Anthony Howell, BSc, MBBS, MSc, FRCP
Professor, Medical Oncology Cancer Research Department Christie Hospital Manchester, UK Editorial Board, The Breast, Endocrine Related Cancer, Women and Cancer

Edited comments by Dr Howell

Lack of benefit from anastrozole/tamoxifen compared to anastrozole in the ATAC trial

I believe these findings were entirely predictable. In animal models, such as the immature rat uterus assay, tamoxifen stimulates uterine growth in a low estrogen environment. In a high estrogen environment, tamoxifen acts as an antiestrogen. The lack of benefit from the combination arm may be related to tamoxifen's action as an agonist rather than an antagonist in a low estrogen environment.

A potential explanation for the superiority of anastrozole is suggested by data from Matt Ellis demonstrating that tamoxifen does not seem to be as active as the aromatase inhibitors in low estrogen receptor conditions. In his data, which revealed a correlation between response rates and Allred's estrogen-receptor score, tamoxifen only works with Allred scores above three; whereas, letrozole worked with an Allred score of 3 and 4, as well as the higher scores. That may be another reason why tamoxifen is not as effective as anastrozole. This data may explain why one set of drugs — the aromatase inhibitors — are better than another set of drugs, the SERMs.

Defining ER positivity

There is variation in defining estrogen receptor positivity in Europe and across the United States. I agree with Kent Osborne that this variation is extraordinarily disturbing — particularly as our hormonal therapies continue to improve. My feeling is that if there is any receptor present in a tumor, it should be considered positive. Clearly, we can miss a very low positive result quite easily, and the result may be that patients who should receive adjuvant endocrine therapy are not receiving it. We need to get this assay correct for every woman.

Approximately 8% of the women in the ATAC trial had ER-negative breast cancer, and there are women whose estrogen receptor status is still unknown. More than 80% of the women in the ATAC trial had ER- and/or PR-positive tumors, which is reassuring. Even if we include the patients with estrogen receptor-negative and unknown disease, there is still a statistical benefit in terms of disease-free survival. There is a benefit in the intent-to-treat analysis of all patients. Overall, anastrozole has an 18% reduction in the recurrence rate compared to tamoxifen. This increases to 23% for those with known ER positive disease.

Implications of the ATAC trial in chemoprevention

The 80% reduction in contralateral tumors in the anastrozole arm of the ATAC trial is very exciting. If this translates into preventive therapy, it augurs well for the future prevention of breast cancer. The IBIS-2 prevention trial is in the planning stages, but it may be a three-arm study involving anastrozole, tamoxifen and placebo. We are also discussing the use of a bisphosphonate in IBIS-2. We have so much data on clodronate, and it has a favorable side-effect profile. Therefore, it may be the bisphosphonate of choice for the trial. We plan to begin the study in September or October, and there is enormous enthusiasm for this trial from investigators around the world.

Impact of anastrozole on bone density: Potential role of bisphosphonates

Overall, anastrozole has a much better toxicity profile than tamoxifen. The risks of thromboembolic complications and endometrial cancer are much lower, which makes it an attractive drug. One of the concerns about anastrozole is how to address its potential effects on bone density.

There was an increase in the fracture rate in the anastrozole arm of the ATAC trial. Women in the control arm were given tamoxifen, which prevents fractures; therefore, the increase in the fracture rate with anastrozole was probably not as big as it looks. We estimate that approximately half of the fracture rate in the ATAC trial was due to the negative effects of anastrozole. In terms of monitoring, I think most patients on anastrozole will need serial bone density measurements.

Given the data from Ingo Diel and Trevor Powles on bisphosophonates in the adjuvant setting, in the future we might be treating elderly women with ERpositive breast cancer with a combination of clodronate and anastrozole. Bisphosphonates may not only make anastrozole safe with regard to bone density, they also have an effect on survival. Clodronate is not available commercially in the United States, but many osteoporosis researchers do not believe there is much difference between the bisphosphonates. We need to find the bisphosphonate with the lowest GI toxicity.

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