Matthew J. Ellis, MD, PhD

1) On behalf of Cancer & Leukemia Group B
Made possible by generous support from Macy's
Co-Invesigators: Richard L. Schilsky, MD, Chairman, Cancer and Leukemia Group B, Chicago; Lisa A. Carey, MD, University of North Carolina at Chapel Hill; and William M. Sikov, MD, Brown University, Providence, RI

Over the past several years, with support from BCRF, Cancer and Leukemia Group B investigators have undertaken a series of large-scale clinical trials that are leading to important improvements in breast cancer therapies: One project is utilizing new technology to generate genetic profiles of breast cancer tumors and to identify which genetic markers are associated with response to paclitaxel chemotherapy. The identification of these markers may make it possible to predict which patients are most likely to respond to paclitaxel treatment. Another project is studying the unique biological characteristics of breast cancer that occurs in older women. This work is a companion to a recently completed clinical trial studying adjuvant chemotherapy in older women with breast cancer. Another project is 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.

In another CALGB project, genetic analysis of breast tumors is being used to determine which patients are most likely to benefit from use of paclitaxel as part of adjuvant chemotherapy. In another, biomarker and genetic analyses of breast tumors are being used to determine which patients are most likely to benefit from use of dose dense chemotherapy. And another 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 of the project is to develop markers to guide patient selection for future therapies targeting the epidermal growth factor receptor.

And two additional CALGB clinical trials, expected to activate in Fall 2007, deal with advances in the postoperative treatment of breast cancer which 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 led to an increasing need to conduct very large clinical trials in order to detect small benefits. In addition, it often takes years before results are available. 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.

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) 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 (Avastin or bevacizumab).

These studies represent a unique opportunity for the CALGB as its researchers will have the ability to see the effects of these treatments on tumors before surgery and they 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, store them until the clinical study is completed, distribute them to collaborating investigators, and perform studies on them. The results of this program will include an increased understanding of how available therapeutics kill cancer and improve treatment approaches. BCRF funds in the coming year will be used for the collection and storage of breast cancer biopsies obtained from patients enrolled in both studies.

Mid-Year Progress Report:
Dr. Schilsky reports that for the project utilizing new technology to generate genetic profiles of breast cancer tumors and to identify which genetic markers are associated with response to paclitaxel chemotherapy, CALGB anticipates that the gene expression data to be available in the next 3 months and primary data analysis to be completed within 6 months. For the project studying the unique biological characteristics of breast cancer that occurs in older women, the researchers report that a total of 633 patients enrolled in the clinical trial and 588 patients registered to the correlative science component. All tissue analysis for IHC has been completed, and CALGB researchers are in the process of data transfer and cleaning up in preparation for analysis. They expect to submit an abstract to the 2008 ASCO Breast Cancer Symposium.

For the BCRF-supported Correlative Studies in Neoadjuvant Trials for Locally Advanced Breast Cancer, magnetic resonance imaging (MRI) and spectroscopy (MRS) and various molecular markers are being evaluated as predictors of clinical response in women receiving chemotherapy and radiation. In another BCRF-funded project, genetic analysis of breast tumors is being used to determine which patients are most likely to benefit from use of paclitaxel as part of adjuvant chemotherapy. In another, biomarker and genetic analyses of breast tumors are being used to determine which patients are most likely to benefit from use of dose dense chemotherapy. Another CALBG project aims to 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 study was activated in September 2006. In the two trials (1) comparing Herceptin versus Tykerb, and 2) testing Avastin, the trial concepts have been approved by NCI and protocols are being finalized with activation anticipated in early 2008.

2) On behalf of the American College of Surgeons Oncology Group
Co-Investigators: Kelly K. Hunt, MD, University of Texas MD Anderson Cancer Center, Houston, TX; Joseph R. Nevins, PhD, Duke University, Durham, NC, and John A. Olson, Jr., MD, PhD, Duke University, Durham, NC

Postmenopausal women with strongly ER positive stage 2 and 3 breast cancer who are at risk for a mastectomy are candidates for preoperative endocrine therapy to down stage the tumor and improve surgical outcomes. This practice is supported by randomized clinical trials that show an increased chance of breast conservation when aromatase inhibitors were utilized in this indication in comparison with tamoxifen.

In this project, the ACOSOG researchers will use tumor samples from ongoing ACOSOG clinical trial Z1031 to address why estrogen receptor positive breast cancers are not universally responsive to this approach. Specifically, they will asks if large gains in DNA segments in tumor cells called "amplicons" are associated with treatment resistance. This information will not only define which patients are suitable for preoperative endocrine therapy, but will aid in the identification of genes that are responsible for treatment failure. This may lead to the development of new treatments that increase the effectiveness of endocrine therapy through the application of targeted pharmacological agents.

Mid-Year Progress Report:
In late January, Dr. Ellis reported that analysis of ACOSOG Z1031samples has been initiated to provide an even larger number of specimens for biomarker research. Z1031 is a phase III clinical trial which is actively enrolling patients to evaluate the efficacy of neoadjuvant aromatase inhibitor (AI) for locally advanced ER + breast cancer in postmenopausal women. The trial was activated in January 2006 with a target accrual goal of 375 patients. The monthly accrual rate is meeting the targeted accrual rate and as of January 29th, 2008, 189 patients have been accrued and 116 have completed surgery. There are 252 approved sites and at the current rate of enrollment, this trial is estimated to close in June 2009. The ACOSOG researchers have now completed expression array analysis on the first 50 baseline samples and 19 post-treatment specimens. By June, they expect to have processed approximately 100 cases for DNA and RNA and to have completed analysis on over 60.

Bio:
Originally from the United Kingdom, Matthew Ellis completed his initial medical training in the U.K. at the Universities of Cambridge and London before coming to the United States in 1991 as a Medical Research Council of Great Britain Traveling Fellow at the Lombardi Cancer Research Center at Georgetown University. He stayed at Georgetown until 2000, at which time he was Assistant Professor of Medicine in the Division of Hematology/Oncology. In 2000, he became Director of the Duke University Breast Cancer Program and Associate Professor in the Department of Medicine.

Dr. Ellis's research has focused on the use of aromatase inhibitors and targeted therapy in treating breast cancer. He is a member of the Cancer and Leukemia Group B (CALGB) Breast Cancer Committee and Chairman of the Working Group for Correlative Science in Breast Cancer.