The prognostic significance of the biomarker p16 in oropharyngeal squamous cell carcinoma.

There is an increasing incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell cancers (OPSCC) mostly associated with favourable outcomes. p16 immunohistochemistry is a surrogate marker for HPV positivity in OPSCC. The prognostic strength of p16 over traditional prognostic factors is not fully characterised. In this study, we evaluated the clinical and demographic differences between p16-positive and -negative OPSCC and characterised its prognostic strength versus traditional prognostic factors. Formalin-fixed, paraffin-embedded blocks and clinical information from 217 OPSCC patients, treated with radiotherapy (alone or in combination with other therapies) between 2000 and 2010 were collected retrospectively. Immunohistochemistry for p16 protein was carried out; cancer-specific survival (CSS), recurrence-free survival (RFS) and locoregional control (LRC) were calculated for both univariate and multivariate analyses. Ninety-two per cent of the OPSCC originated from tonsil and tongue base sites, 61% were p16 positive. Patients with p16-positive OPSCC were younger (P < 0.0001), with lower alcohol (P = 0.0002) and tobacco (P = 0.0001) exposure. The tumours were less differentiated (P = 0.0069), had a lower T stage (P = 0.0027), higher nodal status (P = 0.014) and higher American Joint Committee on Cancer (AJCC) prognostic group (P = 0.0036). AJCC prognostic group was significant for RFS (P = 0.0096) and CSS (P = 0.018) in patients with p16-negative OPSCC, but not those with p16-positive tumours (P = 0.30 and 0.54). Other significant factors for CSS and RFS in univariate analysis were: pretreatment haemoglobin (P < 0.0001 and <0.0001), chemoradiotherapy (P = 0.005 and 0.03) and P16 status (P < 0.0001 and 0.0001). In multivariate analysis, p16 positivity was the strongest independent prognostic variable for both CSS, RFS and LRC (P < 0.0001, hazard ratio 4.15; 95% confidence interval 2.43-7.08), (P < 0.0001, hazard ratio 6.15; 95% confidence interval 3.57-10.61) and (P = 0.001, hazard ratio 3.74; confidence interval 1.76-7.95). This study shows that p16 is the single most important prognostic variable in OPSCC, surpassing traditional prognostic factors for both CSS and RFS. Furthermore, disease stage has no prognostic significance in p16-positive patients, highlighting the need for routine p16 assessment in OPSCC.

Oguejiofor KK ，Hall JS ，Mani N ，Douglas C ，Slevin NJ ，Homer J ，Hall G ，West CM ... -  《-》

Molecular subclassification determined by human papillomavirus and epidermal growth factor receptor status is associated with the prognosis of oropharyngeal squamous cell carcinoma.

Human papillomavirus (HPV) infection is an indicator of good response to chemoradiotherapy in oropharyngeal squamous cell carcinoma (OPSCC), and epidermal growth factor receptor (EGFR) is a molecular-therapeutic target in head and neck squamous cell carcinoma. Here we investigated the prevalence and prognostic significance of HPV infection and EGFR alteration in OPSCC. We analyzed the presence of high-risk HPV using in situ hybridization, protein expressions of p16 and EGFR using immunohistochemistry, and the EGFR gene copy number gain using chromogenic in situ hybridization (CISH) in 105 cases of OPSCC. The biopsy specimens before chemoradiotherapy were used for these analyses. HPV infection and p16 protein overexpression were detected in 53.3% and 52.4% of the OPSCCs, and each factor was associated with better overall survival (P = .0026 and P = .0026) and nonkeratinizing histology (P = .0002 and P = .0004), respectively. EGFR gene copy number gain (high polysomy or amplification) was detected in 12.4% of the OPSCCs and was correlated with EGFR protein overexpression (P = .0667) and worse overall survival (P < .0001). HPV infection and EGFR gene copy number gain (EGFR CISH positive) were mutually exclusive. The HPV-negative/EGFR CISH-positive OPSCCs had significantly worse overall survival than did the HPV-positive/EGFR CISH-negative OPSCCs and HPV-negative/EGFR CISH-negative OPSCCs (P < .0001 and P < .0001, respectively). The EGFR CISH-negative OPSCCs had favorable prognosis irrespective of HPV infection. Our results suggest that EGFR gene copy number gain-positive tumors represent an HPV-negative, aggressive subgroup of OPSCCs. The molecular subclassification of OPSCCs based on HPV infection and EGFR status may serve as important information for appropriate therapeutic strategy.

Nakano T ，Yamamoto H ，Nakashima T ，Nishijima T ，Satoh M ，Hatanaka Y ，Shiratsuchi H ，Yasumatsu R ，Toh S ，Komune S ，Oda Y ... -  《-》

Association of Human Papillomavirus and p16 Status With Outcomes in the IMCL-9815 Phase III Registration Trial for Patients With Locoregionally Advanced Oropharyngeal Squamous Cell Carcinoma of the Head and Neck Treated With Radiotherapy With or Without C

We conducted a retrospective evaluation of the IMCL-9815 study to examine the association of human papillomavirus (HPV) and p16 protein expression status with outcomes in patients with oropharyngeal carcinoma (OPC) receiving radiotherapy (RT) plus cetuximab or RT alone. In the IMCL-9815 study, patients were randomly allocated to receive RT plus weekly cetuximab or RT alone. A subpopulation of patients with p16-evaluable OPC was retrospectively evaluated on the basis of locoregional control (LRC), overall survival (OS), and progression-free survival (PFS). Evaluable samples from patients with p16-positive OPC were also tested for HPV DNA. Tumor p16 status was evaluable in 182 patients with OPC enrolled in the IMCL-9815 study; 41% were p16 positive. When treated with RT alone or RT plus cetuximab, p16-positive patients had a longer OS than p16-negative patients (hazard ratio, 0.40; 95% CI, 0.21 to 0.74 and hazard ratio, 0.16; 95% CI, 0.07 to 0.36, respectively). The addition of cetuximab to RT increased LRC, OS, and PFS in both patients with p16-positive OPC and those with p16-negative disease. Interaction tests for LRC, OS, and PFS did not demonstrate any significant interaction between p16 status and treatment effect (P = .087, .085, and .253, respectively). Similar trends were observed when patients with p16-positive/HPV-positive OPC (n = 49) and those with p16-positive/HPV-negative OPC (n = 14) were compared. p16 status was strongly prognostic for patients with OPC. The data suggest that the addition of cetuximab to RT improved clinical outcomes regardless of p16 or HPV status versus RT alone.

Rosenthal DI ，Harari PM ，Giralt J ，Bell D ，Raben D ，Liu J ，Schulten J ，Ang KK ，Bonner JA ... -  《-》

A systematic investigation of the association between HPV and the clinicopathological parameters and prognosis of oral and oropharyngeal squamous cell carcinomas.

Human papillomavirus (HPV), the causal factor of cervical cancers, was closely linked to the etiology and prognosis of oropharyngeal squamous cell carcinoma (OPSCC), but its role in oral squamous cell carcinoma (OSCC) was unclear. In addition, few researches based on Chinese population were documented. Hence, we sought to investigate the relationship of HPV marker P16 protein to the clinicopathological parameters and survival of OPSCC and OSCC patients systematically to assess the influence of ethnic, regional difference on HPV susceptibility. Specimens from 93 OPSCC patients and 95 OSCC patients were recut, and P16 immunohistochemistry (IHC) was performed. Moreover, survival analysis was conducted to confirm the independent factors that influenced the prognosis. The P16 results were positive in 25.8% and 9.5% of patients with OPSCC and OSCC, respectively. The overall survival (OS) of HPV-positive OPSCC patients was significantly longer than that of HPV-negative OPSCC patients (P = 0.004). Conversely, statistical significance was not observed regarding the OS of OSCC patients (P = 0.343). Cox regression analysis indicated that T stage and P16 status were independent factors that affected the prognosis of OPSCC patients, and the smoking index influenced the prognosis of OSCC patients. Among OPSCC patients who received radiochemotherapy (RCT), HPV-positive patients had a better survival rate than their HPV-negative counterparts (P = 0.015). Conversely, no significant difference was observed between HPV-positive and HPV-negative OSCC patients who received RCT (P = 0.237). P16 is a credible surrogate by which to define HPV status. HPV expression had a favorable effect on OPSCC patients as opposed to their OSCC counterparts in this single center population-based study.

Wang F ，Zhang H ，Xue Y ，Wen J ，Zhou J ，Yang X ，Wei J ... -  《Cancer Medicine》

The prognostic role of sex, race, and human papillomavirus in oropharyngeal and nonoropharyngeal head and neck squamous cell cancer.

Human papillomavirus (HPV) is a well-established prognostic marker for oropharyngeal squamous cell cancer (OPSCC). Because of the limited numbers of women and nonwhites in studies to date, sex and racial/ethnic differences in prognosis have not been well explored. In this study, survival differences were explored by the tumor HPV status among 1) patients with OPSCCs by sex and race and 2) patients with nonoropharyngeal (non-OP) head and neck squamous cell cancers (HNSCCs). This retrospective, multi-institution study included OPSCCs and non-OP HNSCCs of the oral cavity, larynx, and nasopharynx diagnosed from 1995 to 2012. Race/ethnicity was categorized as white non-Hispanic, black non-Hispanic, Asian non-Hispanic, and Hispanic of any race. Tumors were centrally tested for p16 overexpression and the presence of HPV by HPV16 DNA and high-risk HPV E6/E7 messenger RNA in situ hybridization. Kaplan-Meier and Cox proportional hazards models were used to evaluate overall survival (OS). The study population included 239 patients with OPSCC and 621 patients with non-OP HNSCC with a median follow-up time of 3.5 years. After adjustments for the tumor HPV status, age, current tobacco use, and stage, the risk of death was lower for women versus men with OPSCC (adjusted hazard ratio, 0.55; P = .04). The results were similar with p16. In contrast, for non-OP HNSCCs, HPV positivity, p16 positivity, and sex were not associated with OS. For OPSCC, there are differences in survival by sex, even after the tumor HPV status has been taken into account. For non-OP HNSCC, the HPV status and the p16 status are not of prognostic significance. Cancer 2017;123:1566-1575. © 2017 American Cancer Society.

Fakhry C ，Westra WH ，Wang SJ ，van Zante A ，Zhang Y ，Rettig E ，Yin LX ，Ryan WR ，Ha PK ，Wentz A ，Koch W ，Richmon JD ，Eisele DW ，D'Souza G ... -  《-》