Section 2
Neoadjuvant Therapy with Aromatase Inhibitors

NEOADJUVANT THERAPY AS AN IN VIVO SENSITIVITY ASSAY

We now know from three randomized trials that patients don’t necessarily live longer if they receive neoadjuvant versus postoperative therapy, but they do have a higher likelihood of undergoing breast-conserving surgery. The more important advantage of neoadjuvant therapy is its use as a research tool. It provides a way to know which combinations are going to be the most active,and for an individual patient, it might also allow us to make treatment decisions.

If someone receives doxorubicin/cyclophosphamide and she’s not responding, then you would know that you might want to add a taxane. You wouldn’t have known that if you had already removed her tumor.

We also have a surrogate marker that might help us to make decisions as well, and that is the degree of complete pathological response, which predicts an improved long-term outcome. Neoadjuvant therapy — in a much shorter time period — allows you to say, “This particular regimen has a 50 percent complete pathologic response, whereas this other regimen only has 20 percent,” and in a much shorter period of time you could identify a drug that’s going to be more effective.

It’s a little too early to actually use that as the definitive answer in trying to identify and target therapies to the patient’s tumor, but at least it’s a way to prioritize what regimens you might want to take into the adjuvant setting.

—Debu Tripathy, MD

NEOADJUVANT THERAPY AND BREAST PRESERVATION

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 excellent for invasive disease, but it is not great for DCIS. So the presence of widespread malignant microcalcifications should be considered a contraindication to using these drugs to attempt to conserve the breast.

—Patrick Borgen, MD

INTEGRATION OF NEOADJUVANT ENDOCRINE THERAPY AND CHEMOTHERAPY

The use of hormonal therapy in the neoadjuvant setting doesn’t take away from the fact that chemotherapy does still improve on survival, and a lot of these patients are still candidates to receive chemotherapy after surgery. We use aromatase inhibitors preoperatively, based on the randomized trials showing that at least in that four-month period before surgery, aromatase inhibitors are more effective than tamoxifen in inducing a response.

What the neoadjuvant studies did not look at is what patients should receive after surgery over a longer-term basis.In the absence of any data to suggest otherwise, we’re still using tamoxifen for five years. An alternative option would be to continue with the aromatase inhibitor for five years, but I’m reluctant to do that now, because I think that what you’re seeing in the short term versus the long term may be two different things.

There is a huge body of data showing that tamoxifen cuts the risk of recurrence by almost half when used for five years,and we don’t have long-term aromatase inhibitor data yet, although the ATAC trial is about to be reported, comparing anastrozole to tamoxifen to the combination.

—Debu Tripathy, MD

MSKCC TRIALS OF NEOADJUVANT THERAPY IN DCIS

We’re just beginning a couple of different trials using neoadjuvant hormonal therapy in ductal carcinoma in situ — doing a core biopsy followed by a brief course of hormonal ablative therapy followed by definitive surgery. We are examining tamoxifen in younger patients with high-risk DCIS and anastrozole in postmenopausal patients.

We’d like to have a better understanding, in vivo, of the effects of these drugs. There’s a companion study that we’ve just started where we are putting a radioactive seed into invasive cancers, both before and after core biopsy — under ultrasound guidance — to evaluate radiosensitivity in vivo. We’d like to learn more about what happens biologically with tamoxifen, an aromatase inhibitor and with ionizing radiation. The problem is that we don’t have an intermediate biomarker, so we really don’t have a way to assess therapies short of looking for recurrences.

—Patrick Borgen, MD

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