Integrated pathway analysis of small cell lung cancer: NOTCH alterations as an independent favorable prognostic factor and DNA damage repair alterations as correlates of tumor mutational burden

Aim: Small cell lung cancer (SCLC) is characterized by near-universal TP53/RB1 inactivation and high mutation burden, yet prognostic biomarkers beyond clinical stage remain limited. This study aimed to characterize pathway-level genomic alterations—including DNA damage repair (DDR), NOTCH, mismatch repair (MMR), and MYC family—and evaluate their associations with tumor mutational burden (TMB) and overall survival in a whole-genome sequenced SCLC cohort.

Materials and Methods: We analyzed genomic and clinical data from 120 primary SCLC tumors in the University of Cologne cohort, accessed via cBioPortal. A 34-gene panel spanning homologous recombination, DNA damage signaling, Fanconi anemia, MMR, NOTCH (NOTCH1/2), cell cycle regulators (TP53, RB1), and MYC family genes was interrogated. Pathway co-occurrence was assessed using Fisher's exact tests. TMB comparisons used Mann-Whitney U tests. Overall survival was analyzed via Kaplan-Meier estimates, log-rank tests, and multivariable Cox proportional hazards regression adjusted for age, sex, tumor stage, and chemotherapy.

Results: TP53 (85.8%) and RB1 (72.5%) alterations co-occurred strongly (odds ratio [OR] = 20.6, p < .001). DDR pathway alterations were present in 26.7% of tumors, with homologous recombination-altered cases showing markedly elevated TMB (median 12.6 vs 7.0, p = .001). NOTCH pathway alterations occurred in 16.7% of tumors. In multivariable Cox regression, NOTCH alterations were an independent favorable prognostic factor (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.24 – 0.94, p = .03) after adjustment for age, sex, advanced stage, and chemotherapy. DDR alterations did not independently predict survival (HR 1.14, p = .64). Advanced stage independently predicted worse survival (HR 2.38, p < .001), while chemotherapy was associated with better survival (HR 0.44, p = .001).

Conclusion: In this SCLC cohort, NOTCH and DDR pathways demonstrate distinct biological roles: NOTCH alterations serve as an independent favorable prognostic marker, while DDR alterations associate with elevated TMB without independent prognostic impact. These findings validate NOTCH as a prognostic biomarker in SCLC and support pathway-level genomic assessment in clinical risk stratification.