J Michael Dixon, MD, FRCS
Consultant Surgeon, Edinburgh Breast Unit Department of Oncology Western General Hospital Edinburgh, United Kingdom

Edited comments by Dr Dixon

Neoadjuvant anastrozole trial

Several years ago, we conducted a trial using three months of neoadjuvant anastrozole in 23 postmenopausal women with estrogen receptor-positive breast cancer. Interestingly, 22 of those patients continued on adjuvant anastrozole after the trial ended. It has now been four years since these patients started on adjuvant anastrozole, so we have a reasonable follow-up period from which to gather additional data.

We evaluated whether the response rate to anastrozole was dependent on the initial tumor’s HER2 status. It was a small study with only 23 patients, but we obtained reasonable material from 22. We found that six patients had tumors with a 3+ score for HER2 protein overexpression, and all six responded clinically to anastrozole. All six of the patients’ tumors decreased in size by more than 50 percent in bidimensional area, thereby fulfilling the criteria for a partial response with only a three-month treatment period.

This supports previous evidence that the aromatase inhibitors are effective for patients with HER2 3+ tumors, and it's the first data showing that anastrozole is effective in this group. A slightly lower response rate was seen in patients with tumors that were not HER2 3+, but there was no statistically significant difference between response rates. When we looked at the percentage reduction in tumor volume, there was a trend for the HER2 3+ tumors to shrink more than the tumors that were HER2-negative. This fits in with the data suggesting a better response rate with the aromatase inhibitors in patients with HER2 3+ tumors.

It also contrasts with the data presented by Matt Ellis last year at San Antonio, in which patients with HER2 3+ tumors did not have a consistent reduction in proliferation when treated with neoadjuvant tamoxifen. We, too, have evaluated tamoxifen in the neoadjuvant setting, and found the same results as Matt Ellis — HER2 3+ tumors don’t have a consistent change in proliferation with tamoxifen.

All of the tumors — HER2-positive and negative — also demonstrated a reduction in proliferation over the three-month neoadjuvant period. The order of reduction in proliferation was the same for the tumors that were HER2-positive and negative.

Proliferation decreases within a few days of starting anastrozole, and this opens up a new avenue for treatment. The idea is — if you see a postmenopausal woman with breast cancer, you don’t really have to worry about the date of surgery, because you can put her on anastrozole and know that by the time you operate, her tumor will be biologically different.

The IMPACT trial of neoadjuvant anastrozole

The neoadjuvant anastrozole study, known as the IMPACT trial, has finished recruiting 330 patients who were randomized to anastrozole alone, anastrozole and tamoxifen or tamoxifen alone. From this study, we should be able to determine whether there are any differences in response rates to these agents in patients with HER2-positive tumors. We will also be able to evaluate biological end points, and that should tell us a little bit more about the interaction between anastrozole and HER2.

The IMPACT trial will tell us a lot about how these drugs work, and I think it is a very important study. I’m pleased we have completed it. The results, however, won’t be available until the middle of next year.

After surgery, if the patient had responded to the three months of neoadjuvant endocrine therapy, they continued on the same medication and remained blinded. There are some patients still on the combination. If the patient did not respond, then they were unblinded and put on the other agent.

Biologic effects of the tamoxifen and anastrozole combination

We don’t know what happens in the tumor when we give both anastrozole and tamoxifen, but we could guess. I think it will be like the effects of tamoxifen. Many of us thought that the combination was never going to work anyway, because when you reduce estrogen levels with anastrozole, tamoxifen acts like a partial estrogen agonist. I don’t think there was ever any good scientific rationale to the combination.

It’s interesting to speculate about what will be seen inside the tumor with the combination. The good news is that we have sequential biopsies and we will be able to look at which genes are switched on or off by the three treatments in the IMPACT trial. That will give us real insight into how the combination arm works.

Resistance to tamoxifen in patients with HER2-positive cancer

I think resistance occurs because tamoxifen’s mode of action is through the HER2 pathway, whereas anastrozole works independently of HER2. That may be too simple. In the series of patients on the IMPACT trial, and others we’re treating with aromatase inhibitors, we will be able to look at more details, because we have fresh tissue before diagnosis, during treatment and after treatment.

I’m using micro-array techniques and proteomics, and we are about to see — in great detail — how these drugs interact. The simplistic way we now look at how these drugs work will be overshadowed by what we learn from these studies.

Selection of patients for neoadjuvant endocrine therapy

Patients who express the most estrogen receptor (ER) will have the greatest reductions in tumor volume with neoadjuvant endocrine therapy. We only treat patients with Allred scores of 6, 7 or 8.

The Allred score is a composite of the percentage of cells that stained and the intensity of their staining. The percentage of cells staining is classified from 0 through 5, and the intensity of cells staining is rated as 1, 2 or 3. Then if you add, for example, 5 and 3 together, you have an Allred score of 8. In order to initiate therapy, the cutoff we use for positivity would be over one-third of the cells staining strongly or over two-thirds staining moderately.

Fortunately, the majority of postmenopausal women are strongly ER-positive, and these are the women most likely to benefit. Their median reduction in tumor volume with three months of neoadjuvant anastrozole therapy is over 80 percent. Not only does a large part of the tumor disappear within that three-month period, but the nature of the tumor also changes — there is reduced cellularity and proliferation.

If you select patients for treatment carefully, the response rates to neoadjuvant endocrine therapy are very high. In a poster we presented at the San Antonio Breast Cancer Symposium, the response rate to anastrozole in that group of patients was 80 percent and they had a greater than 50 percent reduction in a bidimensional area with three months of neoadjuvant therapy. We were able to convert two-thirds of the patients requiring mastectomy to breast-conserving surgery.

Underutilization of neoadjuvant endocrine therapy

I believe neoadjuvant endocrine therapy is underutilized. It is valuable in some patients, particularly the elderly, and the biggest increase in breast cancer incidence over the next decade will be in older patients. Currently, 40 percent of women with breast cancer are over 70 years of age, and that is likely to go up to nearly 50 percent over the next decade. These are women whom you wouldn’t necessarily want to give neoadjuvant chemotherapy. We have very good drugs, such as the aromatase inhibitors, that produce consistently high response rates and reductions in tumor volume.

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