Characterizing Trastuzumab-Induced Alterations in Intratumoral Heterogeneity with Quantitative Imaging and Immunohistochemistry in HER2+ Breast Cancer

Anum K. Syed, Ryan Woodall, Jennifer G. Whisenant, Thomas Yankeelov, Anna G. Sorace

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Abstract

The purpose of this study is to investigate imaging and histology-based measurements of intratumoral heterogeneity to evaluate early treatment response to targeted therapy in a murine model of HER2+ breast cancer. BT474 tumor-bearing mice (N = 30) were treated with trastuzumab or saline and imaged longitudinally with either dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) or 18F-fluoromisonidazole (FMISO) positron emission tomography (PET). At the imaging study end point (day 4 for MRI or 7 for PET), each tumor was excised for immunohistochemistry analysis. Voxel-based histogram analysis was performed on imaging-derived parametric maps (i.e., Ktrans and ve from DCE-MRI, SUV from 18F-FMISO-PET) of the tumor region of interest to measure heterogeneity. Image processing and histogram analysis of whole tumor slice immunohistochemistry data were performed to validate the in vivo imaging findings. Trastuzumab-treated tumors had increased heterogeneity in quantitative imaging measures of cellularity (ve), with a mean Kolmogorov-Smirnov (K-S) distance of 0.32 (P = .05) between baseline and end point distributions. Trastuzumab-treated tumors had increased vascular heterogeneity (Ktrans) and decreased hypoxic heterogeneity (SUV), with a mean K-S distance of 0.42 (P < .01) and 0.46 (P = .047), respectively, between baseline and study end points. These observations were validated by whole-slice immunohistochemistry analysis with mean interquartile range of CD31 distributions of 1.72 for treated and 0.95 for control groups (P = .02). Quantitative longitudinal changes in tumor cellular and vascular heterogeneity in response to therapy may provide evidence for early prediction of response and guide therapy for patients with HER2+ breast cancer.

Original languageEnglish (US)
Pages (from-to)17-29
Number of pages13
JournalNeoplasia (United States)
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2019

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Immunohistochemistry
Breast Neoplasms
Neoplasms
Positron-Emission Tomography
Magnetic Resonance Imaging
Blood Vessels
Therapeutics
Trastuzumab
Histology
Control Groups
fluoromisonidazole

ASJC Scopus subject areas

  • Cancer Research

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Characterizing Trastuzumab-Induced Alterations in Intratumoral Heterogeneity with Quantitative Imaging and Immunohistochemistry in HER2+ Breast Cancer. / Syed, Anum K.; Woodall, Ryan; Whisenant, Jennifer G.; Yankeelov, Thomas; Sorace, Anna G.

In: Neoplasia (United States), Vol. 21, No. 1, 01.01.2019, p. 17-29.

Research output: Contribution to journalArticle

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