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1.
Clin Cancer Res ; 9(13): 4722-9, 2003 Oct 15.
Article in English | MEDLINE | ID: mdl-14581342

ABSTRACT

PURPOSE: High circulating insulin-like growth factor (IGF) -I and/or low IGF-binding protein (IGFBP) -3 levels are associated with increased breast cancer risk in unaffected premenopausal women. We determined whether IGF-I and IGFBP-3 predict second breast cancer risk, and whether their changes during fenretinide explain observed reductions in second breast cancer in women

Subject(s)
Anticarcinogenic Agents/therapeutic use , Breast Neoplasms/prevention & control , Breast Neoplasms/secondary , Fenretinide/therapeutic use , Insulin-Like Growth Factor Binding Protein 3/blood , Insulin-Like Growth Factor I/biosynthesis , Adult , Female , Humans , Middle Aged , Neoplasm Metastasis/prevention & control , Premenopause , Prognosis , Proportional Hazards Models , Risk , Time Factors
2.
J Am Coll Surg ; 195(2): 149-58, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12168960

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.


Subject(s)
Biomarkers, Tumor/metabolism , ErbB Receptors/metabolism , Leukoplakia, Oral/drug therapy , Leukoplakia, Oral/metabolism , Transforming Growth Factor alpha/metabolism , Aged , Carcinoma, Squamous Cell/prevention & control , Disease Progression , Double-Blind Method , ErbB Receptors/drug effects , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Isotretinoin/therapeutic use , Male , Mouth Neoplasms/prevention & control , Prospective Studies , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction
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