Purpose: To characterize expression of neuregulin-1 (NRG1), an HER3 ligand, in HER2-positive breast cancer and its relation with the efficacy of trastuzumab with or without pertuzumab. Experimental Design: Characterization of NRG1 expression in tumor cell lines, in tumor specimens, and in cancer-associated fibroblasts (CAFs). Patient-derived CAFs were used to investigate NRG1 impact on the activity of trastuzumab with or without pertuzumab in HER2-positive breast cancer cells. The relationship between NRG1 expression and pathologic response to anti-HER2–based neoadjuvant therapy was assessed in a retrospective patient cohort and in the NeoSphere trial. Results: NRG1 was expressed in HER2-positive breast cancer–derived fibroblasts at significantly higher levels than in cancer cells. NRG1 and the conditioned media (CM) from CAFs phosphorylated HER3 and AKT in cancer cells and mediated trastuzumab resistance. Stable genetic depletion of NRG1 from CAFs overcame trastuzumab resistance. Pertuzumab effectively suppressed trastuzumab resistance mediated by either NRG1 or CAF's CM. NRG1 engaged an epithelial-to-mesenchymal transition that was prevented by trastuzumab and pertuzumab. In clinical samples, stromal and/or tumor cell expression of NRG1 determined by immunohistochemistry was uncommon (13.2%) yet significantly linked with residual disease following trastuzumab-based neoadjuvant therapy. In the NeoSphere trial, the magnitude of the difference of pathologic complete response rates favoring the pertuzumab arm was higher in the NRG1- high group. Conclusions: CAF-derived NRG1 mediates trastuzumab resistance through HER3/AKT, which might be reverted by pertuzumab. In patients with HER2-positive breast cancer, high expression of NRG1 was associated to poor response to trastuzumab, but not in combination with pertuzumab.

中文翻译：

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成纤维细胞衍生的 Neuregulin-1 对 HER2 阳性乳腺癌中曲妥珠单抗和帕妥珠单抗活性的临床前和临床表征

目的：表征 HER3 配体 neuregulin-1 (NRG1) 在 HER2 阳性乳腺癌中的表达及其与曲妥珠单抗联合或不联合帕妥珠单抗疗效的关系。实验设计：肿瘤细胞系、肿瘤标本和癌症相关成纤维细胞 (CAF) 中 NRG1 表达的表征。患者来源的 CAF 用于研究 NRG1 对曲妥珠单抗联合或不联合帕妥珠单抗对 HER2 阳性乳腺癌细胞活性的影响。在回顾性患者队列和 NeoSphere 试验中评估了 NRG1 表达与对基于抗 HER2 的新辅助治疗的病理反应之间的关系。结果：NRG1 在 HER2 阳性乳腺癌衍生的成纤维细胞中的表达水平显着高于癌细胞。NRG1 和来自 CAF 的条件培养基 (CM) 磷酸化癌细胞中的 HER3 和 AKT 并介导曲妥珠单抗耐药。CAF 中 NRG1 的稳定遗传消耗克服了曲妥珠单抗的耐药性。帕妥珠单抗有效抑制了由 NRG1 或 CAF 的 CM 介导的曲妥珠单抗耐药。NRG1 参与了由曲妥珠单抗和帕妥珠单抗阻止的上皮-间质转化。在临床样本中，通过免疫组织化学测定的 NRG1 的基质和/或肿瘤细胞表达不常见（13.2%），但与基于曲妥珠单抗的新辅助治疗后的残留疾病显着相关。在 NeoSphere 试验中，有利于帕妥珠单抗组的病理完全缓解率差异幅度在 NRG1 高组中更高。结论：CAF 衍生的 NRG1 通过 HER3/AKT 介导曲妥珠单抗耐药，这可能会被帕妥珠单抗逆转。在 HER2 阳性乳腺癌患者中，NRG1 的高表达与对曲妥珠单抗的不良反应有关，但与帕妥珠单抗联合使用时没有相关性。