Targeting HER2-Activating Mutations in ER-Positive, Metastatic Breast Cancer
Abstract
Background: Human epidermal growth factor receptor 2 (HER2) is a cell surface receptor that is overexpressed in about 20% of breast cancers as a result of gene amplification. Drugs that target or inhibit HER2 signaling have dramatically improved the survival rate of patients with HER2-amplified breast cancer. However, the majority of breast cancers are negative for HER2 gene amplification and as a whole do not benefit from HER2-directed drugs. Recent genomic sequencing studies identified HER2 mutations (HER2mut) in HER2 non-amplified breast cancers, and further studies in our laboratory indicated that HER2mut renders cancer cells sensitive to the HER inhibitor neratinib. In our recently reported Phase II trial of neratinib in patients with HER2mut non-amplified metastatic breast cancer (MBC) (MutHER trial), 31% (5 of 16) patients achieved positive therapeutic benefit, including 1 complete response, 1 partial response, and 3 with stable disease lasting over 24 weeks. In addition, a 70-gene next-generation sequencing analysis of circulating tumor DNA (ctDNA) obtained from the blood was found to be highly accurate in detecting HER2mut and that the dynamic changes in the ctDNA HER2mut mutation fraction, after as short as 4 weeks on therapy, could serve as an early indicator of tumor response. This trial provides the first evidence that neratinib, a HER2-directed drug, could be effective for HER2mut non-amplified MBC. However, further studies are needed to improve therapeutic efficacy, increase survival, and identify causes of resistance. In analyzing other mutations in HER2mut breast cancer, we found that mutations in the TP53 and PIK3CA genes are often associated with treatment resistance, while mutations in the CDH1 gene are associated with sensitivity to neratinib therapy. We also noted that the majority of HER2mut breast cancers are estrogen receptor positive (ER+) and that the combination of fulvestrant, a selective estrogen receptor downregulator, and neratinib is more effective than either drug alone in ER+, HER2mut breast cancer cell lines. We hypothesize that targeting ER and pathways associated with resistance (including PI3K and CDK4/6) could improve neratinib effectiveness in ER+ HER2mut patients. In addition, ctDNA analysis and tumor mutation profiles may predict tumor response. In Aim 1, we will conduct a Phase II clinical trial of neratinib plus fulvestrant in ER+, HER2mut MBC to assess the clinical activity of this combination in two groups of patients: one cohort that has not received fulvestrant, and one cohort who has previously received fulvestrant. In addition, ctDNA and tumor specimens will be collected and subjected to genomic analysis to identify predictors of response and mechanisms of resistance. Aim 2 will conduct a co-clinical trial in the laboratory using HER2mut patient-derived xenograft mouse models (PDXs) and novel, HER2mut genetically altered mice to determine the effect of drug combinations containing neratinib. Inhibitors of the PI3K andCDK4/6 pathways, as well as fulvestrant and trastuzumab, will be tested alone and in combination with neratinib in these mouse models. These studies will provide the rationale for future clinical trials. Aim 3 will use sophisticated protein and genomic analysis of tumors from HER2mut PDX models that developed resistance to neratinib to uncover underlying growth signaling abnormalities. These studies will generate additional insights into the biology of HER2mut breast cancer to support the design of targeted approaches that overcome patient tumor resistance to neratinib. This application addresses the following Overarching Challenges: (1) Identify what drives breast cancer growth; determine how to stop it. (2) Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and improve survival. Impact: The results of this research will lead to better treatments for patients with HER2mut MBC, a populat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810084
Entities
People
- Ron Bose
Organizations
- United States Army
- Washington University in St. Louis