Transforming growth factor-alpha: a surrogate endpoint biomarker?

Academic Article

Abstract

  • BACKGROUND: Dysplastic oral leukoplakia (DOL) has been the index lesion in prevention trials for upper aerodigestive tract squamous cell carcinoma (SCC). Vitamin A derivatives, including 13-cis retinoic acid (13-CRA), have been used to treat DOL and to reduce the risk of subsequent SCC. Results from a trial of 13-CRA in patients with DOL are presented here. Transforming growth factor-alpha (TGF-alpha) and the epidermal growth factor receptor messenger RNA (mRNA) expression were studied to validate their use as surrogate endpoint biomarkers in prevention trials for SCC. STUDY DESIGN: In a prospective, randomized, double-blind trial of 13-CRA in 28 patients with DOL, TGF-alpha and epidermal growth factor receptor mRNA expression were analyzed in sequential biopsy specimens of DOL and of adjacent normal-appearing mucosa, utilizing a quantitative, competitive, reverse transcriptase polymerase chain reaction and were compared using the Wilcoxon signed-rank test for paired comparisons. RESULTS: In biopsy specimens of DOL, TGF-alpha mRNA expression at baseline, but not baseline expression of epidermal growth factor receptor mRNA, was significantly elevated when compared with its expression in specimens from adjacent normal-appearing mucosa (p = 0.003). In patients randomized to 13-CRA who had > or = 50% clearance of DOL during treatment, significant modulation of TGF-alpha mRNA overexpression was seen after 6 months of treatment (p = 0.016). TGF-alpha mRNA overexpression at baseline predicted a subsequent response to 13-CRA (p 0.066). CONCLUSIONS: The full extent of the association between TGF-alpha overexpression and the development of SCC is unknown. Evidence is presented in this article that TGF-alpha overexpression mediates the relationship between 13-CRA and DOL, but there is no direct evidence that it mediates the relationship between 13-CRA and the prevention of SCC. Determination of the extent to which TGF-alpha overexpression mediates this relationship and complete validation of TGF-alpha's role as a surrogate endpoint biomarker await the results of animal and human trials that utilize reduction in the incidence of SCC as their endpoint.
  • Keywords

  • Aged, Biomarkers, Tumor, Carcinoma, Squamous Cell, Disease Progression, Double-Blind Method, ErbB Receptors, Female, Gene Expression Regulation, Neoplastic, Humans, Isotretinoin, Leukoplakia, Oral, Male, Mouth Neoplasms, Prospective Studies, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Transforming Growth Factor alpha
  • Author List

  • Beenken SW; Hockett R; Grizzle W; Weiss HL; Pickens A; Perloff M; Malone WF; Bland KI
  • Start Page

  • 149
  • End Page

  • 158
  • Volume

  • 195
  • Issue

  • 2