EGFR, p16, HPV Titer, Bcl-xL and p53, Sex, and Smoking As Indicators of Response to Therapy and Survival in Oropharyngeal Cancer

Abstract

Purpose-To prospectively identify markers of response to therapy and outcome in an organsparing trial for advanced oropharyngeal cancer.Patients and Methods-Pretreatment biopsies were examined for expression of epidermal growth factor receptor (EGFR), p16, Bcl-xL, and p53 as well as for p53 mutation. These markers Authors' Disclosures of Potential Conflicts of Interest:Although all authors completed the disclosure declaration, the following author (s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure were assessed for association with high-risk human papillomavirus (HPV), response to therapy, and survival. Patient variables included smoking history, sex, age, primary site, tumor stage, and nodal status.Results-EGFR expression was inversely associated with response to induction chemotherapy (IC) (P = .01), chemotherapy/radiotherapy (CRT; P = .055), overall survival (OS; P = .001), and diseasespecific survival (DSS; P = .002) and was directly associated with current smoking (P = .04), female sex (P = .053), and lower HPV titer (P = .03). HPV titer was significantly associated with p16 expression (P < .0001); p16 was significantly associated with response to IC (P = .008), CRT (P = . 009), OS (P = .001), and DSS (P = .003). As combined markers, lower HPV titer and high EGFR expression were associated with worse OS (ρ EGFR = 0.008; ρ HPV = 0.03) and DSS (ρ EGFR = 0.01; ρ HPV = 0.016). In 36 of 42 biopsies, p53 was wild-type, and only one HPV-positive tumor had mutant p53. The combination of low p53 and high Bcl-xL expression was associated with poor OS (P = . 005) and DSS (P = .002).Conclusion-Low EGFR and high p16 (or higher HPV titer) expression are markers of good response to organ-sparing therapy and outcome, whereas high EGFR expression, combined low p53/ high Bcl-xL expression, female sex, and smoking are associated with a poor outcome. Smoking cessation and strategies to target EGFR and Bcl-xL are important adjuncts to the treatment of oropharyngeal cancer.

HPV and oral lesions: preventive possibilities, vaccines and early diagnosis of malignant lesions

“…All this would support the existing evidence of oral/oropharyngeal cancer etiologically associated with HPV having an increased survival and a better prognostic (85-90% to five years), but due to the transmission mode, patients with HPV associated HNSCC are younger (30-50 years old) (28)(29)(30)(31).…”

Individualizing therapy for oropharyngeal cancer patients

“…The expression of the other biomarkers, such as the EGF receptor (EGFR) and Bcl-xL, has also been found to be related to the prognosis in HPV-positive tumors [1]. Bcl-x, a member of the Bcl-2 family, has two alternatively spliced forms, Bcl-xL and Bcl-xS.…”

“…Although the main etiologic risk factors for OPC are tobacco and alcohol consumption, studies demonstrated that the HPV plays an important role as both an etiologic and a prognostic factor in recent years, compared with past decades in which smoking-related OPC was dominant [13,14]. HPV, observed in 40-65% of head and neck squamous cell carcinomas, is isolated from either the tonsil or the base of the tongue [1,[15][16][17].…”

“…The responses to chemotherapy/radiotherapy, and the chance of cure, depend on individual tumor-specific factors that govern tumor sensitivity to therapy [1].…”

“…Bcl-xL is able to protect cells from a wide variety of apoptotic stimuli [28]. Overexpression of the Bcl-xL protein inhibits apoptosis in tumors with mutant p53 and is associated with chemotherapy and radiation resistance [1,29,30]. EGFR is a member of the ErbB family of receptors.…”