Current breast cancer clinical trials

Randomized clinical trials have demonstrated that while neoadjuvant systemic therapy downstages tumors and improves the chance for breast conservation, disease-free and overall survival seem to be about the same compared to using treatment postoperatively. A new generation of studies is evaluating a variety of strategies including taxanes, dose intensive chemotherapy and endocrine treatment, particularly with the third-generation aromatase inhibitors. The neoadjuvant setting is also being utilized to evaluate new systemic agents and predictors of tumor response, including DNA microarray analysis.

 

 

SELECT PUBLICATIONS

Aapro MS. Neoadjuvant therapy in breast cancer: Can we define its role? Oncologist 2001;6 Suppl 3:36-9. Abstract

Dixon JM et al. The effects of neoadjuvant anastrozole (Arimidex) on tumor volume in postmenopausal women with breast cancer: A randomized, double-blind, single-center study. Clin Cancer Res 2000;6(6):2229-35. Abstract

Ellis MJ. Preoperative endocrine therapy for older women with breast cancer: Renewed interest in an old idea. Cancer Control 2000;7(6):557. Full-Text

Ellis MJ et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: Evidence from a phase III randomized trial. J Clin Oncol 2001;19:3808-3816. Abstract

Geisler J et al. Influence of neoadjuvant anastrozole (Arimidex) on intratumoral estrogen levels and proliferation markers in patients with locally advanced breast cancer. Clin Cancer Res 2001;7(5):1230-6. Abstract

Kuerer HM et al. Neoadjuvant chemotherapy in women with invasive breast carcinoma: Conceptual basis and fundamental surgical issues. J Am Coll Surg 2000;190(3):350-363. Abstract

Smith IC, Miller ID. Issues involved in research into the neoadjuvant treatment of breast cancer. Anticancer Drugs 2001;12 Suppl 1:S25-9. Abstract

 

 

 

 

 

 

 

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NEOADJUVANT CHEMOTHERAPY
I view induction chemotherapy as a positive trend, because you do not lose anything, and there is a higher likelihood of being able to do a lumpectomy with a much better cosmetic result. It also provides an in vivo chemosensitivity assay. This trend will also allow us to start looking at minimally invasive surgery to the primary tumor. I predict that in the next decade we will move away from axillary node dissection, and sentinel node biopsy may be a transition maneuver in this regard, because people do not yet feel totally comfortable giving up the nodal status information. But once we start using systemic therapy first, the remaining question relates to treatment of what’s left of the primary tumor. The research question then would be, "Do you need to take the patient to the operating room at all?"

— Eva Singletary, 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 do good. There are a lot of data for chemotherapy, and I am certain that similar data will emerge for endocrine therapy.
The studies that were done 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

TRIALS OF NEOADJUVANT ENDOCRINE THERAPY
We’ve been involved in a number of randomized neoadjuvant trials. The IMPACT study is in a neoadjuvant setting, with 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. 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 the 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.

You can get a very good idea of what’s happening in tumors by looking at biological markers rather than clinical endpoints. In these studies we’ve been taking biopsies at 10 to 14 days and looking at what effect drugs have on proliferation, cell death and a variety of genetic markers to see if we can start to predict very early on whether the patient is going to get a benefit from a drug. And that is potentially a very useful tool, because a lot of patients wait 10 to 14 days (at least in the U.K.) from the time of diagnosis to the time of surgery.

If you got a core biopsy at the time of diagnosis and you put a patient on a drug and then you operate on them and you see that that drug has done something to the tumor and you know that that change is associated with long-term benefit for a patient, then you have a potential method to individualize treatment.

— J Michael Dixon, MD, FRCS
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