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

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.

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.

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.

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.