State-Aware Interaction MIL for Rare Joint Molecular Phenotype Prediction in Colorectal Cancer and Lung Adenocarcinoma

Joint molecular phenotype prediction is complicated by small joint-positive populations and overlapping histological features across alternative molecular states. Existing computational pathology approaches typically predict biomarkers independently or formulate the joint-positive phenotype as a binary endpoint. Independent prediction does not model interactions between biomarker-specific histological representations, whereas binary joint prediction collapses the double-negative and two single-positive configurations into a single negative class. We propose State-Aware Interaction MIL, a weakly supervised method that preserves biomarker-specific histological representations, models their interaction, and supervises the complete four-state molecular configuration. We evaluate the proposed approach for joint BRAF+/MSI+ prediction in colorectal cancer and EGFR+/TP53+ prediction in lung adenocarcinoma using frozen UNI2-h and CONCH pathology foundation-model representations. With UNI2-h, State-Aware Interaction MIL achieved an average precision of 0.5566 in colorectal cancer (joint-positive prevalence 6.8%) compared with 0.5161 for NaiveMTL, and 0.2784 in lung adenocarcinoma (joint-positive prevalence 8.6%) compared with 0.2525 for IndependentPair. With CONCH, State-Aware achieved an average precision of 0.4410 compared with 0.3932 for DirectJoint in colorectal cancer and 0.1659 compared with 0.1226 for DirectJoint in lung adenocarcinoma. Four-state analysis showed that joint-positive prediction scores differed across molecular configurations, and the joint-positive group had elevated median scores in both cohorts. These results indicate that pathology foundation-model representations contain predictive information for rare joint molecular phenotypes and that preserving biomarker-specific representations within a structured molecular-state formulation can improve prediction of these phenotypes from histopathology.