Combined analysis of HPV‐DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer

Abstract

Molecular prognostic indicators for oropharyngeal squamous cell carcinoma (OSCC), including HPV-DNA detection, epidermal growth factor receptor (EGFR) and p16 expression, have been suggested in the literature, but none of these are currently used in clinical practice. To compare these predictors, 106 newly diagnosed OSCC for the presence of HPV-DNA and expression of p16 and EGFR were analyzed. The 5-year disease-free survival (DFS) and overall survival (OS) were calculated in relation to these markers and a multivariate Cox analysis was performed. Twentyeight percent of the cases contained oncogenic HPV-DNA and 30% were positive for p16. The p16 expression was highly correlated with the presence of HPV-DNA (p < 0.001). Univariate analysis of the 5-year DFS revealed a significantly better outcome for patients with p16-positive tumors (84% vs. 49%, p 5 0.009). EGFR-negative tumors showed a tendency toward a better prognosis in DFS (74% vs. 47%, p 5 0.084) and OS (70% vs. 45%, p 5 0.100). Remarkable and highly significant was the combination of p16 and EGFR expression status, leading to 5-year DFS of 93% for p161/EGFR2 tumors vs. 39% for p162/EGFR1 tumors (p 5 0.003) and to a 5-year OS of 79% vs. 38%, respectively (p 5 0.010). In multivariate analysis p16 remained a highly significant prognostic marker for DFS (p 5 0.030) showing a 7.5-fold increased risk for relapse in patients with p16-negative tumors. Our data indicate that p16 expression is the most reliable prognostic marker for OSCC and further might be a surrogate marker for HPV-positive OSCC. HPV1/p161 tumors tended to have decreased EGFR expression, but using both immunohistological markers has significant prognostic implications. ' 2007 Wiley-Liss, Inc.

CD56-positive lymphocyte infiltration in relation to human papillomavirus association and prognostic significance in oropharyngeal squamous cell carcinoma

“…In this study, we found an HPV prevalence of 24.3% in our cohort, which is lower than the prevalence in OSCC and tonsillar cancer reported for the USA (45-83%) 4,5 or northern Europe (26-93%), 5,23,24 but comparable to data for central Europe (14-33%) [25][26][27] . We considered HPV-association of samples when high risk HPV-DNA was detected along with p16INK4a expression.…”

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

“…5,7,[14][15][16] HPV-negative tumors, in contrast, often show inactivation of p16 INK4A , p53 overexpression as a result of gene mutations, cyclin D1 gene amplification and overexpression, as well as EGFR accumulation. 3,[17][18][19] The literature, however, shows conflicting data with respect to HPV-associated characteristics and clinical outcome of head-and-neck squamous cell carcinomas. First, although many studies describe a significant association between HPV presence and favorable prognosis, some studies did not find such a correlation.…”

Survey on human papillomavirus/p16 screening use in oropharyngeal carcinoma patients in the United States

“…3 Greater than 86% of HPV-positive tumors over express p16 INK4A (p16), a cyclin-dependent kinase inhibitor, and only 3% of HPV-negative tumors over express p16. 5 Malignant transformation of HPV-induced malignancies involves the E6 and E7 oncoprotein pathways, which functionally inactivate 2 human tumor-suppressor proteins, p53 and pRb, respectively, leading to cellular proliferation, loss of cell cycle regulation, impaired cellular differentiation, increased frequency of spontaneous and mutagen-induced mutations, and chromosomal instability. [5][6][7] Patients with HPV-positive OPSCC reportedly have a better prognosis than patients with HPV-negative OPSCC.…”

“…5 Malignant transformation of HPV-induced malignancies involves the E6 and E7 oncoprotein pathways, which functionally inactivate 2 human tumor-suppressor proteins, p53 and pRb, respectively, leading to cellular proliferation, loss of cell cycle regulation, impaired cellular differentiation, increased frequency of spontaneous and mutagen-induced mutations, and chromosomal instability. [5][6][7] Patients with HPV-positive OPSCC reportedly have a better prognosis than patients with HPV-negative OPSCC. [8][9][10][11] In a prospective clinical trial by Fakhry et al, it was reported that patients who had HPV-positive OPSCC had a 95% overall survival rate at 2 years compared with a rate of 62% for patients who had HPV-negative disease.…”

“…5,20 With the increased importance in HPV-positive OPSCC, we sought to determine whether or not practicing radiation oncologists across the United States have instituted HPV DNA analysis or p16 immunohistochemical staining into their practices, because little is known regarding its status in clinical use. We conducted a national online survey of practicing radiation oncologists to address this issue, and the results are reported here.…”