Tamoxifen has been the predominant form of adjuvant endocrine therapy since the first International Breast Cancer Overview was presented at the 1985 NIH Consensus Conference. Currently, most patients with invasive estrogen receptor-positive cancers are treated with tamoxifen regardless of age, menopausal status and risk to recur. On December 10, 2001, the initial results of the ATAC trial were presented at the San Antonio Breast Cancer Symposium. These groundbreaking data demonstrated that in postmenopausal women with primary invasive breast cancer, the third-generation aromatase inhibitor, anastrozole, conferred an advantage over tamoxifen in terms of efficacy, tolerability and toxicity. No advantage was observed in combining anastrozole with tamoxifen. Clinicians and patients are now struggling with the clinical implications of these early but very promising results from the largest cancer treatment trial ever conducted.

SUMMARY OF ATAC RESULTS

The headline news is that there is something after tamoxifen — there is a significant advantage for anastrozole compared to tamoxifen. The real surprise is that the combination of anastrozole and tamoxifen is no different than tamoxifen alone. What makes these early ATAC results even more extraordinary is that about 15% of the trial population was ER-negative and ER unknown. When you look at the analysis of the known ER-positive patients, the results are even stronger. The hazard ratio for anastrozole compared to tamoxifen is 0.78. This is equivalent to a 22% relative reduction in risk of recurrence compared to tamoxifen.

—Michael Baum, ChM, FRCS

SIDE EFFECTS AND TOXICITIES WITH TAMOXIFEN AND ANASTROZOLE

ATAC demonstrated that fewer side effects are associated with anastrozole than tamoxifen. Thromboembolic complications, vaginal bleeding, spotting and discharge, and endometrial cancer were all substantially lower in the anastrozole arm. In terms of the side effects seen with anastrozole, I have not seen any patient in which arthralgias forced us to change or stop therapy. The potential negative effects on bone of anastrozole can be watched very closely. If there is a change in bone density, highly effective interventions can be provided.

—Aman Buzdar, MD

SUBSTITUTING OTHER AROMATASE INHIBITORS IN THE ADJUVANT SETTING

There are no data to support using letrozole or exemestane in the adjuvant setting. Since anastrozole is the only drug that’s been tested, it is the drug we should use. All of the aromatase inhibitors are slightly different. We need direct comparative data for these drugs. If they are equally effective, it might come down to which one has the fewest side effects and best tolerability. Until we have comparative data, the drug which has been tested in the adjuvant setting should be used.

—J Michael Dixon, MD, FRCS

ATAC TRIAL DESIGN - POSTMENOPAUSAL WOMEN SUMMARY OF ATAC TRIAL OUTCOMES 9,366 evaluable patients At a median treatment duration of 2.5 years, anastrozole demonstrated superior efficacy and tolerability compared to tamoxifen Anastrozole was superior to tamoxifen in terms of disease-free survival in the overall population (relative reduction of 17%) and in estrogen receptor-positive patients (relative reduction of 22%) Anastrozole was superior to tamoxifen in terms of the incidence of contralateral breast cancer in the overall population (relative reduction of 58%) There were 156 patients with distant metastases in the anastrozole arm and 181 in the tamoxifen arm (not statistically different) There were only a total of five breast cancer deaths in the three treatment arms Anastrozole was tolerated better than tamoxifen with respect to: Endometrial cancer events Venous thromboembolic events Vaginal bleeding Hot flashes Vaginal discharge Weight gain Ischaemic cerebrovascular events Tamoxifen was tolerated better than anastrozole with respect to: Musculoskeletal disorders (arthralgias) Fractures Derived from a presentation by Michael Baum, 24th Annual San Antonio Breast Cancer Symposium Baum M. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) adjuvant breast cancer trial in postmenopausal (PM) women. Breast Cancer Res Treat 2001; 69(3): Abstract 8. How would you manage a 65-year-old woman with a 0.8 cm tumor/neg nodes (ER+, HER2-negative)? O N C O LO G I S T S Tamoxifen 35% Anastrozole 35% Letrozole 10% None/Other 20% S U R G E O N S Refer to oncologist 50% Start tamoxifen 5% Start anastrozole 35% Manage without adjuvant systemic therapy 5% Manage primarily with tamoxifen 5% If the ATAC data are widely accepted, and anastrozole generally replaces tamoxifen as adjuvant endocrine therapy for postmenopausal women, how likely is it that surgeons will prescribe anastrozole? S U R G E O N S Very likely 30% Likely 25% Somewhat Likely 25% Very unlikely 15% Undetermined 5% Which of the following best describes your intended use, in the near future, of aromatase inhibitors as adjuvant therapy? O N C O LO G I S T S Anastrozole 25% Generally anastrozole, occasionally letrozole 30% Anastrozole or letrozole interchangeably 30% Generally letrozole, occasionally anastrozole 5% Letrozole 5% None 5%

Baum M. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) adjuvant breast cancer trial in post-menopausal women. Breast Cancer Res Treat 2001;69(3): Abstract 8.

ATAC Trialists’ Group. Pharmacokinetics of anastrozole and tamoxifen alone and in combination during adjuvant endocrine therapy for early breast cancer in postmenopausal women: A sub-protocol of the “Arimidex® and Tamoxifen Alone or in Combination” (ATAC) trial. Br J Cancer 2001;85(3):317-324. Abstract

Goss PE, Strasser K. Aromatase inhibitors in the treatment and prevention of breast cancer. J Clin Oncol 2001;19:881-94. Abstract

Ingle JN. Aromatase inhibition and antiestrogen therapy in early breast cancer treatment and chemoprevention. Oncology (Huntingt) 2001;15:28-34. Abstract

Kuerer HM et al. Biologic basis and evolving role of aromatase inhibitors in the management of invasive carcinoma of the breast. J Surg Oncol 2001;77:139-47. Abstract

Nabholtz JM et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: Results of a North American multi-center randomized trial. J Clin Oncol 2000;18(22):3758-3767. Abstract

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