Elaine Mardis, PhD
Co-Director, Genome Center
2011-2012 BCRF Project:
On behalf of the Alliance for Clinical Trials in Oncology
Associate Professor of Genetics
Washington University School of Medicine
St. Louis, Missouri
Co-Investigators: Matthew J. Ellis, MD, PhD Washington University School of Medicine, St. Louis, MO; D. Craig Allred, MD Washington University School of Medicine, St. Louis, MO; Kelly K. Hunt, MD, FACS, University of Texas MD Anderson Cancer Center, Houston, TX; John A. Olson, Jr., MD, PhD, Duke University, Durham, NC; and David Ota, MD, Duke University, Durham, NC
In 2004, Dr. Matthew Ellis engaged the American College of Surgeons Oncology Group (ACOSOG) and the Cancer Treatment Evaluation Program at 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 growth of estrogen receptor positive breast cancer is fueled by estrogen; aromatase inhibitors work by blocking the enzyme aromatase, which turns the hormone androgen into small amounts of estrogen in the body. This means that less estrogen is available to stimulate the growth of ER+ breast cancer cells.
The Z1031 trial, activated from April 2006 to August 2009, is a randomized open label comparison between the three FDA approved aromatase inhibitors (letrozole, anastrozole, and exemestane. The trial enrolled 377 postmenopausal women with clinical stage II or III ER+ breast cancer. Analysis of these volunteers suggested dramatic improvements in their surgical outcomes from applying aromatase inhibitors before surgery; after 16 to 18 weeks of aromatase inhibitor treatment, 51% only eligible for mastectomy at baseline were able to undergo successful breast conserving surgery.
To further test the value of this regimen, Dr. Ellis's team activated an amendment (A6) to include an additional patient cohort (Z1031-Cohort B) to test a simple biopsy-based test taken at two weeks (Ki67) to identify patients whose tumor cells maybe resistant to aromatase inhibitor therapy. These patients were then switched to chemotherapy to ascertain the effectiveness. This initiative aims to be able to spare patients of unnecessary treatments if it can be determined through a biopsy whether or not aromatase inhibitors will work for that person. As of June this year, 200 patients have been accrued to Cohort B. Accrual to Cohort B is on schedule and due to close in early fall 2011.
Mid-year Progress: Tumor biomarker profiling to identify patients with endocrine therapy resistant disease is a major priority for the research led by Dr. Ellis and his team of collaborators. By designing a prospective validation trial that utilizes their early "on-endocrine treatment" evaluation using a CLIA Ki67 proliferation index to tailor systemic therapy for ER+ breast cancer in postmenopausal women, there is significant potential to rapidly change the standard of care for patients with ER+ disease. Dr. Ellis's team has completed accrual to Cohort B of the trial with 245 patients accrued and 35 triaged to chemotherapy. All patients are offered the option to participate in genome consent. Large scale sequencing projects are now illuminating, on a genome wide scale, the underlying genetic mechanisms that determine why tumors do not always respond to aromatase inhibitor therapy. This will lead to improved prognostic models and new avenues for the treatment of resistant disease.