title: Influence of neoadjuvant anastrozole (Arimidex) on intratumoral estrogen levels and proliferation markers in patients with locally advanced breast cancer.
abstract: Anastrozole (Arimidex) is a novel, selective, and potent aromatase inhibitor used for the treatment of postmenopausal breast cancer. The drug has been shown to inhibit in vivo aromatization by 96--97% and to suppress plasma estrogen levels by 84--94%. However, the effects of anastrozole on intratumoral estrogen levels have not been studied. Here we report the effects of neoadjuvant treatment with anastrozole on intratumoral levels of estrone (E(1)), estradiol (E(2)), and estrone sulfate (E(1)S), measured by a highly sensitive RIA following a multistep purification procedure involving high-pressure liquid chromatography. Tumor tissue was obtained prior to treatment and after 15 weeks on therapy with anastrozole (1 mg once daily) from 12 postmenopausal women with locally advanced breast cancer (T(3)--T(4) and/or N(2)). Pretreatment tissue levels of E(2), E(1), and E(1)S were 217.9 (69.8--679.9), 173.6 (83.9--358.9), and 80.7 (31.4--207.3) fmol/g tissue (geometric mean values with 95% confidence interval, respectively). Treatment with anastrozole suppressed tissue E(2), E(1), and E(1)S levels by 89.0% (73.2--95.5%), 83.4% (63.2--92.5%), and 72.9% (47.3--86.1%), respectively, compared with baseline levels, with no significant difference between responders and nonresponders. Plasma levels of E(2), E(1), and E(1)S were suppressed by 86.1, 83.9, and 94.2%, respectively. Anastrozole caused a decrease in the immunoexpression of the proliferation markers Ki67 and pS2 in all of the patients, with a trend for a more profound suppression in those achieving an objective response. The mean percentage of apoptotic cells was found to be decreased in responders and increased in nonresponders after 15 weeks of anastrozole therapy. Our results reveal anastrozole to cause a significant suppression of tissue estrogen levels and to influence the biology of primary estrogen receptor-positive breast cancers in postmenopausal women.
authors.affiliation: Department of Oncology, Haukeland University Hospital, N-5021 Bergen, Norway.
authors.forename: J
authors.initials: J
authors.lastname: Geisler
authors.forename: S
authors.initials: S
authors.lastname: Detre
authors.forename: H
authors.initials: H
authors.lastname: Berntsen
authors.forename: L
authors.initials: L
authors.lastname: Ottestad
authors.forename: B
authors.initials: B
authors.lastname: Lindtjørn
authors.forename: M
authors.initials: M
authors.lastname: Dowsett
authors.forename: P
authors.initials: P
authors.lastname: Einstein Lønning
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006728:Hormones / Q000378:metabolism; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism*; D008875:Middle Aged; D009367:Neoplasm Staging; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D017698:Postmenopause; D011506:Proteins / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D000071163:Trefoil Factor-1; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D025521:Tumor Suppressor Proteins
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004967:Estrogens; D006728:Hormones; D019394:Ki-67 Antigen; D009570:Nitriles; D011506:Proteins; D017978:Receptors, Growth Factor; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D014230:Triazoles; D025521:Tumor Suppressor Proteins; D000077384:Anastrozole