A long noncoding RNA-based serum signature predicts ado-trastuzumab emtansine (T-DM1) treatment benefit in HER2+ metastatic breast cancer patients: a multicenter cohort study

Ado-trastuzumab is considered a standard treatment for patients with HER2+ metastatic breast cancer (mBC). Current clinical practices do not reliably predict therapeutic outcomes for patients who are refractory to therapy. Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression and therapeutic resistance, and the use of lncRNAs as tumor biomarkers is becoming more common in other diseases. However, whether they may also be used to predict therapy response in HER2+ mBC is unclear. Using lncRNA microarray profiling, we identified 23 differentially expressed lncRNAs in the serum of HER2+ mBC patients with unique responses to trastuzumab-emtansine (T-DM1). Following RT-PCR validation and machine learning-based selection in the training cohort, four lncRNAs were selected to construct the signature panel and used for T-DM1 response prediction. This four-lncRNA signature classifies patients into high- and low-risk groups and significantly and distinctively predicts patient survival. Importantly, identical outcomes were obtained from the two validation cohorts, confirming that the signature accurately predicts the T-DM1 response of HER2+ mBC patients. Integrative analysis demonstrated that this four-lncRNA signature is primarily released by immune and tumor cells and is correlated with immune activity. Our findings indicate that the four-lncRNA signature is a potentially promising biomarker for predicting T-DM1 treatment outcome, as it may reliably predict the T-DM1 treatment response in HER2+ mBC.