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.
2013-2014 BCRF Project:
1) On behalf of Alliance for Clinical Trials in Oncology, formerly American College of Surgeons Oncology Group
Co-Investigators: Cynthia Ma, MD, PhD, Washington University in St. Louis School of Medicine, St. Louis, MO
BCRF has provided critical support for the development of neoadjuvant endocrine therapy for women with larger estrogen receptor-positive and HER2-negative (ER+, HER2-) breast cancers. This type of breast cancer presents as a lump in the breast because mammography has failed to detect the tumor earlier because of marked mammographic density or because the growth pattern of the tumor is difficult to detect with a mammogram (lobular carcinoma). These patients were often treated with a mastectomy, however the Z1031 study, supported by BCRF, successfully demonstrated that 16 to 18 weeks of treatment with an estrogen-lowering agent can reduce the mastectomy rate by 50%. The treatment of a patient with an aromatase inhibitor before surgery has another important benefit – an ability to assess the response of each tumor to treatment. This is a critical advantage for patient management because non-responsive patients can receive more intense therapy, and highly responsive patients can be treated with endocrine therapy alone. BCRF supported a pilot study whereby patients whose tumors showed evidence of resistance to treatment because a sample taken at two weeks showed growing cells had their treatment changed to chemotherapy. Of 35 patients treated this way, only two showed signs of adequate chemotherapy responsiveness. It is therefore critical to better understand these chemotherapy and endocrine therapy resistant tumors, and Dr. Ellis’s team has been deeply analyzing samples from responding and non-responding tumors to derive deep insights into the nature of the DNA changes that drive poor outcome. These investigations have recently been published and were remarkable in startling complexity of the breast cancer genome. However, Dr. Ellis and colleagues were clearly able to identify genes that are driving outcomes and they are now seeking to further understand the data by also sequencing RNA because this will help them decide which DNA changes are likely to be causal in causing endocrine therapy resistance and therefore represent critical drug targets.
The ALNERNATE trial (“ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment in postmenopausal women”) is a phase III neoadjuvant endocrine therapy with two primary objectives. The first primary objective is to prospectively validate that the achievement of the Modified Preoperative Endocrine Prognostic Index (PEPI) score of 0 in the neo-adjuvant (prior to surgery) setting predicts success in disease free survival. The second primary objective is to determine whether the experimental neoadjuvant endocrine treatment with either fulvestrant, or the combination of fulvestrant and anastrozole, is superior to the standard neoadjuvant treatment with anastrozole. The trial has a maximum sample size of 2,820 patients with a planned enrollment period of five to six years; it is anticipated that patients will enroll at the rate of 36 per month. BCRF will provide funding for biopsy kits and measurement of Ki67, a tumor marker which measures proliferation.
The goal of this BCRF funded research is to identify the underlying genomic structures of estrogen receptor positive breast cancer so that more effective treatment could be developed to prevent recurrence and to increase survival of patients. Another goal is to develop molecular tests that would predict whether a patient will do well with endocrine therapy alone so that chemotherapy could be avoided. Neoadjuvant endocrine therapy, endocrine therapy prior to surgery, allows us to follow tumor response and obtain tumor samples at various time points for molecular analysis. Using this approach, the researchers have conducted the ASCOG Z1031 trial which investigated three aromatase inhibitors in the neoadjuvant setting to correlate tumor response with genomic structures.The success of Z1031 trial led to the current ongoing phase III study entitled “ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment (ALTERNATE) in postmenopausal women: A Phase III Study” to validate and discover novel approaches that predict tumor responsiveness to endocrine therapy and to uncover novel therapeutic target for estrogen receptor positive breast cancer. This research has the promise to change the way estrogen receptor positive breast cancer is treated.
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.
NSABP has activated Discovery Protocol 1 ("DP-1"), and the researchers report that each of the five participating NSABP Member sites, of which all are major universities and health systems, have activated the study at their institutions. To date, Washington University has enrolled one patient. Study Marketing - DP-1 was presented at two meetings of NSABP investigators in Chicago (October) and San Antonio (December). Also, in keeping with plans to build awareness of this novel study at the site level, NSABP has worked closely with each site during its local activation to identify a surgeon and a nurse coordinator, whose responsibility it is to work as a team to identify DP-1 eligible patients at the sites, explain the protocol and consent the patient. In addition, the local study activation process on the NSABP Foundation website contains educational information geared to key study personnel at participating sites. The major focus for the remainder of BCRF support Year 2 is to enroll and collect specimens from as many of the 50 patient sample size as possible. The projection for Year 2 was to accrue between 3 and 7 patients, and this remains achievable. While the research team has made substantial progress in bringing this novel Discovery Protocol to its current state, each step along the way has presented special challenges in the timing of its completion. Currently, a meeting of PIs from participating sites is scheduled for late January to address patient enrollment. Further discussion is planned at the NRG Oncology meeting in February. The plan is now to focus on patient enrollment and to reassess project progress in the spring.
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.