Originally published as JCO Early Release 10.1200/JCO.2007.12.7662 on May 12 2008

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

Bhavna Kumar, Kitrina G. Cordell, Julia S. Lee, Francis P. Worden, Mark E. Prince, Huong H. Tran, Gregory T. Wolf, Susan G. Urba, Douglas B. Chepeha, Theodoros N. Teknos, Avraham Eisbruch, Christina I. Tsien, Jeremy M.G. Taylor, Nisha J. D’Silva, Kun Yang, David M. Kurnit, Joshua A. Bauer, Carol R. Bradford, Thomas E. Carey

From the Department of Otolaryngology–Head and Neck Surgery, Department of Periodontics and Oral Medicine, Department of Pathology, Comprehensive Cancer Center, Department of Internal Medicine, Division of Hematology-Oncology, Department of Radiation Oncology, Department of Biostatistics, Department of Pediatrics, and Department of Pharmacology, University of Michigan, Ann Arbor, MI

Corresponding author: Thomas E. Carey, PhD, Department of Otolaryngology–Head and Neck Surgery, University of Michigan Comprehensive Cancer Center Head and Neck Cancer Program, 5311 Med Sci I, 1150 W Medical Ctr Dr, Ann Arbor, MI 48109; e-mail: careyte{at}umich.edu

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 (_EGFR = 0.008; _HPV = 0.03) and DSS (_EGFR = 0.01; _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.

Supported by Grants No. R01 DE13346 from the National Institutes of Health (NIH) NIDCR, P30 DC 05188 from the NIH NIDCD, and R01 CA83087 from the NIH National Cancer Institute; Head and Neck Cancer SPORE Grant No. P50 CA97248 from the NIH-NCI NIDCR; NCI National Cancer Center Support Grant No. P30 CA46592 from the Cancer Center Support; and Grant No. MEDC-410, and Loan No. MEDC-239 (to Sensigen) from the state of Michigan.

Presented in part at the 4th International Meeting on Cancer Molecular Markers, September 8-10, 2006, Stone Mountain, GA and at the Multidisciplinary Head and Neck Cancer Symposium, January 18-20, 2007, Rancho Mirage, CA.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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