Neoadjuvant clinical trial designs: Challenges of the genomic era

The modern era has brought huge changes in the way we approach breast cancer clinical trials. The neoadjuvant, or preoperative, approach is increasingly popular because of several advantages over traditional adjuvant trials in terms of size, speed, capacity for embedded correlative science, and design flexibility. True neoadjuvant trials test the administration of a new drug or regimen preoperatively, with clinical or pathologic evaluation post-therapy at the time of surgery serving as the primary endpoint. The most commonly used and validated neoadjuvant endpoint is pathologic complete response, or pCR, which is itself not clinically meaningful but has been amply demonstrated to be prognostic of both disease-free and overall survival. However, it has also become clear that the association of pCR to outcome is not clean and that we lack a formula for pCR augmentation that will translate into significant improvements in clinically meaningful endpoints such as survival. Breast cancer is well recognized to be comprised of multiple biologically distinct molecular subsets, which has driven the move to more economical approaches such as neoadjuvant clinical trials, but also produces considerable confounding since we lack clinical assays that accurately reflect underlying biology. In this sense, the challenge for the clinical research community is multifaceted; we need to delineate the breast cancer biologic entities that we want to target, develop and validate the assays to identify those entities, and test the targeted drugs in the appropriate setting.