Open AccessIntratumor heterogeneity defines treatment‐resistant HER 2+ breast tumors
Author(s) -
Rye Inga H.,
Trinh Anne,
Sætersdal Anna B.,
Nebdal Daniel,
Lingjærde Ole Christian,
Almendro Vanessa,
Polyak Kornelia,
BørresenDale AnneLise,
Helland Åslaug,
Markowetz Florian,
Russnes Hege G.
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12375
Subject(s) - breast cancer , targeted therapy , genetic heterogeneity , oncology , cancer research , estrogen receptor , chemotherapy , medicine , cancer , in situ hybridization , pathology , phenotype , biology , gene expression , gene , genetics
Targeted therapy for patients with HER 2‐positive ( HER 2+) 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 HER 2 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, HER 2 protein expression, and HER 2 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 HER 2+ breast tumors. The samples were taken both before and after neoadjuvant chemotherapy plus HER 2‐targeted treatment, enabling us to study tumor evolution as well. We found that intratumor heterogeneity for HER 2 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 HER 2 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 HER 2+ breast cancer patients and the power of computational scoring methods to evaluate in situ molecular markers in tissue biopsies.