Prediction of pathological complete response to chemotherapy for breast cancer using deep neural network with uncertainty quantification.

backgroundThe I-SPY 2 trial is a national-wide, multi-institutional clinical trial designed to evaluate multiple new therapeutic drugs for high-risk breast cancer. Previous studies suggest that pathological complete response (pCR) is a viable indicator of long-term outcomes of neoadjuvant chemotherapy for high-risk breast cancer. While pCR can be assessed during surgery after the chemotherapy, early prediction of pCR before the completion of the chemotherapy may facilitate personalized treatment management to achieve an improved outcome. Notably, the acquisition of dynamic contrast-enhanced magnetic resonance (DCEMR) images at multiple time points during the I-SPY 2 trial opens up the possibility of achieving early pCR prediction. PURPOSE: In this study, we investigated the feasibility of the early prediction of pCR to neoadjuvant chemotherapy using multi-time point DCEMR images and clinical data acquired in the I-SPY2 trial. The prediction uncertainty was also quantified to allow physicians to make patient-specific decisions on treatment plans based on the level of associated uncertainty.

methodsThe dataset used in our study included 624 patients with DCEMR images acquired at 3 time points before the completion of the chemotherapy: pretreatment (T0), after 3 cycles of treatment (T1), and after 12 cycles of treatment (T2). A convolutional long short-term memory (LSTM) network-based deep learning model, which integrated multi-time point deep image representations with clinical data, including tumor subtypes, was developed to predict pCR. The performance of the model was evaluated via the method of nested 5-fold cross validation. Moreover, we also quantified prediction uncertainty for each patient through test-time augmentation. To investigate the relationship between predictive performance and uncertainty, the area under the receiver operating characteristic curve (AUROC) was assessed on subgroups of patients stratified by the uncertainty score.

resultsBy integrating clinical data and DCEMR images obtained at three-time points before treatment completion, the AUROC reached 0.833 with a sensitivity of 0.723 and specificity of 0.800. This performance was significantly superior (p < 0.01) to models using only images (AUROC = 0.706) or only clinical data (AUROC = 0.746). After stratifying the patients into eight subgroups based on the uncertainty score, we found that group #1, with the lowest uncertainty, had a superior AUROC of 0.873. The AUROC decreased to 0.637 for group #8, which had the highest uncertainty.

conclusionsThe results indicate that our convolutional LSTM network-based deep learning model can be used to predict pCR earlier before the completion of chemotherapy. By combining clinical data and multi-time point deep image representations, our model outperforms models built solely on clinical or image data. Estimating prediction uncertainty may enable physicians to prioritize or disregard predictions based on their associated uncertainties. This approach could potentially enhance the personalization of breast cancer therapy.