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.

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); < PR, stable disease or progressive disease (≤ 50% response to induction chemotherapy); DoC, died of other causes; DoD, died of disease; DM, distant metastases; XRT, radiation therapy.