Intratumor heterogeneity defines treatment‐resistant HER2+ breast tumors. Issue 11 (21st September 2018)

• Record Type: Journal Article
• Authors: Rye, Inga H.; Trinh, Anne; Sætersdal, Anna B.; Nebdal, Daniel; Lingjærde, Ole Christian; Almendro, Vanessa; Polyak, Kornelia; Børresen‐Dale, Anne‐Lise; Helland, Åslaug; Markowetz, Florian; Russnes, Hege G.
• Is Part Of: Molecular oncology. Volume 12:Issue 11(2018)
• Page Start: 1838
• Page End: 1855
• Publication Date: 2018-09-21
• Subjects: breast cancer -- HER2 -- heterogeneity -- in situ analysis -- outcome -- therapy response; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12375
• Languages: English
• ISSNs: 1574-7891

Abstract

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. Abstract : A subset of breast carcinomas exhibits substantial heterogeneity with regard to HER2 protein expression, HER2 gene copy number alteration, and estrogen receptor protein expression both between cases but also within cases (inter‐ and intratumor heterogeneity). Highly heterogeneous tumors were associated with significantly shorter disease‐free survival and fewer long‐term survivors. Addressing cell‐to‐cell variation may be of importance in diagnostic settings.