Francisco J. Esteva, MD, PhD

Trastuzumab (Herceptin) and lapatinib represent a paradigm shift in the treatment of breast cancer, from nonspecific chemotherapy (particularly in estrogen receptor-negative tumors) to a more rational and targeted therapy. However, in the future it will be important to differentiate what therapy (or combination of therapies) would be optimal for each patient with HER2-positive breast cancer. Dr. Esteva's proposed studies will provide important information related to this gap in knowledge. Importantly, the researchers will know at the completion of these studies whether a panel of molecular markers can predict which patients with HER2-positive breast cancer will be most likely to benefit from trastuzumab-based therapy. Future studies will aim to develop a clinically useful test that would differentially predict response to trastuzumab, lapatinib or other novel HER2- targeted agents for breast cancer.

Mid-Year Progress Report:
One of Dr. Esteva’s projects supported by BCRF has had a goal of characterizing mechanisms of action of lapatinib (Tykerb; GlaxoSmithKline) in trastuzumab-resistant HER2-overexpressing breast cancer cells, and to determine whether the efficacy of lapatinib could be improved by blockade of the insulin-like growth factor receptor I (IGF-IR). His results showed that lapatinib induces apoptosis in trastuzumab-resistant cells derived from the HER2-overexpressing SKBR3 breast cancer line. Lapatinib inhibited EGFR and HER2 signaling in resistant cells, blocking activation of downstream Akt, MAPK, and S6 kinases, and inducing expression of p27kip1. The researchers were able to show that lapatinib can inhibit IGF-I signaling and growth-promoting effects in SKBR3 breast cancer cells (both in parental and trastuzumab resistant cells). In their experimental model, the cytotoxic effects of lapatinib were further enhanced by the IGF-IR blocking antibody alpha-IR3. As increased IGF-IR signaling has been implicated in trastuzumab resistance, the data strongly support further study of lapatinib as a potential therapeutic in breast cancers that have progressed on trastuzumab.

The goal of Dr. Esteva’s second BCRF-supported project is to develop predictive markers of response to trastuzumab-based therapy in breast cancer patients. His 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 have 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.

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.