Francisco J. Esteva, MD, PhD

The goal of this project is to develop predictive markers of response to trastuzumab (Herceptin)-based therapy in breast cancer patients. Dr. Esteva's team performed gene expression analysis in breast cancer tissue from patients undergoing preoperative trastuzumab-based chemotherapy. They obtained pretreatment fine-needle aspiration specimens from 45 patients with HER-2-overexpressing stage II to IIIA breast cancer.

The tissue was subjected to transcriptional profiling. They examined for differential expression of various genes and gene sets. Results of gene set enrichment analysis suggested that the lower expression of genes involved with CD40 signaling is associated with a greater risk of residual cancer after the preoperative chemotherapy that includes trastuzumab.

In the coming year, the researchers will continue to investigate novel molecular markers in primary tumor from patients treated with trastuzumab-based therapy for metastatic breast cancer. In addition, they will conduct in vitro studies in breast cancer cell lines to identify novel mechanisms of resistance to HER2-directed therapies using siRNA libraries to evaluate the role of approximately 20,000 genes in breast cancer cell lines treated with trastuzumab and lapatinib.

Mid-year Progress Report:
The goal of this project is to develop predictive markers of response to HER2-directed therapy in breast cancer patients. Trastuzumab (Herceptin) is a monoclonal antibody directed against the HER2 protein, and the first FDA-approved targeted therapy for patients with HER2+ metastatic breast cancer. Lapatinib (Tykerb) is a small molecule inhibitor of EGFR and HER2 that has been shown to be effective in patients who have failed trastuzumab. However, only about 30% of patients with HER2+ metastatic breast cancer respond to single-agent trastuzumab or lapatinib therapy. The combination of either of these agents with chemotherapy increases the response rate, but it is not complete, and many patients that initially respond develop progressive disease within one year.

Trastuzumab is also effective in women with HER2+ early-stage breast cancer, but again, about 15% of HER2+ ESBC patients develop metastatic breast cancer despite trastuzumab and chemotherapy in the adjuvant setting. The safety and efficacy of lapatinib has not been reported on early-stage breast cancer patients yet, but at least partial efficacy is anticipated. Both drugs are expensive, and may potentially cause undesirable side-effects including cardiotoxicty (particularly true for trastuzumab). Therefore, it would be useful to develop a test that is more predictive of response than HER2 status, and most importantly, allows physicians to predict which HER2-directed therapy would be most effective.

Bio:
Dr. Esteva received his MD and PhD degrees from the University of Zaragoza School of Medicine in Spain. He completed an internship and residency in internal medicine at Cooper Hospital/University Medical Center (Camden, NJ). He continued on to Georgetown University Medical Center (Washington, DC) for a clinical fellowship in medical oncology at the Vincent T. Lombardi Cancer Center. Dr. Esteva is board certified in medical oncology, and a Fellow of the American College of Physicians.

Dr. Esteva has served on the American Society of Clinical Oncology (ASCO)'s Scientific Program Committee and Education Committee; and as faculty for the ASCO annual meeting for several years. He is a member of the Southwest Oncology Group (SWOG) Breast Cancer Committee. He was awarded a Career Development Award from the NCI in 1999. He is a co-author in over 100 publications including peer-reviewed research articles, invited reviews and book chapters.