Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy

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 and Christina Curtis ()
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Jennifer L. Caswell-Jin: Stanford University School of Medicine
Katherine McNamara: Stanford University School of Medicine
Johannes G. Reiter: Stanford University School of Medicine
Ruping Sun: Stanford University School of Medicine
Zheng Hu: Stanford University School of Medicine
Zhicheng Ma: Stanford University School of Medicine
Jie Ding: Stanford University School of Medicine
Carlos J. Suarez: Stanford University School of Medicine
Susanne Tilk: Stanford University
Akshara Raghavendra: The University of Texas MD Anderson Cancer Center
Victoria Forte: Maimonides Medical Center
Suet-Feung Chin: University of Cambridge
Helen Bardwell: University of Cambridge
Elena Provenzano: Cambridge University Hospitals NHS Foundation Trust
Carlos Caldas: University of Cambridge
Julie Lang: Norris Comprehensive Cancer Center
Robert West: Stanford University School of Medicine
Debu Tripathy: The University of Texas MD Anderson Cancer Center
Michael F. Press: Norris Comprehensive Cancer Center
Christina Curtis: Stanford University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08593-4

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