Early On-treatment Transcriptional Profiling as Predictor of Response in Early-stage HER2-positive Breast Cancer

This is a prospective study of paired tumor samples from patients with newly diagnosed HER2-positive breast cancer eligible for neoadjuvant treatment to evaluate whether early on-treatment biomarkers can improve the accuracy of predicting response over pre-treatment samples alone. Sequential tumor biopsies will be obtained at two time points: before initiation of neoadjuvant dual HER2-blockade (pre-treatment, day 1) and 1 week later (day 8), before introduction of paclitaxel to the neoadjuvant treatment. Following the completion of neoadjuvant paclitaxel, trastuzumab and pertuzumab (THP) for 16 weeks, patients will proceed to surgery. After surgery, adjuvant treatment (including need for Anthracyclines) will be followed as per clinical practice. The study will comprise two phases: a discovery phase (n=60) where sequential paired tumor biopsies will be used for RNA-Seq analysis and assessment of tumor infiltrating lymphocytes (TILs) and CelTIL score. Radiomic characteristics of MRI, HER2Dx® and spatial transcriptomics (using GeoMx®) will be also evaluated. This phase will be followed by a validation phase (n=20) in which prediction accuracy observed in the discovery phase will be validated by Nanostring gene expression analysis using a new cohort of patients with HER2-positive breast cancer eligible for neoadjuvant therapy.