Cynthia Ma, MD, PhD

2012-2013 BCRF Project:
(made possible by Genentech)

On behalf of Alliance for Clinical Trials in Oncology, formerly American College of Surgeons Oncology Group

Co-Investigators: Matthew J. Ellis, MD, PhD, Washington University in St. Louis School of Medicine, St. Louis, MO; 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; 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.