Abstract
Through the use of surrogate markers of efficacy, neoadjuvant studies may facilitate the implementation of new treatments into clinical practice. However, disease-free survival is the current standard outcome endpoint for registration of a novel treatment. The coupling of smaller neoadjuvant 'proof of principle' studies with larger adjuvant registration trials offers the promise of speeding up the time to market of new therapies. Clever new designs, such as the 'biological window' and 'learn on the way', can provide valuable insight regarding mechanisms of action and resistance of these novel drugs by identifying patients who are most likely to respond to a novel therapy early in the drug development process. Using the ongoing neoadjuvant trials with HER2 (human epidermal growth factor receptor 2)-directed therapy as a paradigm, this article discusses recent innovations in study design and the challenges of conducting translational research in the neoadjuvant setting.
Highlights
Neoadjuvant chemotherapy is the standard of care for patients with locally advanced and inflammatory breast cancer (IBC) [1], with the goal of improving operability and eradicating micrometastatic disease
In primary operable breast cancer, neoadjuvant chemotherapy increases the rate of breast conservation [2] and achieves similar overall survival (OS) as adjuvant chemotherapy [3] without compromising local control provided that careful multidisciplinary coordination is planned from the outset [4]
The initiation of chemotherapy prior to surgery allows for the identification of two distinct prognostic groups: patients able to attain a pathologic complete response with a favourable long-term outcome and those with residual disease at surgery who are at a high risk of relapse [6]
Summary
Neoadjuvant chemotherapy is the standard of care for patients with locally advanced and inflammatory breast cancer (IBC) [1], with the goal of improving operability and eradicating micrometastatic disease. Trials investigating trastuzumab as the only HER2 agent were excluded from the review as we wished to focus on the neoadjuvant trials introducing novel therapies for early breast cancer With this strategy, nine studies were identified and these are listed in Table 1 and Figure 1. The majority of ongoing HER2-targeted trials are investigating the efficacy of lapatinib in the neoadjuvant setting for HER2+ breast cancer (Table 1) [16,17,18,19,20,21,22,23,24] Most of these studies use pCR as a primary endpoint. A similar model has been employed by the recently completed neo-tAnGo and tAnGo trials in nonselected
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