Abstract ML-1: William l. McGuire Memorial Lecture: Neoadjuvant Systemic Therapy: Promising Experimental Model, or Improved Standard of Care?

Abstract Neoadjuvant chemotherapy (NACT) was developed to improve the management of largely inoperable breast cancers (BC), including inflammatory BC. In the early 1970s, despite heroic efforts combining radical surgical resection with high doses of radiotherapy, local failure rate remained between 20% and 50% and 5-year overall survival (OS) rates rarely approached 20%. With the introduction of anthracycline-containing combination chemotherapy regimens, most large primary tumors responded to chemotherapy, with greater than 50% reductions in almost 90% of patients. Clinical complete remissions (CR) were reported in about 10% of such large tumors. These results were obtained when adjuvant chemotherapy was in its earliest clinical evaluation. Our group at the MD Anderson Cancer Center and others pioneered multidisciplinary strategies consisting of NACT, followed by surgery and radiotherapy. Such strategies rapidly became the standard of care for locally advanced BC and inflammatory BC, improving local control rates to >80%, and 5-year OS rates to >30%. In the early 1980s, we described the concept of pathological CR (pCR) and its correlation with favorable long-term OS. We also described the clinical and pathological correlates of pCR: thus, most pCRs were observed in patients with estrogen receptor (ER)-negative, high grade and highly proliferative tumors. pCRs were rarely observed when tumors had the opposite characteristics. Achieving major clinical responses expanded breast conserving surgery to patients with large, even locally advanced BC. Additional advantages to these strategies included the ability to monitor response to NACT, both clinically and through serial biopsies, thus documenting the biological effects of systemic treatments. By 1990, the first neoadjuvant endocrine therapies were introduced in patients with ER-positive BC, who were largely refractory to NACT. With the initial steps in high throughput genomic assays, our group focused on the development of prognostic, and later predictive profiles based on gene expression. These research directions rapidly established the importance of molecular subtypes. The old paradigm, based on a monolithic concept of BC was rapidly displaced by the 4–5 main molecular (and biomarker defined) BC subtypes. In little over 10 years, selection of standard treatment became dependent on four clinical biomarkers, while novel, RNA, DNA and protein based profiles became rapidly established in our diagnostic toolbox. Our field is rapidly evolving toward baseline identification of molecular anomalies that might serve as targets for novel, targeted agents (antibodies, kinase inhibitors, etc.). The proof of concept was trastuzumab and other HER-2-directed agents. Drug development is rapidly moving from advanced, refractory metastatic BC to the neoadjuvant setting, where modest size clinical trials promise to accelerate clinical assessment of new drugs, delivering them to the patients most likely to benefit from them. Neoadjuvant systemic therapy is at least equivalent to adjuvant systemic therapy and provides practical and scientific advantages that make it preferable in many subsets of BC. It is a new standard of care while continuing to serve as an excellent research tool. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ML-1.