Assessment of the response of primary breast cancer at the completion of pre-operative (neoadjuvant) chemotherapy provides an opportunity to rapidly evaluate the effectiveness of specific treatments in clinical trials. Tumor response is a surrogate marker for survival and hence the effectiveness of the treatment. Clinical trials have consistently shown that complete remission of cancer in the breast after neoadjuvant chemotherapy is associated with excellent patient survival. However, most breast cancers (60'-80') achieve only a partial response, and these are not further stratified. Currently, response is not measured but is assigned to categories. If there were more specific measurement of tumor response to neoadjuvant chemotherapy, then the information that is learned from these clinical trials could be much more specific.

A minority of good and poor extreme responses greatly influences the results from clinical trials using neoadjuvant chemotherapy, yet most women achieve a partial tumor response (defined as >50' reduction in size). It is important to be able to measure (and therefore separate) these different responses because they are likely to be clinically significant. Also, women with partial response will probably benefit the most from additional or new treatments, because a partial response may be improved. Thus, it will be important to measure how much improvement a new treatment offers. The proportion of the original breast cancer that remains after treatment would provide a measure of the relative response to treatment. Data from our pilot study demonstrated that initial apoptotic responses (cell killing) in breast cancer after the first dose of paclitaxel chemotherapy appeared to be related to tumor response. This was clearly demonstrated when each relative tumor response was calculated as the proportion of residual volume of cancer, as compared with the standard categories of response. The clinical trial that we have selected to evaluate in this proposed research compares weekly with every three weekly paclitaxel treatments. Preliminary data indicates more frequent complete remissions in the weekly treatment group (predicted from our pilot study). We intend to calculate the change in volume of breast cancer from treatment and to compare those values with the results from standard analyses of outcomes from the clinical trial.

There are four specific aims for this proposed research. The first two aims are to develop a method to quantify response using radiologic and pathologic techniques that are inexpensive and widely available. Aim 1 is to determine their accuracy of measurement of tumor size, to use before and after treatment. Aim 2 is to measure the proportion of cancer cells within these tumors in order to calculate the proportion (percentage) of the original cancer volume that is residual after treatment, for comparison with standard categories of response and with follow-up information from the clinical trial. Aim 3 is to evaluate the relevance of specific pathologic findings after chemotherapy to determine if they are related to the amount of cancer reduction from treatment. There is uncertainty among pathologists about how to interpret some pathologic findings in residual breast cancer after treatment. Results from Aim 3 will help to determine if those findings indicate viable cancer that is capable of growth or not. Aim 4 is to test the ability of certain tumor characteristics (biomarkers) in pretreatment biopsy samples to actually predict the tumor response to treatment. We will test their ability to predict the result of treatment using three assessments of treatment outcome: our calculation of percentage of residual cancer volume, the standard categories of response, and clinical follow-up results from the trial.

This research should produce and validate a method to quantify breast cancer response to neoadjuvant treatment. Actual measurements of tumor response could provide a powerful tool to evaluate chemotherapy treatments for breast cancer and to evaluate potential predictors of treatment response.