HPV-positive Oropharyngeal Squamous Cell Cancer Research Articles

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.

Stage I HPV-positive oropharyngeal cancer: Should all patients receive similar treatments?

Patients with clinical stage I human papillomavirus (HPV)-positive oropharyngeal squamous cell cancer (OPSCC) according to the American Joint Committee on Cancer (AJCC) eighth edition classification comprise a heterogeneous group formerly classified as stage I to stage IVA according to the seventh edition of the AJCC classification. These patients historically were treated with disparate treatment regimens, particularly with respect to the use of concurrent chemotherapy. The National Cancer Data Base was queried for patients with AJCC eighth edition clinical stage I HPV-positive OPSCC (AJCC seventh edition stage T1-2N0-2bM0) who were diagnosed from 2010 to 2014 and underwent definitive radiotherapy. Concurrent chemotherapy with definitive radiotherapy was defined as chemotherapy administered within 7days of the initiation of radiotherapy. The current analysis included 4473 patients with HPV-positive stage I OPSCC with a median follow-up of 36.3months. A total of 3127 patients (69.9%) received concurrent chemotherapy. Concurrent chemotherapy was found to be associated with improved overall survival on multivariable analyses (hazard ratio [HR], 0.782; 95% CI, 0.645-0.948 [P=.012]). The effect of chemotherapy on survival varied based on lymph node involvement (P for interaction = .001). Specifically, chemotherapy was associated with improved survival for patients with lymph node-positive stage I disease (stage III-IVA according to the AJCC seventh edition: HR, 0.682; 95% CI, 0.557-0.835 [P<.001]), but not for patients with N0 disease (stage I-II according to the AJCC seventh edition: HR, 1.646; 95% CI, 1.011-2.681 [P=.05]). Similar results were noted among propensity score-matched cohorts. Treatment with concurrent chemotherapy was associated with improved overall survival for patients with lymph node-positive, but not lymph node-negative, AJCC eighth edition stage I HPV-positive OPSCCundergoing definitive radiotherapy, thereby supporting different treatment paradigms for these patients.

Significant association of PD-L1 expression with human papillomavirus positivity and its prognostic impact in oropharyngeal cancer

BackgroundThe programmed death pathway plays a role in persistent human papillomavirus (HPV) infection as well as in resistance to immune elimination during malignant progression. In this study, we examined PD-L1 expression by immunohistochemistry and tumour infiltrating lymphocytes (TIL) in 214 patients with oropharyngeal squamous cell cancer (OPSCC) to assess its clinical significance. ResultsHPV-positive OPSCC were significantly more likely to express PD-L1 than HPV-negative OPSCC (85.2% vs 57.1%, p < 0.05). PD-L1 staining was more likely to be associated with TILs in HPV-positive OPSCC (67.9% vs 49.6%, p = 0.01). Relative to those patients with HPV-positive/PD-L1-positive OPSCC, patients with HPV negative/PD-L1 negative OPSCC were 6.4 times more likely to develop a local recurrence, 5.8 times more likely to develop an event and 6.5 times more likely to die. Within the HPV positive cases, PD-L1 expression also significantly impacted on the outcomes with PD-L1 negative cases more likely to develop a locoregional recurrence (HR 4.16), to have an event (HR 2.5) and to die (HR 3.16). Evidence of an interaction between HPV status and PD-L1 expression was found for overall survival (p < 0.005). ConclusionOur findings suggested that different immune profiles in oropharyngeal cancer by HPV status and the effect of HPV on the outcomes is modified by PD-L1 expression.

Staging of oropharyngeal squamous cell carcinoma of the head and neck: Prognostic features and power of the 8th edition of the UICC staging manual

IntroductionRecognizing the prognostic power differentiating HPV-associated oropharyngeal squamous cell cancer (OPSCC) from OPSCC with other causes, the UICC Cancer Staging Manual 8th edition realizes significant changes from the 7th edition. Purpose of this study was to evaluate the differences of prognostic impact between the 7th and the latest edition of TNM Classification as well as to examine risk factors like extranodal extension (ENE) and lymph node ratio (LNR) for HPV-mediated OPSCC. Material and methodsThe study includes 255 patients with OPSCC and initial diagnosis between 2008 and 2015. HPV status was determined according to p16 immunohistochemistry (IHC) and all patients were classified as defined by 7th and 8th edition of UICC. Prognostic influence of ENE and LNR was analyzed for patients with HPV-mediated OPSCC. Results41.2% of the OPSCC were p16-positive. Implementation of the 8th edition of the UICC lead to a better differentiation between the respective stages. Regarding HPV-positive OPSCC, Kaplan-Meier survival curves showed a significantly better overall survival (OS) for patients with a LNR ≤10% as well as for patients with negative ENE status (p = 0.004, p = 0.008). Conclusion8th edition of UICC achieves to differentiate properly between the UICC stages. However, the staging rule of ignoring ENE in HPV-mediated OPSCC should be further analyzed. Moreover LNR might be a possible additional prognostic factor – especially regarding HPV-positive tumors.

De-intensified adjuvant (chemo)radiotherapy versus standard adjuvant chemoradiotherapy post transoral minimally invasive surgery for resectable HPV-positive oropharyngeal carcinoma.

More than 400,000 cases of oropharyngeal squamous cell cancer (OPSCC) are diagnosed every year worldwide and this is rising. Much of the increase has been attributed to human papillomavirus (HPV). HPV-positive OPSCC patients are often younger and have significantly improved survival relative to HPV-negative patients. Traditional management of OPSCC has been with radiotherapy with or without chemotherapy, as this was shown to have similar survival to open surgery but with significantly lower morbidity. Techniques have evolved, however, with the development of computerised planning and intensity-modulated radiotherapy, and of minimally invasive surgical techniques. Acute and late toxicities associated with chemoradiotherapy are a significant burden for OPSCC patients and with an ever-younger cohort, any strategies that could decrease treatment-associated morbidity should be investigated. To assess the effects of de-intensified adjuvant (chemo)radiotherapy in comparison to standard adjuvant (chemo)radiotherapy in patients treated with minimally invasive transoral surgery (transoral robotic surgery or transoral laser microsurgery) for resectable HPV-positive oropharyngeal squamous cell carcinoma. The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 26 April 2018. Randomised controlled trials (RCTs) in patients with carcinoma of the oropharynx (as defined by the World Health Organization classification C09, C10). Cancers included were primary HPV-positive squamous cell tumours originating from the oropharyngeal mucosa. Tumours were classified as T1-4a with or without nodal spread and with no evidence of distant metastatic spread. The intervention was minimally invasive transoral surgery followed by de-intensified adjuvant therapy (either omission of chemotherapy or reduced-dose radiotherapy). The comparator was minimally invasive transoral surgery followed by standard concurrent chemoradiotherapy or standard-dose radiotherapy. The treatments received were of curative intent and patients had not undergone any prior intervention, other than diagnostic biopsy. We used the standard methodological procedures expected by Cochrane. Our primary outcomes were overall survival (disease-related survival was to be studied where possible) and disease-free survival, measured at one, two, three and five years. Our secondary outcomes included assessment of swallowing ability and voice, measured at one, six, 12 and 24 months. We planned to use GRADE to assess the quality of evidence for each outcome. We did not identify any completed RCTs that met our inclusion criteria. However, three eligible studies are in progress:ADEPT is a phase III trial comparing postoperative radiotherapy with or without cisplatin in HPV-positive T1-4a OPSCC patients. Included patients must have received minimally invasive surgery and demonstrated extra-capsular spread from disease in the neck.ECOG-E3311 is a phase II trial of treatment for HPV-positive locally advanced OPSCC (stages III-IVa + IVb without distant metastasis). Patients are stratified after minimally invasive surgery. Medium-risk patients are randomised to either standard or reduced-dose radiotherapy.PATHOS is a phase III trial of treatment for HPV-positive OPSCC (T1-3, N0-2b). Patients are stratified after minimally invasive surgery. Medium-risk patients are randomised to either standard or reduced-dose radiotherapy. High-risk patients are randomised to radiotherapy with or without concurrent cisplatin. This review highlights the current lack of high-quality randomised controlled trials studying treatment de-escalation after minimally invasive surgery in patients with HPV-positive OPSCC. However, trials that will meet the inclusion criteria for this review are in progress with results expected between 2021 and 2023.

Upregulation of pAKT(Ser473) expression in progression of HPV-positive oropharyngeal squamous cell carcinoma.

PIK3CA alterations have been shown to be a frequent event in oropharyngeal squamous cell cancer (SCC), especially in human papillomavirus (HPV)-related tumors. Tissue microarrays (TMAs) were used to evaluate pAKT(Ser473)/(Thr308), total protein kinase B (AKT)(pan) and phosphatase and tensin homolog (PTEN) expression in primary tumors and corresponding nodal disease in oropharyngeal SCC. The HPV status was determined in regard of HPV16 DNA and RNA. Survival analysis was performed by using Kaplan-Meier curves, log-rank testing, and multivariate Cox regression analysis. HPV16 is a prognostic predictive marker for advanced oropharyngeal SCC. pAKT(Ser473) and PTEN are highly expressed in HPV-related oropharyngeal SCCs in contrast to pAKT(Thr308). The pAKT(Ser473) expression increased from primary tumors to progressive nodal disease (21.1%; P < .011). Activation of phosphoinositide 3-kinase (PI3K)/pAKT(Ser473) frequently occurs in advanced HPV-positive oropharyngeal SCC and elevated pAKT(Ser473) levels represent a feature during progression of oropharyngeal SCC, indicating a critical role of the mammalian target of rapamycin (mTOR) complex. Further studies are required to evaluate specific drugs targeting PI3K/AKT/mTOR in consideration of PIK3CA alterations.

Oral HPV prevalence in women positive for cervical HPV infection and their sexual partners: a German screening study.

The incidence of human papillomavirus (HPV) associated oropharyngeal squamous cell cancer (OSCC) is on the rise. With the HPV-positive uterine cervix as a reservoir, HPV-positive OSCC is discussed as a sexually transmitted disease. Mechanisms of HPV transmission to the oral cavity are poorly understood. To gain more insight into HPV-transmission routes, cervically HPV-positive women and their sexual partners are screened for oral HPV infection. Women with cervical dysplasia underwent HPV testing of the uterine cervix and tonsillar region via brush test. In addition, sexual partners received oral HPV testing. Tonsillar brush tests of patients admitted for routine surgery served as the control group. The HPV-PCR (Roche Linear Array Kit) was used to differentiate 37 HPV types. All participants completed a risk-factor questionnaire focusing on sexual habits. 101 women were tested HPV-positive at the cervix. Only 3/101 (3%) were tested HPV-positive in the oropharynx. In 60/101 (60%) women the sexual partner could be tested for oral HPV infection: testing was positive in 3/60 (5%). No oral HPV was detected in the control group. The risk-factor questionnaire revealed significant differences between the female study- and control group in terms of age at first sexual intercourse and smoking habits. The limited data suggest that among sexual partners in Germany, HPV transmission to the oropharynx by oral-genital sex or by autoinoculation is a rare and unlikely event with low HPV concordance. Another explanation for the low oral prevalence could be an independent clearance of HPV from the oropharyngeal site compared to cervix uteri or at different time intervals.

Discussing a diagnosis of human papillomavirus oropharyngeal cancer with patients: An exploratory qualitative study of health professionals.

BackgroundThe role of human papillomavirus (HPV) in oropharyngeal squamous cell cancer (SCC) has now been well established. Clinicians' experiences and challenges of talking to patients about HPV have yet to be explored.MethodsFifteen health professionals caring for patients with oropharyngeal SCC were interviewed. Interviews were analyzed thematically.ResultsParticipants expressed mixed views about explaining the causal role of HPV to their patients. Normalizing HPV and emphasizing the positive prognosis associated with it were regarded as key messages to be communicated. Challenging experiences included managing couples in a consultation and patients' concerns about transmitting HPV to their partners. Some participants described limitations to their HPV knowledge and identified the need for further information and training.ConclusionThis study identified challenges experienced by health professionals working with patients with oropharyngeal SCC and highlights some key messages to convey to patients. Clinical guidance for health professionals and further information for patients about HPV‐positive oropharyngeal SCC are needed. © 2015 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: 394–401, 2016

Abstract 650: IGSF4 methylation is an independent marker of HPV positive OPSCC.

Abstract Human papilloma virus (HPV) is a known causative agent for oropharyngeal squamous cell cancer (OPSCC). The goal of our study was to determine the relationship of HPV type 16 (HPV16) infection and methylation status in an OPSCC cohort. HPV16 was detected using real-time quantitative PCR (qPCR) in a retrospective cohort of 111 primary OPSCC. A 24 tumor suppressor gene candidate panel was assessed for methylation using the methylation specific-multiplex ligation-dependent probe amplification (MS-MLPA) assay. Univariate associations with HPV and gene methylation, age, gender, race and smoking were analyzed using Fisher's exact tests and logistic regression. A final multiple logistic regression model, to include patient characteristics and genes significant on univariate analysis, was built using backwards selection of genes. Statistical significance was set at p&amp;lt;0.05 and all analyses were done using SAS 9.2. In univariate analyses, Caucasian American (CA) OPSCC were more likely to be HPV positive as compared to African American (AA) OPSCC (OR=3.01, 95% CI 1.28, 7.07, p=0.011). Also, smoking (never vs current) [OR=3.60 (1.06, 12.24), p=0.04], and TIMP3, DAPK1, ESR1, and IGSF4 were associated with HPV positive status (OR=5.03, p=0.021; OR=3.71, p=0.04; OR=5.03, p=0.021; OR=7.68, p=0.012, respectively). The final model, after controlling for patient characteristics and after backward elimination of genes, indicated IGSF4 methylation is an independent predictor of HPV positive status [OR=7.07 (1.22, 40.79), p=0.029]. HPV infection status is independently associated with methylation of IGSF4, indicating interplay of DNA methylation and HPV in OPSCC pathogenesis. Citation Format: Kang Mei Chen, Josena K. Stephen, Meredith Mahan, Shaleta Havard, George Divine, Glendon Gardner, Vanessa P. Schweitzer, Maria J. Worsham. IGSF4 methylation is an independent marker of HPV positive OPSCC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 650. doi:10.1158/1538-7445.AM2013-650

1040P - The Impact of Induction Chemotherapy on Cisplation Dose Intensity During Chemo-Radiotherapy (CTRT) in Oropharyngeal Squamous Cell Cancer (OPC)

ABSTRACT Background Induction (IC) with TPF (Taxotere, Cisplatin, 5-FU) has been associated with improved outcome in advanced head and neck squamous cell cancer patients (pts). Full dose of cisplatin (300 mg/m2) during CTRT has been demonstrated to impact on patients' outcome. The aim of the current study is to investigate whether the IC could impact on cisplatin dose intensity during CTRT in a homogeneous population of OPC. Materials and methods The study population consisted of 101 pts with stage III-IV OPC treated from 07/2004 to 12/2011 with IC (n = 53) plus CTRT or CTRT alone (n= 48). IC consisted of TPF, while weekly 50 mg/m2 or 3-weekly 100 mg/m2 cisplatin was administered concurrently with RT (planned chemotherapy dose = 300 mg/m2; planned RT dose = 66-70 Gy, 3DRT or IMRT with a conventional or accelerated fractionation). Carboplatin substituted cisplatin in case of creatinine clearance less than 60 mL/min. HPV status, concurrent cisplatin dose intensity and RT overall treatment time (OTT) were analyzed. Results Stage IV pts were 100% in the IC group and 83% in CTRT, while HPV positive OPCs were detected in 58% and 63% of the cases respectively. TPF median number of cycles was 3, with induction cisplatin median dose administered of 200 mg/ m2. RT median total dose administered was 70 Gy in both group. Accelerated fractionated RT was adopted in 65% of CTRT alone group and in 21% of IC group. Two pts (1 in each group) did not complete CTRT because of cardiovascular events. Mean and median dose intensity of cisplatin concurrent to RT in the IC group was 77.7% and 75% (35%-100%) while in CTRT group was 86% and 91.7% (33%-100%), with a p value = 0.014. In 11 pts (21%) treated with IC and only in 1 pts (2%) treated with CTRT alone cisplatin was substituted with carboplatin. No different cisplatin dose intensity was identified in HPV positive versus HPV negative cases. Prolonged OTT (longer than 5 days) was observed in two patients in IC group due to sepsis and severe mucositis as well as in one patient in CTRT group due to machine failure. Conclusions Concurrent cisplatin dose intensity was significantly reduced in pts receiving IC compared to CTRT alone, irrespective of HPV status. Whether this has an impact on the results of IC followed by full dose CT/RT has to be clarified. Disclosure All authors have declared no conflicts of interest.

Human papillomavirus (HPV) transmission from oropharyngeal cancer patients to sexual partners.

5527 Background: Human papillomavirus (HPV), especially serotype 16, is implicated in causing a subset of head and neck cancers. Preventing this HPV-related disease and the epidemiology of transmission are important research questions. To define the risk of HPV transmission between patients with HPV-associated head and neck cancer and their respective sexual partners, we performed HPV genotyping on cytology brushings of the oral cavity (OC)/oropharynx (OP). Methods: Patients with confirmed oropharyngeal squamous cell cancer (OPC) and their sexual partners underwent OC/OP swabs/brushings (bilateral buccal mucosa, lateral tongue, tonsillar and base-of-tongue regions, inside upper and lower lips) and answered a questionnaire; swabs and diagnostic biopsies underwent HPV genotyping. Standard PCR assay using consensus primer GP5+\/GP6+ tested for HPV serotypes (including 16, 18 and 31); if positive for HPV, this assay was followed by HPV genotyping via real-time PCR for HPV 16, 18, 31, 33, 35, 45, 52, and 58. Results: We tested 174 patient-partner pairs (n=348 persons); there were 29 HPV-positive OPC patients (17%), of whom 19 partners (66%) had HPV-positive swabs. All 19 HPV-positive partners (100%) were concordant with the OPC patient for at least one HPV type. In 4 of the 29 pairs with an HPV-positive patient, a prior history of HPV-related disease occurred in either the patient (1 rectal cancer) or the partner (3 abnormal Pap smears). Among the 29 HPV-positive patients, smoking status was current in 6 (21%), former in 10 (34%), and never in 13 (45%) and alcohol use was heavy in 4 (14%) and former in 5 (17%). 11 HPV-negative OPC patients (of which 6 were never-smokers) had HPV-positive partners, which will be evaluated further to verify primary-tumor HPV status. Conclusions: We found a high rate of transmission and 100% HPV-genotype concordance between patients and partners. Further analysis and correlation of HPV status with patient-partner characteristics, survey results, treatment outcomes, and HPV genotyping in primary tumor biopsies will be presented. No significant financial relationships to disclose.

Retrovirus-mediated delivery of short hairpin RNA targeting human papillomavirus (HPV) 16 E6 and E7 oncogenes and induction of apoptosis in oropharyngeal squamous cell cancer (OSCC) cell line

6002 Background: Human papillomavirus type 16 is identified in almost 50% of the cases of OSCC. The E6 and E7 genes of HPVs encode oncoproteins that bind and degrade the tumor suppressor proteins p53 and Rb, respectively. We are exploring the potential use of short hairpin RNA (sh RNA) for gene therapy of HPV-positive OSCC. Methods: Small hairpin RNAs targeting E6 or E7 genes were delivered by a retrovirus vector to 93VU147T (bearing integrated HPV16 DNA) and 92VU040T (HPV negative) oropharyngeal cancer cell lines. Flow cytometry analysis was used to assess apoptosis after the retrovirus infection. The E6 and E7 mRNA downregulation was assessed by reverse transcription polymerase chain reaction (RT-PCR). At protein level p53 and Rb expression were evaluated with Western blotting analysis. Results: Apoptosis was seen in over 90% of 93VU147T cells 48 hours after infection whereas 92VU040T cells were not affected. RT-PCR demonstrated that HPV16 E6/E7 mRNA levels decreased significantly in infected 93VU147T cells. 93VU147T infected cells also showed a marked increase in p53 and Rb protein levels. Conclusions: Downregulation of E6/E7 gene expression in HPV16+ OSCC cells results in apoptosis and reactivation of p53 and Rb tumor suppression pathways. These results have significant implications in treating HPV-associated OSCC with HPV-targeted gene therapy. No significant financial relationships to disclose.