identified. Therefore, HPV16 was associated with OSCCs among individuals with accessible oropharyngeal lesions but not with cytologic evidence of dysplasia among high-risk individuals without such lesions. An oropharyngeal Pap-test equivalent may not be feasible, likely due to limitations in sampling the relevant tonsillar crypt epithelium. Cancer Prev Res; 4(9); 1378–84. ©2011 AACR.

Relationship between prevalent oral and cervical human papillomavirus infections in human immunodeficiency virus-positive and -negative women.

ABSTRACT Human papillomavirus (HPV) is an etiologic agent for both oropharyngeal and cervical cancers, yet little is known about the interrelationship between oral and cervical HPV infections. Therefore, we compared the prevalences and type distributions of oral and cervical HPV infections and evaluated infection concordance in a cross-sectional study within the Womens Interagency HIV Study cohort. Oral rinse and cervical-vaginal lavage samples were concurrently collected from a convenience sample of 172 human immunodeficiency virus (HIV)-positive and 86 HIV-negative women. HPV genomic DNA was detected by PGMY09/11 L1 consensus primer PCR and type specified by reverse line blot hybridization for 37 HPV types and β-globin. Only 26 of the 35 HPV types found to infect the cervix were also found within the oral cavity, and the type distribution for oral HPV infections appeared distinct from that for cervical infections (P < 0.001). Oral HPV infections were less common than cervical infections for both HIV-positive (25.2% versus 76.9%, P < 0.001) and HIV-negative (9.0% versus 44.9%, P < 0.001) women. Oral HPV infections were more common among women with a cervical HPV infection than those without a cervical HPV infection (25.5% versus 7.9%, P = 0.002). The majority of women (207; 93.7%) did not have simultaneous oral and cervical infections by the same HPV type; however, the number of women who did (14; 6.3%) was significantly greater than would be expected by chance (P = 0.0002). Therefore, the oral and cervical reservoirs for HPV infection are likely not entirely independent of one another.

Differences in oral sexual behaviors by gender, age, and race explain observed differences in prevalence of oral human papillomavirus infection.

Purpose This study explores whether gender, age and race differences in oral sexual behavior account for the demographic distribution of oral human papillomavirus infection (HPV) and HPV-positive oropharyngeal cancer (HPV-OSCC) Methods This analysis included 2,116 men and 2,140 women from NHANES (2009–10) who answered a behavioral questionnaire and provided an oral-rinse sample for HPV detection. Weighted prevalence estimates and prevalence ratios (PR) were calculated for sexual behaviors and oral HPV infection by gender, age-cohort (20–29, 30–44, 45–59, 60–69), and race, and contrasted with incidence rate ratios (IRR) of OSCC from SEER 2009. Multivariate logistic regression was used to evaluate predictors of oral sexual behavior and oral HPV16 infection. Results Differences in oral sexual behavior were observed by gender, age-cohort and race. Most men (85.4%) and women (83.2%) had ever performed oral sex, but men had more lifetime oral and vaginal sexual partners and higher oral HPV16 prevalence than women (each p<0.001). 60–69 year olds (yo) were less likely than 45–59 or 30–44 (yo) to have performed oral sex (72.7%, 84.8%, and 90.3%, p<0.001), although oral HPV16 prevalence was similar. Prevalence ratios (PR) of ever oral sex in men vs. women (PR = 1.03), and 45–59 vs. 30–44 year-old men (PR = 0.96) were modest relative to ratios for oral HPV16 infection (PRs = 1.3–6.8) and OSCC (IRR = 4.7–8.1). In multivariate analysis, gender, age-cohort, and race were significant predictors of oral sexual behavior. Oral sexual behavior was the primary predictor of oral HPV16 infection; once this behavior was adjusted for, age-cohort and race were no longer associated with oral HPV16. Conclusion There are differences in oral sexual behaviors when considering gender, age-cohort and race which explain observed epidemiologic differences in oral HPV16 infection across these groups.