Intra-tumor heterogeneity defines treatment-resistant HER2+ breast tumors

Rye, I. H.; Trinh, A.; Saetersdal, A.; Nebdal, D.; Lingjaerde, O. C.; Almendro, V.; Polyak, K.; Borresen-Dale, A.-L.; Helland, A.; Markowetz, F.; Russnes, H. G.

doi:10.1101/297549

bioRxiv · 10.1101/297549

Intra-tumor heterogeneity defines treatment-resistant HER2+ breast tumors

Rye, I. H.·Trinh, A.·Saetersdal, A.·Nebdal, D.·Lingjaerde, O. C.·Almendro, V.·Polyak, K.·Borresen-Dale, A.-L.·Helland, A.·Markowetz, F.·Russnes, H. G.

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Abstract

Targeted therapy for patients with HER2 positive (HER2+) breast cancer has improved the overall survival, but many patients still suffer relapse and death of the disease. Intra-tumor 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.\n\nIn this study, we explored the clinical impact of intra-tumor 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.\n\nWe found that intra-tumor 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.\n\nThis work shows the impact of intra-tumor 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.

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Rye, I. H., Trinh, A., Saetersdal, A., Nebdal, D., Lingjaerde, O. C., Almendro, V., Polyak, K., Borresen-Dale, A.-L., Helland, A., Markowetz, F., Russnes, H. G.. 2018-04-18. Intra-tumor heterogeneity defines treatment-resistant HER2+ breast tumors. https://doi.org/10.1101/297549

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