Prognostic Significance of p16^INK4A and Human Papillomavirus in Patients With Oropharyngeal Cancer Treated on TROG 02.02 Phase III Trial

Abstract

A B S T R A C T PurposeTo determine the prognostic importance of p16 and human papillomavirus (HPV) in patients with oropharyngeal cancer treated on a phase III concurrent chemoradiotherapy trial. Patients and MethodsPatients with stage III or IV head and neck squamous cell cancer were randomly assigned to concurrent radiotherapy and cisplatin with or without tirapazamine. In this substudy, analyses were restricted to patients with oropharyngeal cancer. p16 was detected by immunohistochemistry, and HPV was detected by in situ hybridization and polymerase chain reaction. ResultsSlides were available for p16 assay in 206 of 465 patients, of which 185 were eligible, and p16 and HPV were evaluable in 172 patients. One hundred six (57%) of 185 were p16-positive, and in patients evaluable for both p16 and HPV, 88 (86%) of 102 p16-positive patients were also HPV-positive. Patients who were p16-positive had lower T and higher N categories and better Eastern Cooperative Oncology Group (ECOG) performance status. p16-positive tumors compared with p16-negative tumors were associated with better 2-year overall survival (91% v 74%; hazard ratio [HR], 0.36; 95% CI, 0.17 to 0.74; P ϭ .004) and failure-free survival (87% v 72%; HR, 0.39; 95% CI, 0.20 to 0.74; P ϭ .003). p16 was a significant prognostic factor on multivariable analysis (HR, 0.45; 95% CI, 0.21 to 0.96; P ϭ .04). p16-positive patients had lower rates of locoregional failure and deaths due to other causes. There was a trend favoring the tirapazamine arm for improved locoregional control in p16-negative patients (HR, 0.33; 95% CI, 0.09 to 1.24; P ϭ .13). ConclusionHPV-associated oropharyngeal cancer is a distinct entity with a favorable prognosis compared with HPV-negative oropharyngeal cancer when treated with cisplatin-based chemoradiotherapy.

Human papillomavirus DNA load and p16INK4aexpression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy

“…6,7 In clinical series of head and neck as well as cervical SCC, recent data indicate that treatment response to radiotherapy (RT) or chemoradiotherapy (CRT) is superior in HPV-positive tumors as compared with their HPV-negative counterparts. [8][9][10] An increased sensitivity of HPV-positive tumor cells towards irradiation and chemotherapeutic agents was also observed in vitro and in animal studies. [11][12][13] However, as the detection rate of HPV DNA in anal SCC commonly exceeds 90%, a comparison between sole HPV-positive and HPV-negative cancers with respect to treatment response and long-term outcome is challenging.…”

“…8,9,18,42 Moreover, response towards RT or CRT is superior in HPV-carrying tumors indicating an increased RT/CRT sensitivity in HPVinfected tumor cells. 13 The mechanisms involved are likely multifactorial and include elevated levels of DNA nucleotide excision repair gene expression, 43 increased radiation-induced residual DNA double-strand breaks (DSBs), extensive G2 cell cycle arrest, 12,44 modulation of AKT activation, 45 increased apoptotic cell death and up-regulation of tumor suppressor TP53 and multiple genes in the TP53 pathway.…”

“…13,[15][16][17] In line with that, several studies indicated that p16 INK4a detection by immunohistochemistry (IHC) is predictive for a significantly improved response to treatment with RT/CRT and a more favourable prognosis in patients with HPV-associated malignancies. 5,8,9,18 The present study aimed to investigate the impact of tumor HPV genotype, HPV16 DNA load, and p16 INK4a immunohistochemical expression on local failure rates, risk of distant metastases, cancer specific survival (CSS) and overall survival (OS) in patients uniformly treated by standard CRT for anal SSC. Our data demonstrate that low initial HPV16 DNA load and low p16 INK4a expression were associated with an increased risk of local failure and decreased OS following standard CRT, indicating that these tumors may represent a high-risk subpopulation of anal SCC that may require intensified or alternative treatment strategies.…”

p16 Immunohistochemistry As a Standalone Test for Risk Stratification in Oropharyngeal Squamous Cell Carcinoma

“…There is an extremely large amount of data looking at p16 IHC and HPV-specific testing in oropharyngeal SCC. Most of the studies are retrospective, but several prospective studies have been performed and analyzed as well [2,3,5,9,12]. There is very high correlation between the HPVspecific tests (of all types) [7,9] and also between p16 immunohistochemistry and HPV-specific testing, particularly with the newer HPV RNA tests (Table 1) [2,3,5,[8][9][10][11][13][14][15].…”

Adenosquamous Carcinoma of the Head and Neck: Relationship to Human Papillomavirus and Review of the Literature

“…It has also been documented in several studies that HPV-related carcinomas of the upper aerodigestive tract have more favorable prognosis than HPV negative ones [11][12][13]. Most previous studies investigated HPV in tumors using DNA-based polymerase chain reaction (PCR) [14] while in more recent years DNA-based in situ hybridization (ISH) has been used [5,13,15]. However, it is becoming increasingly recognized that HPV can be present without necessarily being biologically active, such that mere presence of the virus (as detected by these methods) may not indicate biological/clinical significance.…”