What is the optimal neoadjuvant endocrine therapy and when should it be used?

OVERVIEW: Chemotherapy is the most frequent form of neoadjuvant systemic therapy in the United States; while in Europe, endocrine therapy has been utilized extensively in women with ER-positive cancers. Numerous phase 2 and 3 clinical trials have demonstrated that the antitumor effect of endocrine therapy in these patients is comparable to what has been observed with chemotherapy, although the time to response is somewhat longer. Tamoxifen and ovarian ablation/suppression were initially utilized, and more recently, studies of third generation aromatase inhibitors have demonstrated significant antitumor activity.

A 65-year-old woman with an ER-positive, HER2-negative breast tumor is referred to you for possible neoadjuvant systemic therapy. She has C cup size breasts, and wishes to have breast-conserving therapy if possible. This would be suboptimal if she went for surgery at the present time. What would be your usual preoperative endocrine systemic therapy?

TUMOR SIZE		TAMOXIFEN ANASTROZOLE LETROZOLE EXEMESTANE NONE 20% 25% 5% - 50% 20% 25% 10% 5% 40%
2.8 cm
6.5 cm

TUMOR SIZE		TAMOXIFEN ANASTROZOLE LETROZOLE EXEMESTANE NONE 20% 25% 15% 0% 40%
Inflammatory Breast Cancer

What would be your usual preoperative endocrine therapy if she were 77-years-old with a 2.8 cm tumor?

2.8 cm

TAMOXIFEN ANASTROZOLE LETROZOLE EXEMESTANE NONE 15% 45% - 0% 40%

NEOADJUVANT ENDOCRINE THERAPY RESEARCH BACKGROUND

We began studying neoadjuvant systemic therapy about 15 years ago. 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.

To determine if we can predict early on whether a patient is going to receive benefit from therapy, we take biopsies 10 to 14 days after treatment and examine effects on proliferation, cell death and a variety of genetic markers. This becomes a potential method to individualize treatment. We found 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. 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. After three months of anastrozole, 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

NEOADJUVANT TRIAL OF ANASTROZOLE VS TAMOXIFEN VS THE COMBINATION

We are currently studying in the 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. The reason it downgrades is because proliferation is turned off.

If you look at tamoxifen, about half of the patients will also downgrade. That downgrade however, is completely different. What you see is an increase in glandular differentiation. Tamoxifen also tends to induce the progesterone receptor (PR), 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. If they act by different mechanisms, then combinations— like in ATAC — could be more effective than one agent alone.

—J Michael Dixon, MD

CLINICAL USE OF NEOADJUVANT ENDOCRINE THERAPY

If patients are selected properly, a similar change in tumor volume can be achieved with neoadjuvant endocrine therapy 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 neoadjuvant 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. Patients can then have much less deforming surgery.

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 surger y, 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

NEOADJUVANT ENDOCRINE THERAPY

Neoadjuvant therapy allows you to determine in a couple of months whether or not an agent is going to have a favorable impact as opposed to giving a drug blindly for years after local therapy and hoping that it will help. There is a lot of data for chemotherapy, and similar data will emerge for endocrine therapy. The studies in ER-positive, postmenopausal women showed a very high degree of antitumor activity in patients treated with aromatase inhibitors. In one trial, anastrozole showed dramatic tumor reductions — 70% or 80% of the patients showed objective shrinkage of their disease, and close to two-thirds of the women became candidates for breast preservation after approximately four months of therapy with anastrozole.

—Aman Buzdar, MD

EORTC STUDY 10963

The preoperative EORTC trial evaluates one injection of fulvestrant after the diagnosis of breast cancer but before surgery. The idea is for the fulvestrant injection to cover the operative period as a potent antiestrogen that will lower estrogen receptor levels. We want to test the hypothesis of Bernie Fisher and others that adverse events related

to metastases occur during the perioperative period. Hopefully, we can alter that with fulvestrant. The aim is to enroll more than 3,000 women into this study.

—Professor Anthony Howell, FRCP

PROPOSED NEOADJUVANT TRIAL

We are looking for a trial to replace ATAC and are considering evaluating conventionally timed versus perioperative endocrine therapy. Fulvestrant lends itself to that because of its rapid effects on the tumor in situ, and you can measure surrogate markers. We would like to take the best arm of ATAC and compare it with fulvestrant in a factorial way — looking at drug against drug and timing against timing. Hopefully, we’ll have a pilot protocol ready to go next year. This type of trial — where you’re looking at the tumor intact — can be a gold mine in the search for the valuable surrogate markers of response.

—Michael Baum, ChM, FRCS

IMPACT TRIAL: A RANDOMIZED DOUBLE BLIND TRIAL OF PREOPERATIVE TAMOXIFEN, ANASTROZOLE OR THE COMBINATION IN POSTMENOPAUSAL BREAST CANCER PATIENTS No Protocol Link

STUDY CONTACT Ian Smith, MD, Chair Royal Marsden Hospital London, United Kingdom

PROACT: PREOPERATIVE ANASTROZOLE COMPARED TO TAMOXIFEN No Protocol Link

Pathological assessment of excised tumor is performed.

STUDY CONTACT: MD Anderson Cancer Center Aman Buzdar, MD Houston, Texas

A RANDOMIZED DOUBLE-BLIND MULTICENTER STUDY OF PREOPER ATIVE TAMOXIFEN VERSUS LETROZOLE FOR POSTMENOPAUSAL WOMEN WITH ER+ AND/OR PGR+ BREAST CANCER INELIGIBLE FOR BREAST-CONSERVING SURGERY. CORRELATION OF CLINICAL RESPONSE WITH TUMOR GENE EXPRESSION AND PROLIFERATION No Protocol Link

Tumor molecular markers were analyzed before and after treatment. Ellis MJ et al. J Clin Oncol 2001;19:3808-16, Abstract

EORTC-10963: PHASE III RANDOMIZED NEOADJUVANT STUDY OF ICI 182780 IN WOMEN WITH STAGE I OR II PRIMARY BREAST CANCER OPEN PROTOCOL

STUDY CONTACTS Cornelis J H van de Velde, Ph: 31-71-5262309 EORTC Breast Cancer Group Anthony Howell, Ph: 161-446-8037 Breast International Group

ANASTROZOLE AS NEOADJUVANT THERAPY IN HORMONE-DEPENDENT LOCALLY ADVANCED [STAGE IIIA (N=29) AND IIIB (N=45)] POSTMENOPAUSAL PATIENTS

Neoadjuvant anastrozole ( n =74) Objective Response (PR + CR) 61 (83%) 61 (83%)     Partial Response (PR) 42 (57%)     Complete Response (CR) 19 (26%) Pathological Complete Response 14 (23%) Pathological Partial Response 47 (64%) No Response 13 (18%)

Derived from Milla-Santos A et al. Breast Cancer Res Treat 2001; Abstract 302.

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

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