A Randomized Trial of Exemestane after Two to Three Years of Tamoxifen Therapy in Postmenopausal Women with Primary Breast Cancer

Abstract

Tamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausal women with primary, estrogen-receptor-positive breast cancer. Despite this treatment, however, some patients have a relapse. methodsWe conducted a double-blind, randomized trial to test whether, after two to three years of tamoxifen therapy, switching to exemestane was more effective than continuing tamoxifen therapy for the remainder of the five years of treatment. The primary end point was disease-free survival. resultsOf the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane, and 2380 to continue to receive tamoxifen. After a median follow-up of 30.6 months, 449 first events (local or metastatic recurrence, contralateral breast cancer, or death) were reported -183 in the exemestane group and 266 in the tamoxifen group. The unadjusted hazard ratio in the exemestane group as compared with the tamoxifen group was 0.68 (95 percent confidence interval, 0.56 to 0.82; P<0.001 by the log-rank test), representing a 32 percent reduction in risk and corresponding to an absolute benefit in terms of disease-free survival of 4.7 percent (95 percent confidence interval, 2.6 to 6.8) at three years after randomization. Overall survival was not significantly different in the two groups, with 93 deaths occurring in the exemestane group and 106 in the tamoxifen group. Severe toxic effects of exemestane were rare. Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group (P=0.04). conclusionsExemestane therapy after two to three years of tamoxifen therapy significantly improved disease-free survival as compared with the standard five years of tamoxifen treatment.

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

“…The fracture rate of letrozole-treated patients in the MA-17 trial was 3.6% versus 2.9% in placebo, following 5 years of tamoxifen treatment [95]. Similar small increases in osteoporosis and/or fractures (7.41%) were associated with the steroidal aromatase inhibitor, exemestane compared to tamoxifen (5.7%) in the IES trial [96].It is suggested that patients are evaluated for baseline bone mineral density and receive bisphosphonate therapy if indicated [99]. No significant changes in serum cholesterol, HDL cholesterol, LDL Cholesterol, triglycerides or Lp(a) occur in non-hyperlipidemic postmenopausal women treated for three years following five years of adjuvant tamoxifen [100].…”

Aromatase inhibitors and the syndrome of arthralgias with estrogen deprivation

“…Compared with women assigned to treatment with placebo or tamoxifen, those treated with aromatase inhibitors have consistently shown higher rates of arthralgia. In trials of women with advanced breast cancer, arthralgias have been more common in women treated with aromatase inhibitors than in the comparator group despite their lower rates of metastases, which might also cause bone pain (20)(21)(22)(23)(24).…”

Comparing the cost of adjuvant anastrozole with the benefits of managing less patients with relapsed breast cancer

“…The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial showed that anastrozole, given from diagnosis for 5 years, improved disease-free survival by 4.1% compared to 5 years tamoxifen (100 months median follow up data) [1]. Other adjuvant aromatase inhibitors studies have shown similar benefits [2][3][4]. These strategies, although initially expensive, reduce the risk of relapse and hence involve long-term cost savings [5].…”

“…Health economic analyses of anastrozole have been conducted in the past [6], but all estimate the cost of a relapse using predictive modelling, questionnaires or interviews with clinicians [2,3,[7][8][9]]. An independent United Kingdom (UK) trial, now 6 years old, estimated hospital costs of relapsed breast cancer by sending questionnaires to UK oncologists, and estimated a cost of £12,500 per patient [10,11].…”