A New Paradigm for De-Escalation of Treatment in HER2-Positive Breast Cancer: Revolutionizing Care with More Effective and Less Toxic Therapy
Abstract
HER2 is a protein with high expression in 15%-20% of breast cancer because of an abnormal increase in the number of its gene copies. HER2 is a strong driver of tumor cell growth and invasion, a process called "oncogene addiction." Several treatments that target HER2 have been developed and have made a remarkable difference in improving the outcomes for women with this kind of cancer. However, these anti-HER2 agents are usually combined with chemotherapy, which has distressing and potentially serious toxicity as well as significant cost. Our group has been developing treatments for this group of patients without chemotherapy. We studied this concept in the lab first and then confirmed the concept in two multicenter clinical trials in women with newly diagnosed curable HER2-positive breast cancer. We and others reported that about 20%-30% of women with HER2-positive breast cancer have complete tumor disappearance (pathologic complete response) using two anti-HER2 agents (dual anti-HER2 therapy), without chemotherapy. This means these women may be spared chemotherapy. The main question remaining is how to identify these women upfront. Our group and others identified important factors that relate to resistance to dual anti-HER2 therapy, like the PI3K pathway, the degree of dependence on HER2 (degree of oncogene addiction), and interaction with the immune system. However, no one has attempted yet to come up with a way to test tumors upfront and decide who needs chemotherapy and who can be spared its toxicity and cost. Based upon direct input from our consumer advocates, we decided to tackle this issue. The overarching challenge we are addressing is to "Revolutionize treatment regimens by replacing them with ones that are more effective and less toxic." We have assembled a unique research team with strong collaborations and hypothesize that we can test tumors and predict upfront whether they need chemotherapy or not. To carry out this research, we have secured access to tumors samples from two clinical trials and have coordinated efforts with a third. All patients on these trials were treated with dual anti-HER2 therapy without chemotherapy. Therefore, all of our analyses on these tissues will be potentially more accurate since we don t have to account for the effect of chemotherapy. After assembling the test to predict need for treatment (a molecular classifier), we will then design and activate a clinical trial to test the concept that this classifier will be able to identify patients who don t need chemotherapy and treat them with dual anti-HER2 therapy, while giving others the chemotherapy they need. To improve our understanding of how tumors develop resistance, we will also study pairs of tumor samples before and after HER2-targeted treatment from our trials and identify new mechanisms of resistance. Our goal is to have our research findings directly impact patient care within the next 5-7 years and to improve our understanding of breast cancer to better tailor its therapy for each individual patient.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710579
Entities
People
- Mothaffar F Rimawi
Organizations
- Baylor College of Medicine
- United States Army