[en] Background
Vasomotor symptoms and bone loss are complications frequently induced by adjuvant treatment for breast cancer. Tibolone prevents both side-effects, but its effect on cancer recurrence is unknown. The aim of this study was to show non-inferiority of tibolone to placebo regarding risk of recurrence in breast-cancer patients with climacteric complaints.
Methods
Between July 11, 2002, and Dec 20, 2004, women surgically treated for a histologically confirmed breast cancer (T1–3N0–2M0) with vasomotor symptoms were randomly assigned to either tibolone 2·5 mg daily or placebo at 245 centres in 31 countries. Randomisation was done by use of a centralised interactive voice response system, stratified by centre, with a block size of four. The primary endpoint was breast-cancer recurrence, including contralateral breast cancer, and was analysed in the intention-to-treat (ITT) and per-protocol populations; the margin for non-inferiority was set as a hazard ratio of 1·278. This study is registered with ClinicalTrials.gov, number NCT00408863.
Findings
Of the 3148 women randomised, 3098 were included in the ITT analysis (1556 in the tibolone group and 1542 in the placebo group). Mean age at randomisation was 52·7 years (SD 7·3) and mean time since surgery was 2·1 years (SD 1·3). 1792 of 3098 (58%) women were node positive and 2185 of 3098 (71%) were oestrogen-receptor positive. At study entry, 2068 of 3098 (67%) women used tamoxifen and 202 of 3098 (6·5%) women used aromatase inhibitors. The mean daily number of hot flushes was 6·4 (SD 5·1). After a median follow-up of 3·1 years (range 0·01–4·99), 237 of 1556 (15·2%) women on tibolone had a cancer recurrence, compared with 165 of 1542 (10·7%) on placebo (HR 1·40 [95% CI 1·14–1·70]; p=0·001). Results in the per-protocol population were similar (209 of 1254 [16·7%] women in the tibolone group had a recurrence vs 138 of 1213 [11·4%] women in the placebo group; HR 1·44 [95% CI 1·16–1·79]; p=0·0009). Tibolone was not different from placebo with regard to other safety outcomes, such as mortality (72 patients vs 63 patients, respectively), cardiovascular events (14 vs 10, respectively), or gynaecological cancers (10 vs 10, respectively). Vasomotor symptoms and bone-mineral density improved significantly with tibolone, compared with placebo.
Disciplines :
Reproductive medicine (gynecology, andrology, obstetrics)
Author, co-author :
Kenemans, P.
Bundred, N. J.
Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique - Labo de biologie des tumeurs et du développement
Howell A., Cuzick J., Baum M., et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365 (2005) 60-62
Goodwin P.J., Ennis M., Pritchard K.I., Trudeau M., and Hood N. Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 17 (1999) 2365-2370
Hickey M., Saunders C.M., and Stuckey B.G. Management of menopausal symptoms in patients with breast cancer: an evidence-based approach. Lancet Oncol 6 (2005) 687-695
Col N.F., Hirota L.K., Orr R.K., Erban J.K., Wong J.B., and Lau J. Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk. J Clin Oncol 19 (2001) 2357-2363
Modelska K., and Cummings S. Tibolone for postmenopausal women: systematic review of randomized trials. J Clin Endocrinol Metab 87 (2002) 6-23
Kenemans P., and Speroff L. Tibolone: clinical recommendations and practical guidelines. A report of the International Tibolone Consensus Group. Maturitas 51 (2005) 21-28
Kloosterboer H.J. Tibolone: a steroid with a tissue-specific mode of action. J Steroid Biochem Mol Biol 76 (2001) 231-238
De Gooyer M.E., Deckers G.H., Schoonen W.G., Verheul H.A., and Kloosterboer H.J. Receptor profiling and endocrine interactions of tibolone. Steroids 68 (2003) 21-30
Lundström E., Christow A., Kersemaekers W., et al. Effects of tibolone and continuous combined hormone replacement therapy on mammographic breast density. Am J Obstet Gynecol 186 (2002) 717-722
Valdivia I., Campodónico I., Tapia A., Capetillo M., Espinoza A., and Lavín P. Effects of tibolone and continuous combined hormone therapy on mammographic breast density and breast histochemical markers in postmenopausal women. Fertil Steril 81 (2004) 617-623
Conner P., Christow A., Kersemaekers W., et al. A comparative study of breast cell proliferation during hormone replacement therapy: effects of tibolone and continuous combined estrogen-progestogen treatment. Climacteric 7 (2004) 50-58
Beral V., and Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362 (2003) 419-427
Opatrny L., Dell'Aniello S., Assouline S., and Suissa S. Hormone replacement therapy use and vartiations in the risk of breast cancer. Br J Obstet Gynaecol 115 (2008) 169-175
Cummings S.R., Ettinger B., Delmas P.D., et al. The effects of tibolone in older postmenopausal women. N Engl J Med 359 (2008) 697-708
Kroiss R., Fentiman I.S., Helmond F.A., et al. The effect of tibolone in postmenopausal women receiving tamoxifen after surgery for breast cancer: a randomised, double-blind, placebo-controlled trial. Br J Obstet Gynaecol 112 (2005) 228-233
Dimitrakakis C., Keramopoulos D., Vourli G., Gaki V., Bredakis N., and Keramopoulos A. Clinical effects of tibolone in postmenopausal women after 5 years of tamoxifen therapy for breast cancer. Climacteric 8 (2005) 342-351
Pollow K., Schaffrath M., Kölbl H., et al. Phase II study of goserelin adjuvant therapy combined with exemestane with or without tibolone in premenopausal women with receptor positive, node negative mammary carcinoma: ADAGIO Study. Geburtsh Frauenheilk 65 (2005) 612-619
Kubista E., Planellas J.G., Dowset M., et al. Effect of tibolone on breast cancer cell proliferation in postmenopausal ER+ patients: results from STEM trial. Clin Cancer Res 13 (2007) 4185-4190
Kenemans P., Kubista E., Foidart J.M., et al. Safety of tibolone in the treatment of vasomotor symptoms in breast cancer patients-design and baseline data 'LIBERATE' trial. Breast 16 (2007) S182-S189
Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351 (1998) 1451-1467
CPMP/EWP/021/97, Points to consider on hormone replacement therapy. The European Agency for the Evaluation of Medicinal Products (19 November 1997). http://www.emea.europa.eu/pdfs/human/ewp/002197en.pdf (accessed Oct 6, 2008).
Cline J.M., Register T.C., and Clarkson T.B. Effects of tibolone and hormone replacement therapy on the breast of cynomolgus monkeys. Menopause 9 (2002) 422-429
Gallagher J.C., Baylink D.J., Freeman R., and McClung M. Prevention of bone loss with tibolone in postmenopausal women: results of two randomized, double-blind, placebo-controlled, dose-finding studies. J Clin Endocrinol Metab 86 (2001) 4717-4726
Verheul H.A., van Iersel M.L., Delbressine L.P., and Kloosterboer H.J. Selective tissue distribution of tibolone metabolites in mature ovariectomized female cynomolgus monkeys after multiple doses of tibolone. Drug Metab Dispos 35 (2007) 1105-1111
Suzuki T., Miki Y., Nakata T., et al. Steroid sulfatase and estrogen sulfotransferase in normal human tissue and breast carcinoma. J Steroid Biochem Mol Biol 86 (2003) 449-454
Von Schoultz E., Rutqvist L.E., and Stockholm Breast Cancer Study Group. Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst 97 (2005) 533-535
Holmberg L., Anderson H., and HABITS steering and data monitoring committees. HABITS (hormonal replacement therapy after breast cancer-is it safe?), a randomised comparison: trial stopped. Lancet 363 (2004) 453-455
Holmberg L., Iversen O.E., Rudenstam C.M., et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst 100 (2008) 475-482
Stefanick M.L., Anderson G.L., Margolis K.L., et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 295 (2006) 1647-1657
Chlebowski R.T., Hendrix S.L., Langer R.D., et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289 (2003) 3243-3253