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The prognosis after primary (chemo-)radiotherapy for oropharyngeal squamous cell carcinoma (OPSCC) is affected by Human Papillomavirus (HPV) status, with a better prognosis in HPV-positive OPSCC. HPV-status is routinely assessed by p16 immunohistochemistry (IHC), but additional HPV DNA testing is debated. Also, there are numerous HPV genotypes, which prognostic role may need clarification. The purpose of this study was: (1) to test a custom-made targeted HPV next generation sequencing (NGS) panel in OPSCC, (2) to determine correlation with p16 IHC, and (3) to assess the impact of HPV DNA testing on outcome in the prospectively randomized clinical trial DAHANCA 19. We included 271 patients with OPSCC treated with primary (chemo-)radiotherapy in the DAHANCA 19 trial. Of these, 199 (73%) were p16-positive. HPV-status was determined by targeted HPV next generation sequencing (NGS), using a custom-made HPV genotyping panel. HPV was detected in 194 tumor samples. p16 IHC and NGS HPV status were concordant in 265 (98%) of 271 patients, whereas we did not detect HPV DNA in 5 p16-positive tumors. HPV16 accounted for 169 of 194 HPV-positive cases (87%). HPV genotypes 18, 31, 33, 35, and 59 were also detected. Loco-regional failure and overall survival were similar whether patients were separated by p16 IHC, or HPV DNA status (p < 0.0001 for all) and did not depend on HPV genotype (p = 0.9 and p = 0.7). In the present study, HPV DNA testing or typing in a Danish OPSCC cohort did not add additional information to p16 IHC, the most widely used and accepted prognostic indicator. [ABSTRACT FROM AUTHOR]

The article focuses on correlation and prognostic impact of human papilloma virus and p16-expression in advanced hypopharynx and larynx cancer treated with definitive radiotherapy. Topics include the human papilloma virus (HPV) is a well-established aetiological factor in oropharynx cancer (OPC), the global variation in the incidence of HPV plus OPC is considerable, and the countries with high age standardized incidence rates of the disease are located in Northern America and Europe.

Background and purpose HPV is found in head and neck cancer from all sites with a higher prevalence in oropharynx cancer (OPC) compared to non-OPC. HPV/p16-status has a significant impact on radiotherapy (RT) outcome in advanced OPC, but less is known about the influence in non-OPC. We analyzed HPV-associated p16-expression in a cohort of patients with stage III–IV pharynx and larynx cancer treated with primary, curatively intended (chemo-)RT, aiming to test the hypothesis that the impact of HPV/p16 also extends to tumors of non-oropharyngeal origin. Material and methods 1294 patients enrolled in previously conducted DAHANCA-trials between 1992 and 2012 were identified. Tumors were evaluated by p16-immunohistochemistry and classified as positive in case of staining in >70% of tumors cells. Results Thirty-eight percent (490/1294) of the tumors were p16-positive with a significantly higher frequency in OPC (425/815) than in non-OPC (65/479), p < .0001. In OPC p16-positivity significantly improved loco-regional control (LRC) (adjusted HR [95% CI]: 0.43 [0.32–0.57]), event-free survival (EFS) (HR 0.44 [0.35–0.56]), and overall survival (OS) (HR: 0.38 [0.29–0.49]), respectively, compared with p16-negativity. In non-OPC no prognostic impact of p16-status was found for either endpoint: LRC (HR: 1.13 [0.75–1.70]), EFS (HR: 1.06 [0.76–1.47]), and OS (HR: 0.82 [0.59–1.16]). Conclusions The independent influence of HPV-associated p16-expression in advanced OPC treated with primary RT was confirmed. However, RT-outcome in the group of non-OPC did not differ by tumor p16-status, indicating that the prognostic impact may be restricted to OPC only. [ABSTRACT FROM AUTHOR]

Abstract: Aim: EGFR and HPV-associated p16 are among the most investigated biomarkers in head and neck cancer. The aim was to investigate the correlation and interaction between these two markers and to evaluate their potential prognostic significance when combined. Materials and methods: 336 Oropharyngeal carcinomas treated with primary radiotherapy (66–68Gy, 2fx/day, 10–12Gy/week) and with known EGFR/p16-status estimated semiquantitatively by immunohistochemistry were included in the study. Data were evaluated by EGFR-expression (high/low) and p16-status (positive/negative) consequently dividing tumours into four groups by combination of the biomarkers. Patient/tumour characteristics and complete 5-year follow-up were available. Results: Low EGFR-expression was significantly more common in p16-positive tumours compared to p16-negative, p <0.0001. p16 positivity showed a strong prognostic impact (p <0.0001, HR=0.22 [0.13–0.38]), whereas EGFR was a weak prognostic marker when local control was used as endpoint (p =0.03, HR=0.53 [0.29–0.94]). Combination of EGFR/p16 did not add significant information to p16 alone and by multivariable analysis only p16 showed significant prognostic information for all evaluated endpoints. Conclusions: Both EGFR and p16 bear prognostic information in oropharyngeal cancer, although p16 is, by far, the strongest prognostic factor. The markers seem to be correlated and this might have influence when evaluating the effect of EGFR inhibition in oropharyngeal tumours. [Copyright &y& Elsevier]

Abstract: Background and purpose: Tumour HPV-positivity is a favourable prognostic factor in the radiotherapy of HNSCC, but the optimal radiotherapy regimen for HPV-positive HNSCC is not yet defined. Reducing overall treatment time is known to improve outcome in the radiotherapy of HNSCC as was also demonstrated in the randomised DAHANCA 6&7 trial. We aimed to assess the influence of tumour HPV-status, expressed by p16, on the response to accelerated fractionated radiotherapy in HNSCC through evaluation of the DAHANCA 6&7 trial. Materials and methods: Immunohistochemical detection of HPV-associated p16-expression was performed on FFPE-pre-treatment tumour-tissues from 794 patients enrolled in the DAHANCA 6&7 trial. The influence of tumour p16-status on loco-regional tumour control and survival as a function of fractionation schedule (5Fx/week vs 6Fx/week) was evaluated 5years after the completion of radiotherapy. Results: The significant and independent prognostic value of tumour p16-positivity in HNSCC radiotherapy was confirmed, with adjusted hazard ratios (HR) of 0.58 [0.43–0.78], 0.47 [0.33–0.67] and 0.54 [0.42–0.68] for loco-regional control, disease-specific and overall survival, respectively. Accelerated radiotherapy significantly improved loco-regional tumour control compared to conventional radiotherapy, adjusted HR: 0.73 [0.59–0.92] and the benefit of the 6Fx/week regimen was observed both in p16-positive (HR: 0.56 [0.33–0.96]) as well as in p16-negative tumours (HR: 0.77 [0.60–0.99]). Disease-specific survival was also significantly improved with accelerated radiotherapy in the group of p16-positive tumours (adjusted HR: 0.43 [0.22–0.82]). Conclusion: Accelerated radiotherapy significantly improves outcome in HNSCC compared to conventional fractionation. The observed benefit is independent of tumour p16-status and the use of a moderately accelerated radiotherapy regimen seems advantageous also for HPV/p16-positive HNSCC. [Copyright &y& Elsevier]

Abstract: The profound influence of Human papillomavirus (HPV) on the epidemiological pattern and clinical course of head and neck cancer (HNSCC) has led to a change in the traditional understanding of this disease entity. Separate therapeutic strategies based on tumour HPV status are under consideration and in this light provision of knowledge concerning the influence of tumour HPV on the radiation response in HNSCC appears highly relevant. This review provides a summary of the current understanding of the role of HPV in head and neck cancer with specific focus on the viral impact on radiotherapy outcome of HNSCC. [Copyright &y& Elsevier]

Abstract: Background: HPV/p16-positive head and neck cancers (HNSCC) show superior response to radiotherapy, compared with virus-negative tumours. Tumour hypoxia induces radioresistance and the randomised DAHANCA 5 trial found that the hypoxic cell radiosensitiser nimorazole significantly improved the outcome in HNSCC. Using p16-status as a retrospective stratification parameter, we aimed to assess the influence of p16-expression on the response to nimorazole in HNSCC. Materials and methods: Pre-treatment tumour blocks were available from 331 of the 414 patients in the DAHANCA 5 trial and evaluated by immunohistochemistry for p16-expression. The influence of p16-expression on outcome was analysed as a function of treatment group (nimorazole/placebo) 5years after radiotherapy. Results: Overall, patients treated with nimorazole had significantly better loco-regional control than did those given placebo: hazard ratio (HR) 0.70 [95% CI 0.52–0.93]. Positive expression of p16 also significantly improved outcome after radiotherapy (0.41 [0.28–0.61]). In the subgroup of patients with p16-negative tumours, loco-regional failure was more frequent in the placebo group than in the nimorazole group (0.69 [0.50–0.95]). However, in the p16-positive group, patients treated with nimorazole had a loco-regional control rate similar to patients given placebo (0.93 [0.45–1.91]). Conclusions: HPV/p16-expression significantly improved outcome after radiotherapy in HNSCC. Hypoxic modification improved outcome in HPV/p16-negative tumours but was of no significant benefit in HPV/p16-positive tumours, suggesting that hypoxic radioresistance may not be clinically relevant in these tumours. [Copyright &y& Elsevier]

Objectives: To demonstrate the correlation between p16 overexpression and HPV in oropharyngeal carcinoma and to evaluate the prognostic impact of p16 status in a prospectively analyzed cohort of Danish oropharyngeal cancer patients. Materials and Methods: 32 tunsillar carcinomas were arranged in a Tissue Micro Array and evaluated by IHC for p16 overexpression. HPV-16 DNA detection was done by in situ hybridization. Between 1986 and 1999 The Danish Head and Neck Cancer group conducted the DAHANCA 5&7 randomized trials. In the present study 335 pre-treatment oropharyngeal tumour blocks from patients enrolled in these trials were evaluated by IHC for p16 status. Results: 20 of 32 (62.5%) tonsillar carcinomas were HPV-16 positive and 19 of these were p16 positive (sensitivity: 0.95). 12 turnouts were H PV-16 negative and 10 of these were p16 negative (specificity: 0.83). The two markers matched in 29 of 32 (90%) of the tumours. In total 135 of 335 (40%) oropharyngeal tumours were p16 positive. In univariate analysis, loco-regional turnout control was significantly improved for p16 positive tumours with 5-year actuarial values of 67% versus 36%, p < 0.0001. A similar beneficial outcome for p16 positive tumours was observed for cancer specific survival (69% versus 35%, p < 0.0001) and overall survival (54% versus 18%, p < 0.0001). In multivariate analysis p16 overexpression remained a very strong independent prognostic factor for loco-regional tumour control [OR: 0.35 (95% C.I. 0.24-0.51)], cancer specific death [OR: 0.28 (0.18-0.42)] and overall death [OR: 0.33 (0.24 0.46)] respectively. p16 was an even stronger prognostic factor related to these outcomes than T-stage and Nodal-status. Conclusions: p16 overexpression proved to be the strongest independent prognostic factor related to survival and loco-regional tumour control in our study and so we conclude that HPV infection is significantly correlated to improved prognosis and response to radiotherapy in oropharyngeal cancer patients. [ABSTRACT FROM AUTHOR]