D. Craig Allred, MD

2012-2013 BCRF Projects:

1) (made possible by Nestlé Waters North America, Inc.)

The majority of invasive breast cancers evolve from non-invasive precursors referred to as ductal carcinoma in situ (DCIS). This change from increasingly abnormal premalignant cells takes place over many years, decades in most cases. Dr. Allred's research, supported by BCRF, focuses on understanding the development and progression of premalignant cells to cancer for the purpose of developing new strategies for breast cancer prevention.

In the short run, Dr. Allred and his team are trying to understand how some normal breast epithelial cells grow into microscopic tumors called hyperplasias, which are the earliest identifiable precursor of breast cancer. To accomplish this, the scientists are evaluating the ability of normal cells to repair DNA damage caused by our everyday environment. Unless this damage is repaired, it results in mutations that promote the development of breast cancer. The researchers are also evaluating how stem cells in the breast become altered to grow and mature into cancer precursor cells rather than normal cells.

For the longer term, Dr. Allred's team has recently discovered several genes that regulate the progression of highly abnormal but still non-invasive premalignant cells into invasive and potentially lethal cancer cells. Understanding these mechanisms will, hopefully, lead to new and better strategies for detecting, treating, and even preventing the development of premalignant cells before they become cancerous.

2) (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; 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.

Bio:
Dr. Allred is a Professor in the Department of Pathology and Immunology at Washington University School of Medicine. He is a practicing pathologist and authority on the diagnosis of breast diseases. His research focuses on understanding genetic alterations responsible for the development and progression of premalignant lesions to breast cancer - for the purpose of developing molecular strategies for breast cancer prevention. With support from BCRF, Dr. Allred has made important contributions to our understanding of precursors of breast cancer. His current research focuses on genetic alterations involved in the life-threatening transition of non-invasive to invasive breast cancer.