Abstract PL01-04: The neoadjuvant model in breast cancer research: Stories of success.
Authors: Cosimo Serena Di 
Published: June 2012

Abstract
Clinical cancer research is undergoing a period of fast and unprecedented transformation. Huge progress has been achieved in the deep understanding of multiple malignancies, allowing us to identify the oncogenic molecules and signaling pathways that drive them. The consensus is now to make the emerging knowledge in tumor biology the basis for drug discovery, development and clinical testing, with the aim of targeting specific patient populations that may most likely benefit.
Breast cancer, like a number of other malignancies, is a heterogeneous disease with different molecular alterations driving its growth, survival and response to therapy. The current classification of breast cancer subtypes is mainly based on the pattern of expression of hormone receptors (HR) -estrogen receptor and/or progesterone receptor- and the human epidermal growth factor receptor 2 (HER2), which result in three major and distinct molecular breast cancer subtypes: luminal, which is HR positive and HER2 negative; HER2-overexpressed (HER2 positive); and those that lack expression of the three receptors, frequently referred to as triple negative breast cancer (TNBC). While this division is far from perfect and, in addition, subgroups within these groups clearly exist, tumors within these subtypes have similar gene expression patterns, clinical outcomes and responses to therapy.
Intertwined with the advances in molecular biology and genomic approaches, which continue increasing our detailed understanding of cancer, has come a torrent of targeted drug candidates. The cancer drug pipeline is nowadays a broad-based pyramid, with lots of molecules in early development that never make it to the top. The new generation of targeted therapies continue to build on their widely used predecessors, trastuzumab and lapatinib, and now include novel anti-HER2 strategies. In addition, targets have diversified to encompass modulators of proliferative signal transduction and cell cycle transit, apoptosis, invasion, angiogenesis and metastasis. Moreover, there are classes of therapies under evaluation that include agents against critically important signaling pathways such as the PI3K/Akt/mTOR inhibitors and inhibitors of DNA repair.
The challenges that are being brought by these novel therapies are different from those faced by traditional antitumor strategies. They not only include the identification of appropriate dose and schedule, safety issues, etc., but also the selection of patient populations most likely to benefit. Not less important, central to targeted therapy development is a clear understanding of the molecular biology of signaling pathways and the development of combinatorial strategies, either with chemotherapy, hormonal therapy or other targeted agents. Another layer of complexity is what constitutes a reasonable measure or response and the selection of an attainable and clinically meaningful endpoint.
Personalized treatment strategies are without any doubt the way of the future. While the pouring of novel drug candidates is encouraging, challenges arise as to how to better allocate resources and make the development process more efficient. Substantial investments of time and other resources are required for the development of drugs that ultimately fail. But if our drug development process is not working as expected, where is the bottleneck?
Traditionally, drug development in oncology has focused mainly on advanced disease. New drugs are usually tested in patients for whom no other approved alternatives are available. Once a drug is proven beneficial -and safe-in this setting, the compound works its way backwards to earlier lines of treatment. Consequently, novel agents are not demonstrated truly beneficial until late in the game, making the drug development process lengthy, expensive, and demanding of patient numbers in the thousands. Also to consider is the fact that advanced tumors usually complex entities, with many accumulated mutations, likely resistant, and with distant foci that do not necessarily share their genetic makeup. It would not be daring to speculate that more than a few clinically active drug candidates have not been pursued due to failure in this setting. The question is, is there a better way?
A novel approach to clinical development has been gaining momentum in the breast cancer arena with the advent of neoadjuvant trials. The neoadjuvant setting presents a unique opportunity for the investigation of a molecule's proof-of-concept. Preoperative treatment periods are short, a clinical outcome is objectively measured at the time of surgery, and biomarker analyses can be easily implemented and correlated with clinical results. Additionally, for patients who do not respond optimally, adjuvant treatment with a different regimen can be administered. The use of biomarkers of response in this context could facilitate the efficient evaluation of new agents in focused early clinical trials while enabling the design of more informed, smaller phase II/III trials. In fact, preoperative studies connect clinicians, translational researchers, and radiologists with a new model for the evaluation of treatments in the setting of primary breast cancer: bringing together data from multiple molecular biomarker studies with imaging.
In regards to the HER2 positive subtype, trials such as NeoALTTO and NeoSphere have consolidated the notion that dual HER2 blockade is the optimal therapeutic strategy, building upon the NOAH study, which demonstrated the efficacy of trastuzumab and chemotherapy in this setting. Additional findings open the door for possible chemotherapy-free regimens, and the evaluation of early responses by FDG-PET/CT imaging, not to mention the various biomarker analyses being carried out as we speak. Adjuvant trials for both pertuzumab and lapatinib in combination with trastuzumab are currently being conducted with confidence based on the early readout of response. In the case of luminal B breast cancer, a neoadjuvant study including everolimus and letrozole therapy provided the foundation for the design of the BOLERO-2 trial, whose impressive results have been widely celebrated just recently. Finally, in populations that are targetless such as TNBC, the neoadjuvant model is no less important because of the possibility to early evaluate the response and to switch therapies.
The neoadjuvant model in breast cancer research is indeed a success. But success is not determined only by the continued development or the regulatory approval of a particular agent or combination; it also represents the early dismissal of drug candidates that do not offer significant clinical activity, in benefit of the allocation of time and resources to other runners.
One can only wonder what the story of trastuzumab or lapatinib would have been if they had been developed in this fashion, as opposed to debuting in the metastatic setting. In all likelihood, the adjuvant trials would have been conducted earlier, and perhaps nowadays we would be further ahead in the management of HER2 positive disease. Certainly, a paradigm shift is not without its challenges. Drastic change will always be met with resistance, but the time has come to seriously consider such a brave new world. We owe it to our patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr PL01-04.