Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy
Year: 2019
Type: article
Abstract: Genomic changes observed across treatment may result from either clonal evolution or geographically disparate sampling of heterogeneous tumors. Here we use computational modeling based on analysis of fifteen primary breast tumors and find that apparent clonal change between two tumor samples can frequently be explained by pre-treatment heterogeneity, such that at least two regions are necessary to detect treatment-induced clonal shifts. To assess for clonal replacement, we devise a summary statistic based on whole-exome sequencing of a pre-treatment biopsy and multi-region sampling of the post-treatment surgical specimen and apply this measure to five breast tumors treated with neoadjuvant HER2-targeted therapy. Two tumors underwent clonal replacement with treatment, and mathematical modeling indicates these two tumors had resistant subclones prior to treatment and rates of resistance-related genomic changes that were substantially larger than previous estimates. Our results provide a needed framework to incorporate primary tumor heterogeneity in investigating the evolution of resistance.
Source: Nature Communications
Authors: Jennifer L. Caswell-Jin, Katherine McNamara, Johannes G. Reiter, Ruping Sun, Zheng Hu, Zhicheng Ma, Jie Ding, Carlos J. Suarez, Susanne Tilk, Akshara Raghavendra, Victoria Forte, Suet-Feung Chin, Helen Bardwell, Elena Provenzano, Carlos Caldas, Julie Lang, Robert West, Debu Tripathy, Michael F. Press, Christina Curtis
Institutions: Stanford Medicine, Stanford University, Stanford Cancer Institute, The University of Texas MD Anderson Cancer Center, Maimonides Medical Center, USC Norris Comprehensive Cancer Center, University of Cambridge, Cancer Research UK, Cambridge University Hospitals NHS Foundation Trust, NIHR Cambridge Biomedical Research Centre, University of Southern California
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: U.S. Department of Defense, Breast Cancer Research Foundation, Damon Runyon Cancer Research Foundation, Tower Cancer Research Foundation, Cancer Research UK, National Institute for Health and Care Research, Austrian Science Fund, Cambridge University Hospitals, National Institutes of Health, National Cancer Institute, Stanford Cancer Institute
Awards: G111615301, Integrated genomic analysis and multi-scale modeling of therapeutic resistance, G225866562, Evolutionary dynamics of metastatic cancers, NIHR Senior Investigator Award, NIHR Senior Investigator Award, G3713257798, G4119534169, G5850682332, G7218465289, G736146644, G8209230444, University of Southern California Norris Comprehensive Cancer Center Support Grant (CCSG)
OpenAlex ID: W2914039047