title: A Randomized Phase IIb Trial of myo-Inositol in Smokers with Bronchial Dysplasia.
abstract: Previous preclinical studies and a phase I clinical trial suggested that myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia. Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once a day for 2 weeks, and then twice a day for 6 months. The primary endpoint was change in dysplasia rate after 6 months of intervention on a per-participant basis. Other trial endpoints reported herein include Ki-67 labeling index, blood and bronchoalveolar lavage fluid (BAL) levels of proinflammatory, oxidant/antioxidant biomarkers, and an airway epithelial gene expression signature for PI3K activity. Seventy-four (n = 38 myo-inositol and n = 36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (P = 0.76). Compared with placebo, myo-inositol intervention significantly reduced IL6 levels in BAL over 6 months (P = 0.03). Among those with a complete response in the myo-inositol arm, there was a significant decrease in a gene expression signature reflective of PI3K activation within the cytologically normal bronchial airway epithelium (P = 0.002). The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent. Cancer Prev Res; 9(12); 906-14. ©2016 AACR.
authors.affiliation: British Columbia Cancer Agency, Vancouver, British Columbia, Canada. slam2@bccancer.bc.ca.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Sumithra J
authors.initials: SJ
authors.lastname: Mandrekar
authors.affiliation: Boston University Medical Center, Boston, Massachusetts.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Gesthalter
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Allen Ziegler
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Drew K
authors.initials: DK
authors.lastname: Seisler
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: David E
authors.initials: DE
authors.lastname: Midthun
authors.affiliation: New Mexico Veteran's Health Care System, Albuquerque, New Mexico.
authors.forename: Jenny T
authors.initials: JT
authors.lastname: Mao
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Marie Christine
authors.initials: MC
authors.lastname: Aubry
authors.affiliation: Fiona Stanley Hospital, Palmyra DC, Western Australia.
authors.forename: Annette
authors.initials: A
authors.lastname: McWilliams
authors.affiliation: St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
authors.affiliation: British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Tawimas
authors.initials: T
authors.lastname: Shaipanich
authors.affiliation: Boston University Medical Center, Boston, Massachusetts.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Boston University Medical Center, Boston, Massachusetts.
authors.forename: Evan
authors.initials: E
authors.lastname: Johnson
authors.affiliation: University of Utah, Salt Lake City, Utah.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bild
authors.affiliation: Boston University Medical Center, Boston, Massachusetts.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Lenburg
authors.affiliation: British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Diana N
authors.initials: DN
authors.lastname: Ionescu
authors.affiliation: Vancouver General Hospital, Vancouver, British Columbia.
authors.forename: John
authors.initials: J
authors.lastname: Mayo
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Joanne Eunhee
authors.initials: JE
authors.lastname: Yi
authors.affiliation: Mayo Clinic, Scottsdale, Arizona.
authors.forename: Henry
authors.initials: H
authors.lastname: Tazelaar
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: William S
authors.initials: WS
authors.lastname: Harmsen
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Judith
authors.initials: J
authors.lastname: Smith
authors.affiliation: Boston University Medical Center, Boston, Massachusetts.
authors.forename: Avrum E
authors.initials: AE
authors.lastname: Spira
authors.affiliation: Boston University Medical Center, Boston, Massachusetts.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Beane
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Limburg
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Eva
authors.initials: E
authors.lastname: Szabo
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D001706:Biopsy; D001980:Bronchi / Q000187:drug effects* / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid; D001999:Bronchoscopy; D018890:Chemoprevention; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy / Q000473:pathology; D007294:Inositol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D019394:Ki-67 Antigen / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008679:Metaplasia / Q000188:drug therapy / Q000473:pathology; D008875:Middle Aged; D061848:Optical Imaging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D012907:Smoking / Q000009:adverse effects*; D036542:Tomography, Spiral Computed; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D014803:Vitamin B Complex; D007294:Inositol; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose