Aromatase Inhibitors Vs Tamoxifen: A Changing of the Guard?

Harold J. Burstein, MD, PhD


February 13, 2002

In This Article

Aromatase Inhibitors in the Adjuvant Setting: Available Data

Two large studies have now reported experience with aromatase inhibitors in the adjuvant setting. The most relevant study, the ATAC trial, was a traditional randomized trial for women with operable breast cancer.[15] The second study, a neoadjuvant trial comparing tamoxifen with letrozole as preoperative therapy, does not have data on long-term disease outcomes. While data from these trials are of recent vintage, the large scale of the ATAC study in particular (it is the largest prospective treatment study in cancer medicine) makes the results quite powerful.

The ATAC study, supported by AstraZeneca, the manufacturer of both tamoxifen and anastrozole, was an international effort, recruiting patients from 29 countries, and representing the largest randomized trial ever reported among cancer patients. More than 9000 women were enrolled on the study between July 1996 and March 2000. An original accrual goal of approximately 6000 patients was extended to more than 9000 when it was clear that the event rate among the initial 6000 was relatively low.

Eligible women were postmenopausal, and had ER-positive or unknown early stage breast cancer. Patients were randomized to 3 treatment arms: anastrozole, tamoxifen, or both, and the study was placebo-controlled. The major findings of the ATAC trial are summarized in Table 3. Data were presented with median follow-up of 2.5 years, representing 1079 events, and 766 events among women with ER-positive tumors.

Overall, there was a statistically significant reduction in events for anastrozole compared with tamoxifen (hazard ratio [HR] 0.83), but not for combination therapy compared with tamoxifen (HR 1.02). This translated into an absolute difference in event recurrence of approximately 1.5% at 42 months follow-up. Most patients had a very good prognosis, with an actuarial event-free survival at 3.5 years of 90% or better.

Among women with ER-positive tumors, the HR for events was 0.78 in favor of anastrozole compared with tamoxifen or combination therapy. There was an approximately 60% reduction in the incidence of contralateral breast cancer among women on anastrozole vs tamoxifen or the combination. Given the large size of the study, these differences were highly statistically significant.

The side effect profiles of therapy differed slightly. Women taking anastrozole were less likely to report hot flashes, weight gain, vaginal bleeding or dryness, or to have endometrial cancer or thromboembolic events. Women on tamoxifen reported fewer arthralgia symptoms and had fewer bone fractures, including fewer fractures in the hip, spine, and wrist, which are common sites for osteoporotic fractures.

There are several points to consider when reviewing these preliminary data:

  1. The initial events reported include nonbreast cancer deaths (which greatly outnumbered breast cancer deaths) and contralateral breast cancers. The reduction in contralateral breast cancer risk seen with anastrozole contributes a disproportionate benefit to the anastrozole arm when measuring event-free survival. The occurrence of distant metastases also tended to favor anastrozole, but the differences were smaller between the groups. Thus, the effect of anastrozole vs tamoxifen on the natural history of the primary breast cancer may be more modest than suggested by the aggregate data.

  2. There were very few reported breast cancer deaths -- 5 among 9366 patients. There were no differences in the numbers of breast cancer or nonbreast cancer deaths between the groups.

  3. It is not clear why the combination therapy arm yielded results similar to tamoxifen as opposed to anastrozole. It was hypothesized that in the very low estrogen environment achieved in postmenopausal women treated with aromatase inhibitors, tamoxifen may paradoxically act as an estrogen agonist.

In addition, several significant "caveats" need to be borne in mind when considering whether to use anastrozole in preference to tamoxifen. This is but a single trial, albeit a very large one. Confirmatory trials are currently underway (see below).

The optimal duration for adjuvant aromatase inhibitor therapy is not known. The 5 years of therapy proposed in ATAC were designed to mirror the current recommendation for tamoxifen. However, that duration of tamoxifen therapy was derived through randomized trials comparing 1, 2, 5, and 5+ years of treatment. The follow-up in the ATAC study remains quite short, the number of cancer-related events relatively low, and there are minimal data for women having taken 5 years of anastrozole. Finally, the longer-term side effects of that therapy, perhaps including osteoporosis, are not yet known.

Neoadjuvant use of aromatase inhibitors has also been evaluated in a large, prospective, randomized comparison with tamoxifen.[16] In this trial, postmenopausal women with ER- and/or PR-positive primary breast tumors were randomized to 4 months of preoperative therapy with either letrozole or tamoxifen. The major findings are shown in Table 4.

This trial demonstrated that aromatase inhibitor therapy achieved a higher rate of clinical response in the neoadjuvant setting, with an important clinical consequence: a greater likelihood of breast-conserving surgery.


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