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Section 5
Aromatase inhibitors in the adjuvant setting

OVERVIEW

Randomized clinical trials of aromatase inhibitors (AIs) in postmenopausal women with advanced disease have now demonstrated that, for the first time, an endocrine intervention has been identified with improved efficacy compared to tamoxifen. In the next few months, initial results are expected from the ATAC adjuvant trial comparing anastrozole versus tamoxifen versus the combination in invasive disease, and several additional studies are evaluating AIs following adjuvant tamoxifen. Other trials in noninvasive disease and the high-risk setting are being planned.

ATAC TRIAL

On the basis of emerging data in premenopausal women with chemical ovarian ablation and tamoxifen, one would expect that the combination arm of ATAC would be superior to the other two arms. On the other hand, there are some preclinical data suggesting that the combination of tamoxifen and anastrozole will not be advantageous, so we'll have to wait for the data. In terms of the single agent ATAC arms, I am impressed by the data from the large aromatase inhibitor trials in first-line metastatic breast cancer, and on that basis, we have the hypothesis that the same type of comparison in the adjuvant setting may have a similar or magnified outcome.

-Gabriel Hortobagyi, MD

COMBINATION ARM OF ATAC

The combination arm of ATAC is difficult to predict, but the in vivo effects of Arimidex and tamoxifen are very different - they work through different mechanisms - and this is the major background basis to believe that the combination arm might be better.

-J Michael Dixon, MD, FRCS

ATAC SUBPROTOCOLS

The ATAC trial has subprotocols looking at bone, lipids and the endometrium that are appropriately powered to answer those important questions. However, in the first-line trials of aromatase inhibitors, there was no increase in bone-related complications such as compression fractures. I would expect a higher fraction of patients to remain disease-free in the anastrozole arm, and the main question is the combined arm - where you may have greater antitumor activity plus some of the benefits of tamoxifen, for example, on bone. We don't have many patients in the metastatic setting exposed to aromatase inhibitors for extended periods of time. If ATAC looks positive, I would have serious reservations about substituting another aromatase inhibitor for Arimidex as long-term adjuvant therapy, particularly because of safety concerns.

-Aman Buzdar, MD

TOXICITY PROFILE

Aromatase inhibitors are better than tamoxifen in the metastatic setting, not only in terms of antitumor activity but also the safety profile, because of the risk of thromboembolic complications with tamoxifen and the agonist effect on the endometrium. Even though there were few such events in the first-line metastastic trials, the risk of vaginal bleeding was almost 50 percent lower with anastrozole compared to tamoxifen.

-Aman Buzdar, MD

AIs IN WOMEN WITH THROMBOTIC HISTORIES

From the data in the metastatic and neoadjuvant setting, it's quite clear that aromatase inhibitors are superior to tamoxifen. I would expect that superiority to carry through into the adjuvant setting, although it may take some time to observe. The use of aromatase inhibitors in the adjuvant setting is not currently approved, but for high-risk, ER-positive, postmenopausal patients with a previous stroke or DVT, we consider substituting an aromatase inhibitor.

-Hyman Muss, MD

SECONDARY EFFECTS OF AROMATASE INHIBITORS

In ATAC, I expect some impact of Arimidex on the bones, but probably not a major effect. Many of our neoadjuvant patients have taken anastrozole or letrozole for five years, and we have not seen major problems as far as side effects are concerned. One reason that the UK prevention study decided not to have a combination arm is that there's not enough information yet on the safety profile of combining Arimidex and tamoxifen. Everybody's waiting with baited breath to see the results of the ATAC study. In the combination arm, there are competing effects of Arimidex lowering estrogen levels and tamoxifen's estrogen-mimicking action on bone and lipids. The hope is that any adverse effects of Arimidex will be countered by the positive effects of tamoxifen. So, from a theoretical point of view, you'd expect either no effect or perhaps even a positive effect. In terms of the endometrium, theoretically the combination should be no worse than tamoxifen alone. Arimidex causes less vaginal problems than tamoxifen and no leukorrhea.

-J Michael Dixon, MD, FRCS

PROPOSED NSABP DCIS TRIAL: TAMOXIFEN VERSUS ARIMIDEX IN POSTMENOPAUSAL PATIENTS WITH DUCTAL CARCINOMA IN SITU

PROPOSED IBIS 2 TRIAL: INTERNATIONAL BREAST INTERVENTION STUDY 2

PROPOSED NSABP DCIS TRIAL

The driving force of current research is to move away from the concept that DCIS is simply a surgical problem - and that if you obtain 10 mm margins, the patient is cured and no adjuvant therapy is needed. Even if we take out the index DCIS, the risk for these women to have another tumor in either breast in the future is at least as high or higher than the risk for women in the NSABP P-1 prevention trial. So, chemoprevention in DCIS is an important issue, and we need to find out how to do this best. The ATAC trial, which has past accrual and is nearing analysis, will answer the question about anastrozole in invasive breast cancer. We need to ask the same question in noninvasive disease.

-Richard Margolese, MD

PROPOSED IBIS 2 PREVENTION TRIAL

This will be an international trial, and we have two good models for big multinational trials - the AT LAS trial of tamoxifen duration and the ATAC trial - which ran very similar treatment arms to IBIS 2. The entry criteria of IBIS 2 will be similar to IBIS 1, but restricted to postmenopausal women. We don't use the Gail model. Family history is factored in, along with nulliparity and pathologic entities such as atypical hyperplasia and LCIS. We're also adding a new category of women who have mammographic dysplasia covering 50 percent or more of their breasts. That links it in nicely with screening which is really where prevention belongs. Screening programs should not only detect small cancers, but also identify women at high risk and offer them preventative strategies. IBIS 2 is also going to have a DCIS component. The trial will enter 12,000 high-risk women and another 4,000 patients with DCIS.

-Jack Cuzick, PhD

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