Biomarker-Driven Targeted Therapy for Late-Recurring ER-Positive Breast Cancer
Abstract
Estrogen-receptor positive (ER+) breast cancer is both the most common type of breast cancer and the most common cause of breast cancer mortality. While most women with ER+ breast cancer do well, a substantial number are subsequently diagnosed with recurrence at a distant site such as the lung, brain, liver, or bone, with the majority of recurrences and deaths occurring more than 5 years after diagnosis. After distant recurrence, breast cancer is not curable with current treatment approaches, though therapy can palliate symptoms and prolong survival. Preventing and treating metastasis in ER+ breast cancer therefore remains a major unmet medical need. One interesting and novel approach to addressing this need comes from the field of tumor genomics, where the DNA and RNA of cancer cells is studied to understand how they differ from normal tissue and from other tumors. Our team led the analysis of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), collecting the genomic information and clinical follow-up of nearly 2000 breast tumors. This work suggested that breast cancer can be classified into a series of integrative subtypes, or clusters. Several of these integrative subtypes are specific for ER+ breast cancers, and some predict a high risk of relapse despite thorough and appropriate primary therapy. A deeper look at these aggressive integrative subtypes suggests that they are characterized by specific patterns of genomic changes and that these patterns can be measured in primary breast cancer biopsies. Why may this observation prove important for breast cancer patients? The answer is that the specific genomic changes that appear to drive these dangerous subtypes may be treatable with new drugs that are currently in development. These new drugs have not yet been shown to benefit breast cancer patients, but they have passed the hurdle of initial safety testing and dose-finding studies. We propose to test newly diagnosed tumors to identify early-stage breast cancer patients whose tumors harbor the dangerous genomic changes and to treat those patients with the new targeted agents in what is called a “window of opportunity” trial. In a “window of opportunity” trial, patients receive the new drug during the few weeks in between when they are first diagnosed with cancer by biopsy and when they undergo surgery to remove the tumor. The effect of the new targeted agent on the patient’s disease is then measured, looking specifically at whether the targeted therapy is slowing down cancer cell growth. If it does in a substantial number of patients’ cancers, then the agent is worthy of being tested in larger trials where outcomes such as tumor shrinkage or disease-free survival can be determined. The investigators are a “dream team” composed of respected and productive laboratory and clinical researchers with long track records of conducting important clinical and translational trials. The proposal combines cutting-edge genomic research with an innovative clinical trial to target novel agents to high-risk ER+ breast cancer patients who are in need of more effective treatments. The ultimate goal is to reduce breast cancer mortality by preventing lethal metastasis in patients with aggressive ER+ disease. We consider this an exciting prospect.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910740
Entities
People
- George Sledge
Organizations
- Stanford University
- United States Army