Predicting survival and response to therapy using diagnostic biopsies: A machine learning approach to facilitate treatment decisions for oesophageal adenocarcinoma


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Abstract Background Standard of care for locally advanced oesophageal adenocarcinoma is neoadjuvant chemotherapy or chemoradiotherapy followed by surgery. Only a minority of patients (<25%) derive significant survival benefit from neoadjuvant treatment and there are no reliable means of establishing prior to treatment in whom this benefit will occur. Moreover, accurate prediction of survival prior to treatment is also not possible. The availability of machine learning techniques provides the potential to use complex data sources to answer these problems. In this study, we assessed the utility of high-resolution digital microscopy of pre-treatment biopsies in predicting both response to neoadjuvant therapy and overall survival. Methods A total of 157 cases were included in the study. Pre-treatment clinical information, including neoadjuvant treatment, was obtained, along with diagnostic biopsies. Diagnostic biopsies were converted into high-resolution whole slide-images and features extracted using the pre-trained convolutional neural network Xception. Single representative images were converted into patches from which predictive models were trained. Elastic net regression classifiers were derived and validated with bootstrapping and 1000 resampled datasets. The response to treatment was considered according to Mandard tumour regression grade (TRG). Model performance was quantified using the C-index (for TRG) and time-dependent AUC (tAUC, fo Overall survival) along with calibration plots. Results Median survival was 78.9months (95%CI 35.9 months – not reached). Survival at 5-years was 52.1%. Neoadjuvant treatment was received by 123 patients (78.3%), with a significant response seen in 45 cases (36.6%). A response was more likely in those patients who received chemoradiotherapy than chemotherapy (53.3% vs 23.1% p < 0.001) and in older patients (median age 69.4 vs 66.0 years, p = 0.038), with other characteristics similar. A predictive model for response to neoadjuvant treatment derived from image features and clinical data achieved good discrimination (C-index 0.767, 95%CI 0.701-0.833) and calibration. Accuracy of prediction of overall survival was more modest (tAUC 0.640, 95%CI 0.518-0.762). Conclusions Using a small dataset, utility of a feature extraction pipeline in prediction of patient level outcomes has been demonstrated. This was more marked in prediction of response to neoadjuvant treatment than overall survival, which may reflect the importance of pre-treatment clinical data in determining the former outcome. Further study to refine the methodology and confirmation in larger datasets are required before expansion to clinical settings.
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Key words
diagnostic biopsies,p-ogc
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