أخوان متحولان: لماذا تغيّر استبدال واحد في الجين مصير سرطان الرئة سريع

الملخص الأصلي

كما كتبه المؤلفون، بالإنجليزية arXiv:2602.19295

Background: KRAS mutations are the largest oncogenic subset in NSCLC. While KRAS G12C is now targetable, no approved therapies exist for G12D. We examined time-to-next-treatment (TTNT) and overall survival (OS) differences between G12C and G12D, allowing for time-varying hazard effects. Methods: De-identified data from AACR Project GENIE BPC NSCLC v2.0-public were analyzed. TTNT served as a real-world surrogate for progression-free survival. Co-mutations (TP53, STK11, KEAP1, SMARCA4, MET), TMB, and PD-L1 were harmonized. Kaplan-Meier, multivariable Cox, and a pre-specified piecewise Cox model (split at median TTNT = 23 months) were applied. Schoenfeld residuals assessed proportional hazards; bootstrap resampling (B=1000) evaluated stability. Results: Among 162 TTNT-evaluable patients (G12C n=130; G12D n=32), median TTNT was 28.6 versus 32.0 months (log-rank p=0.79). Adjusted Cox regression showed no overall hazard difference (HR=0.85; 95% CI 0.53-1.37; p=0.50), but Schoenfeld testing indicated borderline non-proportionality (p=0.053). Piecewise Cox modeling revealed time-varying effects: early TTNT hazard favored G12D (HR=0.41; 95% CI 0.17-0.97; p=0.043) with significant KRAS x period interaction (HR=3.33; p=0.021) and late-period attenuation (HR=1.38; 95% CI 0.77-2.47; p=0.285). Bootstrap resampling confirmed this pattern (median HRearly=0.39; HRlate=1.41). Among 278 OS-evaluable patients (133 deaths), G12D showed improved OS (adjusted HR=0.63; 95% CI 0.39-0.99; p=0.048). G12C tumors exhibited higher TMB (9.79 vs 7.83 mut/Mb; p=0.002) and greater STK11/KEAP1 enrichment. Conclusions: KRAS G12D demonstrated early TTNT advantage and improved OS. Late-period TTNT differences were non-significant (post-hoc power: 12.3%). These exploratory findings require validation in larger cohorts but support allele-specific therapeutic development for G12D.