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Mol Oncol. 2018 Nov;12(11):1838-1855. doi: 10.1002/1878-0261.12375. Epub 2018 Sep 21.

Intratumor heterogeneity defines treatment-resistant HER2+ breast tumors.

Author information

1
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Norway.
2
Cancer Research UK, Cambridge Institute, University of Cambridge, UK.
3
Department of Oncology, Oslo University Hospital, Norway.
4
Biomedical Informatics Division, Department of Computer Science, University of Oslo, Norway.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
6
Department of Clinical Medicine, University of Oslo, Norway.
7
Department of Pathology, Oslo University Hospital, Norway.

Abstract

Targeted therapy for patients with HER2-positive (HER2+) breast cancer has improved overall survival, but many patients still suffer relapse and death from the disease. Intratumor heterogeneity of both estrogen receptor (ER) and HER2 expression has been proposed to play a key role in treatment failure, but little work has been done to comprehensively study this heterogeneity at the single-cell level. In this study, we explored the clinical impact of intratumor heterogeneity of ER protein expression, HER2 protein expression, and HER2 gene copy number alterations. Using combined immunofluorescence and in situ hybridization on tissue sections followed by a validated computational approach, we analyzed more than 13 000 single tumor cells across 37 HER2+ breast tumors. The samples were taken both before and after neoadjuvant chemotherapy plus HER2-targeted treatment, enabling us to study tumor evolution as well. We found that intratumor heterogeneity for HER2 copy number varied substantially between patient samples. Highly heterogeneous tumors were associated with significantly shorter disease-free survival and fewer long-term survivors. Patients for which HER2 characteristics did not change during treatment had a significantly worse outcome. This work shows the impact of intratumor heterogeneity in molecular diagnostics for treatment selection in HER2+ breast cancer patients and the power of computational scoring methods to evaluate in situ molecular markers in tissue biopsies.

KEYWORDS:

HER2; breast cancer; heterogeneity; in situ analysis; outcome; therapy response

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