Cross-Attention Multimodal Learning for Predicting Response to Neoadjuvant Imatinib in Gastrointestinal Stromal Tumors: A Multicenter Retrospective Study
Authors: Fariba Tohidinezhad, Douwe J. Spaanderman, Natalia Oviedo Acosta, Kaouther Mouheb, Karthik Prathaban, David F. Hanff, Dirk J. Grünhagen, Cornelis Verhoef, +9 more
Organizations: Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands. · Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands. · Department of Surgical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands. · Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands. · Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, the Netherlands. · Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. · Department of Medical Oncology, Netherlands Cancer Institute, Antoni Van Leeuwenhoek, Amsterdam, the Netherlands. · Shared last author.
Abstract
Background: Response to neoadjuvant imatinib in gastrointestinal stromal tumors (GISTs) is highly variable and cannot be reliably predicted using current clinical or molecular markers. This study developed and evaluated an explainable multimodal deep learning framework integrating computed tomography (CT) imaging and clinical variables to predict treatment response. Methods: Patients from four tertiary centers were retrospectively included between 2000-2023 in independent pretraining (n=935) and prediction (n=213) cohorts. A cross-attention framework integrating clinical variables and tumor-centered CT imaging was developed to predict response to neoadjuvant imatinib. Two training strategies were evaluated: (1) self-supervised pretraining with low-rank adaptation and (2) training from scratch. Hyperparameters were optimized using SMAC3. Performance was assessed through internal cross-validation and external testing. Ablation analyses and attention-based explanations were used to quantify modality contributions. Results: Among 213 patients (54.5% responders), responders had larger tumors (112 vs. 89 mm, P=0.026), higher mitotic index (3 vs. 0, P<0.001), and more frequent KIT mutations (69.0% vs. 56.7%, P=0.019). Cross-attention models achieved the highest internal performance (AUC up to 0.99) but lower external performance (AUC 0.60-0.63). Clinical-only performance was moderate (AUC 0.66), whereas imaging-only models showed limited generalizability (AUC 0.56-0.66). Explainability analyses identified significant differences in feature importance between responders and non-responders, including CD117, BRAF, PDGFRA, age, sex, disease status, and comorbidities (FDR-adjusted P<=0.036). Conclusion: The cross-attention framework shows potential for improving imatinib response prediction in GIST while providing interpretable insights into multimodal determinants of treatment response.
Ovarian cancer is the most lethal gynecologic malignancy: around 60% of patients are diagnosed at an advanced stage, with an associated 5-year survival rate of about 30%. Early identification of non-responders to neoadjuvant chemotherapy remains a key unmet need, as it could prevent ineffective therapy and avoid delays in optimal surgical management. This work proposes a non-invasive deep learning framework to predict neoadjuvant chemotherapy response from pre-treatment contrast-enhanced CT by leveraging automatically derived 3D lesion masks. The approach encodes axial slices with a partially fine-tuned pretrained image encoder and aggregates slice-level representations into a volumetric embedding through an attention-based module. Training combines classification loss with supervised contrastive regularization and hard-negative mining to improve separation between ambiguous responders and non-responders. The method was developed on a retrospective single-center cohort from the European Institute of Oncology (Milan, IT), including 280 eligible patients (147 responder, 133 non-responder). On the test cohort, the model achieved a ROC-AUC of 0.73 (95% CI: 0.58-0.86) and an F1-score of 0.70 (95% CI: 0.56-0.82). Overall, these results suggest that the proposed architecture learns clinically relevant predictive patterns and provides a robust foundation for an imaging-based stratification tool.
Francesco Pastori, Francesca Fati, Marina Rosanu +8
Pathological complete response (pCR) is a key prognostic factor in breast cancer patients undergoing neoadjuvant therapy, strongly associated with long-term survival and treatment personalization. However, accurate pre-treatment pCR prediction remains challenging due to severe class imbalance and limited generalizability across diverse clinical settings. In this work, we propose a multimodal stepwise clinically-guided attention learning framework for pCR prediction from breast magnetic resonance imaging (MRI), designed to address these limitations through medically grounded spatial guidance and multimodal integration. The approach follows a stepwise training strategy inspired by physician reasoning: the model first learns global discriminative imaging patterns, then attention mechanisms are introduced to constrain the network toward tumor regions, and finally clinical variables are integrated to refine decision-making. This guidance strategy encourages prioritization of task-relevant features, improving identification of responders despite their limited representation in the dataset. Moreover, grounding attention in anatomically consistent tumor regions reduces reliance on dataset-specific patterns, thereby enhancing cross-institutional generalization. The framework is evaluated through external validation across heterogeneous MRI cohorts. Compared to non-guided single-stage baselines, the proposed approach improves sensitivity while maintaining competitive specificity, and produces anatomically coherent attention maps that support interpretation of the model's predictions. These findings highlight the potential of clinically-guided multimodal attention learning for robust and generalizable pCR prediction in breast cancer.
Alice Natalina Caragliano, Valerio Guarrasi, Michela Gravina +2
Attention-based multiple instance learning (ABMIL) is the predominant approach for slide-level prediction in computational pathology, yet its attention maps provide only local explanations: they indicate where a model focuses but not which histological features drive its predictions or how the model behaves across a patient cohort. We present Semantic Attention Global Explanations (SAGE), a post-hoc framework that extracts global, language-grounded explanations from a frozen ABMIL model. Using a pathology vision-language model, SAGE scores image patches against a dictionary of 25 histological concepts, aggregates these scores according to the model's learned attention, and quantifies how each concept relates to prediction risk across a cohort. Applied to survival prediction using seven TCGA cancer cohorts and three foundation models, SAGE recovered established prognostic features, such as the adverse association of necrosis, while revealing cancer-specific biology, including a favorable angiogenic signature in renal cell carcinoma consistent with known molecular subtypes. Ablation studies demonstrated that these associations depend on the model's learned attention rather than concept prevalence alone, and that the concept dictionary captures much of the prognostic information encoded by the foundation model features. Through semantically-grounded explanations, SAGE provides a scalable, model-agnostic framework for understanding what ABMIL survival models learn, enabling pathologists to interpret model behavior at the cohort level and offering the potential for biomarker identification.
Abdallah Lamane, Abdul Rahman Diab, Ren-Chin Wu +1