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.
Bibliographical noteFunding Information:
We thank research advocates Susie Brain, Diane Heditsian, and Vivian Lee for helpful discussions. We gratefully acknowledge the TRACERx Consortium and Cancer Research Technology Limited for making genomic data available. This research was funded by the National Cancer Institute at the National Institutes of Health (R01CA182514 to C. Curtis) and Susan G. Komen (IIR13260750 to C. Curtis and PDR17481769 to J.L.C.-J.). C. Curtis is also supported by a Breast Cancer Research Foundation award. J.L.C.-J. is supported by a Damon Runyon Physician Scientist Training Award and a Stanford Cancer Institute Fellowship Award. J.G.R. is supported by an Erwin Schrödinger Fellowship (Austrian Science Fund FWF J-3996). Z.H. is supported by an Innovative Genomics Initiative Postdoctoral Fellowship. J.L. is supported in part by a National Institutes of Health grant P30CA014089. M.F.P. is supported by grants from the Breast Cancer Research Foundation and Tower Cancer Research Foundation. The acquisition of some of the samples was funded by the Department of Defense (W81XWH-10-BCRP-IDEA to D.T.).
Competing interests: J.L. reports research funds from ANGLE Parsortix and is a member of the speaker bureau of Genomic Health. M.F.P. holds consulting or advisory role with honoraria at Karyopharm Therapeutics, Puma Biotechnology, Biocartis, Eli Lilly & Company, Novartis Pharmaceuticals, F. Hoffmann La-Roche Ltd. C. Caldas is a Scientific Advisor to Astrazeneca-iMed and has received research funding from Astrazeneca, Servier, Genentech/Roche. M.F.P. has received research grants to his institution from: Cepheid, Eli Lilly & Company, Novartis Pharmaceuticals, F. Hoffmann La-Roche Ltd. C. Curtis is a Scientific Advisory Board member and shareholder of GRAIL and consultant for GRAIL and Genentech. The remaining authors declare no competing interests.
© 2019, The Author(s).