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Studies have reported an increased incidence of oropharyngeal cancer predominantly among younger birth cohorts in developed countries [1–8]. This upsurge has been attributed to an increase in human papillomavirus (HPV)–driven oropharyngeal cancers [7], primarily due to HPV-16 infection, which accounts for approximately 90% of HPV-positive oropharyngeal cancers [9, 10]. Detection of oral HPV-16 DNA in oral rinse/gargle samples was associated with a substantial increase in the odds of prevalent oropharyngeal cancer [10]. However, little is known about the epidemiology of oral HPV infection. To our knowledge, only 3 large studies (≥1000 participants), based predominantly in the United States, have examined the epidemiology of oral HPV in healthy individuals [11–13]. Prevalence of any type of oral HPV ranged from approximately 2% to 7%; reported risk factors included increasing age, male sex, higher number of sexual partners, and tobacco use [11–13]. Additionally, these studies focused on detection of oral mucosal HPV types from the genus Alphapapillomavirus. Yet, recent evidence suggests that the oral region of healthy individuals also contains a high prevalence of cutaneous HPV types (predominantly Betapapillomavirus and Gammapapillomavirus), which have previously been thought to uniquely infect keratinized epithelium and are associated with skin lesions [14–18]. Few studies have reported the prevalence of oral HPV in resource-poor regions. In Latin America, only 5 small studies (

Epidemiological studies indicate that most men and women in the USA will acquire a sexually transmitted human papillomavirus (HPV) infection in their lifetime. While most HPV infections are transient with no clinical symptoms, a minority of infections result in clinical disease such as warts or malignancies. For example, HPV is the underlying cause of cervical cancer, of which there were an estimated 493 000 cases and 274 000 deaths worldwide in 2002, with most cases occurring in developing countries. Sexual behavior, especially the number of sexual partners, is a primary risk factor associated with genital HPV infection among men and women. Prophylactic vaccines are highly immunogenic, efficacious, and well tolerated. Coordinated strategies are needed to promote population delivery of these vaccines.

Background Human papillomavirus (HPV) infection, particularly with type 16, causes a growing fraction of oropharyngeal cancers, whose incidence is increasing, mainly in developed countries. In a double-blind controlled trial conducted to investigate vaccine efficacy (VE) of the bivalent HPV 16/18 vaccine against cervical infections and lesions, we estimated VE against prevalent oral HPV infections 4 years after vaccination. Methods and Findings A total of 7,466 women 18–25 years old were randomized (1∶1) to receive the HPV16/18 vaccine or hepatitis A vaccine as control. At the final blinded 4-year study visit, 5,840 participants provided oral specimens (91·9% of eligible women) to evaluate VE against oral infections. Our primary analysis evaluated prevalent oral HPV infection among all vaccinated women with oral and cervical HPV results. Corresponding VE against prevalent cervical HPV16/18 infection was calculated for comparison. Oral prevalence of identifiable mucosal HPV was relatively low (1·7%). Approximately four years after vaccination, there were 15 prevalent HPV16/18 infections in the control group and one in the vaccine group, for an estimated VE of 93·3% (95% CI = 63% to 100%). Corresponding efficacy against prevalent cervical HPV16/18 infection for the same cohort at the same visit was 72·0% (95% CI = 63% to 79%) (p versus oral VE = 0·04). There was no statistically significant protection against other oral HPV infections, though power was limited for these analyses. Conclusions HPV prevalence four years after vaccination with the ASO4-adjuvanted HPV16/18 vaccine was much lower among women in the vaccine arm compared to the control arm, suggesting that the vaccine affords strong protection against oral HPV16/18 infection, with potentially important implications for prevention of increasingly common HPV-associated oropharyngeal cancer. ClinicalTrials.gov, Registry number NCT00128661

Importance Prospective studies are needed to examine the temporal relationship between oral human papillomavirus (HPV) detection and risk of head and neck squamous cell carcinoma (HNSCC). Moreover, the oral cavity contains a wide spectrum of α-, β-, and γ-HPV types, but their association with risk of HNSCC is unknown. Objective To prospectively examine associations between α-, β-, and γ-HPV detection in the oral cavity and incident HNSCC. Design A nested case-control study was carried out among 96 650 participants, cancer free at baseline, with available mouthwash samples in 2 prospective cohort studies: (1) the American Cancer Society Cancer Prevention Study II Nutrition Cohort and (2) the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Incident cases of HNSCC (n = 132) were identified during an average 3.9 years of follow-up in both cohorts. Three controls per case (n = 396) were selected through incidence density sampling and matched on age, sex, race/ethnicity, and time since mouthwash collection. Methods Through a next-generation sequencing assay, DNA from α-, β-, and γ-HPV types were detected. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% CIs, adjusting for smoking history, alcohol consumption, and detection of HPV-16 for β- and γ-HPVs. Main Outcomes and Measures Incident HNSCC, which includes cancers of the oropharynx, oral cavity, and larynx. Results A total of 132 participants developed HNSCC during the follow-up period (103 men and 29 women; average age at baseline, 66.5 years). Oral HPV-16 detection was associated with incident HNSCC (OR, 7.1; 95% CI, 2.2-22.6), with positive association for oropharyngeal SCC (OR, 22.4; 95% CI, 1.8-276.7), but not for oral cavity (OR, 4.5; 95% CI, 0.6-34.7) or laryngeal SCCs (OR, 0.11; 95% CI, 0.01-834.80). Detection of β1-HPV-5 and β2-HPV-38 types, as well as γ-11 and γ-12 species, had ORs for HNSCC that ranged from 2.64 to 5.45 ( P P = .054), oral cavity (OR, 5.34; 95% CI, 1.51-18.80; P = .01), and laryngeal SCCs (OR, 2.71; 95% CI, 1.00-7.43; P = .05), whereas γ11- and γ12-HPV species were associated with both oral cavity (OR, 7.47; 95% CI, 1.21-46.17; P = .03; and OR, 6.71; 95% CI, 1.47-30.75; P = .01, respectively) and laryngeal SCCs (OR, 7.49; 95% CI, 1.10-51.04; P = .04 and OR, 5.31; 95% CI, 1.13-24.95; P = .03, respectively). Conclusions and Relevance This study demonstrates that HPV-16 detection precedes the incidence of oropharyngeal SCC. Associations of other HPVs, including γ11- and γ12-HPV species and β1-HPV-5 type suggest a broader role for HPVs in HNSCC etiology.

Background U.S. incidence rates of anal cancer have increased steadily over time, and are generally higher in women than men. It has been proposed that the HIV epidemic may have influenced U.S. anal cancer trends. Compared to the general population, anal cancer rates are strongly elevated in HIV-infected individuals. Anal cancer rates in HIV-infected individuals have also increased over time. We estimated the impact of the HIV epidemic on U.S. anal cancer trends during 1980-2007.

BACKGROUND: Three-dose regimens for human papillomavirus (HPV) vaccines are expensive and difficult to complete especially in settings where the need for cervical cancer prevention is greatest. METHODS: We evaluated the vaccine efficacy of fewer than three doses of the HPV16/18 vaccine Cervarix in our Costa Rica Vaccine Trial. Women were randomly assigned to receive three doses of the HPV16/18 vaccine or to a control vaccine and were followed for incident HPV16 or HPV18 infection that persisted in visits that were 10 or more months apart (median follow-up 4.2 years). After excluding women who had no follow-up or who were HPV16 and HPV18 DNA positive at enrollment 5967 women received three vaccine doses (2957 HPV vaccine vs 3010 control vaccine) 802 received two doses (422 HPV vs. 380 control) and 384 received one dose (196 HPV vs. 188 control). Reasons for receiving fewer doses and other pre- and post-randomization characteristics were balanced within each dosage group between women receiving the HPV and control vaccines. RESULTS: Incident HPV16 or HPV18 infections that persisted for 1 year were unrelated to dosage of the control vaccine. Vaccine efficacy was 80.9% for three doses of the HPV vaccine (95% confidence interval [CI] = 71.1% to 87.7%; 25 and 133 events in the HPV and control arms respectively) 84.1% for two doses (95% CI = 50.2% to 96.3%; 3 and 17 events) and 100% for one dose (95% CI = 66.5% to 100%; 0 and 10 events). CONCLUSION: Four years after vaccination of women who appeared to be uninfected this nonrandomized analysis suggests that two doses of the HPV16/18 vaccine and maybe even one dose are as protective as three doses.

Risk of recurrent CIN2+ (including cervical intraepithelial neoplasia grade 2 [CIN2], CIN3, carcinoma and in situ, adenocarcinoma in situ or cancer) remains elevated for years following treatment. The role of long-term post-treatment human papillomavirus (HPV) presence on subsequent risk of CIN2+ was evaluated in the 10,049-women Guanacaste cohort. Six hundred eighty-one women were referred to colposcopy because of high-grade cytology, positive cervicography and/or suspicion of cancer based on visual assessment; 486 were judged to require treatment. After excluding women with

We assessed the oral cancer (OC) knowledge, including risk factors and clinical symptoms, among patients attending dental departments within Italian university hospitals. Two thousand and two hundred questionnaires were sent to four hospitals in order to assess patients' knowledge regarding clinical and epidemiological aspects of OC; OC knowledge was evaluated overall and stratified by oral cancer family history. Participants frequently identified cigarette smoking (87.8%) and heavy alcohol consumption (58.6%) as a risk factor for oral cancer, knew the clinical signs of OC (65-79% depending on the specific symptom) and reported that early detection was related to better prognosis of oral cancer (94%). Individuals with a positive family history for oral cancer were significantly more likely to identify risk factors for oral cancer correctly yet family history of OC did not affect smoking status. Less than 15% of patients reported having received OC counseling by a dentist or physician.

Background: Oral human papillomavirus type-16 (HPV16) infection is a risk factor for oropharyngeal cancer. We examined oral HPV infection among healthy men. Methods: Oral rinse/gargle specimens and questionnaire data were collected from 1,688 healthy men aged 18 to 74 (median = 31 years), from the United States, Mexico, and Brazil. HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59, and noncarcinogenic HPV types were detected using Roche Linear Array. Results: Oral HPV DNA was detected in 67 of 1,680 (4.0%, 95% CI = 3.1%–5.0%) β-globin–positive specimens; carcinogenic HPVs were detected in 1.3% (95% CI = 0.8%–2.0%; n = 22) and HPV16 was the most commonly detected carcinogenic HPV type (0.6%, 95% CI = 0.2%–1.1%; n = 10). The prevalence of oral HPV infection was similar by country except for HPV55, which had notably higher prevalence in Mexico (3.0%) than Brazil (0%) or the United States (0.2%). Oral HPV prevalence nonsignificantly increased over increasing age categories (Ptrend = 0.096). The strongest predictor of oral HPV was current tobacco use, which increased the odds 2.5-fold (95% CI = 1.4–4.4). Oral sexual behaviors were not associated with oral HPV infection. Conclusions: Oral HPV16 infection was rare in healthy men, especially at younger ages, and was positively associated with current tobacco use. Impact: Oral HPV appears to be about 10-fold less prevalent than infection at genital sites in men (4% vs. ∼40%, respectively). It remains unclear whether this reflects reduced exposure or if the oral region is more resistant to HPV infection compared with anogenital sites. Cancer Epidemiol Biomarkers Prev; 20(1); 172–82. ©2011 AACR.

Background Human papillomavirus type 16 (HPV16) is a common infection in the anogenital tract. HPV16 DNA detected in oral specimens has recently been identified as a risk factor for some oropharyngeal cancers. The reported prevalence of oral HPV infection from individual studies is highly variable. Methods We systematically reviewed and abstracted data from published studies (n = 18) that detected oral HPV DNA in 4581 cancer-free subjects to determine the pooled prevalence (and 95% confidence intervals [CI]) of HPV16, carcinogenic HPV, and any HPV. Results 1.3% (95% CI: 1.0-1.7%) of 3977 healthy subjects had oral HPV16, 3.5% (95% CI: 3.0-4.1) of 4441 subjects had carcinogenic HPV, and 4.5% (95% CI: 3.9-5.1) of 4070 subjects were positive for any HPV. Oral HPV16 accounted for 28% of all HPV detected in the oral region. Men (47 of 1017) and women (117 of 3690) had nearly exactly the same prevalence of any oral HPV detected (4.6% vs. 4.4%, respectively). Conclusions HPV-16, a common anogenital infection, was rarely detected in oral specimens. However, a small but noteworthy proportion of healthy individuals have oral HPV infections with types known to cause cancer in the oral region.

Background Multidisciplinary attempts to understand the etiology of breast cancer are expanding to increasingly include new potential markers of disease risk. Those efforts may have maximal scientific and practical influence if new findings are placed in context of the well-understood lifestyle and reproductive risk factors or existing risk prediction models for breast cancer. We therefore evaluated known risk factors for breast cancer in a cancer screening trial that does not have breast cancer as a study endpoint but is large enough to provide numerous analytic opportunities for breast cancer. Methods We evaluated risk factors for breast cancer (N = 2085) among 70,575 women who were randomized in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Using Poisson regression, we calculated adjusted relative risks [RRs, with 95% confidence intervals (CIs)] for lifestyle and reproductive factors during an average of 5 years of follow-up from date of randomization. Results As expected, increasing age, nulliparity, positive family history of breast cancer, and use of menopausal hormone therapy were positively associated with breast cancer. Later age at menarche (16 years or older vs. < 12: RR = 0.81, 95% CI, 0.65–1.02) or menopause (55 years or older vs. < 45: RR = 1.29, 95% CI, 1.03–1.62) were less strongly associated with breast cancer than was expected. There were weak positive associations between taller height and heavier weight, and only severe obesity [body mass index (BMI; kg/m2) 35 or more vs. 18.5–24.9: RR = 1.21, 95% CI, 1.02–1.43] was statistically significantly associated with breast cancer. Conclusion The ongoing PLCO trial offers continued opportunities for new breast cancer investigations, but these analyses suggest that the associations between breast cancer and age at menarche, age at menopause, and obesity might be changing as the underlying demographics of these factors change. Clinical Trials Registration http://www.clinicaltrials.gov, NCT00002540.

Background: Previous reports from the Costa Rica Vaccine Trial demonstrated strong vaccine efficacy against HPV16/18 at the cervical, anal, and oral regions separately. However, the combined “woman-level” vaccine efficacy against infections at all three anatomic sites has not been examined in women with and without previous HPV16/18 exposure. Methods: Women aged 18-25 from the Costa Rica Vaccine Trial were randomized to be vaccinated with the HPV16/18 Vaccine (Cervarix) or a Hepatitis A vaccine at enrollment. Cervical samples were collected at every annual visit, while oral and anal samples were collected only at the four year follow-up visit. Samples were tested for alpha mucosal HPV DNA types utilizing the SPF10 PCR-DEIA-LiPA25 version 1 method. An event in the multi-site woman-level vaccine efficacy analysis (n = 4,186) was defined as a women with prevalent HPV16/18 DNA at the cervical, anal, or oral regions. Vaccine efficacies (VEs) and 95% confidence intervals (95%CIs) were computed for one-time detection of HPV16/18 in the cervical, anal, and oral regions in this intention-to-treat analysis. Results: Four years following initial vaccination, the combined multi-site woman-level vaccine efficacy against HPV16/18 infections was 64.8%, 95%CI = 54.8-72.8. Multi-site woman-level efficacy was stronger among women without evidence of previous HPV exposure (HPV16/18 seronegative and cervical HPV16/18 DNA negative at enrollment): VE = 83.1%, 95%CI = 72.6-89.6, but was also demonstrated among women with evidence of previous HPV16/18 exposure (HPV16/18 seropositive and cervical HPV16/18 DNA negative at baseline): VE = 49.6%, 95%CI = 2.7-73.9. Further supporting the partial protection of the vaccine in previously HPV16/18-exposed women, we observed a particularly strong vaccine efficacy against HPV16/18 at more than one anatomic site (VE = 91.4%, 95%CI = 81.4-96.6). Indeed, HPV16/18-infected women were significantly less likely to be HPV16/18-infected at two or more anatomic sites in the HPV vaccine arm than the control arm (6 of 81 (7%) vs. 70 of 230 (30%), p Discussion: This is the first study to present a combined multi-site woman-level HPV16/18 vaccine efficacy. This study found strong multi-site efficacy among those not previously exposed to cervical HPV16/18, but also suggests the vaccine may provide some protection against HPV16/18 at multiple anatomic sites among women previously exposed to HPV16/18. If confirmed, the partial protection against cervical, anal, and/or oral HPV16/18 in women previously exposed to HPV16/18 could be considered in HPV vaccination catch-up program decision-making. Citation Format: Daniel C. Beachler, Aimee R. Kreimer, Mark Schiffman, Rolando Herrero, Sholom Wacholder, Ana Cecilia Rodriguez, Douglas R. Lowy, Carolina Porras, John T. Schiller, Silvia Jimenez, Linda Struijk, John Schussler, Allan Hildesheim, Paula Gonzalez, Costa Rica Vaccine Trial Group. Efficacy of the HPV16/18 vaccine against cervical, anal, and oral HPV infection among women with and without previous HPV16/18 exposure. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4680. doi:10.1158/1538-7445.AM2015-4680

Background: Alpha HPV16 detection in the oral cavity is associated with head and neck squamous cell carcinoma (HNSCC), particularly oropharyngeal cancer. However, there have been no prospective studies examining the temporal relationship between oral HPV detection and subsequent risk of HNSCC. Moreover, recent data indicates that the oral cavity contains a plethora of HPV types in addition to alpha HPVs (e.g. beta and/or gamma HPVs), but their association with risk of HNSCC is unknown. Methods: We examined prospective associations between alpha, beta and gamma HPVs and risk of HNSCC, using a nested case-control design among >120,000 participants with available mouthwash samples in the American Cancer Society (ACS) Cancer Prevention Study-II Nutrition Cohort (CPS-II) and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. A total of N = 132 incident cases of HNSCC (oropharyngeal, oral and laryngeal SCCs) were identified during an average 3.94 years of follow-up (range 0.02-9.0) in both cohorts. Three controls per case (N = 396) were selected using incidence density sampling, with matching on age (±2 years), race/ethnicity, gender, and time since mouthwash collection (±3 months). Detection of HPV DNA in mouthwash samples was carried out using (1) a novel next-generation sequencing assay designed to detect all HPV types, (2) the MY09/MY11 assay targeting alpha-HPV types, and (3) a RT-PCR specific for HPV16. Associations of alpha, beta and gamma HPVs with risk of HNSCC were evaluated using conditional logistic regression models for matched risk sets to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusting for smoking and alcohol as well as alpha HPV16 for beta and gamma HPVs. Results: The prevalence of oral HPV16 was 1.8% in controls. HPV16 detection was associated with a 7.1-fold higher risk of overall HNSCC (95% CI 2.2-22.6); the risk was highest for oropharyngeal cancer (OR = 22.41, 95% CI 1.8 - 276.7), while no excess was found for oral cavity or larynx cancers. There were no associations between other alpha HPVs and risk of HNSCC. Oral prevalence of any beta or gamma HPVs was 59.4% and 38.2%, respectively in controls. Detection of any beta HPV (OR = 1.74, p = 0.05) or any gamma HPV (OR = 2.11, p = 0.005) was also associated with risk of HNSCC, with several beta (β1 HPV5, β2 HPV17, β2 HPV38) and gamma (γ11, γ12) HPVs having statistically significant increased risks (ORs from 3.92 to 7.36). In regard to tumor location, β1HPV5 was associated with oropharyngeal (OR = 7.42, p = 0.05), oral cavity (OR = 5.34, p = 0.01) and laryngeal cancers (OR = 2.71, p = 0.05); while β2 HPV38 was associated with oropharyngeal cancer (OR = 7.28, p = 0.02) only. Gamma HPV species groups 11 and 12 were associated with both oral cancer (OR = 7.47, p = 0.03; and OR = 6.71, p = 0.01, respectively) and laryngeal cancers (OR = 7.49, p = 0.04 and OR = 5.31, p = 0.03). Conclusion: This study is the first to demonstrate that alpha HPV16 detection precedes the incidence of oropharyngeal cancers. Risks identified with other HPV types from gamma11 and 12 species as well as beta HPV5, previously associated with skin cancer, suggests a broader role for HPVs in HNSCC etiology. Readily-collected oral wash samples provide a strong prospective marker for oropharyngeal cancer and, with the incorporation of other HPV types, may indicate risk for a broader spectrum of HNSCC. Citation Format: Ilir Agalliu, Zigui Chen, Tao Wang, Rebecca Ludvigsen, Lauren Teras, Aimee R. Kreimer, Richard B. Hayes, Susan Gapstur, Robert D. Burk. Oral HPV DNA detection and subsequent risk of head and neck cancers in two prospective cohorts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-181. doi:10.1158/1538-7445.AM2015-LB-181

Background: Loop electrosurgical excision procedure (LEEP) is the predominant treatment for cervical intraepithelial neoplasia grade 2 or 3 (CIN2+) in the United States, yet following treatment ∼10% of women are diagnosed again with CIN2+, necessitating close follow-up of such patients. Methods: Surveillance strategies using cytology and/or human papillomavirus (HPV) testing were compared among women who underwent LEEP (n = 610) in the Atypical Squamous Cells of Undetermined Significance (ASCUS) Low-Grade Squamous Intraepithelial Lesion (LSIL) Triage Study. Cervical specimens, collected at 6-month visits for 2 years, were used for cytology, Hybrid Capture 2 (HC2) detection of carcinogenic HPVs, and PCR for genotyping of carcinogenic and noncarcinogenic HPV types. At exit, women had colposcopy for safety and disease ascertainment. Results: At the visit post-LEEP (median time: 4.5 months after LEEP), 36.9% [95% confidence interval (95% CI), 32.7-41.1%] of women were positive for carcinogenic HPV by PCR and 33.7% (95% CI, 29.7-37.9) had ASCUS or more severe (ASCUS+) cytology. The overall 2-year cumulative incidence of histologically confirmed posttreatment CIN2+ was 7.0%; this could be further stratified by the HPV risk category detected at the 6-month visit after LEEP. The 2-year risk associated with HPV16 positivity was 37.0%, significantly higher than for other carcinogenic HPV types (10.8%, P < 0.001), noncarcinogenic types (1.5%, P < 0.001), or testing HPV negative (0%). Post-LEEP cytology (using a positive threshold of ASCUS+) was 78.1% (95% CI, 60.0-90.7%) sensitive for detection of posttreatment CIN2+. By comparison, PCR for carcinogenic HPV and combination testing (using a positive result from carcinogenic HPV testing or cytology as the test threshold with HPV-negative ASCUS not referred) were significantly more sensitive (96.9% for each, P = 0.03); HC2 alone was nonsignificantly more sensitive (90.6%, P = 0.3). Specificity was similar for ASCUS+ cytology (69.1%, 95% CI, 64.6-73.3%) and PCR for carcinogenic HPV (67.1%, P = 0.5), yet was lower for HC2 (63.8%, P = 0.048) and combination testing (62.9%, P = 0.02). Conclusion: Women who tested positive after LEEP for carcinogenic HPV types, especially HPV16, had high risk of subsequent CIN2+. HPV-based detection methods, alone or in combination with cytology, may be useful to incorporate in post-LEEP management strategies. (Cancer Epidemiol Biomarkers Prev 2006;15(5):908–14)

Tobacco and alcohol use are the main risk factors for oral and oropharyngeal cancers, yet, dietary habits may also be of importance. Data from a series of case-control studies conducted in 9 countries worldwide (1,670 cases and 1,732 controls) were used to investigate the role of several food groups and body mass index (BMI). Low BMI significantly increased the odds ratio (OR) of cancer more than 2-fold among ever- and never-tobacco users and ever- and never-alcohol drinkers. After adjustment for potential confounders, high intake of fruits and vegetables significantly reduced the OR of cancer compared to low intake among ever-tobacco users (OR 0.4, 95% confidence interval [CI] 0.3-0.6), although not among never-tobacco users (OR 1.1, 95% CI 0.6-2.0). Similarly, the protective effect of high fruit and vegetable consumption was present among ever-drinkers (OR 0.4, 95% CI 0.3-0.6), but not among never-drinkers (OR 1.0, 95% CI 0.6-1.6). In conclusion, low BMI increases the risk of oral cancer, and vegetables and fruits may modulate the carcinogenic effects of tobacco and alcohol.

A considerable subset of oropharyngeal squamous cell carcinomas (SCCs) are positive for human papillomavirus (HPV); however, delineating etiologically-associated HPV infections from SCCs with concurrent HPV infection unrelated to tumorigenesis is challenging. Viral load assessment in biopsy specimens may help facilitate such differentiation. HPV16 viral load and serologic markers were assessed among oral and oropharyngeal cases from a multinational study conducted by the International Agency for Research on Cancer (IARC). HPV16 viral load, measured semiquantitatively by PCR-enzyme immunoassay, was dichotomized as high or low based on the median optical density value. Serologic antibodies to HPV16 virus-like particles (VLPs) and to HPV16 E6 and E7 proteins were measured by ELISA. Compared to HPV DNA-negative cases (n = 852), HPV16 DNA-positive cases with high viral load (n = 26) were significantly more likely to originate in the oropharynx (odds ratio [OR], 12.0; 95% confidence interval [CI], 5.2-27.5) and, after adjustment for tumor site (AdjOR), have antibodies against HPV16 VLPs (AdjOR, 14.6; 95% CI, 6.0-35.6), E6 (AdjOR, 57.6; 95% CI, 21.4-155.3) and E7 (AdjOR, 25.6; 95% CI, 9.3-70.8). HPV16 DNA-positive cases with low viral load (n = 27) were more commonly oropharyngeal (OR, 2.7; 95% CI, 1.1-6.2) and seropositive for HPV16 VLPs (AdjOR, 2.7; 95% CI, 1.1-6.9), E6 (AdjOR, 3.0; 95% CI, 0.7-14.0) and E7 (AdjOR, 3.5; 95% CI, 0.7-16.3), compared to HPV DNA-negative cases; the associations, however, were neither as strong nor as significant as the associations for high viral load. As there appears to be a strong association between HPV16 serologic markers and viral load, in the absence of data on serologic markers, HPV16 viral load may be used to help delineate the subset of HPV16 DNA-positive oral and oropharyngeal cancers that may be the consequence of HPV infection.

The prevalence and risk factors for oral human papillomavirus (HPV) infection are unknown, despite evidence for an etiological role for HPV in oral cancers. Oral samples from human immunodeficiency virus (HIV)-seronegative (n=396) and HIV-seropositive (n=190) adults were tested for HPV DNA. High-risk HPV infections were present in 2.1% of tonsil and 6.3% of oral-rinse specimens. The prevalence of oral high-risk HPV infection was greater in HIV-seropositive individuals (13.7% vs. 4.5%; P.001). In multiple logistic regression, odds of oral HPV infection increased with age, male sex, and herpes simplex virus (HSV)-2 seropositivity in HIV-seronegative individuals and with CD4 cell count200 cells/mL, HSV-2 seropositivity, oral mucosal abnormalities, and1 oral sex partner during the previous year (odds ratio, 12.8; 95% confidence interval, 3.1-52.7) among HIV-seropositive individuals. HPV type 16, which is present in most HPV-associated tonsillar cancers, was the most prevalent high-risk oral HPV infection.

In this issue of the Journal, D’Souza et al. [1] demonstrate that oral sexual behaviors are associated with the detection of prevalent oral human papillomavirus (HPV) infection. With their study, D’Souza and colleagues have taken an additional step toward improving our understanding of the epidemiologic profile of oral HPV transmission. HPV is an important human carcinogen that is increasingly implicated in human cancers occurring at multiple anatomical sites [2]. Over the past decade, there has been accumulating molecular and epidemiologic evidence demonstrating that HPV causes a subset of head and neck cancers, specifically in the oropharynx [3, 4]. This evidence mandates the need for additional novel research along multiple areas of the disease continuum. Important research topics include (1) elucidating the natural history and epidemiologic profile of oral HPV infection in healthy individuals, (2) determining whether the HPV vaccine is efficacious in preventing oral HPV infections and related diseases, and (3) determining whether the HPV status of the tumor should be used in clinical decision-making pertaining to treatment. D’Souza et al. [1] used 2 distinct populations and differing study methods to evaluate associations between self-reported sexual behaviors and detection of prevalent oral HPV infection. The oral HPV point prevalence was 2.9% among 210 college-aged men and 4.8% among 332 controls in a hospital-based case-control study. Although these percentages are not statistically different, it is noteworthy that the point prevalence among college-aged men (median age, 19 years) was lower than that in the older hospital-based control group (median age, 57 years); this finding has been observed in previous studies [5, 6]. This finding does not parallel the striking inverse trend of decreasing cervical HPV prevalence with increasing age [7]. Differences in the methods of specimen collection in the study (specifically, the addition of the use of an oropharynx brush in the hospital-based control population, compared with the use of oral rinse and gargle alone by college-aged men) may have accounted for some of this difference, as a result of the improved sensitivity of detection of oral HPV infections in the hospital-based study. In addition, the hospital-based controls may have come from a higher-risk population, and, therefore, findings for this group would not be reflective of the true prevalence among older adults. Similarly, older adults may be more likely to have persistent infection detected, which could also inflate the point prevalence. Alternatively, it may be that the natural history of oral HPV infection actually differs from that of the cervix. This finding highlights the importance of developing and standardizing specimen collection, storage, and testing methods that reliably measure infection with high sensitivity, and it strongly argues for additional large, welldesigned studies to better understand the natural history of oral HPV infection. Despite the use of different study designs and populations, as well as different questionnaire variables assessing exposure, the findings that sexual behaviors and, specifically, oral sex are associated with prevalently detected oral HPV infection are consistent in the 2 populations. In addition, open-mouthed kissing (inquired about in the study of college-aged men only) was significantly associated with oral HPV infection. Even among the men who reported never having had oral sexual contact, more kissing partners significantly increased the risk of oral HPV infection, suggesting the independence of kissing as a risk factor for oral HPV infection. Although the finding that oral HPV may be transmitted through kissing is intriguing, it is based on a small sample size (6 infections in men from the college study and even smaller numbers in the subset of individuals who reported no Received 5 December 2008; accepted 8 December 2008; electronically published 25 March 2009. Potential conflicts of interest: none reported. Financial support: none provided. Reprints or correspondence: Dr. Aimee R. Kreimer, 6120 Executive Blvd., EPS/7084, Rockville, MD 20852 (kreimera@mail.nih.gov). The Journal of Infectious Diseases 2009; 199:1253– 4 This article is in the public domain, and no copyright is claimed. All rights reserved. 0022-1899/2009/19909-0001 DOI: 10.1086/597756 E D I T O R I A L C O M M E N T A R Y

Ruth Pfeiffer and colleagues describe models to calculate absolute risks for breast, endometrial, and ovarian cancers for white, non-Hispanic women over 50 years old using easily obtainable risk factors. Please see later in the article for the Editors' Summary, Background Breast, endometrial, and ovarian cancers share some hormonal and epidemiologic risk factors. While several models predict absolute risk of breast cancer, there are few models for ovarian cancer in the general population, and none for endometrial cancer. Methods and Findings Using data on white, non-Hispanic women aged 50+ y from two large population-based cohorts (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO] and the National Institutes of Health–AARP Diet and Health Study [NIH-AARP]), we estimated relative and attributable risks and combined them with age-specific US-population incidence and competing mortality rates. All models included parity. The breast cancer model additionally included estrogen and progestin menopausal hormone therapy (MHT) use, other MHT use, age at first live birth, menopausal status, age at menopause, family history of breast or ovarian cancer, benign breast disease/biopsies, alcohol consumption, and body mass index (BMI); the endometrial model included menopausal status, age at menopause, BMI, smoking, oral contraceptive use, MHT use, and an interaction term between BMI and MHT use; the ovarian model included oral contraceptive use, MHT use, and family history or breast or ovarian cancer. In independent validation data (Nurses' Health Study cohort) the breast and ovarian cancer models were well calibrated; expected to observed cancer ratios were 1.00 (95% confidence interval [CI]: 0.96–1.04) for breast cancer and 1.08 (95% CI: 0.97–1.19) for ovarian cancer. The number of endometrial cancers was significantly overestimated, expected/observed = 1.20 (95% CI: 1.11–1.29). The areas under the receiver operating characteristic curves (AUCs; discriminatory power) were 0.58 (95% CI: 0.57–0.59), 0.59 (95% CI: 0.56–0.63), and 0.68 (95% CI: 0.66–0.70) for the breast, ovarian, and endometrial models, respectively. Conclusions These models predict absolute risks for breast, endometrial, and ovarian cancers from easily obtainable risk factors and may assist in clinical decision-making. Limitations are the modest discriminatory ability of the breast and ovarian models and that these models may not generalize to women of other races. Please see later in the article for the Editors' Summary, Editors' Summary Background In 2008, just three types of cancer accounted for 10% of global cancer-related deaths. That year, about 460,000 women died from breast cancer (the most frequently diagnosed cancer among women and the fifth most common cause of cancer-related death). Another 140,000 women died from ovarian cancer, and 74,000 died from endometrial (womb) cancer (the 14th and 20th most common causes of cancer-related death, respectively). Although these three cancers originate in different tissues, they nevertheless share many risk factors. For example, current age, age at menarche (first period), and parity (the number of children a woman has had) are all strongly associated with breast, ovarian, and endometrial cancer risk. Because these cancers share many hormonal and epidemiological risk factors, a woman with a high breast cancer risk is also likely to have an above-average risk of developing ovarian or endometrial cancer. Why Was This Study Done? Several statistical models (for example, the Breast Cancer Risk Assessment Tool) have been developed that estimate a woman's absolute risk (probability) of developing breast cancer over the next few years or over her lifetime. Absolute risk prediction models are useful in the design of cancer prevention trials and can also help women make informed decisions about cancer prevention and treatment options. For example, a woman at high risk of breast cancer might decide to take tamoxifen for breast cancer prevention, but ideally she needs to know her absolute endometrial cancer risk before doing so because tamoxifen increases the risk of this cancer. Similarly, knowledge of her ovarian cancer risk might influence a woman's decision regarding prophylactic removal of her ovaries to reduce her breast cancer risk. There are few absolute risk prediction models for ovarian cancer, and none for endometrial cancer, so here the researchers develop models to predict the risk of these cancers and of breast cancer. What Did the Researchers Do and Find? Absolute risk prediction models are constructed by combining estimates for risk factors from cohorts with population-based incidence rates from cancer registries. Models are validated in an independent cohort by testing their ability to identify people with the disease in an independent cohort and their ability to predict the observed numbers of incident cases. The researchers used data on white, non-Hispanic women aged 50 years or older that were collected during two large prospective US cohort studies of cancer screening and of diet and health, and US cancer incidence and mortality rates provided by the Surveillance, Epidemiology, and End Results Program to build their models. The models all included parity as a risk factor, as well as other factors. The model for endometrial cancer, for example, also included menopausal status, age at menopause, body mass index (an indicator of the amount of body fat), oral contraceptive use, menopausal hormone therapy use, and an interaction term between menopausal hormone therapy use and body mass index. Individual women's risk for endometrial cancer calculated using this model ranged from 1.22% to 17.8% over the next 20 years depending on their exposure to various risk factors. Validation of the models using data from the US Nurses' Health Study indicated that the endometrial cancer model overestimated the risk of endometrial cancer but that the breast and ovarian cancer models were well calibrated—the predicted and observed risks for these cancers in the validation cohort agreed closely. Finally, the discriminatory power of the models (a measure of how well a model separates people who have a disease from people who do not have the disease) was modest for the breast and ovarian cancer models but somewhat better for the endometrial cancer model. What Do These Findings Mean? These findings show that breast, ovarian, and endometrial cancer can all be predicted using information on known risk factors for these cancers that is easily obtainable. Because these models were constructed and validated using data from white, non-Hispanic women aged 50 years or older, they may not accurately predict absolute risk for these cancers for women of other races or ethnicities. Moreover, the modest discriminatory power of the breast and ovarian cancer models means they cannot be used to decide which women should be routinely screened for these cancers. Importantly, however, these well-calibrated models should provide realistic information about an individual's risk of developing breast, ovarian, or endometrial cancer that can be used in clinical decision-making and that may assist in the identification of potential participants for research studies. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001492. This study is further discussed in a PLOS Medicine Perspective by Lars Holmberg and Andrew Vickers The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information about breast cancer, ovarian cancer, and endometrial cancer; Information on the Breast Cancer Risk Assessment Tool, the Surveillance, Epidemiology, and End Results Program, and on the prospective cohort study of screening and the diet and health study that provided the data used to build the models is also available on the NCI site Cancer Research UK, a not-for-profit organization, provides information about cancer, including detailed information on breast cancer, ovarian cancer, and endometrial cancer The UK National Health Service Choices website has information and personal stories about breast cancer, ovarian cancer, and endometrial cancer; the not-for-profit organization Healthtalkonline also provides personal stories about dealing with breast cancer and ovarian cancer

Background. Human papillomavirus (HPV) infection, in particular HPV16, is causing an increasing number of oropharyngeal cancers in Europe and the United States. HPV16 E6 antibodies are a marker of tumour integration and would be expected to be present among cases with a HPV related tumour but absent or very low in individuals without a HPV related cancer. We investigated the presence of HPV16 E6 antibodies in two large European studies - (i) a retrospective case-control study of 1219 cases (366 oral cavity, 324 oropharynx and 529 hypopharynx/larynx) and 1425 controls with blood samples collected at the time of diagnosis among the cases (the ARCAGE study), and (ii) a nested case-cnotrol study of 638 incident head and neck cancers (including 180 oral, 135 oropharynx, and 247 hypopharynx/larynx), and 1599 comparable controls from the EPIC cohort study, with blood samples collected between 1 and 14 years before diagnosis among the cases. Methods. Plasma from all cases and controls was analyzed for antibodies against multiple proteins of HPV16, with a particular focus on HPV16 E6. Odds ratios (OR) of cancer and 95% confidence intervals (CI) were calculated adjusting for potential confounders. All-cause mortality was evaluated among cases using Cox proportional hazards regression. Findings. Within ARCAGE, HPV16 E6 seropositivity was present in 0.8% (11/1425) of controls and 30.2% (97/324) of oropharynx cases (OR=132.0, 95% CI 65-266). A much weaker association was also seen for larynx cancer (8/529 cases positive; OR=4.2 95%CI 1.5-11.3). No association was seen for oral cancer (4/366 cases positive; OR=1.9 95% CI 0.6-6.2). Within the EPIC nested case-control study 34.8% of oropharyngeal cancer cases and 0.6% of controls were HPV16 E6 positive (OR= 274, 95% CI 110 to 681), although no association was seen with other cancer sites. The increased risk of oropharyngeal cancer among HPV16 E6 seropositive participants was independent of time between blood collection and diagnosis and was observed more than 10 years before diagnosis. Interpretation. Our results indicate that (i) HPV16 E6 antibodies are rare in controls, and less than 1%, (ii) about 30% of oropharynx cancer cases are positive for HPV16, with blood samples taken at the time of diagnosis, and (iii) HPV16 E6 seropositivity is present more than 10 years prior to diagnosis of oropharyngeal cancers. Further, because of its near absence in controls, it may potentially be useful as a biomarker for early detection of oropharyngeal cancer that is presumably HPV-positive. Citation Format: Paul Brennan, Mattias Johannson, Devasena Anantharaman, Michael Pawlita, Aimee Kreimer, on behalf of the EPIC and ARCAGE study groups. An analysis of human papilloma virus (HPV) E6 antibodies and risk of head and neck cancer: two large European studies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3625. doi:10.1158/1538-7445.AM2013-3625

1503 Background: Multiple cancer screening tests have been advocated for the general population. However, providers and patients are not always well-informed of the burdens incurred by screening. We sought to determine the cumulative risk of a FP screen, and resulting diagnostic procedure risk, for an individual in a multiple modality screening program. Methods: Data were analyzed for a 3-year period from the intervention arm of the randomized PLCO Cancer Screening Trial. Eligible individuals were 55 to 74 years of age with no prior history of prostate, lung, colorectal, or ovarian cancer. Additional exclusion criteria were: 1) death before/refusal to take/missing all screens, and 2) less than 3-year follow-up. 68,415 participants were included. The control arm received “usual care.” Women randomized to screening were offered annual CA-125, transvaginal ultrasound, CXR, and baseline plus 3- or 5-year sigmoidoscopy (FSG). Men randomized to screening were offered annual digital rectal exam, PSA, CXR, and baseline plus 3- or 5-year FSG. Fourteen exams were possible for each sex over the study period. We defined a FP as a positive screen with no target cancer diagnosis after at least 3-years follow-up. Advanced adenomas (villous histology, severe cellular dysplasia, or =1cm in diameter) were considered true positives. Results: 42.6% (N=29,152) of participants had at least one FP. Using a geometric distribution model, the cumulative risk of a FP after 1 screen was 5.7% for men, and 2.2% for women. After 14 tests, the risk was 62.2% for men and 50.7% for women. Sensitivity analysis for FP risk after 14 tests by Kaplan-Meier method demonstrated a cumulative FP risk of 61.5% for men and 54.5% for women. The consequent cumulative risk of a diagnostic procedure was about 27% for men and 18% for women after 14 tests. Conclusions: For an individual participating in a multiple modality cancer screening trial, the risk of a FP exceeded 50% by the 14th test. Physicians should educate patients about the risks of FP tests and resulting diagnostic interventions when counseling about cancer screening regimens. [Table: see text]

Antibodies against the Human papillomavirus 16 (HPV16) E6 oncoprotein appear years prior to clinical diagnosis of anal and oropharyngeal cancer, but whether they develop around the time of HPV infection is unclear. Serum samples from 173 cancer-free men from the Human Papillomavirus Infection in Men (HIM) Study were tested for HPV antibodies and DNA. HPV16 E6 seropositivity was low among men with oral HPV16-infection (1/28; 3.6%, 95%CI=0.0–18.4%), anal HPV16-infection (1/61; 1.6%, 95%CI=0.0–8.8%), and 24-month persistent genital HPV16-infection (1/84; 1.2%, 0.0–6.5%). This suggests E6 seroconversion may not occur around the time of oral, anal, or genital HPV16 acquisition. Keywords: HPV, HPV16 E6 seropositivity, Oropharyngeal cancer, Anal cancer, Penile cancer