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Baseline Tumor Proliferation and Ki-67 Are Associated With Pathologic Response to Neoadjuvant Chemoimmunotherapy in NSCLC
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DOI：10.1016/j.modpat.2026.101028.png)
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Abstract
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Heterogeneity in the pathological response to neoadjuvant chemoimmunotherapy underscores the need for predictive biomarkers in resectable non-small cell lung cancer (NSCLC). This study identified baseline molecular features—particularly tumor proliferation signatures—associated with pathological response. Two retrospective cohorts (Test, n=81; Validation, n=107) of patients with NSCLC who received neoadjuvant chemoimmunotherapy were analyzed. Bulk RNA sequencing was performed on baseline biopsies from the Test cohort, with immunohistochemistry (IHC) for PD-L1 and Ki-67 in both cohorts. Outcomes included major pathological response (MPR), pathological complete response (pCR), and event-free survival (EFS). In the Test cohort, transcriptomic analysis showed that responders had significant upregulation of proliferation-related genes (e.g., TP63, SOX2, NTRK2, HMGA2) and activation of proliferation signatures (e.g., CINSARC, core ESC-like module), without activation of canonical immune-inflamed pathways. PD-L1 expression had limited predictive value (AUCs: 0.56–0.59 for MPR; 0.52–0.54 for pCR). In contrast, proliferation markers demonstrated higher performance: MKI67 mRNA predicted both MPR and pCR with an AUC of 0.71, and the Ki-67 IHC index yielded AUCs of 0.71 for MPR and 0.64 for pCR. The predictive value of the Ki-67 IHC index was validated in the independent cohort, with AUCs of 0.74 for MPR and 0.70 for pCR, and this association was generally consistent across squamous cell carcinoma and adenocarcinoma. A Ki-67 index ≥50% was significantly correlated with improved EFS in both cohorts (both p<0.05). These findings indicate baseline tumor proliferation, particularly MKI67/Ki-67, as predictors of pathological response in NSCLC patients receiving neoadjuvant chemoimmunotherapy, supporting its potential clinical utility for patient selection.
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