Menopause Live - IMS Updates

Date of release: 09 March, 2009

Tibolone increases the risk of recurrence in breast cancer patients, while relieving vasomotor symptoms and preventing bone loss

Kenemans and colleagues have recently reported the effects of tibolone, as compared to placebo, on risk of recurrence in breast cancer patients with climacteric complaints [1]. During 2002–2004, in the prospective multicenter LIBERATE trial, as many as 3148 women, after surgery for confirmed breast cancer and with vasomotor symptoms, were randomized to receive either tibolone 2.5 mg daily or placebo. Their mean age was 52.7 ± 7.3 years, the mean time since surgery was 2.1 ± 1.3 years, 58% were node-positive, 78% were estrogen receptor-positive, 67% used tamoxifen and 6.5% used aromatase inhibitors. The mean daily number of hot flushes was 6.4 ± 5.1.


After a median follow-up of 3.1 years (range 0.01–4.99 years), 237 of 1556 (15.2%) women on tibolone had a recurrence, compared with 165 of 1542 (10.7%) on placebo (hazard ratio (HR) 1.40; 95% confidence interval (CI) 1.14–1.70; p = 0.001). Tibolone was not different from placebo with regard to other safety outcomes, such as mortality, cardiovascular events or gynecological cancers. Vasomotor symptoms and bone mineral density improved significantly with tibolone compared with placebo.


The management of menopausal symptoms in breast cancer survivors remains an unsolved clinical problem of growing importance [2]. Premature menopause and the recurrence of menopausal symptoms in breast cancer patients have a significant negative impact on quality of life, body image, sexual function and self-esteem. The findings of the LIBERATE trial are certainly disappointing to many clinicians as they clearly show that, although effective against hot flushes, tibolone does increase the risk of breast cancer recurrence in a population of women mostly using adjuvant systemic therapy. There were insufficient data to assess the safety of tibolone in women not on adjuvant therapy.
In the LIBERATE trial, 67% of women were on tamoxifen and 6.5% on aromatase inhibitors. Tibolone seems to interfere with the protective action of these agents and possibly more so with the aromatase inhibitors. In subgroup analyses, the hazard ratio for recurrence among women on aromatase inhibitors was 2.42 (95% CI 1.05–5.79; p = 0.0470), as compared to 1.25 (95% CI 0.98–1.59; p = 0.076) for those on tamoxifen. Data suggest that tibolone exerts a slight estrogen-agonistic effect on dormant tumor cells. Such a stimulatory action would be more adverse in the estrogen-depleted user of an aromatase inhibitor, while during tamoxifen use any estrogenic action should be blocked at the receptor level. This interpretation is also supported by the finding that women with estrogen receptor-negative tumors had no increased risk of recurrence (HR 1.15; 95% CI 0.73–1.80; p = 0.058) in contrast to those who were receptor positive (HR 1.56; 95% CI 1.22–2.01; p = 0.0005).
LIBERATE is by far the largest randomized trial on hormone therapy in women with breast cancer. Previously, two clinical trials on conventional estrogen/progestogen therapy were halted before enrolment could be completed. Although certainly inconclusive, they showed significantly different results. In the Stockholm trial [3], after a median follow-up of 4.1 years (n = 359), there was no increase in risk of recurrence (HR 0.8; 95% CI 0.4–1.9). On the other hand, in the HABITS trial [4,5], after a median follow-up of 2.1 years (n = 345), the HR was 3.3 (95% CI 1.5–7.4); after 4.1 years, the HR was 2.4 (95% CI 1.3–4.2). Differences may reflect a higher proportion of tamoxifen use and attempts to minimize progestogen in the Stockholm trial, but data do not allow any firm conclusions. Although the populations and treatment regimens differ, it seems that the risk figures in the HABITS trial (predominantly continuous estrogen/progestogen) were somewhat higher than for tibolone in the LIBERATE study. Several studies have shown that tibolone has less stimulatory influence on surrogate markers for breast cancer risk, e.g. mammographic density and breast cell proliferation, than continuous combined regimens [6,7].
In summary, the use of menopausal hormone therapy after breast cancer is controversial. Observational data and clinical trials are conflicting. Data from the LIBERATE study show that tibolone should remain contraindicated for women with a history of breast cancer. However, in healthy postmenopausal women, the breast safety profile of this compound seems reassuring. In the recent LIFT trial [8], there was a decrease in risk of invasive breast cancer (HR 0.32; 95% CI 0.13–0.80). Also, in the large GPRD database, there was no increase in risk of breast cancer from tibolone [9].


Bo von Schoultz
Department of Obstetrics and Gynecology, Karolinska Institutet and University Hospital, Stockholm, Sweden


  1. Kenemans P, Bundred NJ, Foidart JM, et al. Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomized, non-inferiority trial. Lancet Oncol 2009;10:135-46. Published February 2009.

  2. Hickey M, Saunders CM, Stuckey BG. Management of menopausal symptoms in patients with breast cancer: an evidence-based approach. Lancet Oncol 2005;6:687-95.

  3. von Schoultz E, Rutqvist LE; Stockholm Breast Cancer Study Group. Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst 2005;97:533-5.

  4. Holmberg L, Anderson H; HABITS steering and data monitoring committees. HABITS (hormonal replacement therapy after breast cancer is it safe?), a randomized comparison trial stopped.Lancet 2004;363:453-55.

  5. Holmberg L, Iversen OE, Rudenstam CM. Increased risk of recurrence after hormone replacement in breast cancer surviviors. J Natl Cancer Inst 2008;100:475-82. Published April 2, 2008.

  6. Lundström E, Christow A, Kersemaekers W, et al. Effects of tibolone and continuous hormone replacement therapy on mammographic breast density. Am J Obstet Gynecol 2002;186:717-22.

  7. Conner P, Christow A, Kersemaekers W, et al. A comparative study of breast cell proliferation during hormone replacement: effects of tibolone and continuous combined estrogenprogestogen treatment. Climacteric 2004;7:50-8.

  8. Cummings SR, Ettinger B, Delmas PD, et al. The effects of tibolone in older postmenopausal women. N Engl J Med 2008;359:697-708. Published August 14, 2008.

  9. Opatrny L, DellAniello S, Assouline S, Suissa S. Hormone replacement therapy use and variations in the risk of breast cancer. Br J Obstet Gynaecol 2008;115:169-75. Published January 2008.