PURPOSE Tumor progression has been linked to stiffening of the extracellular matrix caused by fibrosis. Cancer cells can be mechanically conditioned by stiff extracellular matrix, exhibiting a 1,004-gene signature [mechanical conditioning (MeCo) score]. Nintedanib has demonstrated antifibrotic activity in idiopathic pulmonary fibrosis. This study explores nintedanib's antifibrotic effect on breast cancer outcomes. EXPERIMENTAL DESIGN We present long-term follow-up and analysis of a neoadjuvant randomized phase II trial in early HER2-negative breast cancer. Patients (N = 130) underwent a baseline biopsy and received 12 paclitaxel courses alone (control arm) or in combination with nintedanib (experimental arm). The tumor MeCo score was determined by RNA sequencing. The primary aim was to assess nintedanib's impact on event-free survival based on MeCo scores. RESULTS Follow-up data were retrieved from 111 patients; 75 baseline and 24 post-run-in phase samples were sequenced. After median follow-up of 9.67 years, median event-free survival was not statistically different between arms (P = 0.37). However, in the control arm, high- versus low-MeCo patients had a statistically higher relapse risk: HR = 0.21; P = 0.0075. This risk was corrected by nintedanib in the experimental arm: HR = 0.37; P = 0.16. Nintedanib demonstrated pharmacodynamic engagement, reducing the MeCo score by 25% during the run-in phase (P < 0.01). Patients with low MeCo after run-in had the best long-term prognosis (HR = 0.087; P = 0.03). CONCLUSIONS High MeCo is predictive of poor outcomes in HER2-negative early breast cancer, although this risk can be mitigated by nintedanib, which is able to specifically reduce MeCo.

中文翻译：

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肿瘤细胞外基质刚度的高机械调节是 HER2 阴性乳腺癌抗纤维化治疗的预测生物标志物。


目的 肿瘤进展与纤维化引起的细胞外基质硬化有关。癌细胞可以通过坚硬的细胞外基质进行机械调节，表现出 1,004 个基因特征 [机械调节 （MeCo） 评分]。尼达尼布在特发性肺纤维化中显示出抗纤维化活性。本研究探讨了尼达尼布对乳腺癌结果的抗纤维化作用。实验设计 我们提出了早期 HER2 阴性乳腺癌新辅助随机 II 期试验的长期随访和分析。患者 （N = 130） 接受了基线活检，并单独接受了 12 个紫杉醇疗程 （对照组） 或与尼达尼布联合治疗 （实验组）。通过 RNA 测序确定肿瘤 MeCo 评分。主要目的是根据 MeCo 评分评估尼达尼布对无事件生存率的影响。结果 检索 111 例患者的随访资料;对 75 个基线和 24 个磨合期后样本进行了测序。中位随访 9.67 年后，各组之间的中位无事件生存期无统计学差异 （P = 0.37）。然而，在对照组中，高 MeCo 患者与低 MeCo 患者的复发风险在统计学上更高：HR = 0.21;P = 0.0075。在实验组中，尼达尼布纠正了这种风险： HR = 0.37;P = 0.16。尼达尼布表现出药效学参与，在磨合期将 MeCo 评分降低 25% （P < 0.01）。磨合期后 MeCo 水平低的患者远期预后最佳 （HR = 0.087;P = 0.03）。结论 高 MeCo 可预测 HER2 阴性早期乳腺癌的不良结局，尽管这种风险可以通过尼达尼布减轻，尼达尼布能够特异性降低 MeCo。