Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
Medical Oncology Department, Hospital del Mar-CIBERONC, Barcelona, Spain.
Clin Cancer Res. 2021 Sep 15;27(18):5096-5108. doi: 10.1158/1078-0432.CCR-20-2915. Epub 2021 Aug 12.
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.
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.
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 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 high group.
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.
研究神经调节蛋白 1（NRG1），一种 HER3 配体，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 pertuzumab 的疗效的关系。
在肿瘤细胞系、肿瘤标本和癌相关成纤维细胞（CAF）中对 NRG1 表达进行特征描述。使用患者来源的 CAF 来研究 NRG1 对曲妥珠单抗联合或不联合 pertuzumab 在 HER2 阳性乳腺癌细胞中的活性的影响。在回顾性患者队列和 NeoSphere 试验中评估 NRG1 表达与基于抗 HER2 的新辅助治疗的病理反应之间的关系。
NRG1 在 HER2 阳性乳腺癌衍生的成纤维细胞中表达水平明显高于癌细胞。NRG1 和 CAF 的条件培养基（CM）可使癌细胞中 HER3 和 AKT 磷酸化，并介导曲妥珠单抗耐药。CAF 中 的稳定遗传缺失克服了曲妥珠单抗耐药。培妥珠单抗有效地抑制了由 NRG1 或 CAF 的 CM 介导的曲妥珠单抗耐药。NRG1 参与了上皮-间质转化，而曲妥珠单抗和 pertuzumab 可阻止这种转化。在临床样本中，免疫组化检测到的 NRG1 的基质和/或肿瘤细胞表达并不常见（13.2%），但与基于曲妥珠单抗的新辅助治疗后的残留疾病显著相关。在 NeoSphere 试验中，有利于 pertuzumab 臂的病理完全缓解率差异的幅度在高表达组更高。
CAF 衍生的 NRG1 通过 HER3/AKT 介导曲妥珠单抗耐药，而 pertuzumab 可能逆转这种耐药。在 HER2 阳性乳腺癌患者中，NRG1 高表达与曲妥珠单抗反应不良相关，但与 pertuzumab 联合使用时则不相关。
