Pretreatment MRI reveals a latent, molecular-subtype-independent structural phenotype that organizes treatment trajectories and recurrence risk
Authors: Dattatreya Kantha, Murray H. Loew
Organizations: Medical Imaging & Image Analysis Laboratory, Department of Biomedical Engineering, George Washington University, Science and Engineering Hall, 800 22nd St., NW, Suite 5000, Washington, DC 20052, USA
Abstract
Pathologic complete response and tumor shrinkage measure whether breast cancer responds to neoadjuvant therapy, but not whether that response was structurally favorable, persistent, or hidden beneath volume loss. We built an outcome-blind longitudinal DCE-MRI manifold from I-SPY2 trajectories to test whether pretreatment imaging carries a structural response phenotype missed by conventional descriptors. The dominant axis of response geometry was not recoverable from the full clinical and genomic stack -- age, receptor subtype, MammaPrint, PAM50, treatment arm, and tumor burden -- but became strongly recoverable once baseline structural entropy was added. A constrained representation mapping recovered the same axes as unconstrained decomposition, establishing the structure as intrinsic rather than a post-hoc interpretation. The phenotype persisted through therapy, and as treatment proceeded the volumetric signal faded while entropy stayed separated -- a crossover from burden to structural persistence. Among complete responders, structurally disordered tumors could shrink more early yet remain structurally disordered, a volumetric deception invisible to endpoint labels. External analyses in UCSF, I-SPY1, and Duke established recurrence relevance under representation-dependent boundaries, and a representation-family commensurability assessment showed why feature-name matching is insufficient: the same label can fail, transport, or entangle with extraction geometry. Pretreatment MRI therefore exposes a structural response phenotype that endpoint-based language leaves invisible -- including, among complete responders, a pretreatment imaging signal of structurally distinct response states that awaits prospective validation.
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.
Fidel Omar Tito Cruz, Neda Ghafouri, Zengyan Wang +3
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.
Johannes Kiechle, Richard Osuala, Daniel M. Lang +5
Neoadjuvant chemotherapy (NAC) response prediction is clinically important for treatment stratification in breast cancer. However, robust pre-treatment pathological complete response (pCR) prediction remains challenging due to insufficient cross-modal modeling, multicenter imaging heterogeneity, and weak evidence-grounded interpretability. We propose ClinRAG-GRAPH, a Clinically informed Retrieval-Augmented Generation Graph framework, for pre-treatment pCR prediction from DCE-MRI, structured clinical variables, and biopsy-derived pathological biomarkers. ClinRAG-GRAPH constructs an intra-patient clinical-prior graph and applies a prior-guided relation-aware graph convolutional network for structured multimodal representation learning. To improve cross-center robustness, we introduce a dual-branch domain-adversarial learning strategy to suppress protocol-related MRI bias while preserving pCR-relevant features. To enhance interpretability, we further incorporate large language model (LLM)-driven subgraph RAG module that retrieves clinically analogous historical cases and integrates retrieved evidence for pCR inference. We assemble a large-scale multicenter NAC breast cancer cohort for extensive validation, drawing from two public sources and three in-house centers.Results show that ClinRAG-GRAPH achieves AUCs of 0.815 on the internal test set and 0.774/0.712 on two external test sets, demonstrating robust pre-treatment pCR prediction across centers. The code is available at the anonymized https://github.com/miccai26-1181/ClinRAG-GRAPH.