HPV-positive Oropharyngeal Cancer Research Articles

Abstract 3408: Longitudinal measurement of HPV copy number in cell free DNA predicts progression free survival in HPV positive oropharyngeal cancer

Abstract Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in global prevalence and is divided into two types dependent on association with human papillomavirus (HPV), with a more favorable prognosis in HPV+ve tumors. Assay of HPV copy number in plasma cell-free DNA (cfDNA) provides a minimally invasive method for detecting and monitoring tumor-derived HPV, with potential for enhancing clinical care. We have evaluated the utility of cfDNA droplet digital PCR (ddPCR) as a method for characterisation and longitudinal monitoring of patients with OPSCC in a prospectively recruited cohort of 104 OPSCC patients. ddPCR assay of cfDNA for five HPV types showed overall 95% concordance with p16 immunohistochemistry (IHC) and PCR analysis of solid tumor tissue. Longitudinal sampling in 48 HPV+ve patients, with median follow-up of 20 months, strongly predicted patient outcomes. Progression-free survival, stratified respectively by the presence or absence of detectable HPV cfDNA at a median of 13 weeks post-treatment, was 50% and 88% (p=0.001, hazard ratio 10.0 (95% CI 2.1-47.1)). In two patients, greater reliance on sequential HPV measurement would have avoided surgical intervention which ultimately did not confirm disease recurrence. The high concordance of pre-treatment plasma cfDNA-HPV analysis with p16 IHC and HPV-PCR of solid tissue, together with the predictive value and utility of sequentially measured post-treatment cfDNA-HPV copy number, provide a compelling case for the routine use of cfDNA-HPV ddPCR in management of OPSCC and for clinical trials to assess its impact on treatment outcomes. Citation Format: Martyna Joanna Adamowicz, Sophie J. Warlow, John P. Thomson, Lara M. Carey, Helen Thain, Robert Wescott, Kate Cuschieri, Lucy Q. Li, Brendan Conn, Ashley Hay, Iain J. Nixon, Timothy J. Aitman. Longitudinal measurement of HPV copy number in cell free DNA predicts progression free survival in HPV positive oropharyngeal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3408.

Control of Epstein-Barr Virus (EBV) in the Oral Cavity Is Associated With Persistence of Oral Human Papillomavirus (HPV)16/18 Among Men From the HPV Infection in Men Study.

Human papillomavirus (HPV)-related oropharyngeal cancer (OPC) incidence is increasing among men. Biomarkers that can identify oral HPV16/18 infections likely to persist, the obligate precursor for HPV-OPC, are needed. We assessed the association between oral Epstein-Barr virus (EBV) and oral HPV16/18 persistence among 63 men in the HPV Infection in Men Study who tested positive for HPV16/18 at the baseline visit. Control of oral coinfections, including EBV, could serve as a biomarker of immune competence and the ability to control oral HPV. Detection of oral EBV was significantly associated with oral HPV16/18 ≥12-month persistence. Detection of oral EBV deserves evaluation as a biomarker for oral HPV persistence and HPV-related OPC.

Long-Term Toxic Effects, Swallow Function, and Quality of Life on MC1273: A Phase 2 Study of Dose De-escalation for Adjuvant Chemoradiation in Human Papillomavirus-Positive Oropharyngeal Cancer

Patients with human papillomavirus oropharyngeal cancer are highly curable but risk significant long-term toxic effects with standard therapy. This study investigated a de-escalation strategy of decreased adjuvant radiation therapy and chemotherapy after transoral robotic surgery, and reports on long-term functional and quality of life (QOL) outcomes. Eligible patients had a p16-positive oropharyngeal cancer and ≤10 pack-year smoking history and underwent surgery followed by treatment with either 30 Gy delivered in 1.5-Gy fractions twice per day over 2 weeks with weekly docetaxel (15 mg/m2) if they had intermediate pathologic risk factors or 36 Gy in 1.8-Gy fractions twice per day over 2 weeks with the same chemotherapy if they had extranodal extension. Toxic effects, swallow function, and QOL were measured longitudinally. Seventy-nine patients (89.9% male) were treated and eligible for toxic effect and functional evaluation. Dry mouth was the most common grade 1 toxic effect at 1 year (55.6%), 2 years (53.3%), and 3 years (49.2%). The cumulative rates of grade 2 toxic effects at 1, 2, and 3 years were 1.4%, 6.7%, and 6.8%, respectively. There were only 2 grade 3 toxic effects at ≥1 year, including a grade 3 fatigue at 2.5 years, and a grade 3 superficial soft tissue fibrosis at 4 years. There were no grade 4 to 5 toxic effects. No patients were percutaneous endoscopic gastrostomy-dependent. Swallow function improved by 12 months posttreatment. QOL improved over time by all measurement tools and most patients returned to baseline level of function and QOL. De-escalated adjuvant therapy for select patients with human papillomavirus oropharyngeal cancer resulted in low rates of long-term toxic effects, excellent swallow outcomes, and preservation of global and xerostomia-related QOL.

Presurgical chemotherapy for HPV positive oropharyngeal squamous cancers.

e18022 Background: Human Papilloma Virus (HPV) related tumors of the oropharynx have been associated with an increase in survival for patients. Induction chemotherapy followed by surgery can maintain survival in select oropharyngeal squamous cancers (OPSCC) while avoiding radiotherapy, reducing overall treatment morbidity and deescalating treatment. In this study, all patients underwent planned induction chemotherapy and surgery with selective use of adjuvant, postoperative chemoradiotherapy (CRT). Methods: From 2008 to 2019, sixty-one patients with HPV positive oropharyngeal cancers were treated with induction chemotherapy followed by selective neck dissection and transoral resection of their primary disease. All patients were without distant metastasis at presentation. There were 56 men and 5 women with a mean age of 61 years. All patients were HPV+ via direct HPV immunohistochemistry (ISH). 44 patients were either never or long-term former smokers. 56 patients had primary disease in the tonsil, 4 in the base of tongue, 1 in the soft palate. 57/61 patients had nodal metastasis on presentation. All patients received induction chemotherapy inclusive of Cisplatin and Docetaxel (TP) of 2-4 cycles. 12 patients received either 5-FU or Cetuximab as well. Adjuvant chemoradiotherapy was deferred if patients had complete response (CR) to induction chemotherapy at the primary and neck, or with CR in the neck and partial response (PR) at the primary with negative surgical margins. Mean follow-up time was 3.2 years. Results: A CR to induction chemotherapy was achieved in 35/61 (57%) of patients. There were no treatment deaths or chemotherapy-related hospital admissions. 13/61 (21%) underwent adjuvant chemoradiotherapy. 14/61 (23%) patients with PR deferred chemoradiotherapy. 5 patients deferred chemoradiotherapy due to CR in the neck, 9 patients refused recommended chemoradiotherapy. 9/61 (15%) patients suffered recurrence of disease. Of these, 6 (67%) are currently free of disease (NED) as of most recent follow-up. Overall survival in this cohort was 95% (58/61), disease-free survival in this cohort was 85% (52/61). Smoking status (active vs former/non) was predictive of overall survival (p = .019). In total, 47/61 (77%) of patients were NED without undergoing chemoradiotherapy. Conclusions: This is a select series of patients with limited follow-up. However radiotherapy was avoided in most patients without sacrificing survival in this group with good overall prognosis. Appropriate use of induction chemotherapy and surgical management of oropharyngeal cancers is dependent upon the resectability of the primary on initial presentation (lack of significant local invasion). This study shows, for select HPV positive oropharyngeal cancers, induction chemotherapy followed by selective, trans-oral surgery allows for improved survival while avoiding the additional morbidity of (chemo)radiotherapy.

Expression of Sex Hormones in Oral Squamous Cell Carcinoma: A Systematic Review on Immunohistochemical Studies.

Oral squamous cell carcinoma (OSCC) is the most widespread oral malignancy. In the western world, smoking and alcohol remain the most common risk factors, whereas smokeless tobacco and areca nut consumption are the prevalent etiological factors in South Asia. Numerous markers were studied till date to identify the disease. However, the role of sex hormones in OSCC is poorly defined. Hormonal receptors play a role in breast cancer, prostate cancer, and human papillomavirus (HPV) driven oropharyngeal cancers. It is proven that the expression of estrogen receptor-α improved the overall survival of the patient with HPV-positive oropharyngeal cancer. Thus, this review article aims to determine the expression of sex hormones by immunohistochemistry in OSCC.This systematic review was performed with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement Criteria 2020. Relevant articles were collected from the electronic database in PubMed and Cochrane till 2021. Immunohistochemical studies on sex hormones and their role in OSCC published in English literature were included. We excluded case reports, case series, and abstract-only articles. The sample size of the selected studies varied, and these studies measured the parameters such as sex hormones and OSCC. Furthermore, all the studies used different sex hormones and their association with oral cancer through the immunohistochemical process. Thus, this review summarizes that sex hormones influence the biopathology of oral cancer and have a prognostic significance in the tumor subgroups.

The role of concomitant chemoradiotherapy versus radiation alone in T1-3N0 HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma

ObjectiveTo evaluate the role of curative intent concurrent chemoradiation (CCRT) vs radiation (RT) alone for T1-T3N0 HPV-positive and HPV-negative oropharyngeal squamous cell cancer (OPSCC). MethodsThe NCDB was queried for patients diagnosed between 2010 and 2017 with cT1-3N0M0 OPSCC treated with definitive RT or CCRT. Univariable analysis (UVA) and multivariable analysis (MVA) Cox regression analysis was performed with OS as the endpoint. Propensity score matching (PSM) 1:1 was performed. Interaction test to assess heterogeneity of treatment effect. ResultsA total of 2830 patients were queried. On MVA, CCRT was associated with improved OS for T3N0 tumors (HR 0.49; 95% CI 0.39–0.63) but not for T1N0 (HR 1.43; 95% CI 0.99–2.07) and T2N0 (HR 0.92; 95% CI 0.75–1.13). For T3 patients, CCRT improved OS for HPV-negative (HR 0.43; 95% CI 0.31–0.59) and HPV-positive tumors (HR 0.39; 95% CI 0.25–0.61). After PSM, CCRT was not statistically different to RT for patients with T1-2N0 HPV-negative tumors (HR 1.10; 95% CI 0.85–1.43; p = 0.48) and T1-2N0 HPV-positive tumors (HR 1.15; 95% CI 0.79–1.68; p = 0.45). After PSM, CCRT improved OS compared to RT alone for patients with T3N0 HPV-negative (HR 0.43; 95% CI 0.31–0.59; p < 0.01) and HPV-positive tumors (HR 0.39; 95 %CI 0.25–0.61; p < 0.01). ConclusionsCCRT is associated with improved OS in HPV-positive and HPV-negative T3N0 OPSCC. RT alone vs. CCRT demonstrated similar OS for T1-T2N0 OPSCC for both HPV negative and HPV positive tumors.

Clinical presentation and outcome of human papillomavirus-positive nasopharyngeal carcinoma in a North American cohort.

The objective of this study was to describe the clinical presentation and outcomes of human papillomavirus (HPV)-positive nasopharyngeal cancer (NPC) versus Epstein-Barr virus (EBV)-positive NPC and HPV-positive oropharyngeal cancer (OPC). Clinical characteristics and presenting signs/symptoms were compared between patients who had viral-related NPC versus viral-related OPC treated with intensity-modulated radiotherapy from 2005 to 2020 and who were matched 1:1 (by tumor and lymph node categories, smoking, age, sex, histology, and year of diagnosis). Locoregional control (LRC), distant control (DC), and overall survival (OS) were compared using the 2005-2018 cohort to maintain 2 years of minimum follow-up. Multivariable analysis was used to evaluate the cohort effect. Similar to HPV-positive OPC (n = 1531), HPV-positive NPC (n = 29) occurred mostly in White patients compared with EBV-positive NPC (n = 422; 86% vs. 15%; p < .001). Primary tumor volumes were larger in HPV-positive NPC versus EBV-positive NPC (median volume, 51 vs. 23 cm3 ; p = .002), with marginally more Level IB nodal involvement. More patients with HPV-positive NPC complained of local pain (38% vs. 3%; p = .002). The median follow-up for the 2005-2018 cohort was 5.3 years. Patients who had HPV-positive NPC (n = 20) had rates of 3-year LRC (95% vs. 90%; p = .360), DC (75% vs. 87%; p = .188), and OS (84% vs. 89%; p = .311) similar to the rates in those who had EBV-positive NPC (n = 374). Patients who had HPV-positive NPC also had rates of LRC (95% vs. 94%; p = .709) and OS (84% vs. 87%; p = .440) similar to the rates in those who had HPV-positive OPC (n = 1287). The DC rate was lower in patients who had HPV-positive disease (75% vs. 90%; p = .046), but the difference became nonsignificant (p = .220) when the analysis was adjusted for tumor and lymph node categories, smoking, and chemotherapy. HPV-positive NPC and EBV-positive NPC seem to be mutually exclusive diseases. Patients who have HPV-positive NPC have greater local symptom burden and larger primary tumors but have similar outcomes compared with patients who have EBV-positive NPC or HPV-positive OPC.

Combined chemoradiotherapy showed improved outcome with early-stage HPV-positive oropharyngeal cancers

BackgroundThe revised 8th Edition American Joint Committee on Cancer (AJCC) Head and Neck Staging Manual distinguishes HPV-mediated from non-HPV-mediated oropharyngeal cancer (OpSCC). The objective was to analyze OpSCC treatment modalities and outcomes.MethodsA retrospective study of OpSCC patients treated with radiotherapy or chemoradiotherapy between January 1st, 2000, and December 31st, 2008, as identified from the BC Cancer Registry. All patients received treatment at cancer clinics and had at least 5 years follow-up post-treatment. A total of 1259 OpSCC patients were identified. After initial chart reviews, 288 patients were excluded from further analysis and the majority (n = 198) was due to not receiving curative treatment. Based on the availability of formalin-fixed, paraffin-embedded (FFPE) tissue, patients were divided into two cohorts: Study Cohort (FFPE available, n = 244) and General Cohort (FFPE unavailable, n = 727). The Study Cohort was restaged according to AJCC 8th Edition based on p16 immunohistochemistry status. Kaplan-Meier analysis was used to estimate the 5-year overall survival (OS), disease-specific survival (DSS), and locoregional recurrence-free survival (LFS).ResultsAmong 971 patients, OpSCC age-adjusted incidence rate was observed to have increased from 2.1 to 3.5 per 100,000 between 2000 and 2008. The General Cohort was relatively older than the Study Cohort (60.1 ± 10.5 vs. 57.3 ± 9.4), but both cohorts were predominantly males (78.3% vs. 76.2%). Amongst the Study Cohort, 77.5% were p16-positive, of whom 98.4% were down staged in the 8th Edition. These early-stage patients showed OS improvement for those treated with chemoradiation, compared to radiation alone (85.8% vs. 73.1%, p = 0.05).ConclusionsOpSCC incidence is increasing in BC. The addition of chemotherapy to radiotherapy may portend a benefit in OS even for early-stage p16-positive OpSCC. Additional research is necessary to assess the safety of treatment de-escalation even among early-stage disease.

OC-0625 Differences between HPV positive and negative oropharyngeal cancer detected by Non-Gaussian IVIM

OC-0625 Differences between HPV positive and negative oropharyngeal cancer detected by Non-Gaussian IVIM

Patient Benefit and Quality of Life after Robot-Assisted Head and Neck Surgery.

Robotic systems for head and neck surgery are at different stages of technical development and clinical application. Currently, robotic systems are predominantly used for transoral surgery of the pharynx and larynx. Robotic surgery of the neck, the thyroid, and the middle and inner ear is much less common; however, some oncological and functional outcomes have been reported. This article provides an overview of the current state of robot-assisted head and neck surgery with a special emphasis on patient benefit and postoperative quality of life (QoL). The focus is placed on the role of transoral robotic surgery (TORS) for the resection of oropharyngeal carcinomas. For this application, reported long-term outcomes show functional post-operative advantages for selected oropharyngeal cancer patients after TORS compared to open surgery and primary radiotherapy. Since TORS also plays a significant role in the context of potential therapy de-escalation for HPV-positive oropharyngeal cancer patients, ongoing trials are presented. Regarding the evaluation of the therapeutic benefit and the QoL of cancer patients, special attention has to be paid to the large degree of variability of individual patients' preferences. Influencing factors and tools for a detailed assessment of QoL parameters are therefore detailed at the beginning of this article. Notably, while some robotic systems for ear and skull base surgery are being developed in Europe, TORS systems are mainly used in North America and Asia. In Europe and Germany in particular, transoral laser microsurgery (TLM) is a well-established technology for transoral tumor resection. Future trials comparing TORS and TLM with detailed investigation of QoL parameters are therefore warranted and might contribute to identifying suitable fields for the application of the different techniques.

Racial/ethnic disparities in HPV-related oropharyngeal cancer outcomes among males in the United States: a national cohort study

Racial/ethnic disparities in HPV-related oropharyngeal cancer outcomes among males in the United States: a national cohort study

Long term survival in patients with human papillomavirus-positive oropharyngeal cancer and equivocal response on 12-week PET-CT is not compromised by the omission of neck dissection

Background and AimThe aim of this study was to evaluate the long-term safety of the omission of immediate neck dissections (IND) in patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) achieving a less than complete nodal response on 12-week FDG PET-CT. Material and MethodsPatients with HPV-positive, node-positive HNSCC that were treated with radical (chemo) radiotherapy (RT) between January 2013 and September 2019 were identified. PET-CT responses were classified as complete (CR), incomplete (ICR) or equivocal (EQR) nodal responses. Clinical outcomes were obtained. Results347 patients were identified. Median follow-up was 43.9 (IQR, 30.8–61.2) months.62.8% (218/347) achieved a CR, 23.4% (81/347) EQR and 13.8% (48/347) ICR nodal response.70 of 81 (86.4%) patients with an EQR and 25 of 48 (52.1%) with an ICR had no residual disease during follow up (a pathologically negative ND if surgery undertaken or no subsequent neck or distant relapse clinically/radiologically).Median survival of the EQR and CR groups were not reached, and despite the omission of IND in 95% of the EQR group there was no statistically significant differences in overall survival (OS) between the groups, p = 1.0.Median survival of ICR was not reached. However, OS for ICR group was significantly worse than that of CR, and EQR, both p < 0.001. ConclusionThe omission of IND in those achieving an EQR nodal response does not compromise long-term survival. This supports the safety of extended surveillance in patients with HPV-positive disease and an EQR on 12-week FDG PET-CT.

Integrative genomic analysis reveals low T-cell infiltration as the primary feature of tobacco use in HPV-positive oropharyngeal cancer

SummaryAlthough tobacco use is an independent adverse prognostic feature in HPV(+) oropharyngeal squamous cell carcinoma (OPSCC), the biologic features associated with tobacco use have not been systematically investigated. We characterized genomic and immunologic features associated with tobacco use through whole exome sequencing, mRNA hybridization, and immunohistochemical staining in 47 HPV(+) OPSCC tumors. Low expression of transcripts in a T cell-inflamed gene expression profile (TGEP) was associated with tobacco use at diagnosis and lower overall and disease-free survival. Tobacco use was associated with an increased proportion of T > C substitutions and a lower proportion of expected mutational signatures, but not with increases in mutational burden or recurrent oncogenic mutations. Our findings suggest that rather than increased mutational burden, tobacco’s primary and clinically relevant association in HPV(+) OPSCC is immunosuppression of the tumor immune microenvironment. Quantitative assays of T cell infiltration merit further study as prognostic markers in HPV(+) OPSCC.

Longitudinal measurement of HPV copy number in cell-free DNA is associated with patient outcomes in HPV-positive oropharyngeal cancer

IntroductionOropharyngeal squamous cell carcinoma (OPSCC) is increasing in global prevalence and is divided into two types dependent on association with human papillomavirus (HPV). Assay of HPV copy number in plasma cell-free DNA (cfDNA) provides a minimally invasive method for detecting and monitoring tumour-derived HPV, with potential for enhancing clinical care. Materials and methodsIn a prospectively recruited cohort of 104 OPSCC patients, we evaluate the utility of cfDNA droplet digital PCR (ddPCR) as a method for characterisation and longitudinal monitoring of patients with OPSCC. ResultsddPCR assay of pre-treatment plasma cfDNA for five HPV types showed overall 95% concordance with p16 immunohistochemistry and PCR analysis of tumour tissue. Longitudinal sampling in 48 HPV+ve patients, with median follow-up of 20 months, was strongly associated with patient outcomes. Persistently elevated cfDNA-HPV post-treatment was associated with treatment failure (2/2 patients) and an increase of cfDNA-HPV in patients whose HPV levels were initially undetectable post-treatment was associated with disease recurrence (5/6 patients). No recurrence was observed in patients in whom cfDNA-HPV was undetectable in all post-treatment samples. In two patients, sequential HPV measurement could have avoided surgical intervention which did not confirm recurrence. ConclusionThe high concordance of pre-treatment plasma cfDNA-HPV analysis with tissue-based assays, together with the clinical associations of sequentially measured post-treatment cfDNA-HPV copy number add to a growing body of evidence that suggest utility of cfDNA-HPV ddPCR in management of OPSCC. Standardised clinical trials based on these data are now needed to assess the impact of such testing on overall patient outcomes.

More than cervical cancer: Understanding racial/ethnic disparities in oropharyngeal cancer outcomes among males by HPV status.

Context: Over the last two decades the incidence of male oropharyngeal cancers (OPCa) has increased rapidly in the United States, yet OPCa is mostly preventable. Differences in OPCa incidence and outcomes by race/ethnicity and human papillomavirus (HPV) status have not been previously studied. Objective: Examine racial/ethnic disparities in HPV-related and non-HPV related OPCa outcomes among males. Study Design: Nationwide population-based retrospective cohort study. Setting or Dataset: North American Association of Central Cancer Registries' Cancer in North America Deluxe dataset, covering 93% of the U.S. population. Population studied: Males diagnosed with OPCa in the U.S. between January 2005 and December 2016 (N=175,843). Outcome Measures: OPCa incidence rates by race/ethnicity [Non-Hispanic White, Non-Hispanic Black, Hispanic, Non-Hispanic Other] and HPV status (HPV-related or non-HPV-related); late-stage diagnosis; mean and cumulative survival; cancer-specific mortality. Results: Most male OPCa were HPV-related (92.2%) and in Whites (83.6%), with over 50% increase from 2005 to 2016 in age-adjusted incidence of late-stage HPV-related OPCa among Whites. There was no difference in late-stage diagnosis between Whites and Blacks (aOR, 0.99, 95% CI, 0.94-1.05) or Hispanics (aOR, 0.96, 95% CI, 0.89-1.03), while Other race had 15% lower odds of late-stage diagnosis (95% CI, 0.79-0.95). Independent predictors of late-stage disease included having Medicaid (aOR, 1.37, 95% CI, 1.28-1.46) or no insurance (aOR, 1.44, 95% CI, 1.32-1.57) and HPV-related OPCa (aOR, 3.53, 95% CI, 3.37-3.70). Lower mean survival in HPV-related OPCa compared with Whites (99.63 months, 95% CI, 99.18-100.07) was seen among Blacks (69.72 months, 95% CI, 68.14-71.31) and Hispanics (91.89 months, 95% CI, 89.87-93.91; p < 0.01). Blacks had lowest adjusted cumulative survival for HPV and non-HPV related OPCa (p<0.001). Blacks (aHR, 1.78, 95% CI, 1.70-1.87), Hispanics (aHR, 1.11, 95% CI, 1.03-1.19), and HPV-related OPCa (aHR, 1.25, 95% CI, 1.17-1.34) had higher cancer-specific mortality. Adjusting for treatment eliminated the higher mortality among Hispanics, but not in Blacks. Conclusions: To decrease incidence rates of late stage OPCa, HPV vaccination and possibly, HPV OPCa screening should be advocated, especially in White males. Further research to explicate possible biologic mechanisms and behaviors or comorbidities contributing to the higher OPCa mortality among Black males is needed.

Comparison of next generation sequencing, droplet digital PCR, and quantitative real-time PCR for the earlier detection and quantification of HPV in HPV-positive oropharyngeal cancer

BackgroundHuman papillomavirus (HPV) causes nearly 80% of oropharynx cancers diagnosed in the United States, with incidence increasing each year. Analysis of cfDNA in plasma and oral rinse has the potential to detect these cases earlier than their typical presentation, but their utility and the best method to detect HPV in plasma and oral rinse samples is unknown. Materials and MethodsWe directly compared next generation sequencing (NGS), droplet digital PCR (ddPCR), and quantitative real-time PCR (qPCR) for their ability to detect HPV16 DNA in plasma and oral rinse from 66 patients diagnosed with HPV16-positive oropharyngeal cancer (HPV16-OPC). ResultsHPV DNA detection by NGS and ddPCR in plasma samples both had good sensitivity (70%) for HPV16-OPC compared to 20.6% sensitivity by qPCR (p < 0.001). In oral rinse, NGS demonstrated a superior sensitivity of 75.0% as compared to both ddPCR (8.3%, p < 0.001) and qPCR (2.1%, p < 0.001). In a limited cohort of follow up patients, HPV levels detected in plasma by NGS but not ddPCR or qPCR reflected disease remission or progression. ConclusionsThese results suggest that NGS has the best sensitivity for detecting HPV in both plasma and oral rinse and may play a role in monitoring patients for disease recurrence. Additional studies are needed to define the specificity of NGS for similar patient cohorts.

Rising incidence of HPV positive oropharyngeal cancer in Taiwan between 1999 and 2014 where betel nut chewing is common

BackgroundThe incidence of human papillomavirus (HPV) positive oropharyngeal cancer (OPC) is rising but HPV negative OPC is decreasing in Western countries. In Taiwan, the incidence of HPV negative OPC is common but the incidence of HPV positive OPC remains unknown. The objective of this study is to estimate the incidence trend and the survival of HPV positive OPC in Taiwan.MethodsBetween 1999 and 2014, primary tumor tissues from 425 incident OPCs were obtained from 5 medical centers in Taiwan. 408 OPCs were evaluated by the EasyChip HPV genotyping (King-Car, I-Lan, Taiwan) and 369 OPCs by p16 staining. The clinical data were retrospectively obtained from the medical records.ResultsIn our study, 29% of OPCs were HPV positive. The percentage of HPV positive OPC was stable from 1999 to 2014 (25% (1999–2002), 30% (2003–2006), 30% (2007–2010), 29% (2011–2014)). The estimated crude incidence rate of HPV positive OPC increased significantly from 0.62 (1999–2002), 1.06 (2003–2006), 1.52 (2007–2010) to 1.74 (2011–2014) per 100,000 person-year. The sensitivity and specificity of p16 staining for positive HPV infection were 92% and 91%, respectively. The 5-year overall survival rates for patients with HPV positive OPC and with HPV negative OPC were 67.8% and 49.0%, respectively (HR = 0.52 (0.35–0.76), p = 0.0005). Patients with HPV positive OPC but no betel nut/cigarette exposure had the best overall survival (5-year: 88.2%, p < 0.0001). Patients with HPV negative OPC and betel nut/cigarette exposure had the worst overall survival (5-year: 46.6%, p < 0.0001). Patients with HPV positive OPC but also with betel nut/cigarette exposure had poorer 5-year overall survival (48.3%, p < 0.01).ConclusionThe incidence of HPV positive OPC is increasing along with HPV negative OPC, which leads to stably low percentage of HPV positive OPC in Taiwan. HPV positive OPC may become an important head and neck cancer when the incidence of HPV negative OPC declines in the near future. P16 is a useful surrogate marker for HPV infection in OPC and a good prognostic indicator for treatment outcome of OPC. Patients with HPV positive OPC but no betel nut/cigarette exposure has an excellent prognosis. Betel nut/cigarette exposure significantly worsens the prognosis of HPV positive OPC.

Highlights from the 2021 ASCO and ESMO annual meetings on radiotherapy of head and neck cancer

At this year's annual meetings of the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO), several studies on radiotherapy of locally advanced head and neck cancer were presented. For the indication of definitive radiochemotherapy, particularly the administration of immune checkpoint inhibitors concomitant to radiotherapy was investigated. In the phaseIII GORTEC-REACH trial, combined inhibition of epidermal growth factor receptor (EGFR) and programmed death-ligand (PD-L1) concomitant to radiotherapy of locally advanced head and neck cancer was inferior to platinum-based chemoradiotherapy. However, this therapeutic approach may be more efficient than radiotherapy with simultaneous EGFR inhibition alone. The concept of the phaseII CheckRad-CD8 trial with induction chemoimmunotherapy followed by chemotherapy-free radioimmunotherapy after appropriate patient selection also proved to be highly efficient. In initial phaseII trials, dose de-escalation of radiotherapy seems feasible for HPV-positive oropharyngeal cancer after appropriate patient selection both postoperatively (ECOG-ACRIN E3311 trial) and after induction therapy (OptimaII trial). However, dose de-escalation should currently not be performed outside of clinical trials. In addition, first studies indicate abenefit of functional imaging (diffusion-weighted magnetic resonance imaging [MRI] or F‑fluoromisonidazole positron-emission tomography [FMISO-PET]) to establish personalized dose concepts in radiotherapy.

Kinetics of Circulating Human Papillomavirus (cHPV) DNA in Plasma and Oral Gargles From Patients with HPV-Positive Oropharyngeal Cancer (OPC) Treated with Definitive Radiation Therapy

<h3>Purpose/Objective(s)</h3> Changes in cHPV DNA copy numbers and absence of detectable oral HPV DNA during and after treatment may be biomarkers of treatment response and recurrence. The goal of this study was to assess the kinetics of oral and plasma HPV DNA among HPV positive OPC patients pre, during and post radiation treatment. <h3>Materials/Methods</h3> Patients with T0-2 N0-1 p16 positive OPC were enrolled to a personalized radiation treatment trial where a total dose of 60-70 Gy based on size of largest lesion was delivered. Plasma and oral gargle was collected prior to treatment, during week 4 of treatment, at end of treatment (EOT), and 2-3 months post-treatment. Tumor-tissue-modified human papillomavirus (TTMV) DNA copy numbers were quantified in plasma (Naveris, Natick, MA). HPV genotyping of oral cell DNA was performed utilizing the HPV SPF₁₀ PCR-DEIA-LiPA₂₅ line probe assay system. Statistics were performed via Fisher's exact test. <h3>Results</h3> 33 patients with circulating TTMV and oral HPV genotyping were included. Patients with tonsil primaries were more likely to have detectable oral HPV (9/13) compared with BOT (6/20) (p=0.038). Of the 30 patients that were plasma TTMV positive, 15 were oral gargle positive. Of the 30 pretreatment TTMV positive patients, 11 of 30 (36.7%) had undetectable TTMV levels at week 4 of radiation therapy, 18 of 29 patients (62.1%) were TTMV negative by EOT, and 26 of 27 (96.3%) patients were negative at 3 months post-treatment. The one patient who remained TTMV positive at 3 months had a bone metastasis. Retrospective review of pretreatment imaging revealed that this was an undiagnosed metastasis in the bone at the time of trial enrollment. Oral HPV DNA was cleared in 12 of the 15 initially positive patients (80%) at 4 weeks, 14 of 15 patients (93.3%) at EOT, and 15 of 15 patient (100%) at 3 months. All patients had no evidence of disease clinically and radiologically at their 3 month post-treatment follow up visit, except for the one patient who was metastatic at presentation. TTMV clearance at 4 weeks was associated with a >30% volumetric imaging response at 4 weeks with 13 of 14 patients who had undetectable TTMV levels at 4 weeks also having with a >30% volumetric response as compared to 5 of 13 patients who did not have TTMV HPV clearance at 4 weeks but having a >30% volumetric imaging response (p=0.003). Clearance of oral HPV DNA was not associated with a partial response at 4 weeks. <h3>Conclusion</h3> Circulating TTMV copy numbers are detected in the majority of p16 positive OPC at diagnosis. TTMV clearance at 4 weeks is associated with a robust radiological response, suggesting radiosensitivity. These patients may represent a subset that would be candidates for de-escalation strategies.

A Prospective Study of Mucosal Sparing Proton Beam Therapy in Resected Oropharyngeal Cancer Patients

<h3>Purpose/Objective(s)</h3> Oropharyngeal cancer (OPC) patients (pts) undergoing postoperative radiation therapy (RT) are routinely treated to the postoperative primary site and neck(s) after transoral surgery (TOS). Elimination of the postoperative primary site from the radiation target in select cases may not increase the risk of local recurrence and improve tolerability of RT. We report the results of a prospective study utilizing mucosal sparing proton beam therapy (PBT). <h3>Materials/Methods</h3> From 3/2016-5/2019, 64 pts were enrolled at our multi-site institution on an IRB approved prospective trial with a primary 2 year (yr) local control (LC) endpoint. AJCC 7^th edition stage III/IVA pT1-2 N1-3M0 p16+ OPC pts underwent TOS (negative margins) with neck dissection with indications for adjuvant RT due to pathologic N2 or extranodal extension. PBT was delivered to at risk nodal regions, excluding the primary mucosal site. Secondary to insurance denial for PBT, IMRT was allowed. CTCAE v5.0, EORTC HN-QLQ 35 survey (QOL), and modified barium swallowing impairment profiles (MBSImP) were obtained at baseline prior to RT, then 3 months (mo) and 12 mo post RT. Kaplan-Meier estimates were calculated for time-to-event clinical outcomes and repeated measures mixed models were utilized for explore changes in QOL over time. <h3>Results</h3> There were 61 evaluable pts with a median follow up of 38 mo (range, 10 – 64 mo.). The majority were males (93.4%) and received adjuvant PBT (72.2%). Two yr LC is 98.4% with one local recurrence reported at 9 mo after RT. Two yr locoregional control (LRC) is 96.7%. Two yr overall survival (OS), progression free survival (PFS), and distant metastasis free survival (DMFS) are 100%, 94.9%, and 98.1%, respectively. Six pts reported treatment related grade 3 adverse events (AEs) during treatment (5, dermatitis and 1, nausea) with no grade ≥ 3 reported at 3 mo post PBT and beyond. Two IMRT pts required PEG tube placement during treatment secondary to significant nausea due to dysgeusia. Pts noted significant QOL improvement over time in the pain, swallowing, senses, speech, contact, mouth opening domains (all p < 0.05). MBSImP overall severity score as well as oral and pharyngeal impairment scores showed stability with no significant change over time. Dosimetric analysis of incidental PBT dose to the hypothetical CTV of the primary mucosal site revealed a mean D95 of 963 cGy (SD±930). <h3>Conclusion</h3> Mucosal sparing PBT is tolerated well in select resected HPV related OPC with a low risk of recurrence at the mucosal primary site and reduced toxicity burden.