MRI based unsuperviced clustering on MIBC reveals intratumor heterogeneity phenotypes and neoadjuvant chemotherapy efficacy.

BACKGROUND

To develop and validate a non-invasive imaging-based intratumor heterogeneity (IITH) framework for risk stratification in muscle-invasive bladder cancer (MIBC) and to investigate its association with survival outcomes and molecular subtypes.

METHODS

In this retrospective multicenter study, 437 MIBC patients were enrolled (237 patients of discovery cohort and 102 patients of validation cohort predominantly underwent radical cystectomy (RC); 98 patients of NAC cohort received three to four cycles of gemcitabine-cisplatin chemotherapy prior to surgery). From pretreatment MRI scans, 42 radiomic features were extracted. Unsupervised consensus clustering was performed using the "ConsensusClusterPlus" R package, a resampling-based method which generates a consensus matrix to robustly stratify cohorts into stable IITH subtypes. Prognostic significance for OS, CSS, RFS, PFS was then evaluated based on data reviewed up to July 30, 2024. Molecular correlates were assessed via immunohistochemistry and transcriptomic data from The Cancer Genome Atlas.

RESULTS

The IITH framework significantly stratified patient survival in the discovery cohort (OS: HR = 1.646, p < 0.05; CSS: HR = 1.792, p < 0.05; RFS: HR = 2.06, p < 0.01; PFS: HR = 1.721, p = 0.01), with consistent results in external validation cohorts (OS: HR = 2.604, p < 0.05; RFS: HR = 2.422, p < 0.05; PFS: HR = 2.72, p < 0.05). High-IITH tumors demonstrated greater histological diversity and enriched mixed subtypes. In the NAC cohort, high IITH was associated with markedly worse outcomes (CSS: HR = 7.795, p < 0.05; RFS: HR = 9.529, p < 0.001; PFS: HR = 8.893, p < 0.001). Transcriptomic analysis revealed elevated inflammatory activity and enhanced proliferative/migratory potential in high-IITH groups.

CONCLUSIONS

The MRI-based IITH framework effectively stratified MIBC patients by prognosis and treatment response, with high heterogeneity being associated with adverse outcomes and aggressive molecular tumor biology.