Trial Information

A Randomized Multicenter Trial of Neoadjuvant Taxotere (T) and Adriamycin/Cytoxan (Ac): A Validation

Large clinical trials have confirmed the value of systemic adjuvant therapy in decreasing
the risk of recurrence and death in patients with early breast cancer. However, the need to
identify breast cancer patients who will benefit from adjuvant therapy, while sparing others
from the side effects of futile treatment, is spurring research into predictive markers of
chemotherapy sensitivity and resistance. In the adjuvant setting, extremely large trials and
long follow-up would be required to prospectively validate the predictive value of
biomarkers of chemotherapy sensitivity or resistance. In part this is because response is
not directly observable. Preoperative chemotherapy for large tumors (>3cm) or inoperable
breast cancer is well established and is the standard of care for locally advanced breast
cancer. Data from large series of patients have demonstrated that preoperative (neoadjuvant)
chemotherapy leads to significant reduction of tumor size (downstaging) and improves both
the rate and the cosmetic results of breast- conserving surgery. The degree of response to
neoadjuvant therapy has been shown to predict improved overall survival. This is therefore
an attractive setting to study predictors of response because tissue is accessible from pre-
therapeutic biopsies and tumor response is directly observable.

In an early proof-of-principle pilot study of single agent neoadjuvant docetaxol, we
identified a predictive gene expression pattern, and, using leave-one-cross validation, a
method of internal validation, we demonstrated that the pattern was likely to accurately
discriminate between responders and non-responders (Chang, J.C., et al., Gene expression
profiling for the prediction of therapeutic response to docetaxel in patients with breast
cancer. Lancet, 2003. 362(9381): p. 362-9). A similar pilot study of neoadjuvant AC
undertaken by a collaborator in the UK suggests that different profiles will be predictive
for AC response.

In order to definitively determine predictive patterns for both regimens (T and AC) using
improved technology for RNA preparation and a larger, more comprehensive gene expression
array, we undertook a randomized Phase II trial of these two widely used regimens (Protocol
H-11624 - A RANDOMIZED MULTICENTER TRIAL OF NEOADJUVANT TAXOTERE AND ADRIAMYCIN/CYTOXAN
(AC): A BIOLOGIC CORRELATIVE STUDY). The trial is nearing completion, having recruited more
than 90 patients out of an expected 120 patients. To date, the risks associated with this
study have been modest, and there have been no unexpected adverse events. The laboratory
work is well underway and gives every indication that clinically useful classifiers to
predict treatment efficacy will result.