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Section 9
Neoadjuvant systemic therapy

OVERVIEW

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.

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 limited 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

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 THERAPY AND BREAST PRESERVATION

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 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, and patients can have much less deforming surgery...

...Our initial work with tamoxifen led us to look at some of the more active agents - the aromatase inhibitors. And what impressed us as soon as we started to use the aromatase inhibitors was that we seemed to be getting much quicker responses and much greater responses in terms of percentage reduction in tumor volume. If you give tamoxifen, it takes four to five weeks to build up adequate levels in the circulation. If you give an aromatase inhibitor, it works immediately. So maybe it's just that with tamoxifen if you treat them for three months, you don't really get three months of effective treatment. With aromatase inhibitors, you can get quite marked effects with reductions in tumor volume within four weeks.

-J Michael Dixon, MD, FRCS

MICROCALCIFICATIONS AND DCIS

We have greatly increased our use of neoadjuvant cytotoxic therapies in patients in whom we would like to facilitate breast conservation. The critical rate-limiting step is the presence of malignant microcalcifications. The Italians taught us a few years ago that neoadjuvant therapy is great for invasive disease, but it is not great for DCIS. So the presence of widespread malignant microcalcifications should be considered today a contraindication to trying to use these drugs to conserve the breast.

-Patrick Borgen, MD

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