Matthew J. Ellis, MD, PhD

1) On behalf of Cancer & Leukemia Group B
(made possible by generous support from Genentech)
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

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.

2) On behalf of the American College of Surgeons Oncology Group
Co-Investigators: Karla Ballman, PhD,, Mayo Clinic, Rochester, MN; Kelly K. Hunt, MD, University of Texas MD Anderson Cancer Center, Houston, TX; 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 are using 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 are asking 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. The monthly accrual rate is on target and the trial is estimated to close in summer 2009. The trial continues to provide the availability of pre and post endocrine treatment tissue samples that will allow valuable new insights into the biological basis for the success and failure of endocrine therapy.

Mid-year Progress Report:
The primary objective of the ACOSOG-Z1031 trial is to compare the response rate by clinical examination between three FDA-approved aromatase inhibitors: letrozole, anastrozole and exemestane before surgery in postmenopausal women with clinical stage 2 and 3 ER rich breast cancer.

While clinical response has been used to power most neoadjuvant endocrine therapy trials to date, response by palpation is a problematic primary endpoint that does not provide a very accurate or centrally verifiable assessment of tumor size. Preliminary data from an NCI-funded multicenter Avon/NCI/R01 funded Phase 2 trial of neoadjuvant letrozole led by Dr. Ellis, has shown that image analyses of either digital or digitized mammograms (film mammography scanned by computer), were feasible and robust, providing centrally verifiable and blinded information on the degree of tumor response within the breast.

Since these films are already collected as part of the standard of care, and therefore the data can be made available at minimal cost to the research budget, this proposal supports the validation of digital mammogram response (DMR) measurements, as a novel and robust indicator of tumor response. Patient accrual has now reached over 80% of the target goal with 304 patients enrolled to date at 49 sites and is anticipated to close in September 2009. Specimen acquisition is also going according to plan.

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. After 3 years with Duke University, Dr. Ellis took over as the Head of Medical Oncology at Washington University in St. Louis where he is currently a Tenured Professor of Medicine and Director of the Breast Cancer Program at Siteman Cancer Center.

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.