title: Effects of the aromatase inhibitor letrozole on normal breast epithelial cell proliferation and metabolic indices in postmenopausal women: a pilot study for breast cancer prevention.
abstract: The aromatase enzyme converts androgens to estrogens and is the therapeutic target for aromatase inhibitors in postmenopausal patients with estrogen receptor-positive metastatic breast cancer. Third-generation inhibitors such as letrozole are being considered as potential prophylactic agents for breast cancer. The rationale for their preventive application would be aided by knowledge of their effects on the normal breast and on other estrogen-dependent processes such as bone and lipid metabolism. Thirty-two women without active breast disease were recruited to 3-month treatment with letrozole (2.5 mg/day). Core-cut biopsies from the breast and blood samples were collected before and at the end of treatment. Plasma estradiol levels were markedly suppressed in all but two patients, who were excluded from the efficacy assessment. There was no significant change in the proliferation marker Ki67 (mean change, -23%; 95% confidence interval, -50% to +23%) or estrogen receptor in breast epithelial cells with treatment. Similarly, there were no significant changes in plasma levels of insulin-like growth factor I or lipid profiles. However, there was a significant increase (25%) in the levels of the bone resorption marker C-telopeptide crosslinks (CTx). We conclude that any prophylactic effect of letrozole is not likely to be dependent on antiproliferative effects on normal breast. Studies in healthy patients will need to recognize the potential for enhanced bone resorption.
authors.affiliation: Academic Department of Biochemistry, Royal Marsden Hospital, London SW3 6JJ, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Harper-Wynne
authors.forename: Gillian
authors.initials: G
authors.lastname: Ross
authors.forename: Nigel
authors.initials: N
authors.lastname: Sacks
authors.forename: Janine
authors.initials: J
authors.lastname: Salter
authors.forename: Nazar
authors.initials: N
authors.lastname: Nasiri
authors.forename: Jhangir
authors.initials: J
authors.lastname: Iqbal
authors.forename: Roger
authors.initials: R
authors.lastname: A'Hern
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
mesh_terms: D000284:Administration, Oral; D000368:Aged; D015415:Biomarkers / Q000032:analysis; D001707:Biopsy, Needle; D001941:Breast Diseases / Q000188:drug therapy* / Q000473:pathology*; D001943:Breast Neoplasms / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects; D016001:Confidence Intervals; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis*; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage*; D016017:Odds Ratio; D017698:Postmenopause; D011322:Primary Prevention / Q000379:methods; D011336:Probability; D011960:Receptors, Estrogen / Q000032:analysis*; D012016:Reference Values; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D014230:Triazoles / Q000008:administration & dosage*
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D019394:Ki-67 Antigen; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D000077289:Letrozole