SAN ANTONIO-Discussing decades of work in developing trastuzumab (Herceptin), and looking to the future based on techniques that led to the understanding of HER2/neu, Dennis J. Slamon, MD, PhD, presented the William L. McGuire Memorial Lecture at the 28th Annual San Antonio Breast Cancer Symposium. Dr. Slamon is director of clinical and translational research at the UCLA Jonsson Comprehensive Cancer Center.

Using the HER2/neu oncogene and the monoclonal antibody directed against it as a paradigm, Dr. Slamon described the paradigm shift away from the conventional one-size-fits-all approach to cancer. The evolution, in both concept and therapeutics, is occurring due to the appreciation of cancer as a complex disease controlled by multiple genes and pathways, he said.

Developments in molecular biology have made it possible to identify the specific genes and genetic pathways associated with the major phenotypic characteristics of cancer: self-sufficiency in growth signals, insensitivity to antigrowth signals, tissue invasion and metastasis, limitless replicative potential, sustained angiogenesis, and the ability to avoid apoptosis. This knowledge now forms the basis of preclinical work and emerging clinical trials using targeted approaches to optimize therapeutic strategies, he said.

Two decades ago, Dr. Slamon and his colleagues first applied the concepts of targeted therapy after observing that amplification of the HER2/neu oncogene in breast cancer patients was associated with shortened survival. This finding led to preclinical trials showing that engineered HER2 overexpression in MCF-7 cells increased cell proliferation. Treatment of HER2-positive cells with the anti-HER2 monoclonal antibody trastuzumab led to decreased cell proliferation in a dose-dependent manner. Similarly, treatment of HER2-positive xenografted mice reduced tumor volume.

These early findings were the foundation of trastuzumab's use today, which yields striking improvements in outcomes in metastatic breast cancer and, as has been recently shown, in early breast cancer as well.

Recent studies are revealing the complexity of the HER2 story. "It is unlikely that any one gene acting alone can carry out this broad pleiotrophic phenotype," Dr. Slamon said. "HER2 must be engaging other genes and pathways."

The neoplastic characteristics associated with HER2-positive cells more likely stem from a large group of genes, with HER2 amplification an inciting event. In fact, the use of cDNA microarrays has uncovered nearly 500 detectable differences between HER2-positive and HER2-negative cells out of 40,000 genes queried, he said.