P16-positive Oropharyngeal Cancer Research Articles

Clinical and molecular characteristics of Jordanian oropharyngeal cancer patients according to P16 expression: a retrospective study and a report of a novel biomarker.

The purpose of this study was to assess the clinicopathological features of oropharyngeal cancer patients in Jordan based on their HPV status. Sixty-nine biopsies from two hospitals were included. Tissue microarrays were prepared from formalin-fixed paraffin-embedded (FFPE) specimens andstained with antibodies for CDKN2A/P16, EGFR, PI3K, PTEN, AKT, pS473AKT, PS2mTOR, and TIMAP. The cohort was divided according to P16 expression. Chi-square test and survival analyses were employed to evaluate the variations among the study variables and determine the prognostic factors, respectively. P16 expression was found in 55.1% of patients; however, there was no significant association between P16 expression and the patients' clinicopathological features. The Kaplan-Meier test revealed that smoking in P16-positive group and younger age (< 58years) negatively impacted disease-free survival (DFS) (P = 0.04 and P = 0.003, respectively). Multivariate Cox regression test indicated that smoking, age, PI3K, and AKT were negative predictors of DFS (P = 0.021, P = 0.002, P = 0.021, and P = 0.009, respectively), while TIMAP was a positive predictor (P = 0.045). Elevated P16 expression is found in more than half of the patients' specimens. DFS is negatively affected by younger age and the combined effect of smoking and P16 overexpression. TIMAP is overexpressed in P16-positive oropharyngeal cancer, and it is a favorable predictor of DFS.

A Retrospective Analysis from Western Romania Comparing the Treatment and Survivability of p16-Positive versus p16-Negative Oropharyngeal Cancer.

Oropharyngeal cancer is a global health concern due to its multifaceted nature. Recent molecular studies have linked p16 overexpression, associated with the human papillomavirus, to oropharyngeal cancer and its prognostic implications. This retrospective study in Western Romania examined 60 patients, categorizing them based on p16 biomarker status: 28 were p16 positive, and 32 were p16 negative. Statistical tests, including Fisher's exact and chi2, were used for analysis. Patients with p16-positive oropharyngeal cancer exhibited a better prognosis (3-year survival, p = 0.0477; midtreatment, p = 0.0349) and reported lower alcohol (p = 0.0046) and tobacco (p < 0.0001) use. The study highlights the importance of p16 testing in oropharyngeal carcinoma diagnosis. It suggests modifying treatment approaches based on p16 status and underscores the differing prognoses associated with p16-positive and p16-negative cases.

TSPO is a potential independent prognostic factor associated with cellular respiration and p16 in head and neck squamous cell carcinoma.

Treatment resistance and relapse are common problems in head and neck squamous cell carcinoma (HNSCC). Except for p16, no clinically accepted prognostic biomarkers are available for HNSCC. New biomarkers predictive of recurrence and survival are crucial for optimal treatment planning and patient outcome. High translocator protein (TSPO) levels have been associated with poor survival in cancer, but the role of TSPO has not been extensively evaluated in HNSCC. TSPO expression was determined in a large population-based tissue microarray cohort including 611 patients with HNSCC and evaluated for survival in several clinicopathological subgroups. A TCGA HNSCC cohort was used to further analyze the role of TSPO in HNSCC. TSPO expression was downregulated in more aggressive tumors. Low TSPO expression associated with worse 5-year survival and was an independent prognostic factor for disease-specific survival. Subgroup analyses showed that low TSPO expression associated with worse survival particularly in p16-positive oropharyngeal cancer. In silico analyses supported the prognostic role of TSPO. Cellular respiration had the highest significance in pathway analyses for genes expressed positively with TSPO. Decreased TSPO expression associates with poor prognosis in HNSCC. TSPO is a prognostic biomarker in HNSCC to potentially guide treatment stratification especially in p16-positive oropharyngeal cancer.

Abstract PO-066: Complete pathological response following neoadjuvant chemotherapy and recurrence free survival in patients with p16-positive oropharyngeal cancer

Abstract Introduction: Locoregionally advanced p16+ squamous cell carcinoma of the oropharynx (OPSCC) is most often treated either with primary chemoradiation (CRT) or surgery followed by adjuvant treatment. Surgery alone is often insufficient treatment as adverse features such as extranodal extension, close or positive margins, lymphovascular invasion, or multiple positive lymph nodes are often identified, resulting in the need for adjuvant radiation or CRT. Primary surgery is often not pursued in more advanced cases since surgical pathology may show adverse features requiring adjuvant CRT, resulting in "triple therapy", the effects of which may worsen risk of long-term treatment toxicity. Our institution has demonstrated excellent oncologic and quality of life outcomes using a neoadjuvant chemotherapy (NAC) regimen of cisplatin and docetaxel prior to surgical treatment with TORS and neck dissection. Due to high rates of clinical-to-pathologic downstaging, adjuvant treatment is often avoided entirely. Here, we explore whether the development of a complete pathologic (pCR) response following NAC associates with 2-year recurrence free survival. Methods: A retrospective cohort study of patients receiving neoadjuvant doublet cisplatin and docetaxel followed by surgery (NAC+S) at a single institution between October 2015 and March 2023 was performed and pathologic responses and 2-year recurrence free survival was recorded following IRB exemption. Results: Fifty-four patients with p16+ OPSCC treated with NAC+S were identified. 49 patients (91%) received three cycles of NAC; 5 patients (9%) received two cycles. Comparing clinical staging to pathologic analysis of surgical specimens, 40 of 54 patients (68%) experienced clinical-to-pathologic downstaging after NAC. A pCR was identified in 23 of 54 patients (43%). Of patients that did not develop a pCR, 9 of 31 patients (29%) received adjuvant treatment due to the identification of high-risk pathologic features. Of patients that developed a pCR, 1 of 23 (4%) developed disease relapse within 2 years. Of patients that did not develop a pCR but did not require adjuvant treatment, 2 of 22 (9%) developed disease relapse within 2 years. Of patients that did not develop a pCR but did require adjuvant treatment, 2 of 9 (22%) developed disease relapse within 2 years. A trend toward reduced risk of disease relapse was observed in patients that develop a pCR following NAC compared to those that do not but did not reach statistical significance (1 of 23 relapses with pCR, 4 of 31 relapses without pCR; P&amp;gt;0.05, two-sided Chi-square test). Conclusion: High rates of pCR following NAC were observed in this small retrospective cohort of patients with newly diagnosed p16+ OPSCC despite 84% of patients avoiding any adjuvant treatment. Patients that develop a pCR after NAC trend toward reduced risk of recurrence compared to those that do not. The development of pCR after NAC may be a suitable short-term clinical outcome measure in prospective clinical trials of NAC for patients with newly diagnosed p16+ OPSCC. Citation Format: Alisha R. Pershad, Maxwell Madani, Timothy B. Shaver, Arjun Joshi, Clint T. Allen, Joseph F. Goodman. Complete pathological response following neoadjuvant chemotherapy and recurrence free survival in patients with p16-positive oropharyngeal cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-066.

Protease-Activated Receptor 1 (PAR1) Expression Contributes to HPV-Associated Oropharyngeal Cancer Prognosis.

Human papillomavirus (HPV)-associated oropharyngeal cancer occasionally has a poor prognosis, making prognostic risk stratification crucial. Protease-activated receptor-1 (PAR1) is involved in carcinogenesis, and its expression is regulated by alpha-arrestin domain-containing protein 3 (ARRDC3). It is also involved in the tumor microenvironment. We sought to evaluate the predictive ability of PAR1, ARRDC3, and tumor-infiltrating lymphocyte (TIL) scores in patients with oropharyngeal, hypopharyngeal, and uterine cervical cancers, serving as comparators for HPV-associated oropharyngeal cancer. Immunohistochemical analysis of p16, ARRDC3, and PAR1 expression was performed on 79 oropharyngeal, 44 hypopharyngeal, and 42 uterine cervical cancer samples. The TIL scores were assessed and classified into the following groups based on invasion: low: 0-10%, medium: 20-40%, and high: > 50%. For prognostic analysis, the three groups were evaluated by dividing them into low, medium, and high categories, or alternatively into two groups using the median value as the cutoff. p16 was expressed in 44 (56%) oropharyngeal, 8 (18%) hypopharyngeal, and all uterine cervical cancer samples. ARRDC3 was detected in 39 (49%) oropharyngeal, 25 (57%) hypopharyngeal, and 23 (55%) uterine cervical cancer samples. PAR1 was expressed in 45 (57%) oropharyngeal, 22 (50%) hypopharyngeal, and 22 (50%) uterine cervical cancer samples. Patients diagnosed with p16-positive oropharyngeal cancer had a substantially improved prognosis compared to those diagnosed with p16-negative cancer. The PAR1-negative cases had a considerably improved prognosis compared to the positive cases (disease-specific survival [DSS] and -negative cases (disease-free survival [DFS]). Multivariate analysis revealed that ARRDC3-positive cases had an appreciably better DSS prognosis than patients with p16-negative oropharyngeal cancers. PAR1-positive patients among patients with p16-positive oropharyngeal cancer had a poor prognosis. With respect to DFS, patients with PAR1-positive and p16-negative oropharyngeal cancer had a 35-fold higher recurrence rate than those with PAR1-negative and p16-negative oropharyngeal cancer. Our results suggest that PAR1 expression affects the prognosis and recurrence rate of HPV-associated oropharyngeal cancer.

Tumor immune microenvironment alterations using induction cetuximab in a phase II trial of deintensified therapy for p16-positive oropharynx cancer.

We sought to characterize early changes in CD8+ tumor-infiltrating lymphocytes and tumor transcriptomes after induction cetuximab in a cohort with p16-positive oropharyngeal cancer on a phase II clinical de-escalation trial. Tumor biopsies were obtained before and 1week after a single cetuximab loading dose in eight patients enrolled in a phase II trial of cetuximab and radiotherapy. Changes in CD8+ tumor-infiltrating lymphocytes and transcriptomes were assessed. One week after cetuximab, five patients (62.5%) had an increase in CD8+ cell infiltration with a median (range) fold change of +5.8 (2.5-15.8). Three (37.5%) had unchanged CD8+ cells (median [range] fold change of -0.85 [0.8-1.1]). In two patients with evaluable RNA, cetuximab induced rapid tumor transcriptome changes in cellular type 1 interferon signaling and keratinization pathways. Within 1week, cetuximab induced measurable changes in pro-cytotoxic T-cell signaling and immune content.

The value of serum p53 antibody as a biomarker in oral and pharyngeal squamous cell carcinoma

Background The development of more sensitive biomarkers for the detection of early-stage head and neck squamous cell carcinoma is needed. Aims/Objectives This study was performed to assess the value of serum p53 antibody (s-p53-Ab) as a biomarker for oral and pharyngeal carcinoma. Material and Methods Pre-treatment serum was collected for 71 patients with oral and pharyngeal carcinoma and 117 healthy volunteers as controls and analyzed s-p53-Ab using enzyme-linked immunosorbent assay (ELISA). Results Using 1.3 U/mL as the cut-off value, 14 of 71 patients (sensitivity 19.7%), and 12 of 117 control cases were positive for s-p53-Ab (specificity 89.7%). Excluding 12 cases of p16-positive oropharyngeal and nasopharyngeal cancer which were all negative for s-p53-Ab, the sensitivity in early-stage 1–2 cases was 30.0%, which was higher than conventional tumor markers. Conclusions and Significance The s-p53-Ab was not detected in any cases of virus-related cancer in which p53 gene mutations were not involved in carcinogenesis. Since the s-p53-Ab sensitivity was high even in early-stage disease, s-p53-Ab measurement may be useful as an early diagnostic biomarker in patients with oral, p16- oropharyngeal, and hypopharyngeal cancer.

Importance of the Number and Location of Lymph Node Metastasis in Oropharyngeal Cancer.

The 8th edition of the American Joint Committee on Cancer staging system classifies oropharyngeal cancer (OPC) by the expression of p16. The discrepancy observed in this system between pathological and clinical N-stages in p16-positive OPC has provoked controversy. Therefore, this study investigated prognostic factors not included in the new staging system for p16-positive OPC patients. Patients with non-metastatic OPC receiving radiotherapy were reviewed. Clinical lymph node statuses were reassessed based on contrast-enhanced computed tomography and fluorodeoxyglucose positron emission tomography. Overall survival (OS) and cause-specific survival (CSS) were analyzed using multivariate analyses to adjust baseline imbalances. In total, 166 OPC patients were reviewed. Among them, 81 patients with p16-positive were analyzed. Three or more lymph node metastases (LNM) were observed in 21 p16-positive OPCs. Retropharyngeal lymph node metastasis (Rp) was found in 12. Three-year OS, CSS, and progression-free survival rates in p16-positive patients were 76, 88, and 81%, respectively. In multivariate analyses of p16-positive OPC, LNM ≥3 was a prognostic factor of OS (hazard ratio=9.30, p<0.001) and CSS (hazard ratio=17.80, p=0.005). Rp was associated with poor CSS (hazard ratio=8.73, p=0.03). In N0-1 p16-positive patients, LNM ≥3 trended to be associated with poor OS (hazard ratio=3.93, p=0.06). CSS in patients with Rp was unfavorable (hazard ratio=70.16, p=0.05). LNM ≥3 and Rp may be predictive of OS and CCS in p16-positive OPC. These are also possibly used to subcategorize p16-positive cN0-1 OPC. Further validation of lymph node staging is needed to refine the clinical staging system.

Prognostic stratification of oropharyngeal cancer patients in a betel nut chewing and low HPV area

BackgroundThis study aimed to establish a simple predictive model for oropharyngeal cancer (OPC) in an area with a relatively low prevalence of human papillomavirus (HPV) and frequent betel nut chewing.MethodsA total of 116 patients with OPC were recruited from the clinical research database of a referral cancer center between 2013 and 2018. Patient characteristics—including age, gender, tumor stage, differentiation, and treatment modality—were extracted from the database. Patients diagnosed after 2018 were staged using the 7th AJCC staging system to explore the impact of extra-nodal tumor extension (ENE) on survival. Immunohistochemical analysis was performed for p16, epidermal growth factor receptor (EGFR), p53, and programmed cell death ligand 1 (PD-L1). ENE status was evaluated by pathological analysis or radiological features. Primary outcome was disease-specific overall survival (OS). Univariate and multivariate Cox regression were used to establish a predictive model.ResultsMean age was 57.3 ± 9.9 years; 103 patients (88.8%) were male. P16 positive OPC was positively associated with higher PD-L1 and a tonsillar sub-site and negatively associated with betel nut chewing and cigarette smoking. In Cox regression, age, p16 status, EGFR, cT4, ENE, and cigarette smoking were significantly associated with OS. In survival tree analysis, cT stage was the most important risk stratification parameter, followed by EGFR expression and p16 status. Patients with cT4 stage or high EGFR were classified as the high-risk group and had poorest OS.ConclusionsDue to the low prevalence of HPV and popularity of betel nut chewing in Asia, the relative importance of prognostic predictors for OPC are not identical to Western countries. Identification of significant prognostic biomarkers may improve treatment.Trial registration This study was registered and approved by the Institutional Review Board (IRB) of Kaohsiung Veterans General Hospital (VGHKS19-CT9-07; date of approval: Aug 9, 2019).Graphic

Intra-Treatment Tumor Apparent Diffusion Coefficient, a Quantitative Imaging Metric, is Associated with Neck Nodal Recurrence in De-Escalated Treatment of HPV-Positive Oropharyngeal Cancer (OPC)

<h3>Purpose/Objective(s)</h3> De-escalation strategies for the treatment of HPV-associated OPC show promise for effective, less toxic treatment. However, identifying accurate markers of more aggressive subsets of HPV OPC remains challenging. The 30 Reduction in Radiation for OPC (ROC) trial prospectively used intra-treatment ¹⁸F-FMISO imaging to selectively de-escalate patients to 30Gy chemoradiotherapy, however, a subset of patients still developed nodal recurrence. We hypothesized that diffusion-weighted (DW) MRI-derived quantitative imaging metrics, such as apparent diffusion coefficient (ADC), a surrogate marker of tumor cellularity based on water diffusion patterns, might help identify patients at high risk of recurrence and enable broader use of de-escalation strategies<b>.</b> <h3>Materials/Methods</h3> The 30 ROC trial enrolled patients with p16-positive OPC, cT0-2, N1-2c (AJCC 7^th ed). All patients had pre-treatment ¹⁸F-FMISO (fluoromisonidazole) PET scan and those with baseline nodal hypoxia underwent a 2^nd intra-treatment scan. All patients underwent primary site surgery where negative margin was not required. All patients had gross neck nodal disease. Those with intra-treatment resolution of nodal hypoxia or without initial hypoxia were de-escalated to 30Gy (non-hypoxic group) with 2 cycles of concurrent chemotherapy, while those with persistent radiographic hypoxia (hypoxic group) were treated to 70Gy. Standard T1, T2 weighted, and multiple b-value DW-MRI data were acquired pre-treatment and weekly during the first 4 weeks of treatment. Two radiation oncologists delineated nodal tumor regions of interest (ROIs) in a blinded fashion with ITK-SNAP on DW images (b= 0 s/mm²). Multiple b-value DW data were fitted to a monoexponential model to calculate ADC (mm²/s). The data analysis was performed on ROIs and voxel-wise using the in-house developed tool MRI-QAMPER. Standard statistical analysis was performed using MRI and clinical response data based on RECISTv1.1 provided by a radiologist. <h3>Results</h3> 158 patients were enrolled, of whom 95 had pre-treatment DW-MRI data available with tumor ROI with ADC values. Based on overall ¹⁸F-FMISO imaging, 12.6% (12/95) exhibited persistent hypoxia and 87.4% (83/95) had resolved/no hypoxia. All patients with nodal recurrences were in the de-escalated non-hypoxic group (8/83). Pre-treatment ADC was not different between overall hypoxic and non-hypoxic groups. Among de-escalated patients, those who developed nodal recurrence exhibited significantly different intra-treatment ADC at week 3 (before completing 30Gy) relative to those who did not recur (P<0.05, Wilcoxon rank-sum test). <h3>Conclusion</h3> The quantitative imaging metric, ADC, reflects both the restricted and hindered Brownian motion of water molecules in tumor tissue. Thus, ADC may be a useful intra-treatment marker to identify patients at risk for nodal recurrence to benefit from the incorporation of an upfront planned neck dissection after 30Gy as part of the de-escalation strategy.

The accuracy of clinical neck staging for p16-positive and negative oropharyngeal cancer and its therapeutic implications

PurposeOropharyngeal squamous cell carcinoma (OPSCC) may be treated with primary surgery or primary (chemo)radiation. While surgery with concurrent neck dissection provides definitive pathological staging of the neck, non-surgical treatment relies on clinical staging for treatment planning. To assess the accuracy of clinical neck staging, we compared clinical to surgical staging after primary surgery in patients with p16-negative and p16-positive OPSCC.MethodsRetrospective analysis of clinical, pathological, and oncologic outcome data of patients with OPSCC treated with primary surgery and bilateral neck dissection. Clinical and pathological nodal status were compared for p16-negative and p16-positive patients. Patients with occult metastatic disease were analyzed in detail.Results95 patients were included. 60.5% of p16-negative patients and 66.6% of p16-positive patients had pathologically confirmed metastatic neck disease. p16-positive patients had improved 24-month recurrence-free survival compared to p16-negative patients at 93.3% vs. 69.6%. Pathological N-status differed from clinical N-status in 36.8% of p16-negative patients vs. 31.6% of p16-positive patients. Occult metastatic disease was more common in p16-negative patients at 18.4% vs. 8.8% for p16-positive patients. Clinical detection sensitivity for extranodal extension was low overall; sensitivity was 27.3% and specificity was 91.6% for p16-negative patients vs. 61.5% and 80.0% for p16-positive patients, respectively.ConclusionOur data show a considerable degree of inaccuracy of clinical neck staging results in all OPSCC patients which needs to be taken into consideration during therapy planning. For p16-positive patients, these findings warrant attention in the context of therapy deintensification to avoid undertreatment.

Clinical Study of Prognostic Factors in Patients with P16-positive Oropharyngeal Cancer in Whom Surgery Was Selected as The Initial Treatment

Clinical Study of Prognostic Factors in Patients with P16-positive Oropharyngeal Cancer in Whom Surgery Was Selected as The Initial Treatment

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.

Population-Based Analysis of Trends in Incidence and Survival of Human Papilloma Virus-Related Oropharyngeal Cancer in a Low-Burden Region of Southern Europe.

Introduction: Human papilloma virus (HPV)-related oropharyngeal carcinoma (OPC) can be considered a new subtype of cancer with different clinical characteristics and prognosis than that related to tobacco. Its incidence is increasing worldwide. Its epidemiology has been widely studied in areas such as North America and Northern Europe, but less is known in Southern Europe. Methods: We analyzed the epidemiology of OPC using the database from Girona’s population-based Cancer Registry, in the North-East of Spain, from 1994 to 2018. To analyze differences between neoplasms related to human papillomavirus or not, we determined the immunohistochemical expression of p16 in cases within four time periods: 1997–1999, 2003–2005, 2009–2011, and 2016–2018. Results: Oropharyngeal cancer incidence increased significantly from 2001 to 2018 with an Annual Percentage of Change (APC) of 4.1. OPC p16-positive cases increased with an APC of 11.1. In the most recent period, 2016–2018, 38.5% of OPC cases were p16-positive. European age-standardized incidence rate was 4.18 cases/100.000 inhabitants-year for OPC cancer and 1.58 for those p16-positive. Five-year observed survival was 66.3% for p16-positive OPC and 37.7% for p16-negative. Conclusions: Although with lower burden than in other regions, p16-positive oropharyngeal cancer is increasing in our area and has a better prognosis than p16-negative OPC.

Usefulness of circulating tumor DNA by targeting human papilloma virus-derived sequences as a biomarker in p16-positive oropharyngeal cancer

In head and neck cancer, early detection of recurrence after treatment is important. The contemporary development of therapeutic agents have improved the prognosis after recurrence; however, no biomarker has been established for evaluating therapeutic effects or detecting recurrence. Recently, circulating tumor DNA (ctDNA), which comprises DNA derived from tumor cells and exists in the form of cell-free DNA in the blood, has attracted attention as a minimally invasive and repeatable biomarker for detecting cancer. We validated the usefulness of ctDNA of human papilloma virus (HPV)-derived sequences as a biomarker in HPV-related p16-positive oropharyngeal cancer by assessing 25 patients with p16-positive oropharyngeal cancer. Blood samples were collected from each patient at multiple time points during the treatment, and the plasma was preserved. The ctDNA was extracted from the plasma and analyzed using digital polymerase chain reaction. HPV-derived ctDNA was detected in 14 (56%) of the 25 patients. In all the patients, the samples were found to be ctDNA-negative after initial treatment. Cancer recurrence was observed in 2 of the 14 patients; HPV-derived ctDNA was detected at the time of recurrence. Our results indicate that HPV-derived ctDNA can be a prospective biomarker for predicting the recurrence of p16-positive oropharyngeal cancer.

Salivary High-Risk Human Papillomavirus (HPV) DNA as a Biomarker for HPV-Driven Head and Neck Cancers

High-risk human papillomavirus (HR-HPV) infection is a major risk factor of head and neck cancers (HNCs). Despite the rising prevalence of HPV-driven HNC (HPV-HNC), biomarkers for detection, prognostication, and disease monitoring are lacking. To evaluate the capacity of salivary HR-HPV DNA as a biomarker of HPV-HNC, the salivary HR-HPV statuses of 491 and 10 patients with primary and recurrent HNC, respectively, were determined at diagnosis, using quantitative real-time PCR and MassARRAY. Tumor cyclin-dependent kinase inhibitor 2A (p16) expression was determined by IHC analysis. Patients with oropharyngeal cancer (OPC) (n=215) were followed up for ≤5 years. Survival characteristics were evaluated in terms of event-free and cause-specific survival. Of the primary-HNC cohort, 43.2% were positive for salivary HR-HPV DNA, with most having OPC. Salivary HR-HPV DNA was detected in 81.4% of tumor p16-positive OPC patients at diagnosis. Prognosis in salivary HR-HPV-positive OPC patients was favorable compared with that in salivary HR-HPV-negative patients (event-free survival, hazard ratio = 0.42 [95% CI, 0.21-0.81, P=0.010]; cause-specific survival, hazard ratio = 0.39 [95% CI, 0.18-0.86, P=0.019]). In therecurrent-HNC cohort, salivary HR-HPV DNA was detected in 83.3% of those who previously had tumor p16-positive HNC. These findings indicate that this liquid biopsy-based, noninvasive biomarker can play an essential role in the detection and management of HPV-HNC.

Investigating the association between serum human papillomavirus type 16 E7 antibodies and risk of head and neck cancer.

ABSTRACTHuman papillomavirus (HPV) is recognized as a major cause of oropharyngeal cancer (OPC) in Western countries. Less is known regarding its contribution to the OPC occurring in Asia. The current study aimed to investigate the association between antibody responses to HPV16 E7 and head and neck cancer (HNC) risk in a hospital‐based case–control study conducted in Taiwan with 693 HNC cases and 1,035 controls. A positive association was observed between seropositivity to HPV16 E7 and OPC risk, whereas no significant association was found in the non‐OPC cases. The increased OPC risk associated with seropositivity to HPV16 E7 was more significant among nonbetel quid or noncigarette users. Seropositivity to HPV16 E7 showed moderate agreement with P16 expression in OPC. OPC patients that were seropositive to HPV16 E7 or p16 positive were more highly educated and less likely to use alcohol, betel quids, and cigarettes compared to HPV16 E7 seronegative or p16 negative OPC patients. Furthermore, patients with p16 positive OPC were more likely to be women compared to patients with p16 negative OPC, likely owing to the low prevalence of alcohol, betel quid, and cigarette users among women. Overall, this study suggested that similar to Western countries, HPV may also be an important risk factor of OPC in Taiwan. With the declining consumption of betel quids and cigarettes in Taiwan, a higher percentage of OPC cases in Taiwan will be attributed to HPV in the future. Public health measures, including HPV vaccination, need to be implemented to prevent the occurrence of HPV‐positive OPC.

Oropharyngeal cancer: First relapse description and prognostic factor of salvage treatment according to p16 status, a GETTEC multicentric study.

Although Human Papilloma Virus (HPV)-driven oropharyngeal cancer (OPC) prognosis is significantly better than that of other head and neck cancers, up to 25% of cases will recur within 5 years. Data on the pattern of disease recurrence and efficiency of salvage treatment are still sparse. Observational study of all recurrent OPCs diagnosed, following a curative intent treatment, in seven French centers from 2009 to 2014. p16 Immunohistochemistry was used to determine HPV status. Clinical characteristics, distribution of recurrence site, and treatment modalities were compared by HPV tumor status. Overall survival was examined using Kaplan-Meier and multivariate Cox regression modeling. 350 recurrent OPC patients (246 p16-negative and 104 p16-positive patients). The site of recurrence was more frequently locoregional for p16-negative patients (65.4% versus 52.9% in p16-positive patients) and metastatic for p16-positive patients (47.1% versus 34.6% in p16-patients, p=0.03). Time from diagnosis to recurrence did not differ between p16-positive and p16-negative patients (12 and 9.6 months, respectively, p-value=0.2), as the main site of distant metastasis (all p-values ≥0.10). Overall and relapse-free survival following the first recurrence did not differ according to p16 status (p-values from log-rank 0.30 and 0.40, respectively). In multivariate analysis, prognosis factors for overall survival in p16-negative patients were distant metastasis (HR 2.11, 95% CI 1.30-3.43) and concurrent local and regional recurrences (HR 2.20, 95% CI 1.24-3.88). With the exception of the initial site of recurrence, the pattern of disease relapse and the efficiency of salvage treatment are not different between p16-positive and negative OPCs.

Impact of delayed adjuvant therapy after surgery in p16 positive oropharyngeal cancer: a retrospective analysis.

This study aimed to clarify the impact of delayed adjuvant therapy on the outcome of HPV associated oropharyngeal squamous cell carcinoma (HPV-OPSCC). A total of 157 patients with HPV-OPSCC treated by surgery and adjuvant radiotherapy or chemoradiation therapy were analyzed retrospectively. We divided participants into two groups implementing adjuvant therapy within or after 50 days. Primary endpoints were the rates of locoregional recurrence and distant metastases, overall survival, and disease-specific survival. Adjuvant treatment began within 50 days (average: 38.8 days) in 79 cases compared to 78 cases after 50 days (average: 71.5 days). Five-year overall survival was 85.7% and 87.4% (p=0.588), the rates of local and regional recurrence were 3.8% and 6.4% (p=0.455) and of distant metastases 5.1% and 9% (p=0.369) implementing adjuvant treatment within or later than 50 days, respectively. These results suggest that adjuvant therapy initiated later than seven weeks after primary ablative surgery may still be effective HPV-OPSCC.

A case of untreated p16 positive oropharyngeal cancer during 9 years

A case of untreated p16 positive oropharyngeal cancer during 9 years