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

Objective:

To compare switching to exemestane after 2-3 years of tamoxifen with ongoing tamoxifen as adjuvant therapy for early-stage breast cancer in postmenopausal women. The primary endpoint was disease- free survival measured from the time of randomization.

Introduction:

Exemestane is a third-generation steroidal aromatase inhibitor which irreversibly inhibits the aromatase enzyme, thereby reducing the conversion of androgens to estrogens in peripheral tissues. Randomized trials have shown aromatase inhibitors to be at least as effective as tamoxifen in the treatment of estrogen receptor- positive metastatic breast cancer in postmenopausal women. The role of aromatase inhibitors remains to be characterized in the adjuvant setting. This study, known as the Intergroup Exemestane Study, examines the sequential use of tamoxifen and exemestane after adequate local therapy.

Methods:

* Phase III, randomized, double-blind control study.

* Randomization occurred mid-way through adjuvant tamoxifen therapy. Postmenopausal women who had received between 2-3 years of tamoxifen therapy without disease recurrence were eligible for the study.

* Inclusion criteria were histologically proven, ER-positive or unknown, unilateral breast cancers treated with initial surgical resection and appropriate adjuvant chemotherapy and radiotherapy. Patients were postmenopausal.

* Exclusion criteria included hormone-negative tumors, local or distant relapse and the use of hormone replacement therapy within 4 weeks before randomization.

* Doses were exemestane 25 mg or tamoxifen 20 mg daily, taken for 2-3 years to complete the 5 years of treatment.

Results:

* Four thousand seven hundred and forty-two patients from 37 countries were enrolled in the study of which 2362 received exemestane and 2380 continued to receive tamoxifen.

* Baseline characteristics of both groups were well balanced.

* The second planned interim analysis revealed that trial stoppage criteria had been reached. At this time the median follow- up period was 30.6 months.

* First events included local or metastatic recurrence, contralateral breast cancer or death.

* One hundred eighty-three first events occurred in the exemestane arm versus 266 in the tamoxifen arm, corresponding to a hazard ratio of 0.68 (95% CI 0.56-0.82). This equates to an absolute benefit of 4.7% at 3 years.

* The hazard ratio was 0.63 when non-breast cancer-related deaths were excluded from first events to determine breast cancer-free survival.

* There was no statistically significant difference in overall survival.

* Incidence of contralateral breast cancer was reduced in the exemestane group with a hazard ratio of 0.44 (95% CI 0.2-0.98).

* Vaginal bleeding, thromboembolic events and muscle cramps were more common in the tamoxifen group.

* Exemestane was associated with a higher incidence of arthralgia and diarrhoea and a trend towards a higher rate of fractures, osteoporosis and visual disturbances.

* The development of non-breast malignancies was less common in the exemestane group with a hazard ratio of 0.51 (95% CI 0.32-0.8).

Conclusions:

After 2 – 3 years of adjuvant tamoxifen therapy in postmenopausal women with early stage, estrogen receptor-positive breast cancer, switching to exemestane yields an improvement in disease-free survival. At this time it does not translate into a statistically significant improvement in overall survival. Exemestane in the above setting reduces the incidence of contralateral breast cancer. Exemestane is well tolerated and is associated with a reduction in thromboembolic events, and the development of non-breast cancers compared with tamoxifen.

Commentary:

The standard adjuvant treatment for hormone-sensitive breast cancer in postmenopausal women is 5 years of therapy with tamoxifen. This has been shown to reduce the risk of recurrence by 47% and the risk of death by 26%. While the optimum duration of treatment has been established to be at least 5 years, the bulk of the benefit seems to occur in the first two years, with a relative risk reduction of 18- 19% in studies comparing 5 years versus 2 years of tamoxifen. Resistance to tamoxifen in metastatic breast cancer commonly occurs after 12-18 months, and many patients treated with early-stage breast cancer relapse in the first 5 years, therefore it is logical to speculate that the optimum time to change hormone treatments in sequential regimens is at 2-3 years. Sequential hormone therapy has the theoretical capacity to change the mechanism of action at a time when resistance to tamoxifen may be occurring.

The initial success of the sequential therapy in the Intergroup Exemestane Study contrasts with the lack of benefit of combined therapy in the ATAC study. In this study the treatment arm incorporating the combination of tamoxifen and another aromatase inhibitor, anastrozole, was discontinued after the first interim analysis revealed no difference between this arm and tamoxifen alone. Anastrozole, however, showed an advantage in terms of disease- free survival when used as a single agent. The MA-17 study of letrozole versus placebo given after 5 years of tamoxifen also shows an advantage in disease-free survival and a reduction in the risk of contralateral breast cancer. It would appear from the data from these three studies that if tamoxifen is poorly tolerated we now have the option of substituting an aromatase inhibitor knowing that it offers at least the same, if not better, outcome in terms of prevention of disease relapse.

One limitation in all three studies of aromatase inhibitors in the adjuvant setting is the lack of long-term efficacy and safety data. Tamoxifen has been shown to reduce the risk of recurrence by 33% compared with placebo during the 5 years following cessation of therapy. Aromatase inhibitors have not yet demonstrated this capacity.

The lower incidence of thromboembolism and endometrial cancer in the exemestane group in this trial is not surprising given that both are recognized complications of tamoxifen. Similarly the favorable profile of tamoxifen regarding osteoporosis and bone fractures could be expected, this being a known benefit of selective estrogen modulation. The decreased incidence of other non-breast cancers in the exemestane arm is difficult to explain. The answer to this and other questions will await ongoing review and further studies.

Despite these promising early results, the lack of long-term safety and efficacy data of using sequential exemestane in the adjuvant setting needs to be considered when discussing this option with patients.

Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coatcs AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickievvicz E, Andersen J, Lonning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM. N Engl J Med 2004;350:1081-92

Selected references and further reading:

Baum M, Buzdar A, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 2003 ;98:1802-10

Jones AL, Powles TJ, Law M, et al. Adjuvant aminoglutethimide for postmenopausal patients with primary breast cancer: analysis at 8 years. J Clin Oncol 1992:10:1547-52

Fleming GF. Adjuvant aromatase inhibitors: are we there yet? Cancer 2003;98:1779-81

Paridaens R, Dirix L, Lohrisch C, et al. Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Ann OncoL 2003;14:1391-8

Piccart-Gebhart MJ. New stars in the sky of treatment for early breast cancer. N Engl j Med 2004:350:1140-2

Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793 – 802

Commentary by: Mark Warren, MBRS, and Christopher Steer, FRACP, Border Medical Oncology, Albury-Wodonga, Australia

Copyright CRC Press Jun 2004