Neoadjuvant trials provide endpoints, such as pathological complete response (pCR) to treatment, that will potentially translate into meaningful improvements in overall survival and disease-free survival. Neoadjuvant trials need smaller sample sizes and are less expensive, and the endpoint of pCR is achieved in months, rather than years. For these reasons, the neoadjuvant setting is ideal for testing emerging targeted therapies in early breast cancer. Recently the US Food and Drug Administration has released a draft Guidance to Industry, outlining a pathway to accelerated approval for neoadjuvant breast cancer therapies using pCR. The association between pCR and outcome is clear for chemotherapy in triple-negative breast cancer and for HER2-targeted agents in HER2-positive disease, but might not hold true for other tumor subtypes such as luminal cancers. Since pCR is rarely achieved with either chemotherapy or endocrine therapy in hormone-receptor-positive breast cancer, in this setting we need to identify different intermediate endpoints, which might be translational endpoints within "window-of-opportunity," "residual disease," and "genome forward" trials. Prospective validation of effective noninvasive techniques for monitoring of residual disease burden could enhance the ability to identify promising targeted therapies in the neoadjuvant setting.
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