Section 1
Neoadjuvant Endocrine Therapy

RESEARCH BACKGROUND

We began studying neoadjuvant systemic therapy about 15 years ago, and one major reason was that we thought accurate models of drug action could be derived by taking sequential samples of tumors during treatment.What’s clear is that you can obtain a very good idea of what’s happening within the tumors by looking at biological markers rather than just clinical endpoints.

We take biopsies after 10 to 14 days of treatment and examine effects on proliferation, cell death and a variety of genetic markers to determine if we can predict early on whether a patient is going to receive benefit from therapy.This then becomes a potential method to individualize treatment. We found that the median time to reduce tumor volume is shorter with chemotherapy than with endocrine therapy. However, the same order of response is seen with endocrine therapy — you just have to wait a bit longer.

— J Michael Dixon, MD

NEOADJUVANT AROMATASE INHIBITORS

The time to response and volume of tumor reduction seems to be greater with aromatase inhibitors than with tamoxifen, and quite marked tumor reductions are often seen within four weeks. Defining responses as greater than a 50% reduction in tumor volume, we have observed response rates of 80% to 90% with the aromatase inhibitors, which is quite impressive.

With one milligram of anastrozole, after three months, we saw an 80% overall reduction in tumor volume.These agents suppress circulating estrogen production and intratumoral estrogen production. After a few months of therapy, the levels of intratumoral estrogens are incredibly small.

— J Michael Dixon, MD

Examples of responses to neoadjuvant anastrozole as assessed by changes in tumor volume measured mammographically.

Sahni S et al. Evaluation of local and systemic disease control following breast conserving surgery after neoadjuvant anastrozole treatment. Poster 2001 Miami Breast Cancer Conference. Full Text.

NEOADJUVANT TRIAL OF ARIMIMIDEX® (anastrozole ) VS TAMOXIFEN VS THE COMBINATION

We are currently studying in a neoadjuvant setting the same therapies being evaluated in the ATAC adjuvant trial.From our prior work, we know that anastrozole and tamoxifen have different biological effects on tumors. Anastrozole switches off proliferation. If you look at the tumor before starting anastrozole and then three months later, in about half of the patients the actual histologic grade changes — it downgrades the tumor. So, if it’s a grade 3, it ’ll go to 2, and grade 2 will go to 1. But the reason it downgrades is because proliferation is turned off.

If you look at tamoxifen, about half of the patients will also downgrade, but that downgrade is completely different. What you see is an increase in glandular differentiation. Tamoxifen also tends to induce the progesterone receptor, while anastrozole switches the PR off completely. These observations fit with the fact that different clinical activities have been seen with aromatase inhibitors, which are actually more effective than tamoxifen. So, we’re starting to understand that there’s not one pathway for endocrine therapies. And, of course, if they act by different mechanisms, then combinations — like in ATAC — could be more effective than one agent alone.

— J Michael Dixon, MD

OTHER TRIALS OF NEOADJUVANT AROMATASE INHIBITORS

Proact Protocol

CLINICAL USE OF NEOADJUVANT ENDOCRINE THERAPY

What has always impressed me about neoadjuvant endocrine therapy is that if patients are selected properly, a similar change in tumor volume can be achieved as with chemotherapy. It requires a slightly longer time period, but there are far fewer side effects. Our quality of life studies show that patients don ’t seem to mind taking adjuvant endocrine therapy for a few months, because there are very few side effects. We have a group of elderly patients who avoid medical care, because they don ’t want to undergo extensive surgery. Many of the tumors in these women are quite large and estrogen receptor-rich. After neoadjuvant endocrine therapy, mastectomy is usually not required, and patients can have much less deforming surgery.

Another important issue is that in women over age 70, there ’s a one percent mortality rate in most published series of mastectomy and axillary dissection, because the surgery can be quite stressful. It ’s a longer operation with the potential for more complications. So, by doing less surgery, you have less chance of patients dying of vascular events or developing complications such as hematomas. The women we ’ve treated with neoadjuvant endocrine therapy have been the happiest group of patients in our practice.

— J Michael Dixon, MD

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