title: 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.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 432, Houston, TX 77030, USA. vpapadim@mdanderson.org
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Papadimitrakopoulou
authors.forename: Julie G
authors.initials: JG
authors.lastname: Izzo
authors.forename: Diane D
authors.initials: DD
authors.lastname: Liu
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Myers
authors.forename: Tania L
authors.initials: TL
authors.lastname: Ceron
authors.forename: Jan
authors.initials: J
authors.lastname: Lewin
authors.forename: William N
authors.initials: WN
authors.lastname: William
authors.forename: Anthea
authors.initials: A
authors.lastname: Atwell
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Ann
authors.initials: A
authors.lastname: Gillenwater
authors.forename: Adel
authors.initials: A
authors.lastname: El-Naggar
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.forename: Walter N
authors.initials: WN
authors.lastname: Hittelman
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D019938:Cyclin D1 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D005260:Female; D017313:Fenretinide / Q000627:therapeutic use*; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D015474:Isotretinoin / Q000008:administration & dosage / Q000009:adverse effects; D007818:Laryngeal Diseases / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D007822:Laryngeal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011230:Precancerous Conditions / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D024502:alpha-Tocopherol / Q000008:administration & dosage
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016898:Interferon-alpha; D019938:Cyclin D1; D017313:Fenretinide; D015474:Isotretinoin; D024502:alpha-Tocopherol