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 organ-sparing 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 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 disease-specific 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 (rho(EGFR) = 0.008; rho(HPV) = 0.03) and DSS (rho(EGFR) = 0.01; rho(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.

Conflict of interest statement

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 Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Figures

Fig 1

Representative images of p16 staining. A core showing no p16 expression score = 1 and a core showing high p16 stain proportion score = 4.

Fig 2

Response to induction chemotherapy on the basis of mean p16 stain proportion. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease. Blue box, interquartile range (25th to 75th percentile), not including outliers; yellow dot, mean; blue circle, outlier; blue horizontal bar, median.

Fig 3

Disease-specific survival of patients according to p16 stain proportion.

Fig 4

Representative images of epidermal growth factor receptor (EGFR) staining. Cores showing low score = 2; medium score = 3; and high score = 4; EGFR stain intensities (used in all analyses) correlated strongly with proportion of EGFR-positive cells (P < .0001).

Fig 5

Response to induction chemotherapy on the basis of mean epidermal growth factor receptor intensity. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease. Blue box, interquartile range (25th to 75th percentile), not including outliers; yellow dot, mean; blue circle, outlier; blue horizontal bar, median.

Fig 6

Disease-specific survival of patients according to epidermal growth factor receptor intensity.

Fig 7

(A) Representative core showing p53 staining. (B) Representative core showing Bcl-xL staining.

Fig 8

(A) Disease-specific survival according to epidermal growth factor receptor (EGFR) intensity and HPV16. (B) Disease-specific survival according to EGFR intensity and p16 proportion. (C) Disease-specific survival of patients on the basis of tumor p53 (stain intensity) and Bcl-xL (stain intensity) expression.

Fig 9

(A) Disease-specific survival on the basis of smoking status. (B) Disease-specific survival on the basis of sex. Smoking status of patients and (C) p16 proportion, (D) epidermal growth factor receptor (EGFR) intensity, and (E) Bcl-xL proportion. (F) Mean EGFR intensities on the basis of sex. (C, D, E, F) Blue box, interquartile range (25th to 75th percentile), not including outliers; yellow dot, mean; blue circle, outlier; blue horizontal bar, median.

Fig A1

Schema of patients represented on tissue microarray (TMA) according to treatment. Endoscopy*, endoscopy with biopsy. CRT, chemotherapy/radiotherapy; CR, complete response; PR, partial response; IC, induction chemotherapy; CR/PR, complete response/partial response (> 50% response to induction chemotherapy);