Subclonal Hypermutation as a Driver of Therapy Resistance in HER2+/ER+ Breast Cancer
Abstract
Breast cancers are classified by presence of two distinct proteins: HER2 and estrogen receptor (ER). If a tumor has a single receptor, drugs that turn it off can be quite effective. However, each year ~32,000 people in the U.S. develop a breast tumor that has both HER2 and ER. In early or locally advanced (but operable) breast cancer, our standard of care is to use drugs that target HER2 before surgery. However, “double HER2/ER-positive” tumors respond poorly to pre-surgical (neoadjuvant) HER2-targeted treatment, and combining this with ER-targeted treatment does not improve neoadjuvant treatment outcome. Many metastatic HER2+/ER+ breast cancers are treated with endocrine therapy (ER-targeted treatment) alone, but laboratory studies show that this can reactivate HER2 and make the cancer worse. In these laboratory studies, long-term combined treatment with HER2- and ER-targeted therapy was better at restraining these tumors, but extended combination therapy has, to date, not been successful in eliminating the mortality of metastatic HER2+/ER+ breast cancer. Personalized treatment based on the individual molecular characteristics of each cancer – called precision medicine – is not new. Today’s precision medicine is reactive, tailoring therapy to average, static breast tumor properties, treating with the best therapy for this average state until recurrence. Upon recurrence, this reactive process repeats with a new therapy. This cycle sometimes leads to patient survival benefit, but more often there is temporary tumor shrinkage followed by rapid regrowth or relapse, with net survival benefit measured in months. Our goal is to test a transformational new strategy we call dynamic precision medicine (DPM). Unlike the reactive process of current precision medicine, DPM is innovative because it is proactive, thinking ahead like an expert chess player. DPM does not simply target the majority of the cancer cells within the breast tumor. Instead, it considers that not all the cells within a single tumor are the same, and that they are all constantly changing and evolving. Using high-resolution genetic data and mathematical modeling, DPM weighs two essential goals of breast cancer treatment – eliminating the bulk, visible tumor(s) and preventing the development of resistance to available drugs – with the goal of achieving longer overall survival. This proposal is designed to address two Overarching Challenges for the specific benefit of individuals with HER2+/ER+ breast cancer: identify what drives breast cancer growth, and determine how to stop it; and eliminate the mortality associated with metastatic breast cancer. We suggest that HER2+/ER+ tumors have a subpopulation of “hypermutator cells” that mutate quickly and rapidly evolve therapy resistance. We propose that these error-prone hypermutator cells are responsible for poor response to treatment, and that we can use dynamic precision medicine (DPM) to selectively eliminate these cells before they develop resistance and more effectively treat individuals with HER2+/ER+ breast cancer. This hypothesis is supported by the fact that single positive tumors that express HER2, or those that express ER and are not responsive to treatment, are already known to have more mutations in their DNA, and struggle to correct these errors. Using advanced DNA sequencing technologies, we show there are many more mutations in laboratory grown HER2+/ER+ breast cancer cells resistant to treatment. We then developed a visual method to find and follow hypermutator cells in real time, an important advance that will allow us to test DPM’s ability to improve outcomes for individuals with HER2+/ER+ breast cancer. Our proposal aims are to (1) directly test how hypermutator cells impair response to HER2- and ER-targeted therapy, and develop a model for DPM in HER2+/ER+ breast cancer and (2) test whether we can follow the hypermutator cells in whole HER2+/ER+ tumors and circulating tumor c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010759
Entities
People
- Rebecca B Riggins
Organizations
- Georgetown University
- United States Army