Cynthia X. Ma, MD, PhD
Associate Professor, Medicine
Division of Oncology
Section of Medical Oncology
Washington University School of Medicine
St. Louis, Missouri
2013-2014 BCRF Project:
Co-Investigator: Matthew J. Ellis, MD, PhD Washington University 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.