Deep Learning Can Predict Bevacizumab Therapeutic Effect and Microsatellite Instability Directly from Histology in Epithelial Ovarian Cancer.

Epithelial ovarian cancer (EOC) remains a significant cause of mortality among gynecologic cancers, with the majority of cases being diagnosed at an advanced stage. Before targeted therapies were available, EOC treatment relied largely on debulking surgery and platinum-based chemotherapy. Vascular endothelial growth factors have been identified as inducing tumor angiogenesis. According to several clinical trials, anti-vascular endothelial growth factor-targeted therapy with bevacizumab was effective in all phases of EOC treatment. However, there are currently no biomarkers accessible for regular therapeutic use despite the importance of patient selection. Microsatellite instability (MSI), caused by a deficiency of the DNA mismatch repair system, is a molecular abnormality observed in EOC associated with Lynch syndrome. Recent evidence suggests that angiogenesis and MSI are interconnected. Developing predictive biomarkers, which enable the selection of patients who might benefit from bevacizumab-targeted therapy or immunotherapy, is critical for realizing personalized precision medicine. In this study, we developed 2 improved deep learning methods that eliminate the need for laborious detailed image-wise annotations by pathologists and compared them with 3 state-of-the-art methods to not only predict the efficacy of bevacizumab in patients with EOC using mismatch repair protein immunostained tissue microarrays but also predict MSI status directly from histopathologic images. In prediction of therapeutic outcomes, the 2 proposed methods achieved excellent performance by obtaining the highest mean sensitivity and specificity score using MSH2 or MSH6 markers and outperformed 3 state-of-the-art deep learning methods. Moreover, both statistical analysis results, using Cox proportional hazards model analysis and Kaplan-Meier progression-free survival analysis, confirm that the 2 proposed methods successfully differentiate patients with positive therapeutic effects and lower cancer recurrence rates from patients experiencing disease progression after treatment (P < .01). In prediction of MSI status directly from histopathology images, our proposed method also achieved a decent performance in terms of mean sensitivity and specificity score even for imbalanced data sets for both internal validation using tissue microarrays from the local hospital and external validation using whole section slides from The Cancer Genome Atlas archive.

Deep learning to assess microsatellite instability directly from histopathological whole slide images in endometrial cancer.

Molecular classification, particularly microsatellite instability-high (MSI-H), has gained attention for immunotherapy in endometrial cancer (EC). MSI-H is associated with DNA mismatch repair defects and is a crucial treatment predictor. The NCCN guidelines recommend pembrolizumab and nivolumab for advanced or recurrent MSI-H/mismatch repair deficient (dMMR) EC. However, evaluating MSI in all cases is impractical due to time and cost constraints. To overcome this challenge, we present an effective and efficient deep learning-based model designed to accurately and rapidly assess MSI status of EC using H&E-stained whole slide images. Our framework was evaluated on a comprehensive dataset of gigapixel histopathology images of 529 patients from the Cancer Genome Atlas (TCGA). The experimental results have shown that the proposed method achieved excellent performances in assessing MSI status, obtaining remarkably high results with 96%, 94%, 93% and 100% for endometrioid carcinoma G1G2, respectively, and 87%, 84%, 81% and 94% for endometrioid carcinoma G3, in terms of F-measure, accuracy, precision and sensitivity, respectively. Furthermore, the proposed deep learning framework outperforms four state-of-the-art benchmarked methods by a significant margin (p < 0.001) in terms of accuracy, precision, sensitivity and F-measure, respectively. Additionally, a run time analysis demonstrates that the proposed method achieves excellent quantitative results with high efficiency in AI inference time (1.03 seconds per slide), making the proposed framework viable for practical clinical usage. These results highlight the efficacy and efficiency of the proposed model to assess MSI status of EC directly from histopathological slides.

ATEC23 Challenge: Automated prediction of treatment effectiveness in ovarian cancer using histopathological images.

Ovarian cancer, predominantly epithelial ovarian cancer (EOC), is a global health concern due to its high mortality rate. Despite the progress made during the last two decades in the surgery and chemotherapy of ovarian cancer, more than 70% of advanced patients are with recurrent cancer and disease. Bevacizumab is a humanized monoclonal antibody, which blocks VEGF signaling in cancer, inhibits angiogenesis and causes tumor shrinkage, and has been recently approved by the FDA as a monotherapy for advanced ovarian cancer in combination with chemotherapy. Unfortunately, Bevacizumab may also induce harmful adverse effects, such as hypertension, bleeding, arterial thromboembolism, poor wound healing and gastrointestinal perforation. Given the expensive cost and unwanted toxicities, there is an urgent need for predictive methods to identify who could benefit from bevacizumab. Of the 18 (approved) requests from 5 countries, 6 teams using 284 whole section WSIs for training to develop fully automated systems submitted their predictions on a test set of 180 tissue core images, with the corresponding ground truth labels kept private. This paper summarizes the 5 qualified methods successfully submitted to the international challenge of automated prediction of treatment effectiveness in ovarian cancer using the histopathologic images (ATEC23) held at the 26th International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI) in 2023 and evaluates the methods in comparison with 5 state of the art deep learning approaches. This study further assesses the effectiveness of the presented prediction models as indicators for patient selection utilizing both Cox proportional hazards analysis and Kaplan-Meier survival analysis. A robust and cost-effective deep learning pipeline for digital histopathology tasks has become a necessity within the context of the medical community. This challenge highlights the limitations of current MIL methods, particularly within the context of prognosis-based classification tasks, and the importance of DCNNs like inception that has nonlinear convolutional modules at various resolutions to facilitate processing the data in multiple resolutions, which is a key feature required for pathology related prediction tasks. This further suggests the use of feature reuse at various scales to improve models for future research directions. In particular, this paper releases the labels of the testing set and provides applications for future research directions in precision oncology to predict ovarian cancer treatment effectiveness and facilitate patient selection via histopathological images.

A Survey on Deep Learning for Precision Oncology.

Precision oncology, which ensures optimized cancer treatment tailored to the unique biology of a patient's disease, has rapidly developed and is of great clinical importance. Deep learning has become the main method for precision oncology. This paper summarizes the recent deep-learning approaches relevant to precision oncology and reviews over 150 articles within the last six years. First, we survey the deep-learning approaches categorized by various precision oncology tasks, including the estimation of dose distribution for treatment planning, survival analysis and risk estimation after treatment, prediction of treatment response, and patient selection for treatment planning. Secondly, we provide an overview of the studies per anatomical area, including the brain, bladder, breast, bone, cervix, esophagus, gastric, head and neck, kidneys, liver, lung, pancreas, pelvis, prostate, and rectum. Finally, we highlight the challenges and discuss potential solutions for future research directions.