HPV-positive Oropharyngeal Cancer Research Articles

20 pack-year smoking history as strongest smoking metric predictive of HPV-positive oropharyngeal cancer outcomes

ObjectivesWhile smoking is associated with worse outcomes in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), the magnitude of this association is unclear given the heterogenous smoking definitions and outcomes. Our objective was to investigate the association between smoking, survival, and recurrence in HPV-related OPSCC using multiple smoking metrics reported in the literature. Materials and methodsThis was a retrospective cohort study of 375 adults with p16+ OPSCC undergoing surgical resection (n = 272) or definitive chemoradiation (n = 103) at a tertiary academic institution from 2006 to 2017. The primary outcome was overall survival (OS). Secondary outcomes included disease-free survival (DFS), disease-specific survival (DSS), and recurrence. We used multiple smoking metrics commonly cited in previous studies, including ever versus never smokers, current versus former/never smokers, ≤10 versus >10 pack-year, ≤20 versus >20 pack-year, and continuous pack-year. ResultsThere were 375 patients, median age 58 years, with 326 (87%) males, and median follow-up of 52 months. Of all smoking metrics, >20 pack-year history was the strongest predictor of both OS (HR 2.24, 95% CI: 1.19–4.20) and DFS (HR 1.67, 95% CI: 1.04–2.66) on univariable and multivariable analysis after adjusting for age, overall stage, and comorbidities. Patients with >20 pack-year smoking history were also more likely to have recurrence (HR 1.59, 95% CI: 0.95–2.67) after adjusting for overall stage. ConclusionHeavier smoking >20 pack-years was the strongest smoking metric associated with 2-times worse survival and recurrence. Our findings suggest that >20 pack-year smoking history may be a more useful cutoff for risk stratification models but requires further validation.

Screening Awareness of HPV-Related Oropharyngeal Cancers and Attitudes and Concerns towards HPV Vaccination Among Parents : HPV and Oropharyngeal Cancer.

Baseline population opinions on human papillomavirus (HPV) and HPV vaccination must be understood before physicians can address knowledge gaps in that population and encourage timely vaccination. To determine the opinions of parents of children age 9 to 18 on HPV-related oropharyngeal cancers (OPC); the associations with education level, socioeconomic status, and having a family member/friend with OPC; and the main concerns against having a vaccination., An anonymous survey was created and administered. Parents were asked to complete the survey if they met the inclusion criteria. After the survey, results were tabulated, and the answers for each question were analyzed. The target population was surveyed in the clinic. The target population was parents with children between 9 and 18years old: the background knowledge and awareness of HPV-related OPC and associations with education level, socioeconomic status, having a family member/friend with OPC, and concerns about vaccination. Our study results showed that the age of parents, education level, marital status, personal vaccination status, and gender of the child are significant factors for background knowledge about HPV-related diseases. Similarly, the education level, the gender of the child, and personal vaccination status are significant factors towards attitudes against having children vaccinated. There is a strong correlation between background knowledge and attitudes. The main issues about vaccination are concerns about effectiveness and side effects, concerns about safe sex experiences, and the cost of vaccination. This is the first study designed to provide information on parents' knowledge of HPV-related cancers, prevalence of HPV vaccination, and attitudes and concerns about HPV vaccination in the USA. The lack of awareness of HPV-related cancers is a significant factor in attitudes against HPV vaccination.

Radiological differences in computed tomography findings and texture analysis between cystic lymph node metastases of human papillomavirus-positive oropharyngeal cancer and second branchial cysts.

PurposeThe study aimed to analyse radiological differences in computed tomography (CT) findings and texture analysis between cystic lymph node metastases (CNM) in human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) and second branchial cleft cysts (2nd BC).Material and methodsPatients with pathological evidence of CNM-HPV-OPC and 2nd BC, who underwent contrast-enhanced CT, were retrospectively evaluated. The evaluated characteristics include age, sex, and CT findings. CT findings included the maximum and minimum transverse diameters, maximum caudal diameter, thickness of the peripheral wall, presence of internal septation, presence of surrounding fat stranding, location, and 40 texture parameters.ResultsA total of 13 patients had CNM-HPV-OPC (19 lesions), while 20 patients had 2nd BC (20 lesions). Patients with 2nd BC were significantly younger than those with CNM-HPV-OPC (p < 0.001). In terms of diameter, 2nd BC lesions were significantly larger than the CNM-HPV-OPC lesions (p < 0.001). CNM-HPV OPC lesions had significantly thicker walls than 2nd BC lesions (p < 0.001). CNM-HPV-OPC lesions had significantly higher association with internal septations than 2nd BC lesions (p < 0.001). Second BC lesions were significantly less common at level III than CNM-HPV-OPC lesions (p = 0.047). Among the 40 texture parameters measured, 8 had significant differences (p ≤ 0.001).ConclusionsThere were significant differences in CT findings and textural parameters between CNM-HPV-OPC and 2nd BC lesions. These results may help in differentiating one from the other.

Nutritional Support in Head and Neck Radiotherapy Patients Considering HPV Status.

Malnutrition is a common problem in patients with head and neck cancer (HNC), including oropharyngeal cancer (OPC). It is caused by insufficient food intake due to dysphagia, odynophagia, and a lack of appetite caused by the tumor. It is also secondary to the oncological treatment of the basic disease, such as radiotherapy (RT) and chemoradiotherapy (CRT), as a consequence of mucositis with the dry mouth, loss of taste, and dysphagia. The severe dysphagia leads to a definitive total impossibility of eating through the mouth in 20–30% of patients. These patients usually require enteral nutritional support. Feeding tubes are a commonly used nutritional intervention during radiotherapy, most frequently percutaneous gastrostomy tube. Recently, a novel HPV-related type of OPC has been described. Patients with HPV-associated OPC are different from the HPV− ones. Typical HPV− OPC is associated with smoking and alcohol abuse. Patients with HPV+ OPC are younger and healthy (without comorbidities) at diagnosis compared to HPV− ones. Patients with OPC are at high nutritional risk, and therefore, they require nutritional support in order to improve the treatment results and quality of life. Some authors noted the high incidence of critical weight loss (CWL) in patients with HPV-related OPC. Other authors have observed the increased acute toxicities during oncological treatment in HPV+ OPC patients compared to HPV− ones. The aim of this paper is to review and discuss the indications for nutritional support and the kinds of nutrition, including immunonutrition (IN), in HNC, particularly OPC patients, undergoing RT/CRT, considering HPV status.

Outcomes after salvage for HPV-positive recurrent oropharyngeal cancer treated with primary radiation.

HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) carries a favorable prognosis for patients, yet nearly 30% of patients will experience disease relapse. We sought to detail patterns of failure, associated salvage therapy, and outcomes for patients with recurrent HPV-positive OPSCC. This is a single institution retrospective study of patients with recurrent HPV-positive OPSCC irradiated from 2002 to 2014. The primary study outcome was overall survival (OS, calculated using the Kaplan-Meier method). Secondary aims included patterns of first failure with descriptive details of salvage therapy. Solitary recurrences were defined as initial presentation of recurrence in a single site (primary, neck or oligometastatic), and multi-site was defined as local and regional and/or multiple sites of distant recurrence. Survival outcomes were compared using the log-rank test. The cohort consisted of 132 patients. The median follow-up was 59months for surviving patients. Estimated 2-year and 5-year OS rates were 47% and 32%, respectively. Comparative 2-year and 5-year OS rates were 65% and 46% versus 19% and 9% for the solitary group and multi-site group, respectively (p<.001). Patients with recurrent HPV-positive OPSCC experience 5-year survival of approximately 32%. However, patients with a "solitary" recurrence including disease at the primary site, neck or oligometastatic site have more favorable long-term outcomes.

Knowledge of Human Papillomavirus (HPV) and Oropharyngeal Cancer and Acceptability of the HPV Vaccine among Dental Students.

Objectives:To assess knowledge about human papillomavirus (HPV), vaccination, and HPV-related oropharyngeal cancer (OPC) and to evaluate HPV vaccine acceptability among a sample of undergraduate dental students. Methods:All third- and fourth-year dental students enrolled in any of the dental schools in Jeddah, Saudi Arabia, were invited to participate in this cross-sectional study. In total, 500 students completed a self-administered questionnaire on HPV, HPV vaccines, and HPV-related OPC knowledge. HPV, HPV vaccine and HPV-related OPC knowledge scores were calculated. Associations of participants characteristics with the knowledge scores and with willingness to take the HPV vaccine were assessed. Results:Of the participants, 62% had heard of HPV infections, and 57% of HPV vaccines. Average knowledge scores were low: HPV knowledge score 3.8±4.5 out of 16, HPV vaccination knowledge score 0.9±1.6 out of 7, OPC knowledge score 0.9±1.2 out of 5. Clinical-year students had better knowledge and were more willing to take the HPV vaccine than were preclinical-year students, as were those vaccinated for hepatitis B versus those not vaccinated for hepatitis B. Students with higher HPV knowledge scores were more willing to take the HPV vaccine (66%) than were those with lower scores (43%) (p=0.018). Only 4% of males and 12% of females reported taking the HPV vaccine. Of those who refused it, 51% cited lack of knowledge as the primary reason. Conclusions:Knowledge about HPV, its vaccine, and HPV-related OPC is low among this sample of Saudi undergraduate dental students. Improving knowledge among them may increase their awareness, which could affect the care provided to patients.

Association between human papillomavirus and the oral anatomical subset of head and neck cancer: a systematic review

Background: Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous disease affecting different anatomical subsites. The link between human papillomavirus and oropharyngeal carcinoma is well established and liked to a better prognosis. Clinical trials are currently investigating the role of de-intensifying treatment for HPV positive oropharyngeal cancer. Such an association with the oral anatomical subset is less well characterized. A systematic review of the available literature was therefore conducted to address this issue.

Human papillomavirus and oral health.

Canada is among the world leaders in oral health. Despite this, there are growing concerns about the rising rates of HPV-related mouth and throat cancers. The link between human papillomavirus (HPV) and cervical cancer is well established; fortunately, thanks to detection and vaccination, Canada has one of the lowest incidence rates of cervical cancer in the world. The HPV-related mouth and throat cancers, however, present a different picture. In Canada, about 25% to 35% of mouth and throat cancers are related to oral HPV infection; and in 2012, the incidence rate of HPV-associated oropharyngeal cancer was more than 4.5 times higher in males than females. Furthermore, HPV vaccination uptake in Canada is higher among females than males. Physicians and nurses in public health and clinical settings have a role to play in the fight against HPV transmission, as do oral health professionals. Oral health professionals can play a key role in preventing HPV infection and HPV-related oropharyngeal cancers by raising awareness, educating and offering counselling to their clients, and promoting evidence-based preventive and diagnostic interventions.

PO-0791: Sexual health in HPV-related oropharyngeal cancer survivors after (chemo)radiotherapy

PO-0791: Sexual health in HPV-related oropharyngeal cancer survivors after (chemo)radiotherapy

Impact of Insurance and Socioeconomic Status on HPV-related Oropharyngeal Cancer

Impact of Insurance and Socioeconomic Status on HPV-related Oropharyngeal Cancer

Patient Outcomes and Chemotherapy Use for HPV positive Oropharyngeal Cancer in the United States, 2010-2016

To examine overall survival for HPV positive (+) oropharynx cancer (OPX) patients, and to assess trends in chemotherapy use for HPV+ locally advanced (stage III-IV) OPX in the setting of ongoing de-escalation efforts. The custom Surveillance, Epidemiology, and End Result (SEER) Head and Neck with HPV Status Database (2010-2016) includes collected data on the HPV status of patients (18,586) with head and neck cancer. The proposal of this study to evaluate survival and chemotherapy use was approved by the SEER custom data group. Patients with primary sites other than the OPX (2,673), histology other than squamous cell carcinoma (180), and unknown stage (762) were excluded. Among 14,971 patients, 10,822 (72.3%) were HPV + and 4,149 (27.7%) were HPV -. The 2-year overall survival (OS) for HPV+ vs. HPV-, stage I-II (962 vs. 686), stage III-IV (9,565 vs. 3,226), and stage M1 (295 vs. 237) patients was: 92.3% vs. 74.2% (p<0.001), 87.9% vs. 64.5% (p<0.001), and 45.3% vs.22.0% (p<0.001) respectively. The rate of chemotherapy use for HPV+, stage III-IV OPX for 2010-2016 was 76.4% overall, but decreased steadily from 2010 (85%) to 2016 (71%). Logistic regression test showed the trend to be statistically significant (p<0.01) with an OR = 0.88. The year to year decline in chemotherapy was slightly greater for post-operative treatment (OR = 0.85, p<0.001) then definitive treatment (OR = 0.89, p<0.001). HPV status had a significant impact on predicting OS, including for M1 patients. The rate of chemotherapy use for HPV+, stage III-IV patients has been decreasing in the United States from 2010-2016. Further investigation is indicated to explore the trend in decreasing chemotherapy usage for this population amidst the broader de-escalation effort.

Assessing Dental Students' HPV Health Literacy and Intention to Engage in HPV-Related Oropharyngeal Cancer Prevention.

Oropharyngeal cancer has become the new face of HPV-related cancers, and this alarming growth highlights the pivotal role dentists can play in prevention. This study aims to identify current HPV-related curricula taught across US dental schools and evaluate HPV health literacy and intention to engage in HPV prevention among US dental students. The dental school curricula included responses from 40 Academic Deans (61% response rate). The 4-item survey focused on understanding HPV-related content in dental school curricula and was administered via Qualtrics. A 31-item paper survey was administered to dental students (N= 109) at a southeastern dental school assessing HPV health literacy, scope of practice, willingness to administer HPV vaccine, self-efficacy in HPV prevention, and basic demographics. Data were collected between February and May 2018. Over 40 courses were identified and included HPV-related content in multiple disciplines including oral and general pathology, immunology, oral medicine, microbiology, infectious diseases, public health, and oral health management among others. Among dental students, over half were female (61%), non-Hispanic White (61%), with a mean age of 26 and in their first (48%) or third year of dental school (52%). Results indicate some HPV knowledge gaps. Most dental students believe HPV prevention is within their scope of practice; however, 56% reported feeling somewhat/not at all confident in recommending the vaccine and performing oral cancer exams. Our data supports the timeliness and need to strengthen HPV-related content in dental school curricula to effectively train and engage future dental providers in HPV prevention.

Evaluation of knowledge and awareness of dentists and dental students about human papillomavirus vaccination and oropharyngeal cancer relationship

Objective: As the incidence of oropharyngeal cancer (OPC) associated with human papillomavirus (HPV) has increased rapidly in recent years, the role of dentists on this issue is also increasing. This study aims to determine the knowledge and awareness of dentists and dental students about HPV vaccination and the relationship of OPC.&#x0D; &#x0D; Methods: A total of 209 participants, consisting of 82 dentists and 127 dental students, were filled out the questionnaires about the general HPV knowledge, HPV-OPC relationship, and HPV vaccination. The Fisher Exact and the Mann Whitney U tests were used to determining the difference between the two groups. The analyses were performed in R, and the significance levels were set at 0.05.&#x0D; &#x0D; Results: The majority of the respondents answered the general questions about HPV correctly. Almost all of the participants in our study were found to have high awareness about the HPV-OPC relationship, most of them do not have enough information about the HPV-related OPCs have a better prognosis than other OPCs. Both dentists and dental students stated that they did not think they had enough information about HPV vaccination. Dental students were more conscious and more motivated than dentists in recommending HPV vaccination to their patients (p &lt; 0.05).&#x0D; &#x0D; Conclusion: Our study showed that dentists and dentistry students had a high level of knowledge in general subjects related to HPV. It was determined that the knowledge of both groups was insufficient regarding the HPV-OPC relationship and HPV vaccination, and the participants were eager to overcome these shortcomings.

Nicotine dependence as a risk factor for upper aerodigestive tract (UADT) cancers: A mediation analysis.

PurposeThis study investigated nicotine dependence as an independent risk factor for upper aerodigestive tract (UADT) cancers, including lung and head and neck cancers (HNC). The study aimed to isolate the direct effect of nicotine dependence, independent of tobacco smoking.MethodsA case-control study with a total of 4957 participants was conducted in Ontario, Canada, of which 2964 categorized as either current or former smokers were used in the analysis. Nicotine dependence of ever-smokers (2360 UADT cases and 604 controls) was measured using the Fagerström Test for Nicotine Dependence. Using mediation analyses and adjusted logistic regression models, we decomposed the direct effect of nicotine dependence and the mediated effect of smoking duration to quantify the risks of lung and HNC. The role of human papillomavirus (HPV) and cancer subtypes were assessed.ResultsMost individual nicotine dependence behaviours showed positive associations with lung cancer with approximately 1.8 to 3.5-fold risk increase, and to lesser extent with 1.4 to 2.3-fold risk for HNC. Nicotine dependence is partially accountable for increased risks of lung cancer (OR = 1.20, 95%CI = 1.13–1.28) and HNC (1.12, 95%CI = 1.04–1.19). Nicotine dependence had a greater effect on the risk of HPV-negative oropharyngeal cancer (OR = 3.06, 95%CI = 1.65–5.66) in comparison to HPV-positive oropharyngeal cancer (OR = 1.05, 95%CI = 0.67–1.65). The direct effects of nicotine dependence remained significant after accounting for cumulative tobacco exposures.ConclusionNicotine dependence increases the risks of lung and HNC cancers after accounting for tobacco smoking, suggesting potential toxic effects of nicotine. These results are informative for the safety consideration of nicotine exposures.

Abstract 5241: Differences in PD-L1 expression by smoking status in HPV positive oropharyngeal cancer

Abstract Introduction: As the incidence of human papillomavirus-positive (HPV +) oropharyngeal squamous cell carcinoma (OPSCC) continues to increase, it is important to optimize treatment regimens. There is growing evidence demonstrating the efficacy and safety of anti-PD-1 immunotherapy, either as monotherapy or in combination with chemotherapy, for patients with programmed death-ligand 1 (PD-L1) positive head and neck squamous cell carcinoma. Greater PD-L1 expression has been associated with greater treatment response and improved overall survival independent of treatment modality. Prior studies have observed increased PD-L1 expression and improved treatment response in HPV(+) as compared to HPV(-) tumors. In contrast, HPV(-) disease, in which smoking is causative in most cases, is typically associated with unfavorable outcomes and lower rates of PD-L1 expression. In the present study, we sought to explore the effects of smoking on PD-L1 expression in HPV(+) tumors based on smoking status. We hypothesized that smokers would demonstrate lower levels of PD-L1 expression as compared to non-smokers. Methods: Using an existing tissue bank, we identified a cohort of 52 HPV(+) tumors from patients with available smoking data. A tissue microarray was constructed with cores taken from the paraffin embedded tumor blocks. A single 0.5 micron slide was created and we examined PDL-1 expression by immunohistochemistry in 47 intact cores. Visiopharm software was used for quantitative analysis of area stained per total cellular area (Figure 2). Mann-Whitney U test was then performed to compare PD-L1 expression between current smokers and former/never smokers (Figure 1). Forty-four of the patients in the cohort had RNA-based Nanostring immuno-oncology assay data available. We were able to obtain paired quantitative IHC and Nanostring based PD-L1 (CD274) gene expression values for 40 patients and Spearman's correlation was performed (Figure 3). Results: The primary tumor site was tonsil in 29 (56%) patients, 22 (42%) base of tongue, and 1 (2%) soft palate. Females made up 10% of the cohort. There were 9 (17%) current smokers, 20 (38%) former, and 23 (44%) never smokers. Pack-years was available for 22 (76%) of the current and former smokers (median: 30, range: 1-75 pack years). There were 5 patient deaths, and 10 patients experienced recurrence. PD-L1 expression on IHC was not predictive of death or recurrence (p=0.39 and p=0.07, respectively). Median follow up time was 20.5 months (range: 2.7 to 83 months). There was a significant difference in PD-L1 expression on IHC between current smokers and the former/never group (Figure 1). Relative gene expression of CD274 measured by the Nanostring assay was lower in current smokers as compared to former/never smokers, however this trend did not meet significance. There was a strong positive linear correlation between Nanostring based CD274 gene expression and PD-L1 expression on IHC (r=0.68, p &amp;lt 0.0001). Conclusion: Current smoking status at the time of diagnosis is associated with decreased PD-L1 expression as compared to former and never smokers. These results may have implications when considering immune checkpoint inhibition therapy in smokers with HPV(+) OPSCC. Citation Format: Ricardo J. Ramirez, Benjamin Wahle, Zixing Liu, Angela Mazul, Paul Zolkind, Mena Mansour, Krzysztof Hyrc, Jose P. Zevallos. Differences in PD-L1 expression by smoking status in HPV positive oropharyngeal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5241.

Insurance Status as a Predictor of Treatment in Human Papillomavirus Positive Oropharyngeal Cancer.

The link between human papillomavirus (HPV) and oropharyngeal cancer (OPC) is well known. Locally advanced, HPV-positive OPC (HPV OPC) can be treated with either chemoradiation or primary surgery with or without adjuvant therapy. Head and neck cancer patients with government insurance or uninsured have been shown to have worse prognosis than similar patients with private insurance. In this study, we aimed to determine if insurance status would predict treatment modality in patients with HPV OPC. A retrospective analysis using the National Cancer Database (NCDB). The National Cancer Database was used to identify patients with HPV OPC who underwent primary surgery or primary chemoradiation from 2010-2015. Insurance status was categorized as government, private, or no insurance. The relationship between insurance status and treatment was investigated using Chi square and multivariate regression models. Kaplan-Meier analyses were performed comparing overall survival (OS) by insurance status. There were 10,606 patients were included. There was a statistically significant correlation between insurance status and primary treatment modality for HPV OPC (P < .001). Patients with government insurance were 19.3% less likely to undergo surgery and uninsured patients were 36.9% less likely to undergo primary surgery when compared to those with private insurance (P < .001), even after correcting for TNM stage in multivariate analysis. There was an improved 5-year OS for patients with private insurance (86.6%) versus both government insurance (68.4%) and no insurance (69.9%) (P < .001). Patients with private insurance are more likely to undergo primary surgery in HPV OPC and have improved overall survival. 4 Laryngoscope, 131:776-781, 2021.

Early 18F-FDG-PET Response During Radiation Therapy for HPV-Related Oropharyngeal Cancer May Predict Disease Recurrence

Early indication of treatment outcome may guide therapeutic de-escalation strategies in patients with human papillomavirus (HPV)-related oropharyngeal cancer (OPC). This study investigated the relationships between tumor volume and 18F-fluorodeoxyglucose positron emission tomography (PET) parameters before and during definitive radiation therapy with treatment outcomes. Patients undergoing definitive (chemo)radiation for HPV-related/p16-positive OPC were prospectively enrolled on an institutional review board-approved study. 18F-fluorodeoxyglucose PET/computed tomography scans were performed at simulation and after 2 weeks at a dose of ∼20 Gy. Tumor volume and standardized uptake value (SUV) characteristics were measured. SUV was normalized to blood pool uptake. Tumor volume and PET parameters associated with recurrence were identified through recursive partitioning (RPART). Recurrence-free survival (RFS) and overall survival (OS) curves between RPART-identified cohorts were estimated using the Kaplan-Meier method, and Cox models were used to estimate the hazard ratios (HRs). From 2012 to 2016, 62 patients with HPV-related OPC were enrolled. Median follow-up was 4.4 years. RPART identified patients with intratreatment SUVmax (normalized to blood pool SUVmean) <6.7 or SUVmax (normalized to blood pool SUVmean) ≥6.7 with intratreatment SUV40% ≥2.75 as less likely to recur. For identified subgroups, results of Cox models showed unadjusted HRs for RFS and OS (more likely to recur vs less likely) of 7.33 (90% confidence interval [CI], 2.97-18.12) and 6.09 (90% CI, 2.22-16.71), respectively, and adjusted HRs of 6.57 (90% CI, 2.53-17.05) and 5.61 (90% CI, 1.90-16.54) for RFS and OS, respectively. PET parameters after 2 weeks of definitive radiation therapy for HPV-related OPC are associated with RFS and OS, thus potentially informing an adaptive treatment approach.

Abstract 427: A mouse model for studying oncogenesis of HPV-associated oropharyngeal cancer

Abstract The human papillomavirus (HPV) causes 70% of oropharyngeal cancers in the United States. While the molecular and cellular mechanisms and the stepwise progression of HPV-related cervical cancer have been well studied, oropharyngeal HPV carcinogenesis remains to be unraveled since an equivalent HPV premalignant stage has never been identified in clinical oropharyngeal tissues. In this study, a series of keratinocyte cell lines derived from the base of the tongue of C3H mice were established. These cells formed varying degrees of malignancy in the syngenetic mice and are used to study the biology of HPV-related oropharyngeal cancer in an immunocompetent host. Keratinocytes from the base of the tongue were isolated from C3H newborns and were subsequently retrovirally immortalized with TERT or HPV16 E6E7 oncoproteins, with or without oncogene H-ras. They are designated MOKT1 (TERT), MOKT1/H-ras (TERT/H-ras), MOKE2 (E6E7), or MOKE2/H-ras (E6E7/H-ras). These cells were injected in the masseter muscle of syngeneic mice and the developing lesions were harvested for histological analysis over a time course of 1 month. E6E7 transformed MOKE2 cells exhibited features of HPV associated cancer cells. We found that p63 and phosphorylated STAT3 were upregulated in MOKE2 cells in comparison to MOKT1 cells. MOKE2 cells obtained growth advantages with increased cell proliferation and decreased apoptosis. In addition, MOKE2 cells showed increased cell migration activity in wound healing assays. While all cell lines grew indefinitely in vitro, MOKT1 and MOKT1/H-ras failed to show any sign of malignancy when implanted in vivo. MOKE2 demonstrated features of malignancy, but the phenotype was transient. Host immunity does not appear to be the determining factor for suppressing tumor growth as MOKE2 regressing also occurred when implanted in immunodeficient NSG mice. Only MOKE2/H-ras cells were capable of progressing and establishing permanent cancer. Ourdata suggest that differentiation induced cell growth arrest may contribute to tumor regression and a second hit is required to overcome such arrest. The MOKE2 cells can be used in syngeneic mice to study secondary oncogenic factors in the development of HPV-related oropharyngeal cancer. Citation Format: Eva McGhee, Yi-Ling Lin, Jay Vadgama, Khadijah Lang, Judith Okoro, Victoria Vidal, Naomi Long, Mengtao Li. A mouse model for studying oncogenesis of HPV-associated oropharyngeal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 427.

Epidemiology of human papillomavirus-related oropharyngeal cancer in a classically low-burden region of southern Europe

The incidence of human papillomavirus (HPV)-related oropharyngeal cancer is increasing in some regions. Nevertheless, the epidemiology of this disease has not been extensively investigated in southern Europe. We conducted a retrospective cohort study of patients diagnosed with primary oropharyngeal cancer from 1991 to 2016. Cancer tissues underwent histopathological evaluation, DNA quality control, HPV-DNA detection and p16INK4a immunohistochemistry. Data were collected from medical records. Factors associated with HPV positivity and time trends were evaluated with multivariable Bayesian models. The adjusted prevalence of HPV-related cases in 864 patients with a valid HPV-DNA result was 9.7%, with HPV-DNA/p16INK4a double positivity being considered. HPV-related oropharyngeal cancer was likely to occur in non-smokers and non-drinkers, to be located in the tonsil or diagnosed at advanced stages. Time-trend analysis showed an increasing risk of HPV-related oropharyngeal cancer in the most recent periods (5-year period increase of 30%). This increase was highest and with a clear increasing trend only in the most recent years (2012–2016). The prevalence of HPV-related oropharyngeal cancer started to sharply increase in the most recent years in our setting, as occurred two decades ago in areas where most oropharyngeal cancer cases are currently HPV-related. Our results provide a comprehensive assessment of the epidemiological landscape of HPV-related oropharyngeal cancer in a region of southern Europe.

Chemoradiotherapy plus a SMAC mimetic for locally advanced squamous cell carcinoma of the head and neck

The availability of checkpoint inhibitors has led to substantial progress in the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck. For locoregionally advanced disease, a potentially curable condition, concomitant chemotherapy and radiotherapy (chemoradiotherapy) has remained the mainstay of organ-sparing treatment. However, the treatment outcome of locoregionally advanced squamous cell carcinoma of the head and neck, traditionally associated with alcohol and nicotine consumption, still remains poor. A notable exception is human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma, which represents a distinct disease entity with a more favourable prognosis. Although various regimens are used in daily clinical practice, high-dose cisplatin chemoradiotherapy is considered to be the standard of care and the most effective chemoradiotherapy regimen in terms of oncological outcome. In this regard, HPV-positive locoregionally advanced oropharyngeal squamous cell carcinoma is no exception, as was recently demonstrated in two randomised trials. 1 Oosthuizen JC Doody J De-intensified treatment in human papillomavirus-positive oropharyngeal cancer. Lancet. 2019; 393: 5-7 Summary Full Text Full Text PDF PubMed Scopus (12) Google Scholar Serious treatment-related toxicity resulting from high-dose cisplatin chemoradiotherapy, both acute and chronic, is common, and appropriate patient selection for this treatment is crucial. Additionally, disease recurrence following chemoradiotherapy is prevalent, especially for patients with high-risk HPV-negative squamous cell carcinoma of the head and neck. Upon relapse, prognosis is generally poor because salvage treatment options are often scarce. Therefore, the need for more effective treatment regimens remains. Debio 1143 and high-dose cisplatin chemoradiotherapy in high-risk locoregionally advanced squamous cell carcinoma of the head and neck: a double-blind, multicentre, randomised, phase 2 studyTo our knowledge, this is the first treatment regimen to achieve superior efficacy in this disease setting against a high-dose cisplatin chemoradiotherapy comparator in a randomised trial. These findings suggest that inhibition of inhibitor of apoptosis proteins is a novel and promising approach in this poor prognostic population and warrant confirmation in a phase 3 study with the aim of expanding the therapeutic options for these patients. Full-Text PDF