Changes in bone and lipid metabolism in postmenopausal women with early breast cancer after terminating 2-year treatment with exemestane: A randomised, placebo-controlled study
Introduction
While phase III studies have demonstrated the unequivocal superiority of aromatase inhibitors (AIs) administered as monotherapy or sequentially following tamoxifen over tamoxifen monotherapy as adjuvant treatment for postmenopausal women with hormone-sensitive breast cancers,1, 2, 3, 4, 5 information regarding the long-term toxicity of AIs is lacking.
The two major concerns with respect to the long-term profound oestrogen deprivation resulting from AI administration6, 7 relate to a negative influence on bone metabolism (accelerated bone loss), which could lead to fractures, and to a potential detrimental effect on plasma lipid levels, which could contribute to cardiovascular events. In the latest update of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) study,1 adjuvant treatment with anastrozole monotherapy increased the total fracture rate by 49% compared with tamoxifen. Similarly, the joint report of the Austrian Breast and Colorectal Cancer Study Group (ABCSG 8) and German Arimidex-Nolvadex (ARNO 95) trials reported a significant increase in the frequency of fractures among patients treated with anastrozole following tamoxifen versus patients on continuous tamoxifen treatment (odds ratio 2.14, 95% CI 1.14–4.17),5 while the Intergroup Exemestane Study reported a non-significant increase in fracture rate (35%) during treatment with exemestane in comparison with tamoxifen.3 The first report from the Breast International Group (BIG) 1-98 trial confirmed an increase of 43.5% in fractures, comparing women treated initially with letrozole with those treated initially with tamoxifen.8 Considering vascular events, a higher incidence of thromboembolic events have been recorded in the tamoxifen treatment arms, with a non-significant increase in cardiovascular events on treatment with the different AIs.9
A major challenge in evaluating the toxicity of AIs is the use of tamoxifen as a comparator in the control arm in most studies. Tamoxifen is known to influence bone metabolism, blood lipids and coagulation status in postmenopausal women.10, 11 While letrozole was compared with placebo in the MA17 study,2 the patients enrolled had all received 5 years of tamoxifen therapy prior to treatment with the AI, and tamoxifen may persist in tissue compartments for months.12 The beneficial effects of tamoxifen on bone mineral density (BMD) in postmenopausal women have to be considered whenever AIs are compared with the anti-oestrogen in the same study.10 Thus, to address the issue of potential toxic effects of exemestane on bone and lipid metabolism, we conducted a 2-year double-blind placebo-controlled study evaluating these parameters in patients with early breast cancer who were not candidates for adjuvant endocrine therapy.13 Because a major issue relates to whether any potential changes may be reversible upon terminating treatment, BMD, bone biomarkers, and plasma lipids were evaluated during a 1-year follow-up after termination of treatment. This paper reports the results of this follow-up with respect to BMD, bone biomarkers, plasma lipids and serum homocysteine levels, coagulation parameters and sex steroids. The key finding is that the modest changes in bone and lipids recorded during 2 years of treatment with exemestane were largely reversible 1-year after the termination of treatment. In addition, vitamin D (25-OHD) and parathormone (PTH) were measured in all patients before and during therapy, looking for potential explanations for the high loss in BMD in both treatment arms that was reported previously.13
Section snippets
Study design
The study was designed and conducted by the Norwegian Breast Cancer Group in collaboration with Pfizer Inc. Postmenopausal women with low-risk, surgically treated early breast cancer (n = 129) or ductal carcinoma in situ (n = 18) were randomised (double-blind) either to exemestane 25 mg daily or to oral placebo for 2 years, to be followed up for 1 year after cessation of treatment for the primary (BMD) and secondary (bone biomarkers, plasma lipids, coagulation factors, homocysteine and serum hormone
Results
Of a total of 73 patients initially randomised to exemestane treatment and 74 randomised to placebo, 58 and 65 patients, respectively, completed 24 months of therapy and were available for follow-up. No patient completing 24 months of therapy was lost to subsequent follow-up. The reasons for premature discontinuation in the two arms are given in Table 1.
Discussion
Potential toxicities with respect to bone and lipid metabolism are major concerns regarding long-term AI treatment of women for early breast cancer. These concerns relate to potential detrimental effects during the treatment period, but also the potential for a sustained impact resulting in long-term detrimental effects. According to official national statistics, the expected life-span for normal healthy Norwegian women aged 50, 60 and 70 years is 33 years, 24 years and 16 years, respectively.
Conflict of interest statement
Per E Lønning received research grants from the Pfizer Co. Jurgen Geisler and Per E Lønning both received speakers honoraria and participated in advisory boards for Pfizer Co. Anna Polli, Enrico Di Salle and Jolanda Paolini are all employed by Pfizer Co.
Acknowledgements
Part of this study was presented as posters at the ASCO 2005 (abstract 531), at the San Antonio Breast Cancer Symposium 2005 (abstract 4108), and at the ASCO 2006 (abstract 554).
We are indebted to all the women who participated in this trial. We appreciate the contribution of Gøril Knutsen and Barbara Duncan at Pfizer Inc., and Randi Eikeland, Clinical Cancer Research Office, Haukeland University Hospital.
Regarding bone density measurements, we acknowledge the contribution from Arne Høiseth
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