Cyclin D1 and cancer development in laryngeal premalignancy patients

Abstract

In a previous trial, we found that combined 13-cis-retinoic acid, IFN-alpha, and alpha-tocopherol more effectively reversed advanced premalignant lesions of the larynx than of the oral cavity and that cyclin D1 (CD1) G/A870 single nucleotide polymorphism correlated with cancer risk. We conducted the present trial primarily to confirm the clinical activity of the combination in advanced laryngeal premalignancy and to confirm and extend our findings on CD1, both genotype and protein expression, in association with cancer risk in this setting. Twenty-seven moderate-to-severe laryngeal dysplasia patients underwent induction with combined 13-cis-retinoic acid daily, alpha-IFN twice weekly, and alpha-tocopherol daily for 1 year; 14 nonprogressing patients then were randomized to maintenance fenretinide or placebo for 2 years. During induction, two patients had pathologic complete responses, six had partial responses (30% overall response rate), and five developed laryngeal cancer. There were no significant differences between maintenance fenretinide and placebo in response or cancer rates. Ten patients developed cancer overall. Twenty-four patients were evaluated for the CD1 G/A870 genotype, and 23 for pretreatment and posttreatment CD1 protein expression. Consistent with our earlier report, shorter cancer-free survival was associated with the CD1 AA/AG genotype (P = 0.05). Extending our earlier work, high CD1 expression was associated with worse cancer-free survival overall (P = 0.04) and within each CD1 genotype group. These findings support CD1 genotype and protein expression as important risk markers for laryngeal cancer and suggest future trials targeting upstream regulators of CD1 transcription.

Figure 1

Left panel, Baseline laryngeal dysplasia involving both true vocal folds and immediate subglottis. Right panel, Near-complete resolution of laryngeal dysplasia post-treatment.

Figure 2

CD1 protein expression detected by immunohistochemistry. (A) GG genotype: low nuclear expression; (B) AG genotype: high nuclear expression.

Figure 3

A, Cancer-free survival by cyclin D1 870A genotype. The difference between the groups AA or AG vs GG was tested by Wald test, p=0.05. E = number of events, N = total number of patients per arm. B, Cancer-free survival by cyclin D1 protein expression using weighted mean index (WMI) cut-off of 0.41, (Wald test, p=0.04). C. Cancer-free survival by CD1 G870A genotype stratified by CD1 protein expression using weighted mean index (WMI) cut-off of 0.41. (log-rank test comparing CD1 ≥ 0.41 vs <0.41, p=0.08 for GG group and p=0.17 for AA/AG group, overall log-rank test p=0.04) E = number of events, N = total number of patients per arm.