Dr. Slamon Describes Past, Present, Future of Targeted Rx

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.

"We begin to get a sense that rather than applying these molecular profiles in a one-size-fits-all approach, constraining the data gives us interesting information," Dr. Slamon said. "The most exciting research we have been involved with recently has used this approach."

He was alluding to his laboratory's recent discovery that levels of vascular endothelial growth factor (VEGF) are consistently elevated in HER2-positive cells. Furthermore, xenografts of transfected cells are associated with significantly enhanced angiogenesis. The fact that trastu-zu-mab inhibits these VEGF levels "indicates that there really is an impact and a connection between these two pathways," Dr. Slamon said.

The presence of both HER2 and VEGF in the same tumor is highly correlated with reduced survival in primary breast cancer, which suggests that combination therapy with agents that inhibit both these factors-trastuzumab and bevacizumab (Avastin)-may be an effective treatment approach.

Combination Therapy

Results from small phase I and II trials in metastatic breast cancer patients who have received this combination instead of chemotherapy have shown the strategy to be not only feasible but promising, he said. Out of nine patients, seven have achieved a complete or partial response or stable disease for up to 11 months, with little toxicity. One patient, for example, achieved a substantial reduction of disease on the chest wall, had complete resolution of tumor by 9 months, and has been in complete remission for more than 1 year, Dr. Slamon reported.

These encouraging results justified a phase II study of 50 metastatic patients who will receive the two biologics and no chemotherapy. "If we begin to see these kinds of results, we will start thinking about how to move this regimen forward," he announced.

In summary, Dr. Slamon said that it is critical to identify the molecular targets of the various subgroups of disease preclinically, and to develop specifically targeted therapies aimed at their pathways. "This should significantly improve patient outcomes, compared to what we have been doing traditionally," he said. "The Herceptin story is a paradigm that proves this."