ΠΡΟΣΟΧΗ ΚΑΙ ΣΤΟ Livial

Tibolone for Vasomotor Symptoms and Bone Loss Increases Risk for Breast Cancer Recurrence

Nick Mulcahy

February 19, 2009 — Tibolone (Livial, Schering-Plough) — a synthetic steroid used to treat vasomotor symptoms and prevent bone loss — should not be prescribed to any woman with current, past, or suspected breast cancer. Tibolone is approved for use in European and many other countries, but is not approved the United States.

This advisement accompanies the results of the LIBERATE (Livial Intervention Following Breast Cancer: Efficacy, Recurrence, and Tolerability Endpoints) trial, which showed that tibolone significantly increases the risk for recurrence in breast cancer patients.

The results are published in the February issue of the Lancet Oncology.

"Currently, many patients with breast cancer use tibolone to reduce climacteric symptoms," write the study authors, led by Peter Kenemans, MD, PhD, from the Department of Obstetrics and Gynecology at the VU University Medical Center, in Amsterdam, the Netherlands. This is off-label use because a history of breast cancer is a contraindication for tibolone. However, tibolone has been used to provide women with breast cancer with relief from climacteric symptoms because, as the authors point out, "no reliable evidence of harm is available."

The latest results state that they should not do so.

In the LIBERATE trial, postmenopausal women with a history of breast cancer were treated with tibolone for vasomotor symptoms. The drug significantly improved vasomotor symptoms and bone-mineral density, compared with placebo.

However, an interim analysis found a 40% increase in the risk for breast cancer recurrence with tibolone, and led to the trial being stopped 6 months early. An intent-to-treat analysis found that 237 (15.2%) of the 1516 women taking 2.5 mg of tibolone daily had a recurrence of their cancer, compared with 165 (10.7%) of the 1542 women receiving placebo. The median follow-up was 3.1 years.

The only other randomized placebo-controlled trial with tibolone that assessed breast cancer risk was in osteoporotic women without breast cancer at entry (N Engl J Med. 2008;359:697-708). The LIFT (Long-Term Intervention on Fractures with Tibolone) trial showed that breast-cancer incidence was significantly reduced after 3 years of tibolone use, compared with placebo. It also showed that tibolone more than doubled the risk for stroke, as reported by Medscape Medical News.

Can Women Not on Adjuvant Therapy Use Tibolone?

Women treated with surgery for early-stage breast cancer often have severe flushes, resulting from adjuvant treatment with tamoxifen, aromatase inhibitors, gonadotropin-releasing hormone analogues, or chemotherapy, Dr. Kenemans and colleagues explain.

At entry into the LIBERATE trial, 2068 of the 3098 (67%) women used tamoxifen and 202 (6·5%) used aromatase inhibitors to reduce the likelihood of breast cancer recurrence. "Tibolone is likely to interfere with the protective action of these agents," write the authors, explaining a possible way in which the steroid is associated with recurrence.

So, the question arises: Is tibolone safe to use in women not on adjuvant therapy? The authors say that the study was not powered to assess any differences that may exist between subgroups in the study. "There are insufficient data to establish the safety of tibolone in women who have had breast cancer and do not require or have finished adjuvant therapy," they write.

However, the study authors admit that the generalizability of the study results to future populations of breast cancer survivors is questionable because adjuvant treatment options are "moving rapidly" and because of developments in risk assessment. Symptomatic breast cancer survivor populations are likely to be different in the future, they say.

What About the Protective Effect Seen in the LIFT Trial?

In the LIFT trial, 1.25 mg of tibolone daily (the dose for treatment of osteoporosis) decreased the risk for invasive breast cancer, compared with placebo (hazard ratio, 0.32; 95% confidence interval, 0.13–0.80).

The discrepancy between the results of the 2 major trials of tibolone to date that assessed breast cancer risk, LIBERATE and LIFT, can be explained in 2 outstanding ways, according to the authors.

First, the populations are not comparable, they said. The LIFT population was osteoporotic, older (mean age, 68 years), weighed less (mean body mass index (BMI), 25.7 kg/m2), and had no tamoxifen exposure. The LIBERATE population comprised breast cancer survivors with a mean age of 52.7 years and a mean BMI of 27.0 kg/m2, and more than two thirds of the women had tamoxifen exposure.

Second, the effect of tibolone on healthy breast tissue "most probably" differs from its effect on cancer cells because of differences in the 2 kinds of cells, write the authors.

All authors are members of the scientific advisory board or employees of Schering-Plough (formerly Organon), the funder of the study.

Lancet Oncol. 2009;10:135-146. Abstract