Lisa A. Carey, MD

On Behalf of Cancer and Leukemia Group B
Co-Invesigators: Richard L. Schilsky, MD, Chairman, Cancer and Leukemia Group B, Chicago; Matthew J. Ellis, MD, PhD, Washington University School of Medicine, St. Louis, MO; and William M. Sikov, MD, Brown University, Providence, RI

Advances in the postoperative treatment of breast cancer have led to new challenges in drug development. Recurrence rates from breast cancer have declined substantially in recent years. While there is no question that the decline in recurrence is good news, it has lead to an increasing need to conduct very large clinical trials in order to detect small benefits from new treatments. In addition, it often takes years before results are available. The preoperative administration of systemic therapy (e.g., chemotherapy, hormonal therapy, and/or targeted therapy) is safe and effective. In addition, from a research standpoint, it has two major benefits: 1) researchers can quickly see whether treatment shrinks the cancer and 2) samples of the cancer can be obtained for study before and after treatment to assess the impact of therapies.

Over the next year in the CALGB, researchers are going to test two new targeted therapies using this approach. In patients with tumors that are dependent on HER2, they will compare trastuzumab (Herceptin®) versus lapatinib (Tykerb„µ) versus both. In patients with hormone receptor-poor/HER2-negative tumors (often referred to as triple negative or basal-like), they will test the addition of an antibody that shuts off new blood vessel formation, bevacizumab (Avastin®). These studies represent a unique opportunity for the CALGB as researchers will have the ability to see the effects of their treatments on tumors before surgery and will be able to gather extensive tissues for later study.

With support from BCRF, they will build and maintain the infrastructure needed to collect these tissues, to store them until the clinical studies are completed, to distribute them to collaborating investigators, and to perform studies on them. The results of this program should improve our understanding of how our available therapeutics kill cancer and lead to improved treatment approaches.

Mid-year Progress Report:
The gene expression analyses of breast cancer tumors are underway. The expression data will soon be combined with the clinical outcome data by the study statistician at the CALGB Statistical Center. The researchers expect to have a draft manuscript by early summer 2009 and hope to have the work published by the end of the year.

The clinical trial comparing adjuvant chemotherapy with standard regimens versus capecitabine in older women closed in December 2006; results indicate that capecitabine is inferior to standard adjuvant chemotherapy in preventing tumor recurrence. The manuscript for this study, with preliminary marker analysis, has been completed and will be submitted for publication in the near future. The initial tumor marker analyses have been recently completed and the results indicate that no combination of markers of genetic instability, proliferation, and progression predicted treatment outcome. Additionally, CALGB’s Pathology Coordinating Office is constructing a tissue microarray (TMA) from the tumor blocks provided by patients enrolled in CALGB 49907; these samples will be a source of additional work.

In the project evaluating magnetic resonance imaging (MRI) and spectroscopy (MRS) and various molecular markers as predictors of clinical response in women receiving chemotherapy and radiation for locally advanced breast cancer, eight abstracts have been presented at leading scientific meetings over the past year. The CALGB team has completed the development of a 50 gene qPCR classifier and plans to submit an application to the NCI to apply this classifier to tumor samples collected from CALGB 9344. CALGB 9344 qPCR profiling will begin after the appropriate regulatory approvals are obtained from the NCI. In the project evaluating dose-dense chemotherapy, the initial immunohistochemistry work for is nearing completion and the laboratory data is currently being analyzed at the CALGB statistical center. In the near future, the CALGB group will generate the data for HER2 gene expression.

Another project will correlate tumor epidermal growth factor receptor and Her2 expression with the clinical outcomes of women receiving fulvestrant with or without lapatinib, a novel drug that inhibits EGFR and Her2. The goal is to develop markers to guide patient selection for future therapies targeting the epidermal growth factor receptor. The study activated in September 2006 and as of mid-January 2009, 134 patients (of planned 324) have enrolled.

Recent clinical trials have shown that the preoperative administration of systemic therapy (e.g. chemotherapy, hormonal therapy, targeted therapy) is safe and effective. In addition, from a research standpoint, it has two major benefits: 1) we can quickly see whether drugs shrink the cancer and 2) we can study the cancer cell before and after treatment to assess the impact of our therapies. In the CALGB, researchers will test two new targeted therapies using this approach. In patients with tumors that are dependent on HER2, they will compare trastuzumab (Herceptin®) versus lapatinib (Tykerb®) versus both. In patients with HER2 normal tumors ("HER2 negative") they will test the addition of an antibody that shuts off new blood vessel formation (Avastin® or bevacizumab). These studies represent a unique opportunity for the CALGB as researchers will have the ability to see the effects of treatments on tumors before surgery and will be able to gather extensive tissues for later study. CALGB 40601 was activated and open to accrual in December 2008; CALGB 40603 is in the final stages of development and activation of this trial is anticipated in the spring 2009.

Bio:
Lisa Carey is an Associate Professor in the UNC Department of Medicine, Division of Hematology-Oncology. She graduated from Wellesley College in 1984 with a BA in Biology and Art History, before receiving a MS in Physiology from the University of Kentucky. She received an MD from the Johns Hopkins University School of Medicine in 1990. After a residency in Internal Medicine also at Johns Hopkins, she stayed at Johns Hopkins for a fellowship in Medical Oncology. During her fellowship she completed a ScM. in Clinical Research. Dr. Carey joined the UNC faculty in 1998. She has served since 2003 as the Medical Director of the UNC Breast Center and is the UNC-Lineberger Comprehensive Cancer Center (UNC-LCCC) Protocol Office Executive Committee Breast Disease Group Leader as well as the UNC-LCCC Protocol Review Committee Breast Cancer Chair.

Dr. Carey has a well-defined interest in clinical/translational research in breast cancer, with a particular interest in the clinical implications of different molecular subtypes of breast cancer. She both designs and leads clinical trials as well as working often and well with laboratory investigators. She has successfully translated bench efforts from laboratory science collaborators into clinical research. She was the lead author of a recently published article in JAMA examining racial disparities among breast cancer subtypes. She is the principal investigator (P.I.) of several clinical trials, including a multicenter inter-SPORE (Specialized Program of Research Excellence, National Cancer Institute [NCI]) Phase II study of targeted therapy in metastatic basal-like breast cancer (a subtype identified by gene expression array). This heavily funded trial includes both clinical and laboratory participation from UCSF, Dana Farber, Duke University, Georgetown, Johns Hopkins, Baylor, Washington University, University of Alabama-Birmingham, Mayo, and M.D. Anderson Cancer Center, and is a testament to her ability to provide clinical leadership in translational and early clinical research.

Dr. Carey is the P.I. of a recently published multicenter Phase II study incorporating biologic therapy into chemotherapy for locally advanced breast cancer as well as a proposed cooperative group neoadjuvant trial examining several HER2-targeted strategies for Stage II-III HER2-positive breast cancer. She is the clinical liaison for several correlative science collaborations, including both institutional and cooperative group trials that correlate nucleic acid and protein characterization of breast cancers with response to neoadjuvant therapy.

Dr. Carey has served on the American Society of Clinical Oncology (ASCO) Scientific Program Committee and as faculty for the ASCO annual meeting for several years. She was named to the Cancer and Leukemia Group B (CALGB) Breast Core Committee in 2003. She was awarded a Doris Duke Clinician Scientist Award in 1999 and a Career Development Award from the NCI in 2000.