title: A Randomized, Placebo-Controlled, Phase II, Presurgical Biomarker Trial of Celecoxib Versus Exemestane in Postmenopausal Breast Cancer Patients.
abstract: In breast cancer presurgical trials, the Ki-67 labeling index predicts disease outcome and offers clues to the preventive potential of drugs. We conducted a placebo-controlled trial to evaluate the activity of exemestane and celecoxib before surgery. The main endpoint was the change in Ki-67. Secondary endpoints were the modulation of circulating biomarkers. Postmenopausal women with histologically confirmed estrogen receptor-positive breast cancer were randomly assigned to exemestane 25 mg/day (n = 50), or celecoxib 800 mg/day (n = 50), or placebo (n = 25) for 6 weeks before surgery. Changes in biomarkers were analyzed through an ANCOVA model adjusting for baseline values. Exemestane showed a median absolute 10% reduction in Ki-67 [from 22 (interquartile range, IQR, 16-27), to 8 (IQR 5-18)], and a 15% absolute reduction in PgR expression [from 50 (IQR 3-90) to 15 (IQR -0-30)] after 6 weeks of treatment. Exemestane significantly increased testosterone [median change 0.21 ng/mL, (IQR 0.12-0.35)], decreased SHBG [median change -14.6 nmol/L, (IQR -23.1 to -8.6)], decreased total and HDL cholesterol by -10 mg/dL (IQR -21-2) and -7 mg/dL, (IQR -14 to -2), respectively. Triglycerides were reduced by both agents [median change -0.5 mg/dL (IQR -17.5-13.5) and -8 mg/dL (IQR -28-9) for celecoxib and exemestane, respectively]. Exemestane showed a remarkable antiproliferative effect on breast cancer, whereas celecoxib did not affect breast cancer proliferation. Given the proven preventive efficacy of exemestane, these findings support the use of Ki-67 to explore the optimal exemestane dose and schedule in the prevention setting. Cancer Prev Res; 9(5); 349-56. ©2016 AACR.
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy. valentina.aristarco@ieo.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Aristarco
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Serrano
authors.affiliation: Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Gandini
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy.
authors.forename: Harriet
authors.initials: H
authors.lastname: Johansson
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Macis
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy.
authors.forename: Aliana
authors.initials: A
authors.lastname: Guerrieri-Gonzaga
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Lazzeroni
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Feroce
authors.affiliation: Division of Pathology, European Institute of Oncology, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pruneri
authors.affiliation: Division of Breast Cancer Surgery, European Institute of Oncology, Milan, Italy.
authors.forename: Gianmatteo
authors.initials: G
authors.lastname: Pagani
authors.affiliation: Division of Breast Cancer Surgery, European Institute of Oncology, Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Toesca
authors.affiliation: Division of Breast Cancer Surgery, European Institute of Oncology, Milan, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Caldarella
authors.affiliation: Division of Medical Oncology, Galliera Hospital, Genoa, Italy. Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: DeCensi
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Bonanni
mesh_terms: D000368:Aged; D000730:Androstadienes / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy*; D000068579:Celecoxib / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis / Q000096:biosynthesis; D008875:Middle Aged; D017698:Postmenopause
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D000068579:Celecoxib; C056516:exemestane