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Research Issues Affecting Preoperative Systemic Therapy for Operable Breast Cancer

Antonio C. Wolff, Donald Berry, Lisa A. Carey, Marco Colleoni, Mitchell Dowsett, Matthew Ellis, Judy E. Garber, David Mankoff, Soonmyung Paik, Lajos Pusztai, Mary Lou Smith, JoAnne Zujewski

From the Johns Hopkins Sydney Kimmel Cancer Center, Baltimore; National Cancer Institute, Bethesda, MD; The University of Texas M.D. Anderson Cancer Center, Houston, TX; University of North Carolina, Chapel Hill, NC; European Institute of Oncology, Milan, Italy; Royal Marsden Hospital, London, United Kingdom; Washington University School of Medicine, St Louis, MO; Dana-Farber Cancer Institute, Boston, MA; University of Washington School of Medicine, Seattle, WA; Division of Pathology, National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA; and Research Advocacy Network, Chicago, IL

Corresponding author: Antonio C. Wolff, MD, FACP, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans St, Room 189, Baltimore, MD, 21231-1000; e-mail: awolff{at}jhmi.edu

Preoperative systemic therapy (PST) in operable breast cancer allows a small increase in breast conservation rates and has significant potential as a research platform. PST offers the ability to discern treatment effect in vivo, and may allow smaller trials targeting specific breast cancer subtypes and making more efficient use of resources. Early observations of a specific outcome of interest in individual patient subgroups may improve the design of larger definitive randomized adjuvant trials using survival as a main outcome. PST offers the potential for therapeutic adjustments midcourse, which assumes the existence of validated intermediate end points and effective alternative therapies. This article reviews critical research issues affecting the design of PST trials, including the appropriate selection of trial end points and markers for long-term outcome, baseline marker expression as a predictor of response, and statistical considerations using novel trial designs. Key issues regarding optimal tumor subtype selection for individual trials, novel approaches using nontherapeutic window trial designs, and ethical and advocacy considerations are also discussed. PST requires an experienced and cohesive multidisciplinary team for it to fulfill its potential in both research and clinical care.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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