High mechanical conditioning by tumor extracellular matrix stiffness is a predictive biomarker for anti-fibrotic therapy in HER2-negative breast cancer
Background Tumor progression has been linked to stiffening of the extracellular matrix (ECM) caused by fibrosis. Cancer cells can be mechanically conditioned by stiff ECM, exhibiting a 1004-gene signature (MeCo score). Nintedanib has demonstrated anti-fibrotic activity in idiopathic pulmonary fibrosis. This study explores nintedanib's anti-fibrotic effect on breast cancer outcomes. Methods We present long-term follow-up and analysis of a neoadjuvant randomized Phase 2 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). Tumor MeCo score was determined by RNAseq. The primary aim was to assess nintedanib's impact on event-free survival (EFS) 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 EFS 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: hazard ratio (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 mechanical conditioning. Overall design: Collected tumor samples from NCT01484080 clinical trial were used for retrospective gene expression analysis on breast cancer patients before and after treatment with the antiangiogenic drug bevacizumab. Total RNA from tumors embedded in paraffined blocks was isolated using RNeasy FFPE it (Quiagen, #73504) according to the manufacturer's protocol. RNA quality was determined by Agilent's 2100 Bioanalyzer Lab-Chip technology.