Matthew J. Ellis, MD, PhD
Director, Breast Cancer Program
Anheuser Busch Tenured Professor of Medicine
Washington University in St. Louis
St. Louis, Missouri
Reporting in April 2011, Dr. Ellis and colleagues have sequenced the whole genomes of tumors from 50 breast cancer patients and compared them to the matched DNA of the same individuals' healthy cells. This study, conducted on behalf of the American College of Surgeons Oncology Group (ACOSOG), allows researchers to find mutations that only occurred in the cancer cells.
2012-2013 BCRF Project:
1) (made possible by Genentech)
On behalf of Alliance for Clinical Trials in Oncology, formerly American College of Surgeons Oncology Group
Co-Investigators: D. Craig Allred, MD, Washington University in St. Louis School of Medicine, St. Louis, MO; Kelly K. Hunt, MD , University of Texas MD Anderson Cancer Center, Houston, TX; Cynthia Ma, MD, PhD , Washington University in St. Louis School of Medicine, St. Louis, MO; and A. Marilyn Leitch, University of Texas Southwestern Medical Center, Dallas, TX
In 2004, Dr. Matthew Ellis engaged the American College of Surgeons Oncology Group (ACOSOG), now a part of the Alliance for Clinical Trials in Oncology, and the National Cancer Institute to conduct a trial of treating estrogen receptor positive (ER+) breast cancers with aromatase inhibitors before surgery (or the "neoadjuvant" setting). The resulting trial, called ACOSOG Z1031, was built around the observation that the growth of estrogen receptor positive breast cancer is fueled by estrogen. Aromatase inhibitors, a form of anti-estrogen therapy, work by blocking the enzyme aromatase, which turns the hormone androgen into small amounts of estrogen in the body and produces less estrogen to stimulate the growth of ER+ breast cancer cells.
With BCRF support, the ACOSOG Z1031 trial (cohort B) has completed accrual with 245 patients on study and 35 patients triaged to chemotherapy. All patients have completed therapy and a paper describing the results is planned for the second half of 2012. This trial has had a tremendous impact though the recent publication of a paper in Nature journal entitled "Whole genome analysis informs breast cancer response to aromatase inhibition." The results presented in this publication will accelerate the arrival of a comprehensive personalized approach to breast cancer treatment, with the promise of reduced toxicity and an increase in treatment effectiveness.
Dr. Ellis's team has also launched the ALTERNATE trial, the successor trial to Z1031, which will provide a definitive validation of the Preoperative Endocrine Prognostic Index, as means to spare patients chemotherapy, as well as an opportunity to develop a large validation sets for complex gene expression, gene copy and gene mutation based predictive models they are in the process of developing. This study will help lead to improved prognostic models and new avenues for the treatment of resistant disease.
Mid-year Progress: The ALTERNATE trial is designed to evaluate two primary objectives. The first objective is to examine whether patients with early stage, meaning no disease outside of the breast and the axillary lymph nodes, estrogen receptor positive (ER+) and HER2-negative breast cancer, who had a Modified Preoperative Prognostic Index (PEPI) score of 0 at the time of surgery following six months of endocrine therapy, have a low risk of recurrence in five years without the need of chemotherapy. The second objective is to compare the effectiveness of three different endocrine therapies in the likelihood of leading to a modified PEPI score of 0 when administered for six months prior to surgery, so that the most effective therapies could be studied further. These three different endocrine therapies include anastrozole, a standard drug for treatment of early stage cancer, and fulvestrant, which is a drug that decreases the amount of estrogen receptor (ER) in ER positive breast cancer, either as a single drug or in combination. Fulvestrant has been approved in patients with metastatic breast cancer, but not for early stage cancer.
This trial will help to determine whether fulvestrant could be a better therapy for early stage breast cancer. In addition, tumor biopsies are taken during therapy to check for Ki67, which marks cells that are going through cell proliferation, to determine whether the tumor is responding appropriately. If the tumor is not responding, patients will be switched to other alternative therapies, such as chemotherapy or surgery or other clinical trials. Modified PEPI score is calculated at the time of surgery. The calculation is based on the size of the tumor, whether there are any lymph nodes involved and whether the Ki-67 is high. The Modified PEPI score will help to decide whether a patient needs chemotherapy after surgery. An important aspect of this trial continues to be looking at what molecular factors predict a response or not to therapy and what mechanisms are involved, so that effective drugs could be developed. This trial has the potential to develop better treatments for patients with ER+ breast cancer and methods to determine the risk of recurrence and the need for treatments other than endocrine therapy. Since the start of this award, the researchers have been working on experiments in the laboratory to make sure that the assay that they are using to test for Ki-67 is accurate and reproducible. The results of these experiments are required by Food and Drug Administration and National Cancer Institute for the final approval of this trial. Dr. Ellis's team anticipates completion of these experiments before the end of this grant period so that the trial will be activated in year 2013.
2) On behalf of National Surgical Adjuvant Breast and Bowel Project
Co-Investigators: Samuel A. Jacobs, MD, University of Pittsburgh Cancer Institute, Pittsburgh, PA; and Norman Wolmark, MD, Drexel University School of Medicine, Philadelphia, PA
Technologies for unbiased discovery of the events underlying cancer are improving at a rapid pace. It is, therefore, critically important that scientists evolve their approaches to clinical investigation to match the demands and opportunities that the integrated studies of cancer DNA, RNA, and proteins - collectively referred to as "cancer 'omics" present.
The ready availability of tissue from patients receiving systemic treatment before surgery (neoadjuvant therapy) for breast cancer is of central importance to the 'omics field as serial sample acquisition can be reliably attempted before and after the initiation of therapy. Several National Cancer Institute Clinical Proteomic Tumor Analysis Consortium centers have, therefore, developed a collaboration with the National Surgical Adjuvant Breast and Bowel Project (NSABP) to determine the feasibility of conducting a deep proteogenomic analysis of samples from the phase II randomized clinical trial evaluating neoadjuvant chemotherapy regimens with weekly paclitaxel or eribulin followed by doxorubicin and cyclophosphamide in women with locally advanced HER2 negative breast cancer. The long-term objective of this study is to develop standard operating procedures that will allow integrated cancer 'omics from all neoadjuvant breast cancer protocols conducted by the NSABP, and indeed, by all cooperative groups.
Mid-year Progress: Mid-year Progress: This team has been busy completing pre-activation activities for their 50-patient pilot study, entitled, NSABP Discovery Protocol 1 ("DP-1"). To date, the contracting process has been completed and all the necessary agreements are in place. These agreements form the basis of the infrastructure necessary to support DP-1, including acollaboration between the NSABP, Washington University, and several National Cancer Institute U24 Clinical Proteomic Tumor Analysis Consortium (CPTAC) centers to determine the feasibility of conducting a deep proteogenomic analysis of samples from patients receiving neoadjuvant chemotherapy. Pre-study activities, which include clinical, regulatory, and logistical tasks, are 95% complete, and the group anticipates DP-1 being open to selected sites in early 2013.
The ready availability of tissue from patients receiving systemic treatment before surgery for breast cancer is of central importance to the "omics" field as serial sample acquisition can be reliably attempted before and after the initiation of therapy. The long-term objective of this study is to develop standard operating procedures that will allow integrated cancer "omics" from all neoadjuvant breast cancer protocols conducted by the NSABP, and indeed, by all cooperative groups. By October 2013, Dr. Ellis's team plans to enroll and collect specimens from as many of the 50 patient sample size as possible.
BCRF funding has been also been applied towards a second NSABP study led by grantee Patricia A. Ganz, MD (University of California, Los Angeles). Clinical trials focus primarily on the efficacy of a treatment -- does it prolong survival or disease-free survival? The final outcomes and interpretation of clinical trials are often enhanced through collection of patient reported outcomes (PROs) related to symptoms and quality of life that reflect the experience of the patients receiving the therapy, especially when one treatment arm is expected to be substantially more toxic than the other.
A second kind of outcome study, less frequently included in this setting, is a cost of care study; however, such research is equally important for the interpretation of how best to implement the results of clinical trials in breast cancer once a trial has been completed. As new targeted therapies demonstrate benefit in advanced metastatic breast cancer, they are being moved into the adjuvant treatment of breast cancer. These new agents bring substantial promise for higher cure rates when added to standard adjuvant therapy but can also add substantially to the cost of care. The increased cost of care includes the drug itself, which may be considerable, along with additional costs that can be incurred due to increased toxicities resulting in additional office visits, prescribed medications to manage toxicities, as well as increased hospitalizations. Collecting this type of data prospectively, during the conduct of the trial, is essential in order to assess the additional cost burden of administering a new agent. BCRF funds are allowing researchers to collect data on the extra costs incurred by women who receive the new agent everolimus (Affinitor®) in addition to standard endocrine adjuvant therapy, in a large randomized trial, to determine whether or not the benefits of therapy outweigh the costs. BCRF support will help with the development of the questionnaire to collect the cost data as well as modest support for the additional data collection by the clinical trials staff. The team has started working on amending the study protocol and development of the data collection questionnaire.
Read more about Dr. Ellis's work in The New York Times
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 interests include the identification of genes that affect responses and resistance to endocrine therapy in breast cancer patients. Dr. Ellis is co-principal investigator for the NCI-funded Proteome Characterization Center and co-project leader for The Cancer Genome Atlas (TCGA) Breast Project.