Transforming growth factor-alpha: a surrogate endpoint biomarker?

Area of Science:

• Oncology
• Biochemistry
• Molecular Biology

Background:

• Dysplastic oral leukoplakia (DOL) is a key indicator lesion for upper aerodigestive tract squamous cell carcinoma (SCC) prevention trials.
• Vitamin A derivatives, such as 13-cis retinoic acid (13-CRA), are investigated for treating DOL and reducing SCC risk.
• Transforming growth factor-alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) mRNA expression are explored as potential surrogate endpoint biomarkers for SCC prevention.

Purpose of the Study:

• To evaluate the efficacy of 13-cis retinoic acid (13-CRA) in patients with dysplastic oral leukoplakia (DOL).
• To analyze the expression of TGF-alpha and EGFR mRNA as potential biomarkers in DOL and adjacent normal mucosa.
• To determine if TGF-alpha and EGFR mRNA expression can serve as surrogate endpoints in SCC prevention trials.

Main Methods:

• A prospective, randomized, double-blind trial involving 28 patients with DOL.
• Quantitative, competitive, reverse transcriptase polymerase chain reaction (RT-PCR) was used to analyze TGF-alpha and EGFR mRNA expression in sequential biopsy specimens.
• Statistical comparison of gene expression between DOL and normal mucosa, and before and after treatment, using the Wilcoxon signed-rank test.

Main Results:

• Baseline TGF-alpha mRNA expression was significantly elevated in DOL compared to normal mucosa (p = 0.003).
• Patients achieving >= 50% clearance of DOL showed significant modulation of TGF-alpha mRNA overexpression after 6 months of 13-CRA treatment (p = 0.016).
• Elevated baseline TGF-alpha mRNA expression predicted a subsequent treatment response to 13-CRA (p = 0.066).

Conclusions:

• TGF-alpha overexpression appears to mediate the relationship between 13-CRA treatment and dysplastic oral leukoplakia (DOL) response.
• While TGF-alpha modulation is observed, its direct role in mediating 13-CRA's effect on SCC prevention requires further investigation.
• Full validation of TGF-alpha as a surrogate endpoint biomarker necessitates results from ongoing human and animal trials focused on SCC incidence reduction.