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The LIBERATE Tibolone Trial in Breast Cancer Survivors
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
The livial intervention following breast cancer: Efficacy, Recurrence, And Tolerability Endpoints (LIBERATE) trial was a multinational, placebo-controlled, randomized study of women with vasomotor symptoms who had had breast cancer surgically treated within the previous 5 years.1 The study was designed to demonstrate that tibolone was superior to placebo, but when the DMSB notified the sponsor (Schering-Plough, formerly Organon) that there appeared to be an excess of breast cancers in the treated group, the sponsor canceled the trial on July 31, 2007, 5 months before its scheduled end.
The median duration of participation and treatment was about 3 years, with a wide range from a few weeks to almost 5 years. The participants used a variety of adjuvant treatments, including tamoxifen (66.8%) and aromatase inhibitors (6.5%). The dose of tibolone was 2.5 mg daily. Final numbers for analysis were 1556 women in the treated group and 1542 in the placebo group. The women ranged in age from younger than 40 to 79 years, with a mean age of 52.7 years.
Positive lymph nodes were reported in 57.8%, and 70% had a tumor stage of IIA or higher. Estrogen receptor status was known in 2808 women in whom the tumors were estrogen receptor-positive in 77.8%. In the intent-to-treat analysis, the hazard ratio (HR) for recurrent breast cancer in the tibolone-treated women was 1.40 (confidence interval [CI], 1.14-1.70). The absolute risk for tibolone was 51 cancers per 1000 women per year, and 36 in the placebo group. The increase occurred only in women with estrogen receptor-positive tumors. There was no difference in mortality rates between the 2 groups during the 5-year study period. There were no differences in cardiovascular events or gynecologic cancers, and, not surprisingly, vasomotor symptoms, quality of life measures, and bone density improved with tibolone treatment.
The argument that postmenopausal hormone therapy should not be given to women who have had breast cancer is reasonable. It is based on the recognition of a large body of evidence that indicates that breast cancer is a hormone-responsive tumor. The overriding fear of many clinicians and patients is that metastatic cells are present (perhaps being controlled by various host defense factors) that may be susceptible to stimulation by exogenous hormones. However, many women who have had breast cancer are aware of the benefits of postmenopausal hormone treatment and are asking clinicians to help make this risk-benefit decision. In addition, some women suffer from such severe hot flushes and vaginal dryness that they are willing to consider hormonal treatment.
Because of its unique metabolism, tibolone can exert different hormonal activities at different sites. This unique characteristic is precisely what makes the drug difficult to understand. Tibolone is structurally related to the 19-nortestosterone progestins used clinically in oral contraceptives; however, its activity depends on its metabolism. Tibolone is metabolized by human and nonhuman primates into 3 biologically active metabolites: The 3a-hydroxy (3α-OH) metabolite and the 3b-hydroxy (3β-OH) metabolite have estrogen-agonist properties, whereas the Δ-4 ketoisomer has progestogenic and androgenic effects (the Δ-4 isomer is produced in endometrium, accounting for tibolone's protection against endometrial proliferation). Although tibolone itself binds to the estrogen receptor, in vivo the activity of the 3-hydroxy metabolites is 100 times greater, with a greater affinity for the α-estrogen receptor than for the β-estrogen receptor. The metabolism of the parent compound is rapid and very near total, yielding mainly the 3α-OH and the 3β-OH metabolites in the circulation; the level of the 3α-OH metabolite is three-fold higher compared with the 3β-OH metabolite. Tibolone and the Δ-4 isomer can be detected only at peak levels 2 hours after ingestion, and even then, the levels are very low, at the limit of detection.
Previous Studies with Tibolone
How do the LIBERATE results that indicate an estrogenic action of tibolone in breast cancer survivors jibe with the literature indicating that tibolone exerts a non-estrogenic effect on breast tissue? Indeed, it was realistic to expect tibolone to have a salutary effect on the breast. It is well documented that the breast responds to tibolone with less stimulation compared with estrogen, judged by changes in mammographic breast density and the characteristics of tissue obtained by fine-needle aspiration. In the LIFT clinical trial that had vertebral fractures as the primary endpoint and breast cancer as a secondary endpoint, the risk of breast cancer after 3 years was significantly 68% reduced with tibolone treatment, although the dose was lower, 1.25 mg daily (HR, 0.32; CI, 0.13-0.80).2
The breast is a complicated estrogen factory. Breast tissue, normal and abnormal, contains all the enzymes necessary for the formation of estrogens (sulfatase, aromatase, and 17β-hydroxysteroid dehydrogenase) and the conversion of estrogens into their sulfates (sulfotransferase). The major pathway of estrogen synthesis in human breast tumor cells is by conversion of estrone sulfate to estrone by estrone sulfatase, a pathway that is more important than the aromatase pathway. Estrogen concentrations in the breast are higher in women with breast cancer, and formation of estradiol from sulfated estrogen is the primary pathway. Most importantly, this increase in estrogen activity is independent of the estrogen-receptor status of the tissue.
Tibolone and its metabolites inhibit estrone sulfatase and 17β-hydroxysteroid dehydrogenase in normal stromal cells and in hormone-dependent breast cancer cells (MCF-7 and T-47D). This inhibits conversion of estrone sulfate to estradiol. In addition, tibolone and its 3-hydroxy metabolites increase the conversion of estrone back to estrone sulfate by increasing the activity of sulfotransferase. Tibolone and all 3 metabolites inhibit the conversion of estrone to estradiol by 17β-hydroxysteroid dehydrogenase. Although these effects resemble progestin activity, tibolone is more potent. These biochemical effects in response to tibolone should lower estrogenic stimulation of the breast, and at least with normal breast cells in vitro, tibolone increases cellular differentiation and stimulates apoptosis. Thus, in cell line studies, tibolone acts like progestins and weak androgens as measured by proliferation, differentiation, and apoptosis.
Postmenopausal hormone therapy increases breast density on mammography in about 10-20% of estrogen users and about 20-35% of estrogen-progestin users, an effect that occurs within the first months of treatment. In contrast, tibolone does not increase breast density, and causes far less mastalgia than that seen with estrogen treatment. It is logical to conclude that these favorable responses are a consequence of the tibolone effects on the breast tissue enzymes involved in local estrogen production.
The authors of the LIBERATE report point out that the previous literature documenting beneficial actions of tibolone on the breast reflect the impact of tibolone on normal breast tissue, and tibolone's activity to lower local bioactive estrogen levels in target tissues might be lost in cancer cells. The contrary results in the LIFT trial could reflect its older population of women at high risk for fractures, a population that also differed by having lower body weights, no history of tamoxifen treatment, and lower risk factors for breast cancer.
Studies with Estrogen or Estrogen-Progestin
The rate of recurrent breast cancer in hormone users has been reported in case series totalling more than 1000 breast cancer survivors. It is reassuring that the recurrence rates in these reports are not different from the expected rate of breast cancer recurrence. These patients have had both positive and negative nodes and positive and negative estrogen-receptor status. Although the results conform to an incidence of recurrent disease no greater than expected, the outcomes can reflect biases in clinician and patient decision-making that can only be overcome with a proper long-term, randomized clinical trial. A case-control study of hormone therapy after breast cancer actually found a significant reduction in risk of recurrent disease, breast cancer mortality, and total mortality in hormone users.3 Again, although these are reassuring data that hormone therapy after breast cancer has no adverse impact on recurrence, they are observational in origin.
HABITS (Hormonal Replacement After Breast Cancer—Is It Safe) was initiated in May 1997, recruiting patients from multiple centers in Sweden. A similar trial was initiated in Stockholm. Because recruitment was slower than anticipated, in February 2002, the two trials pooled their patients and used a joint monitoring and safety committee. In October 2003, the safety committee recommended that the trial be discontinued because there were 26 women in the treated group with new breast cancers compared with 7 in the non-treated group.
The HABITS trial was terminated in December 2003. Confronted with this outcome, the Stockholm investigators canceled their trial as well, even though the hazard ratio in the Stockholm patients was 0.82 (CI, 0.35-1.9).
HABITS was a randomized but not placebo-controlled trial in which hormone therapy was compared to management without hormones in women with menopausal symptoms who had been previously treated for Stage I or Stage II breast cancer.4 Concomitant tamoxifen treatment was allowed in the HABITS patients but not aromatase inhibitors. Hormone therapy consisted of the variety of products and methods on the Swedish market, but not tibolone. Most of the treated women used products with the relatively high dose of 2 mg estradiol. After 4 years of follow-up of 442 women, there were 39 cases of new breast cancer in women using hormone therapy compared with 17 in the non-treated group for a hazard ratio of 2.4 (CI, 1.3-4.2).
The treated and non-treated groups of women in HABITS were very different in terms of characteristics and behaviors. More of the women in the treated group had hormone receptor-positive cancers (62.3%) compared with the non-treated group (54.5%). Eleven women in the treated group never received hormones; 43 in the non-treated group did receive hormones. There was a very wide range of exposure times, ranging from 0 to 80 months. About one-third of the women who received hormones changed products during the study. The method of analysis of the HABITS data was intent-to-treat, and thus the impact of these differences cannot be ascertained.
Analysis of the new breast cancers in HABITS (either local recurrences or contralateral cancers) indicated statistically significant increases only in hormone receptor-positive cancers. However, when adjusted for use of hormone therapy before diagnosis of the original breast cancer, use of tamoxifen, and hormone receptor status, the hazard ratio was 2.2 (CI, 1.0-5.1). By definition this is close, but not statistically significant.
The Stockholm trial reported in 2005, after a median follow-up of 4.1 years, 11 new breast cancers in the treated arm and 13 new breast cancers in the non-treated arm.5 Why the difference between the Stockholm trial and HABITS? The HABITS investigators suggest that their patients had more node-positive disease, and thus "probably" had more women with subclinical disease that would be stimulated by hormone therapy. Another possibility was more protection with higher tamoxifen use in the Stockholm trial, although the HABITS trial could detect no impact of tamoxifen. The HABITS investigators believe that another possible explanation was the greater use of norethindrone and norethindrone acetate in HABITS compared with the use of medroxyprogesterone acetate in Stockholm. All of these explanations are speculations; the difference between the two trials remains and calls into question the reliability and accuracy of the data.
The cancellation of HABITS and the Stockholm trials made it impossible for the English and Italian trials to continue recruitment in their trials, and they were also canceled. Thus, we have no ongoing clinical trials of estrogen or estrogen-progestin therapy in breast cancer survivors. In my view, the data from the Swedish trials are confusing and not definitive.
Although the LIBERATE trial may apply to all breast cancer survivors, speaking strictly in a scientific sense, the results were derived mainly from tamoxifen users with 10-fold fewer users of aromatase inhibitors. The possibility that estrogen or tibolone would interfere with the beneficial effects of tamoxifen or aromatase inhibitors has always been one of the objections to treating breast cancer survivors with estrogenic hormones. In a subgroup analysis of the LIBERATE trial, the group of women who had used aromatase inhibitors had a greater risk of recurrent breast cancer compared with tamoxifen; however, the CI was wide because of relatively small numbers. The authors suggest that the estrogenic effect of tibolone would be more pronounced on an occult breast cancer in estrogen-depleted tissue compared with tissue where tamoxifen was bound to the estrogen receptor and prevented estrogenic stimulation.
We don't know if the LIBERATE data are meaningful for future treatment regimens. Nevertheless, until there are new data, the use of tibolone in women with a history of breast cancer remains relatively contraindicated.
Patients and clinicians have to incorporate all of the previously mentioned experimental data into this medical decision. But when all is said and done, patients have to take an unknown risk if they want the benefits of hormone treatment, and clinicians have to take an unknown medical-legal risk. Some patients will choose to take estrogen, judging the benefits to be worth the unknown risk. Until definitive data are available from clinical trials (there will be none in the near future), clinicians should support patients in this decision. Other patients will prefer to avoid any unknown risks. These patients, too, deserve support in their decision.