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Novel preventive interventions are needed to address the rising incidence of human papillomavirus (HPV)-mediated oropharyngeal cancer (HPV+ OPC). This pilot study evaluated the feasibility of a stepped, behavioral and biological screening program for oral oncogenic HPV infection, an intermediate HPV+ OPC outcome.This was a cross-sectional, feasibility study. Eligible 45–74 years old adults identified from three clinical research registries were administered a behavioral risk survey (step 1). Participant tobacco use and sexual behavior history were translated into a quantifiable risk of oral oncogenic HPV DNA, according to prior National Health and Nutrition Examination Survey analyses. Females with >2% risk and males with >7% risk were offered biological screening for oral oncogenic HPV DNA (step 2) via an oral rinse and gargle specimen.A total of 292 individuals were contacted, but only 144 (49%) were reached. Among these, 56 individuals (19%) were uninterested and 18 (13%) were ineligible. Seventy individuals began the survey and 66 completed it (step 1), among whom 46 were classified as low-risk. Among the remaining 20 participants classified as high-risk for an oral oncogenic HPV infection, 5% were current smokers and the median participant had performed oral sex on 10 unique partners. During step 2 (biological screening), 45% (9/20) completed testing, all of whom tested negative for oral oncogenic HPV DNA.In this pilot of a stepped, oral oncogenic HPV screening program, enrollment and study completion were suboptimal. These barriers to screening should be characterized and addressed before reevaluating the feasibility of this program.Prevention Relevance:Novel preventive interventions are needed to address the rising incidence of HPV+ OPC. In this feasibility study, we characterized barriers to a two-step, behavioral and biological screening program for oral oncogenic HPV infection, an intermediate outcome for HPV+ OPC.

Oropharyngeal squamous cell carcinoma (OPSCC), largely fueled by the human papillomavirus (HPV), has a complex biological and immunologic phenotype. Although HPV/p16 status can be used to stratify OPSCC patients as a function of survival, it remains unclear what drives an improved treatment response in HPV-associated OPSCC and whether targetable biomarkers exist that can inform a precision oncology approach. We analyzed OPSCC patients treated between 2000 and 2016 and correlated locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) with conventional clinical parameters, risk parameters generated using deep-learning algorithms trained to quantify tumor-infiltrating lymphocytes (TILs) (OP-TIL) and multinucleated tumor cells (MuNI) and targeted transcriptomics. P16 was a dominant determinant of LRC, DFS and OS, but tobacco exposure, OP-TIL and MuNI risk features correlated with clinical outcomes independent of p16 status and the combination of p16, OP-TIL and MuNI generated a better stratification of OPSCC risk compared to individual parameters. Differential gene expression (DEG) analysis demonstrated overlap between MuNI and OP-TIL and identified genes involved in DNA repair, oxidative stress response and tumor immunity as the most prominent correlates with survival. Alteration of inflammatory/immune pathways correlated strongly with all risk features and oncologic outcomes. This suggests that development of OPSCC consists of an intersection between multiple required and permissive oncogenic and immunologic events which may be mechanistically linked. The strong relationship between tumor immunity and oncologic outcomes in OPSCC regardless of HPV status may provide opportunities for further biomarker development and precision oncology approaches incorporating immune checkpoint inhibitors for maximal anti-tumor efficacy.

Oropharyngeal cancer (OPC) will be among the most common cancers in men by 2045 due to a rapid rise in human papillomavirus (HPV)-related OPC. Those who survive their cancer often suffer life-long treatment effects and early death. HPV vaccination could prevent virtually all HPV-related cancers but is not an effective preventive strategy for those already exposed. Without a dramatic increase in vaccine uptake in the U.S., HPV vaccination will have a negligible effect on OPC incidence through 2045 and no substantial impact until 2060. Additionally, targeted screening for earlier diagnosis may soon be feasible for those inadequately protected by vaccination.PubMed search for English-language articles related to incidence, screening, and prevention of HPV-related malignancies, focused on OPC in the U.S.HPV-related OPC incidence will continue to increase for the foreseeable future with prophylactic vaccination offering no substantial public health impact for decades. Consequently, we must rapidly increase vaccination rates and develop screening methods to identify high-risk individuals. Such individuals would be eligible for potential preventive treatments and screening to diagnose early-stage HPV-related OPC allowing less morbid treatments. These methods will bridge the population into an era of decreasing incidence after vaccination takes effect.

This study investigated the association of hearing loss and tinnitus with overall health-related quality of life (HRQoL) among long-term oropharyngeal cancer (OPC) survivors.This study included OPC survivors treated between 2000 and 2013 and surveyed from September 2015 to July 2016. Hearing loss and tinnitus were measured by asking survivors to rate their "difficulty with hearing loss and/or ringing in the ears" from 0 (not present) to 10 (as bad as you can imagine). Hearing loss and tinnitus scores were categorized as follows: 0 for none, 1-4 for mild, and 5-10 for moderate to severe. The primary outcome was the mean score of MD nderson Symptom Inventory HeadNeck module interference component as a HRQoL surrogate dichotomized as follows: 0 to 4 for none to mild and 5 to 10 for moderate to severe interference.Among 880 OPC survivors, 35.6% (314), reported none, 39.3% (347) reported mild, and 25.1% (221) reported moderate to severe hearing loss and tinnitus. On multivariable analysis, mild (OR, 5.83; 95% CI; 1.48-22.88; p = 0.012) and moderate (OR, 30.01; 95% CI; 7.96-113.10; p 0.001) hearing loss and tinnitus were associated with higher odds of reporting moderate to severe symptom interference scores in comparison to no hearing loss and tinnitus. This association of hearing dysfunction was consistent with all domains of HRQoL.Our findings provide preliminary evidence to support the need for continued audiological evaluations and surveillance to detect hearing dysfunction, to allow for early management and to alleviate the long-term impact on QoL.

Background:High-risk human papillomavirus (HR-HPV) infection is a risk factor for anal cancer, yet no anal cancer screening guidelines exist for women with lower genital tract HPV-related disease. We sought to describe the prevalence of anal HR-HPV or cytologic abnormalities in such women.Methods:This cross-sectional study was performed between October 2018 and December 2021. Inclusion criteria were ≥21 years of age and a prior diagnosis of high-grade dysplasia/cancer of the cervix, vagina, or vulva. Participants underwent anal cytology and anal/cervicovaginal HR-HPV testing. Women with abnormal anal cytology were referred for high-resolution anoscopy (HRA).Results:324 evaluable women were enrolled. Primary diagnosis was high-grade dysplasia/cancer of the cervix (77%), vagina (9%), and vulva (14%). Anal HR-HPV was detected in 92 patients (28%) and included HPV-16 in 24 (26%), HPV-18 in 6 (7%), and other HR-HPV types in 72 (78%) patients. Anal cytology was abnormal in 70 patients (23%) and included atypical squamous cells of undetermined significance (80%), low-grade squamous intraepithelial lesion (9%), high-grade intraepithelial lesion (HSIL; 1%), and atypical squamous cells-cannot rule out HSIL (10%). Of these patients, 55 (79%) underwent HRA. Anal biopsies were performed in 14 patients: 2 patients had anal intraepithelial neoplasia (AIN) 2/3, 1 patient had AIN 1, and 11 patients had negative biopsies. Both patients with AIN 2/3 had a history of cervical dysplasia.Conclusions:Our results suggest an elevated risk of anal HR-HPV infection and cytologic abnormalities in women with lower genital tract dysplasia/cancer.Impact:These results add to the growing body of evidence suggesting the need for evaluation of screening methods for anal dysplasia/cancer in this patient population to inform evidence-based screening recommendations.

Supplementary Table from A Cross-Sectional Study of the Prevalence of Anal Dysplasia among Women with High-Grade Cervical, Vaginal, and Vulvar Dysplasia or Cancer: The PANDA Study

Supplementary Tables 1-3 from A Sex-Specific Association between a 15q25 Variant and Upper Aerodigestive Tract Cancers

Patient selection flowchart

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Propensity score distribution between case and control group

Background: The incidence of oropharyngeal cancer is rising rapidly, with the majority of cases being attributable to human papillomavirus (HPV). Despite the availability of a vaccine, rates of HPV vaccination among Texas youth are low. The healthcare cost of oropharyngeal cancer in Texas is unknown. The aims of this study were to estimate the first 2-year cost of treating new cases of oropharyngeal cancer and determine the predictors of oropharyngeal cancer treatment cost in Texas.Methods: This study included a retrospective cohort of 467 Texas patients with commercial insurance claims data with oropharyngeal cancer diagnosed from 2011 to 2014 and a control group of 467 noncancer patients obtained with propensity score matching. Total healthcare cost during the first 2 years after the index date was measured. A generalized linear model was used to identify predictors of monthly cost during the 2 years after the index date.Results: The mean differential adjusted healthcare cost for oropharyngeal cancer cases was $139,749 in the first 2 years. The mean adjusted monthly cost in the first 2 years was $6,693 for cases and $870 for controls. Age, comorbidity, mental health, prediagnostic healthcare cost, and time index were significant predictors of monthly cost.Conclusions: Medical care cost was about $140,000 in the first 2 years after diagnosis of oropharyngeal cancer among commercially insured patients in Texas.Impact: The cost estimates provide important parameters for development of decision-analytic models to inform decision makers about the potential value of initiatives for increasing the HPV immunization rate in the state. Cancer Epidemiol Biomarkers Prev; 26(9); 1443–9. ©2017 AACR.

Association of frequency of marijuana use, duration of marijuana, and joint years of marijuana use with oropharyngeal and oral tongue cancers

Background: Recent studies reported associations of the relative telomere length (RTL) and TERT variants with risk of several cancers, which have not been comprehensively investigated in squamous cell carcinoma of the head and neck (SCCHN).Methods: We detected RTL in peripheral blood lymphocytes and genotyped six selected functional single-nucleotide polymorphisms (SNP) of the TERT gene in 888 SCCHN cases and 885 cancer-free controls of non-Hispanic whites.Results: Overall, we did not observe significant associations between RTL and SCCHN risk (adjusted OR = 0.97; 95% CI = 0.80–1.17 for below versus above the median; Ptrend = 0.618) nor between the six TERT SNPs and SCCHN risk. We also found no associations between RTL and TERT SNPs.Conclusions: Our results suggest that RTL and TERT functional polymorphisms may not play a major role in the etiology of SCCHN. Large prospective studies are needed to validate our findings.Impact: Although our results suggest no association among RTL, TERT functional polymorphisms, and SCCHN risk, this study may contribute to future meta-analysis. Cancer Epidemiol Biomarkers Prev; 20(12); 2642–5. ©2011 AACR.

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Purpose: Human cell lines are useful for studying cancer biology and preclinically modeling cancer therapy, but can be misidentified and cross-contamination is unfortunately common. The purpose of this study was to develop a panel of validated head and neck cell lines representing the spectrum of tissue sites and histologies that could be used for studying the molecular, genetic, and phenotypic diversity of head and neck cancer.Methods: A panel of 122 clinically and phenotypically diverse head and neck cell lines from head and neck squamous cell carcinoma, thyroid cancer, cutaneous squamous cell carcinoma, adenoid cystic carcinoma, oral leukoplakia, immortalized primary keratinocytes, and normal epithelium was assembled from the collections of several individuals and institutions. Authenticity was verified by carrying out short tandem repeat analysis. Human papillomavirus (HPV) status and cell morphology were also determined.Results: Eighty-five of the 122 cell lines had unique genetic profiles. HPV-16 DNA was detected in 2 cell lines. These 85 cell lines included cell lines from the major head and neck primary tumor sites, and close examination shows a wide range of in vitro phenotypes.Conclusions: This panel of 85 genomically validated head and neck cell lines represents a valuable resource for the head and neck cancer research community that can help advance understanding of the disease by providing a standard reference for cell lines that can be used for biological as well as preclinical studies. Clin Cancer Res; 17(23); 7248–64. ©2011 AACR.

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Background: The incidence of oropharyngeal and oral tongue cancers has increased over the last 20 years which parallels increased use of marijuana among individuals born after 1950.Methods: A pooled analysis was conducted comprising individual-level data from nine case–control studies from the United States and Latin America in the INHANCE consortium. Self-reported information on marijuana smoking, demographic, and behavioral factors was obtained from 1,921 oropharyngeal cases, 356 oral tongue cases, and 7,639 controls.Results: Compared with never marijuana smokers, ever marijuana smokers had an elevated risk of oropharyngeal [adjusted OR (aOR), 1.24; 95% confidence interval (CI): 1.06–1.47] and a reduced risk of oral tongue cancer (aOR, 0.47; 95% CI, 0.29, 0.75). The risk of oropharyngeal cancer remained elevated among never tobacco and alcohol users. The risk of oral tongue cancer was reduced among never users of tobacco and alcohol. Sensitivity analysis adjusting for potential confounding by HPV exposure attenuated the association of marijuana use with oropharyngeal cancer (aOR, 0.99; 95% CI, 0.71–1.25), but had no effect on the oral tongue cancer association.Conclusions: These results suggest that the association of marijuana use with head and neck carcinoma may differ by tumor site.Impact: The associations of marijuana use with oropharyngeal and oral tongue cancer are consistent with both possible pro- and anticarcinogenic effects of cannabinoids. Additional work is needed to rule out various sources of bias, including residual confounding by HPV infection and misclassification of marijuana exposure. Cancer Epidemiol Biomarkers Prev; 23(1); 160–71. ©2013 AACR.

Supplemental Figure Legends; Supplemental Table 1. Three-digit zip codes for Texas regions; Supplemental Table 2. Procedure codes for identifying OPC treatment modalities; Supplemental Table 3. Summary of the time (days) to initiation of the first modality of therapy during the 2-year follow-up; Supplemental Table 4. Generalized linear model with log link function for the mean monthly cost for the first 2 years after the index date between cases and controls; Supplemental Table 5. Unadjusted and adjusted cost during the first 1 year after the index date for OPC patients and matched controls

Supplementary Tables 1-4, 9-16. Supplemental Table 1. Association results of SNPs with SCCHN risk with P-value {less than or equal to} 1x10-3 in the discovery dataset or with P-value {less than or equal to} 5x10-8 in the meta-analysis. Supplemental Table 2. Association results of SNPs with oral cancer risk with P-value {less than or equal to} 1x10-3 in the discovery dataset or with P-value {less than or equal to} 5x10-8 in the meta-analysis. Supplemental Table 3. Association results of SNPs with oropharynx cancer risk with P-value {less than or equal to} 1x10-3 in the discovery dataset or with P-value {less than or equal to} 5x10-8 in the meta-analysis. Supplemental Table 4. Association results of SNPs with hypopharynx and larynx cancer risk with P-value {less than or equal to} 1x10-3 in the discovery dataset or with P-value {less than or equal to} 5x10-8 in the meta-analysis. Supplemental Table 9. Association results of previously reported SNPs in the discovery dataset. Supplemental Table 10. Association results of HLA variants with overal SCCHN cancer risk with P-value {less than or equal to} 0.05 in the MDACC data. Supplemental Table 11. Association results of HLA variants with oral cancer risk with P-value {less than or equal to} 0.05 in the MDACC data. Supplemental Table 12. Association results of HLA variants with oropharyngeal cancer risk with P-value {less than or equal to} 0.05 in the MDACC data. Supplemental Table 13. Association results of HLA variants with hypo-pharyngeal and laryngeal cancer risk with P-value {less than or equal to} 0.05 in the MDACC data. Supplemental Table 14. Associations of DRB1*1301-DQA1*0103-DQB1*0603 haplotype with the risks of SCCHN and subtyp tumors. Supplementary Table 15. Correlations between standardized polygenic risk score (PRS) and the risk of oropharyngeal cancer risk in the MDACC study and OncoArray study. Supplementary table 16. Function prediction for SNPs with validated P {less than or equal to} 0.05 and meta-analysis P-value {less than or equal to} 5x10-8 with Haploreg 4.1.

Description for sensitivity analysis to adjust for potential unmeasured confounding

The adjusted 2-year cost distributions between case and controls

The unadjusted cost of pre- and post-period between cases and controls

Limit of Detection of HPV serologic assay. Serial dilutions were performed with increasing dilution of a serum positive for E7-GST Abs using the magnetic bead RAPID ELISA assay. Error bars are calculated using 1 SD of the mean.

To identify genetic variants for risk of squamous cell carcinoma of the head and neck (SCCHN), we conducted a two-phase genome-wide association study consisting of 7,858,089 SNPs in 2,171 cases and 4,493 controls of non-Hispanic white, of which, 434,839 typed and 7,423,250 imputed SNPs were used as the discovery. SNPs with P < 1 × 10−3 were further validated in the OncoArray study of oral and pharynx cancer (5,205 cases and 3,232 controls of European ancestry) from databases of Genotypes and Phenotypes. Meta-analysis of the discovery and replication studies identified one novel locus 6p22.1 (P = 2.96 × 10−9 for the leading rs259919) and two cancer susceptibility loci 6p21.32 (rs3135001, HLA-DQB1) and 6p21.33 (rs1265081, CCHCR1) associated with SCCHN risk. Further stratification by tumor site revealed four known cancer loci (5p15.33, 6p21.32, 6p21.33, and 2p23.1) associated with oral cavity cancer risk and oropharyngeal cancer risk, respectively. In addition, one novel locus 18q22.2 (P = 2.54 × 10−9 for the leading SNP rs142021700) was identified for hypopharynx and larynx cancer risk. For SNPs in those reported or novel loci, we also performed functional annotations by bioinformatics prediction and expression quantitative trait loci analysis. Collectively, our identification of four reported loci (2p23.1, 5p15.33, 6p21.32, and 6p21.33) and two novel loci (6p22.1 and 18q22.2) for SCCHN risk highlight the importance of human leukocyte antigen loci for oropharyngeal cancer risk, suggesting that immunologic mechanisms are implicated in the etiology of this subset of SCCHN.Significance:Two novel risk loci for SCCHN in non-Hispanic white individuals highlight the importance of immunologic mechanism in the disease etiology.

Purpose: Oropharyngeal carcinoma positive for human papillomavirus type 16 (HPV16) has a significantly better prognosis than oropharyngeal carcinoma unrelated to HPV. Within HPV16-positive oropharyngeal carcinoma, biomarkers of prognosis are urgently needed to individualize care. We hypothesized that serum antibodies specific to HPV16, the major HPV type causing oropharyngeal carcinoma, have biologic relevance and are potential biomarkers for improved prognosis among patients with HPV16-positive oropharyngeal carcinoma.Experimental Design: IgG antibodies to the HPV16 antigens E1, E4-E7, L1, L2, and the N-terminal and C-terminal fragments of E2 (NE2, CE2) were quantified using a custom programmable enzyme-linked immunosorbent assay. Sera were obtained at diagnosis from 209 oropharyngeal carcinoma patients (96 HPV16-positive). The ratios of median fluorescent intensity (MFI) for each antigen to MFI for control GST protein were determined. Kaplan–Meier survival curves and Cox proportional hazards regression were used to determine survival differences between groups. ROC curves were used to determine the best combination of E antibodies to predict disease recurrence.Results: E1, NE2, and E6 antibody positivity were all strongly associated with improved overall and progression-free survival in the entire cohort and in patients with known HPV16-positive tumors (P < 0.05). For both overall and progression-free survival among HPV-positive patients, hazard ratios were 0.2 for NE2, 0.3 for E1, and 0.3 for E6 antibody positivity.Conclusions: We identified three HPV16-specific antibodies that are associated with improved overall and progression-free survival in patients with HPV-related oropharyngeal carcinoma. These results suggest that differential serologic responses in patients may reflect differential biologic processes within the host and tumor and may have prognostic value. Clin Cancer Res; 21(12); 2861–9. ©2015 AACR.

Purpose: Radiotherapy plays an integral role in the treatment of head and neck squamous cell carcinoma (HNSCC). Although proteins involved in DNA repair may predict HNSCC response to radiotherapy, none has been validated in this context. We examined whether differential expression of double-strand DNA break (DSB) repair proteins in HNSCC, the chief mediators of DNA repair following irradiation, predict for treatment outcomes.Experimental Design: Archival HNSCC tumor specimens (n = 89) were assembled onto a tissue microarray and stained with antibodies raised against 38 biomarkers. The biomarker set was enriched for proteins involved in DSB repair, in addition to established mechanistic markers of radioresistance. Staining was correlated with treatment response and survival alongside established clinical and pathologic covariates. Results were validated in an independent intramural cohort (n = 34).Results: Ku80, a key mediator of DSB repair, correlated most closely with clinical outcomes. Ku80 was overexpressed in half of all tumors, and its expression was independent of all other covariates examined. Ku80 overexpression was an independent predictor for both locoregional failure and mortality following radiotherapy (P < 0.01). The predictive power of Ku80 overexpression was confined largely to HPV-negative HNSCC, where it conferred a nine-fold greater risk of death at two years.Conclusions: Ku80 overexpression is a common feature of HNSCC, and is a candidate DNA repair-related biomarker for radiation treatment failure and death, particularly in patients with high-risk HPV-negative disease. It is a promising, mechanistically rational biomarker to select individual HPV-negative HNSCC patients for strategies to intensify treatment. Clin Cancer Res; 17(7); 2035–43. ©2011 AACR.

Supplementary Figures S1-S3; Supplementary Tables S1-S4.

Background: Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx, and esophagus) in women (OR = 1.24, P = 0.003) with little effect in men (OR = 1.04, P = 0.35).Methods: In a coordinated genotyping study within the International Head and Neck Cancer Epidemiology (INHANCE) consortium, we have sought to replicate these findings in an additional 4,604 cases and 6,239 controls from 10 independent UADT cancer case–control studies.Results: rs16969968 was again associated with UADT cancers in women (OR = 1.21, 95% CI = 1.08–1.36, P = 0.001) and a similar lack of observed effect in men [OR = 1.02, 95% CI = 0.95–1.09, P = 0.66; P-heterogeneity (Phet) = 0.01]. In a pooled analysis of the original and current studies, totaling 8,572 UADT cancer cases and 11,558 controls, the association was observed among females (OR = 1.22, 95% CI = 1.12–1.34, P = 7 × 10−6) but not males (OR = 1.02, 95% CI = 0.97–1.08, P = 0.35; Phet = 6 × 10−4). There was little evidence for a sexdifference in the association between this variant and cigarettes smoked per day, with male and female rs16969968 variant carriers smoking approximately the same amount more in the 11,991 ever smokers in the pooled analysis of the 14 studies (Phet = 0.86).Conclusions: This study has confirmed a sex difference in the association between the 15q25 variant rs16969968 and UADT cancers.Impact: Further research is warranted to elucidate the mechanisms underlying these observations. Cancer Epidemiol Biomarkers Prev; 20(4); 658–64. ©2011 AACR.

This study evaluated the detection accuracy of the Cobas human papillomavirus (HPV) assay for high-risk human papillomavirus (hrHPV) and HPV-16 in head and neck fine-needle aspiration (FNA) specimens with squamous cell carcinoma.Head and neck FNA biopsy specimens from 2012 to 2020 were retrospectively collected. Cobas HPV testing was performed on 90 FNA specimens with valid Cervista HPV testing results. Results of Cobas HPV and Cervista HPV assays were compared. A Linear Array or SPF10-LiPA25 HPV genotyping assay resolved cases with discrepant results. The κ value and accuracy of Cobas HPV testing were calculated. The accuracy of the Cobas HPV assay was also determined in 42 FNA needle-rinse specimens.Cobas HPV was positive in 82% of the FNA specimens (74 of 90). The concordance between Cobas HPV and Cervista HPV test results was 88.9% (80 of 90) with substantial agreement (κ = 0.669; 95% CI, 0.481-0.856). With HPV genotyping confirmation in cases with discrepant results between the 2 HPV assays, Cobas HPV showed 100% sensitivity and specificity for hrHPV. HPV-16 was detected in 88% of HPV-positive cases (65 of 74). HPV genotyping confirmed 1 false-negative HPV-16 result and 1 false-positive HPV-16 result. Overall, the accuracy of Cobas HPV for HPV-16 was 97.8%. The accuracy of Cobas HPV in FNA needle-rinse specimens was 100%.The Cobas HPV assay is highly accurate for determining the HPV status in head and neck FNA specimens. FNA needle rinse is valid for Cobas HPV testing in patients with squamous cell carcinoma.