Quantifying tumor evolutionary dynamics and predictors of response in HER2-positive breast cancer treated with targeted therapy
Abstract/Contents
- Abstract
- Evolution during treatment is a significant clinical problem that leads to treatment failure, resistance, and disease progression in many solid tumors, including breast cancer. Through analysis of clinical tissue samples and using a combination of established genomic techniques, computational modeling, and novel molecular profiling methods, this dissertation explores how HER2-positive breast tumors evolve under systemic therapy and characterizes predictors of treatment response. First using multi-region genomic sequencing and computational modeling, we show that the mutational landscape of a tumor can shift dramatically over a few months of combination chemotherapy and HER2-targeted therapy (termed "clonal replacement"). We then utilized tissue from a neoadjuvant HER2-positive breast cancer clinical trial to explore tumor-associated and immune-associated predictors of treatment response. We demonstrate the utility of spatial proteomic analysis of on-treatment biopsies to define biomarkers that stratify sensitive tumors early during neoadjuvant HER2-targeted therapy with implications for tailoring subsequent therapy. Taken together, our results shed light on the roles of heterogeneity, the frequency of resistance-causing aberrations, and the immune microenvironment in response to HER2-targeted therapy. In addition, our results also provide insights into the design of clinical trials that have a molecular analysis component
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | McNamara, Katherine Lee |
|---|---|
| Degree supervisor | Curtis, Christina |
| Thesis advisor | Curtis, Christina |
| Thesis advisor | Altman, Russ |
| Thesis advisor | Petrov, Dmitri Alex, 1969- |
| Thesis advisor | Sage, Julien |
| Thesis advisor | West, Robert |
| Degree committee member | Altman, Russ |
| Degree committee member | Petrov, Dmitri Alex, 1969- |
| Degree committee member | Sage, Julien |
| Degree committee member | West, Robert |
| Associated with | Stanford University, Cancer Biology Program. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Katherine Lee McNamara |
|---|---|
| Note | Submitted to the Cancer Biology Program |
| Thesis | Thesis Ph.D. Stanford University 2020 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Katherine Lee McNamara
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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