Cancer Prevention Research Cyclin D1 and Cancer Development in Laryngeal Premalignancy Patients

In a previous trial, we found that combined 13-cis-retinoic acid, IFN-α, and α-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, α-IFN twice weekly, and α-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. Premalignant lesions of the head and neck are a useful model for evaluating strategies for chemoprevention of upper aerodigestive tract cancers (1). These lesions most often develop in association with exposure to tobacco and alcohol and frequently precede the development of invasive carcinoma (2). Although early premalignant head and neck lesions (hyperplasia and mild dysplasia) are commonly responsive to single-agent retinoid therapy (3, 4), advanced premalignant head and neck lesions (moderate-to-severe dysplasia) are resistant to retinoid monotherapy (3–5). The combination of retinoids and IFNs (biochemoprevention) enhances the induction of cell differentiation and suppression of cell proliferation (6–10). A clinical trial of combined 13-cis-retinoic acid (13-cRA), IFN-α, and α-tocopherol [based on possible enhancement of activity and attenuation of retinoid toxicity (11, 12)] for 12 months in patients with oral and laryngeal premalignant lesions produced a high response rate of laryngeal lesions (13). In the original study, we also examined cyclin D1 (CD1) G/A870 single nucleotide polymorphism, gene amplification, and protein expression. CD1 is key regulatory protein of the cell cycle and tissue homeostasis, and alterations of both its gene copy number and protein expression are frequently found in premalignancy and neoplasia. The CD1 G/A870 single nucleotide polymorphism is associated with two different splice variant transcripts: CD1a and CD1b. CD1a encodes for the full-length native form of the CD1 protein, which has a short nuclear half-life, tightly regulated by phosphorylation of residues in exon 5, followed by nuclear export and ubiquitination (14). CD1b encodes for a truncated alternate CD1 protein, which lacks exon 5 and is a constitutively nuclear protein with enhanced oncogenic properties (14). The major translational findings were a correlation between CD1 AA or AG genotype and increased cancer risk (versus CD1 GG genotype) and a trend toward an association between modulation of CD1 protein expression and lesion response (15). Authors' Affiliations: Departments of Thoracic/Head and Neck Medical Oncology, Experimental Therapeutics, Biostatistics, Head and Neck Surgery, Pathology, and Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas Received 06/13/2008; revised 08/29/2008; accepted 09/25/2008. Grant support: National Cancer Institute, NIH, Department of Health and Human Services grant U01-CA-79437-01. Note: V. Papadimitrakopoulou and J.G. Izzo contributed equally to this work. Requests for reprints: Vassiliki Papadimitrakopoulou, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 432, Houston, TX 77030. Phone: 713-792-6363; Fax: 713-792-1220; E-mail: [email protected] or Julie G. Izzo, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 432, Houston, TX 77030. E-mail: [email protected]. ©2009 American Association for Cancer Research. doi:10.1158/1940-6207.CAPR-08-0111 14 Cancer Prev Res 2009;2(1) January 2009 www.aacrjournals.org Cancer Research. on June 19, 2017. © 2009 American Association for cancerpreventionresearch.aacrjournals.org Downloaded from We designed the present randomized trial in two phases: induction with combined 13-cRA, IFN-α, and α-tocopherol to confirm the clinical/histologic activity of this regimen in patients with advanced premalignant lesions of the larynx followed by maintenance with fenretinide (versus placebo) to prolong the chemopreventive effects. We chose the synthetic retinoid fenretinide for the maintenance phase because it has a different mechanism of action from that of the related compound 13-cRA, the potential to reverse persistent lesions (16–18), and a favorable toxicity profile (19). The major translational goal of this study was to prospectively confirm and extend the CD1 findings of our earlier trial. Materials and Methods