A Randomized Trial of Low-Dose Tamoxifen on Breast Cancer Proliferation and Blood Estrogenic Biomarkers

• Published in: JNCI : Journal of the National Cancer Institute 2003-06, Vol.95 (11), p.779-790
• Main Authors: Decensi, Andrea, Robertson, Chris, Viale, Giuseppe, Pigatto, Francesca, Johansson, Harriet, Kisanga, Elton R., Veronesi, Paolo, Torrisi, Rosalba, Cazzaniga, Massimiliano, Mora, Serena, Sandri, Maria T., Pelosi, Giuseppe, Luini, Alberto, Goldhirsch, Aron, Lien, Ernst A., Veronesi, Umberto
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents, Hormonal - administration & dosage; Antineoplastic Agents, Hormonal - therapeutic use; Biological and medical sciences; Biomarkers, Tumor - blood; Breast Neoplasms - blood; Breast Neoplasms - chemistry; Breast Neoplasms - drug therapy; Chemotherapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Estrogen Receptor Modulators - administration & dosage; Estrogen Receptor Modulators - therapeutic use; Estrogens - blood; Female; Gene Expression Regulation, Neoplastic - drug effects; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Ki-67 Antigen - blood; Mammary gland diseases; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Research Design; Tamoxifen - administration & dosage; Tamoxifen - therapeutic use; Tumors
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/95.11.779

Background: Tamoxifen reduces the risk of breast cancer in women at high risk for the disease but increases the risk for endometrial tumors and venous thromboembolisms, possibly in a dose-dependent fashion. We compared the effects of tamoxifen at 1 mg/day and 5 mg/day with those of the standard dose of 20 mg/day on breast cancer proliferation using a surrogate endpoint marker (Ki-67 expression) and blood biomarkers associated with breast cancer, cardiovascular disease, and bone fracture risk. Methods: We randomly assigned 120 women with estrogen receptor (ER)-positive breast cancer to tamoxifen at 1, 5, or 20 mg/day for 4 weeks. Expression of the tumor proliferation marker Ki-67 and of biomarkers of breast cancer (insulin-like growth factor-I, sex hormone-binding globulin), cardiovascular disease (cholesterol, triglycerides, ultrasensitive C-reactive protein, fibrinogen, antithrombin-III), and bone fracture (type I collagen C-telopeptide) risk were determined before (baseline) and after treatment. All levels were compared with those in two nonrandomized control groups (34 women with ER-negative breast cancer and 29 additional women with ER-positive breast cancer). Data were analyzed by analysis of covariance. All statistical tests were two-sided. Results: Expression of Ki-67 decreased in all three tamoxifen groups, with no difference in the magnitude of reduction among groups (P = .81). Relative to baseline, Ki-67 expression decreased by a median of 15.0% (95% confidence interval = 0.0% to 24.1%) among the tamoxifen groups but increased by 12.8% (95% confidence interval = 0.0% to 19.6%) among the nonrandomized control groups. Several blood biomarkers showed dose–response relationships with tamoxifen, including decreased insulin-like growth factor-I, increased sex hormone-binding globulin, and decreased low-density lipoprotein-cholesterol, ultrasensitive C-reactive protein, fibrinogen, and antithrombin-III levels. Conclusions: The effects on Ki-67 expression of lower doses of tamoxifen were comparable to those achieved with the standard dose, although the effects on blood biomarkers were variable. The effects of lower doses of tamoxifen should be assessed further in randomized trials.