Development and validation of a prognostic model for HER2-low breast cancer to evaluate neoadjuvant therapy.

Background: Human epidermal growth factor receptor 2 (HER2) low breast cancer (BC) accounts for 30-51% of all BCs. How to precisely assess the response to neoadjuvant therapy in this heterogenous tumor is currently unanswered. With the advance in multi-omics, refining the molecular subtyping other than the current hormone receptor (HR)-based subtyping to guide the neoadjuvant therapy for HER2-low BC is potentially feasible. Methods: The messenger RNA (mRNA), clinical, and pathological data of all HER2-low BC patients (n=368) from the Neoadjuvant I-SPY2 Trial, were retrieved. Ninety-eight patients achieved pathological complete response (pCR) were randomly divided into the training and validation sets with 8:2 ratio. The non-pCR cases were corporated into the above datasets with 1:1 ratio. The rest non-pCR cases were served as the test set. Random forest (RF), support vector machine (SVM), and fully connected neural network (FCNN) were applied to establish a 1-dimensional (1D) model based on mRNA data. The method with best prediction value among the 3 models was selected for further modeling when combining pathological features. A new classification of deep learning (CDn) was proposed based on a multi-omics model. After identifying pCR-related features by the integral gradient and unsupervised hierarchical clustering method, the responses to neoadjuvant therapy associated with these features across different subgroups were analyzed. Results: Compared with the RF and SVM models, the FCNN model achieved the best performance [area under the curve (AUC): 0.89] based on the mRNA feature. By combining mRNA and pathological features, the FCNN model proposed 2 new subtypes including CD1 and CD0 for HER2-low BC. CD1 increased the sensitivity to predict pCR by 23.5% [to 87.8%; 95% confidence interval (CI): 78% to 94%] and improved the specificity to pCR by 12.2% (to 77.4%; 95% CI: 69% to 87%) when comparing with the current HR classification for HER2-low BC. Conclusions: The new typing method (CD1 and CD0) proposed in this study achieved excellent performance for predicting the pCR to neoadjuvant therapy in HER2-low BC. The patients who were not sensitive to neoadjuvant therapy according to multi-omics models might receive surgical treatment directly.