Aromatase Inhibitors in Breast Cancer: An Update

Diana E. Lake, MD, Clifford Hudis, MD

Disclosures

Cancer Control. 2002;9(6) 

In This Article

Adjuvant Therapy

Having demonstrated meaningful activity in post-menopausal patients with metastatic breast cancer, the use of an aromatase inhibitor in adjuvant therapy was the next logical step. The purpose of adjuvant hormonal therapy in breast cancer is to prevent recur-rence and to improve survival in patients with hormone receptor-positive disease. These effects have been well documented with tamoxifen.[15,16,17] Tamoxifen received FDA approval in 1986 as adjuvant therapy in node-positive postmenopausal women with breast cancer,[4] and in 1990, tamoxifen was approved for women of any age with node-negative disease, as long as hormone receptors were positive or unknown.

Such benefits seem additive to prior chemotherapy, and tamoxifen decreases the risk of contralateral breast cancer.[15] The optimum length of treatment with tamoxifen appears to be 5 years, which is superior to treatment for 1 or 2 years and may be superior to longer durations.[15,18] Ten years of treatment have not been shown to be better than 5 years, but additional studies are pending.[19,20] Benefits seem to persist beyond the completion of therapy -- a so-called "carryover effect" -- with a lower risk of recurrence and death beyond the end of active treatment. The absolute overall survival benefit with tamoxifen at 10 years is
5.6% in patients with negative axillary nodes and 10.9% in patients with positive axillary nodes.[4,15]

The toxicities of tamoxifen have been well documented. These include hot flushes, vaginal discharge, increased risk of thrombotic events, increased risk of endometrial cancer and uterine sarcoma, and a probable increased risk of cerebral vascular disease. In the adjuvant setting, these toxicities assume even greater importance than for treatment of metastatic disease. Given the millions of patient-years of experience with tamoxifen and its proven efficacy and safety, any newer hormonal therapy in the adjuvant setting must demonstrate at least equal efficacy to tamoxifen and fewer side effects to gain acceptance and broad use.

It is noted that there are other established hormonal adjuvant therapies in addition to tamoxifen, including ovarian ablation or suppression in premenopausal women with hormone receptor-positive breast cancer, as well as data supporting other SERMS, the nonselective aromatase inhibitors, and aminoglutethimide.[21,22,23]

The aromatase inhibitors are being tested for efficacy as adjuvant therapy in three different randomized trial designs: to compare directly with tamoxifen, to test the hypothesis of an additive effect following tamoxifen, and to compare first-line sequential hormonal therapy of tamoxifen followed by an aromatase inhibitor or vice versa each for a period of 5 years.

The availability of the modern selective aromatase inhibitors, given their promising results in the metastatic setting and coupled with increased experience and understanding of the need for adequately powered adjuvant therapy trials, led to the ATAC trial (Fig 3).[24] This trial was designed to address a comparison between tamoxifen and anastrozole as single agents and between tamoxifen and a combination of the two drugs. A total of 9,366 postmenopausal women with invasive breast cancer completed the primary therapy of the breast and were then randomized to one of three arms: (1) anastrozole 1 mg daily plus tamoxifen placebo (3,125 patients), (2) anastrozole placebo plus tamoxifen 20 mg daily (3,116 patients), and (3) anastrozole plus tamoxifen (3,125 patients). Treatment was planned for 5 years. Among the multiple primary endpoints included in the first-event analysis planned for this trial were disease-free survival, locoregional and distant recurrence, new primary breast cancer, or death from any cause. Safety and tolerability were also evaluated. Secondary endpoints included the incidence of a new contralateral primary breast cancer and the time to distant recur-rence. The survival of the hormone receptor-positive population was a protocol-defined subgroup. Although initial data have been reported, survival data will not mature for approximately 2 more years. With respect to median patient age, weight, hormone receptor status, and primary treatment, which included surgery and chemotherapy, the treatment arms were similar. A small percentage of patients had received prior tamoxifen. The majority of the patients in the trial had T2 tumors or smaller, and one third of the patients were node positive. Approximately one fifth received chemotherapy in addition to study medication.

Trial design: ATAC (Arimidex, Tamoxifen, Alone or in Combination).

Reporting of the first analysis required 1,056 events to occur, and data reported at the San Antonio Breast Cancer Symposium was based on 1,079 events.[24,25] The total number of first events in the receptor-positive population was 766. The median duration of therapy was 30.7 months, and the median follow-up time was 34.3 months. Kaplan-Meier curves of the intent-to-treat population for disease-free survival demonstrated an advantage in patients treated with anastrozole in comparison to those treated with tamoxifen alone or in combination. The disease-free survival at 3 years was 89.4% with anastrozole and 87.4% with tamoxifen (hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.96, P=.013). The combination-therapy arm had similar results to the tamoxifen-alone arm. Analysis of first events in this population showed that 317 events occurred in patients treated with anastrozole, 379 events in patients treated with tamoxifen, and 383 events in patients treated with both drugs. Distant disease comprised the majority of the first events. Of note, contralateral invasive and noninvasive breast cancer occurred to a greater degree in both the combination and tamoxifen arms: 30 and 23 events, respectively, vs 9 events in the anastrozole arm. Deaths from other reasons were similar in all groups: 78 patients on anastrozole, 81 on tamoxifen, and 70 on the combination. In receptor-positive patients, the hazard ratio for disease-free survival was greater with anastrozole (.78) compared with the combination of anastrozole and tamoxifen (1.02). A subanalysis of time to first new contralateral breast primary demonstrated an advantage for anastrozole compared with either the combination or tamoxifen arms, which were similar to each other. Fewer musculoskeletal disorders and fractures occurred in the tamoxifen group.

Early results from the ATAC trial indicate that anastrozole is superior to tamoxifen regarding disease-free survival in the overall population and particularly in the receptor-positive subpopulation of patients, as well as in terms of reducing the incidence of contralateral breast cancer in the overall population. All of the treatment arms were generally well tolerated. Advantages of anastrozole over tamoxifen appear to be a lower risk of endometrial carcinoma and a lower incidence of vaginal side effects such as bleeding and discharge. Also, fewer ischemic cerebral vascular events, fewer thrombotic events (including deep vein thrombosis), less weight gain, and fewer hot flushes were reported.

From the ATAC trial, we may conclude that at a median treatment duration of 2.5 years, anastrozole appears to be superior to tamoxifen in terms of efficacy and tolerability. However, a complete risk-benefit analysis needs longer follow-up with particular attention to issues of overall survival and specific toxicities such as coagulopathy, cognition, and bone density. Based on the ATAC trial, the FDA has approved anastrozole for use as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer.

An important question that may arise from the results of the ATAC trial and other pending studies is whether a patient should change treatment from tamoxifen to an aromatase inhibitor in the adjuvant setting. It is noted that the ATAC trial does not address this question, but ongoing trials with a sequential therapy design will do so. One such trial is the European Breast International Group BIG 01-98, a randomized trial of early-stage ER+ or PR+ patients to one of four arms: (1) tamoxifen for 5 years, (2) letrozole for 5 years, (3) tamoxifen for 2 years followed by letrozole for 3 years, and (4) letrozole for 2 years followed by tamoxifen for 3 years.[26] The NCCTG-CAN-MA-17 trial,[27] an intergroup study that completed accrual of 4,800 postmenopausal women in the spring of 2002, randomized patients to receive 5 years of letrozole or a placebo after they completed 5 years of tamoxifen. The endpoints are diseasefree/overall survival and the issues of quality of life and safety. Results are pending, but at present no direct evidence suggests that patients should be switched from tamoxifen to an aromatase inhibitor outside of a clinical trial. However, if patients have unacceptable toxicity with tamoxifen and have not completed 5 years of adjuvant hormonal therapy, such a switch might be justified based on the indirect evidence discussed.[4]

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