ClinRAG-GRAPH: Clinical-prior Retrieval-Augmented Graph Model with Domain Adversarial Learning for Breast pCR Prediction

In patients with breast cancer, pathological complete response (pCR) has been established as a clinically meaningful surrogate marker for long-term outcomes. While commonly treated with neoadjuvant chemotherapy (NACT), effective treatment decision-making remains challenging, as therapeutic response can vary substantially across patients, calling for predictive models capable of accurately estimating individualized treatment response. To address this, we propose an imaging-based 3D spatio-temporal framework for treatment response prediction that integrates a state-of-the-art graph neural network with relational modeling of temporal interactions across timepoints alongside three novel complementary self-supervised treatment trajectory representation learning objectives. Experiments across a cohort of 585 patients from the public ISPY-2 dataset demonstrate that our method substantially outperforms both vision and self-supervised learning baselines across several classification metrics. Alongside establishing a breast cancer pCR prediction benchmark, we include a principled ablation of our method and further introduce and empirically assess the impact of the available number of DCE-MRI timepoints per patient trajectory and the inclusion of inter-scan time-differences. Overall, our study substantiates the utility of clinically meaningful longitudinal medical imagaging modeling for predicting NACT-induced pCR. We will publicly share our code repository and a user-friendly PyPI library for dataset curation upon publication, effectively promoting reproducible open-source research.

Pathologic complete response (pCR) is an important endpoint in neoadjuvant chemotherapy (NAC) for breast cancer, and predicting pCR from imaging during treatment could support treatment response assessment. Many existing imaging-based approaches rely on a single static timepoint, which fails to capture changes that occur during treatment. In this work, we present a longitudinal framework that combines a frozen 3D foundation encoder (Pillar-0) with our Temporal Dynamics Network (TDN) to predict treatment response from serial Dynamic Contrast-Enhanced (DCE) MRI acquired across four clinical timepoints from pre-treatment to pre-surgery. The TDN combines time-aware volumetric embeddings with clinical and treatment data to predict pCR. Evaluated on 982 patients from the combined I-SPY2 and ACRIN-6698 cohort, the proposed model achieves strong performance across all reported metrics when longitudinal 3D imaging is fused with clinical data (test AUROC: 73.6%, balanced accuracy: 69.1%). While clinical variables provide the strongest individual predictive signal, longitudinal 3D imaging contributes complementary information when fused with clinical data, improving pCR prediction. Our source code is available at: https://github.com/omarftt/longitudinal_temporal_pillar.

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.