Intratumor heterogeneity defines treatment-resistant HER2+ breast tumors.
Intratumor heterogeneity defines treatment-resistant HER2+ breast tumors.
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DOI：
10.1002/1878-0261.12375
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发表时间：
2018-11
影响因子：
6.6
通讯作者：
Russnes HG
中科院分区：
文献类型：
--
作者：
Rye IH;Trinh A;Saetersdal AB;Nebdal D;Lingjaerde OC;Almendro V;Polyak K;Børresen-Dale AL;Helland Å;Markowetz F;Russnes HG
针对HER2阳性（HER2+）乳腺癌患者的靶向治疗改善了总生存期，但许多患者仍然遭受疾病复发和死亡。已经提出雌激素受体（ER）和HER2表达的肿瘤内异质性在治疗失败中起关键作用，但在单细胞水平上全面研究这种异质性的工作很少。在这项研究中，我们探讨了ER蛋白表达，HER2蛋白表达和HER2基因拷贝数改变的肿瘤内异质性的临床影响。使用联合免疫荧光和原位杂交的组织切片，然后经过验证的计算方法，我们分析了超过13000个单一的肿瘤细胞在37个HER2+乳腺肿瘤。这些样本是在新辅助化疗加HER2靶向治疗前后采集的，这也使我们能够研究肿瘤的演变。我们发现肿瘤内HER2拷贝数的异质性在患者样本之间差异很大。高度异质性肿瘤与无病生存期显著缩短和长期生存者较少相关。治疗期间HER2特征未发生变化的患者结局显著更差。这项工作显示了肿瘤内异质性在分子诊断中对HER2+乳腺癌患者治疗选择的影响，以及计算评分方法在组织活检中评价原位分子标记物的能力。
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.
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影响因子：
12.3
作者：
Trinh A;Rye IH;Almendro V;Helland A;Russnes HG;Markowetz F
通讯作者：
Markowetz F
影响因子：
16.6
作者：
Ferrari A;Vincent-Salomon A;Pivot X;Sertier AS;Thomas E;Tonon L;Boyault S;Mulugeta E;Treilleux I;MacGrogan G;Arnould L;Kielbassa J;Le Texier V;Blanché H;Deleuze JF;Jacquemier J;Mathieu MC;Penault-Llorca F;Bibeau F;Mariani O;Mannina C;Pierga JY;Trédan O;Bachelot T;Bonnefoi H;Romieu G;Fumoleau P;Delaloge S;Rios M;Ferrero JM;Tarpin C;Bouteille C;Calvo F;Gut IG;Gut M;Martin S;Nik-Zainal S;Stratton MR;Pauporté I;Saintigny P;Birnbaum D;Viari A;Thomas G
通讯作者：
Thomas G
影响因子：
3.5
作者：
Bartlett, Alastair I.;Starcyznski, Jane;Bartlett, John M. S.
通讯作者：
Bartlett, John M. S.
影响因子：
--
作者：
SHANNON, CE
通讯作者：
SHANNON, CE
影响因子：
--
作者：
KULLBACK, S;LEIBLER, RA
通讯作者：
LEIBLER, RA