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

被引：40

作者：

Caswell-Jin, Jennifer L. ^{[1
,3
]}

McNamara, Katherine ^{[1
,2
,3
]}

Reiter, Johannes G. ^{[4
]}

Sun, Ruping ^{[1
,2
,3
]}

Hu, Zheng ^{[1
,2
,3
]}

Ma, Zhicheng ^{[1
,2
,3
]}

Ding, Jie ^{[1
,2
,3
]}

Suarez, Carlos J. ^{[5
]}

Tilk, Susanne ^{[6
]}

Raghavendra, Akshara ^{[7
]}

Forte, Victoria ^{[8
,9
]}

Chin, Suet-Feung ^{[10
]}

Bardwell, Helen ^{[10
]}

Provenzano, Elena ^{[11
,12
]}

Caldas, Carlos ^{[10
]}

Lang, Julie ^{[9
,13
]}

West, Robert ^{[5
]}

Tripathy, Debu ^{[7
]}

Press, Michael F. ^{[9
,14
]}

Curtis, Christina ^{[1
,2
,3
]}

机构：

[1] Stanford Univ, Dept Med, Sch Med, Div Oncol, Stanford, CA 94305 USA

[2] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA

[3] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA

[4] Stanford Univ, Sch Med, Dept Radiol, Canary Ctr Canc Early Detect, Stanford, CA 94305 USA

[5] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA

[6] Stanford Univ, Dept Biol, Stanford, CA 94305 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA

[8] Maimonides Hosp, Brooklyn, NY 11219 USA

[9] Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA

[10] Univ Cambridge, Dept Oncol, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England

[11] Cambridge Univ Hosp NHS Fdn Trust, Cambridge Expt Canc Med Ctr, Cambridge CB2 0QQ, England

[12] Cambridge Univ Hosp NHS Fdn Trust, NIHR Cambridge Biomed Res Ctr, Cambridge CB2 0QQ, England

[13] Univ Southern Calif, Keck Sch Med, Dept Surg, Los Angeles, CA 90333 USA

[14] Univ Southern Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

美国国家卫生研究院; 奥地利科学基金会;

关键词：

WHOLE-GENOME; MUTATIONAL PROCESSES; RESIDUAL DISEASE; CANCER; CHEMOTHERAPY; REVEALS; EVOLUTION; ARCHITECTURE; POPULATIONS; BIOMARKERS;

D O I：

10.1038/s41467-019-08593-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

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