Cancer Prevention Research A Pilot Surrogate Endpoint Biomarker Study of Celecoxib in Oral Premalignant Lesions Lori J. Wirth, 1 Jeffrey F. Krane, 3 Yi Li, 2 Megan Othus, 2 Amy E. Moran, 4 David M. Dorfman, 3 Charles M. Norris, Jr., 4 Laura Goguen, 4 Marshall R. Posner, 1 Robert I. Haddad 1 and Monica M. Bertagnolli 4 Abstract This study evaluated changes in prostaglandin E 2 (PGE 2 ) levels and related biomarkers in oral premalignant lesions (OPL) in response to celecoxib treatment. Twenty-two subjects were enrolled and treated with celecoxib. Pretreatment and 12-week biopsies were done. Subjects whose biopsy showed ≥30% decrease in PGE 2 remained on celecoxib for a total of 12 months when repeat biopsy was done. Biopsies were examined to assess degree of dysplasia, DNA ploidy, and immunohistochemical expression of BCL2, pAKT-Ser473, Ki-67, and CD31 (microvessel density). In 18 paired biopsies available at baseline and 12 weeks, mean normalized PGE 2 levels decreased by 38% (P = 0.002). After 12 months, PGE 2 decreased by 31% (P = 0.340). Twelve biopsies (67%; P = 0.0129) showed improve- ment in degree of dysplasia after 12 weeks, and 8 of 11 biopsies (73%; P = 0.0703) con- tinued to show an improvement in the degree of dysplasia after 12 months. Trends suggested down-modulation of cyclooxygenase-2 and Ki-67 in some tissues, increased pAKT-Ser473 expression, and an inverse relationship between PGE 2 and BCL2 expres- sion. This study documents the feasibility of measuring potential surrogate endpoint bio- markers of chemopreventive agent response in OPLs. Treatment with celecoxib in subjects with OPLs favorably modulates the primary mediator of cyclooxygenase-2 activity, PGE 2 , after 12 weeks. Oral premalignant lesions (OPL), including leukoplakia and erythroplakia, indicate a high risk of malignancy. As many as 15% to 36% of patients with OPLs will develop squamous cell carcinoma of the head and neck (SCCHN) over 5 to 10 years (1–3). For those who do develop SCCHN, the rate of 5-year survival approximates 60%, and optimizing current treatment has produced an improvement in survival of only 3% over the past 25 years (4, 5). Ideally, successful identification and treat- ment of high-risk OPLs would prevent a significant number of deaths and morbidity from SCCHN. When limited in size and number, OPLs can be readily detected by oral cavity examina- tion and treated by excision. Unfortunately, these lesions typi- cally arise in a background of field cancerization and are therefore subject to multifocal recurrence, limiting the ability of surgery to address the underlying problem (3, 6–11). Tobacco cessation can reduce the risk of SCCHN; however, treatments for tobacco addiction are not always successful, and former smokers remain at risk for cancer long after quitting (12, 13). Given the limitations of local therapy for OPLs, chemopre- vention is an appealing notion. In patients with a history of SCCHN, chemoprevention with high-dose 13-cis-retinoic acid reduced the recurrence rate of OPLs and decreased the risk of second primary tumors (14). Retinoids have not become stan- dard therapy, however, because effective doses are not well tolerated over a meaningful period of time (14–16). No other systemic agents, including vitamin A and β-carotene, have shown both tolerability and efficacy in reducing the risk of cancer in patients with OPLs (17, 18). The study of SCCHN carcinogenesis has identified thera- peutic targets for cancer treatment and prevention that are now under investigation in the treatment setting (19). One promising prognostic and therapeutic target is cyclooxygen- ase-2 (COX-2), an enzyme responsible for elevated prostaglan- din levels in chronic inflammation and cancer (20, 21). COX-2 is expressed in the majority of human epithelial tumors (22) and preclinical studies show that COX-2–associated prosta- glandins suppress tumor cell apoptosis, invasion, and angio- genesis and also activate epidermal growth factor receptor (23–26). A direct role for COX-2 in tumor promotion was shown in studies showing reduced spontaneous intestinal tumor formation in a murine model by targeted deletion of the COX-2 gene (27). Human chemoprevention clinical trials confirmed the effectiveness of selective COX-2 inhibitors Authors' Affiliations: Departments of 1 Adult Oncology and 2 Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard Medical School; Departments of 3 Pathology and 4 Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts Received 12/10/2007; revised 03/20/2008; accepted 04/10/2008. Requests for reprints: Monica M. Bertagnolli, Department of Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Phone: 617-732-8910; Fax: 617-582-6177; E-mail: mbertagnolli@partners.org. ©2008 American Association for Cancer Research. doi:10.1158/1940-6207.CAPR-07-0003 339 Cancer Prev Res 2008;1(5) October 2008 www.aacrjournals.org Cancer Research. on March 7, 2016. © 2008 American Association for cancerpreventionresearch.aacrjournals.org Downloaded from