Characterization of leukemia inhibitory factor and its receptor in lung adenocarcinoma.

e20505 Background: In non-small cell lung cancer (NSCLC), including lung adenocarcinoma (LUAD), biomarker-driven therapy has become a cornerstone, but there is wide variation in effectiveness. As such, further biomarkers are needed to stratify patients based on prognostic and predictive factors and serve as therapeutic targets. This study sought to investigate patterns of prospective biomarkers, leukemia inhibitory factor (LIF) and its receptor (LIFR), in LUAD and their impact on outcomes. Methods: NSCLC tumors with LUAD histology (N=9,920) underwent next-gen sequencing of DNA (592-gene or WES) and RNA (WTS) at Caris Life Sciences (Phoenix, AZ). Tumors were stratified by LIF or LIFR expression quartiles (Q1: low; Q4: high). Quartiles were established within each subpopulation. Significance was calculated using chi-square, Fisher’s exact, or Mann-Whitney U test, with p-values adjusted for multiple comparisons (p < 0.05). Overall survival (OS) was estimated from insurance claims data using Cox proportional hazards model to calculate Hazard Ratio and log-rank tests to calculate p-values. Results: Low LIF expression was associated with improved OS vs high LIF expression (25.1 months (m) vs 18.1 m, HR 0.79, 95% CI 0.75-0.83, p < 0.0001). Low LIF expressors more frequently harbored mutations in EGFR (21.2% vs 12.8%, p < 0.001) and were less frequent in KRAS (26.6% vs 45.9%, p < 0.001). Low LIF expression was prognostic of improved OS in those with EGFR mutation (35.7 m vs 24.7 m, HR 0.68, 95% CI 0.58-0.8, p < 0.0001), KRAS mutation (23 m vs 16.9 m, HR 0.83, 95% CI 0.75-0.91, p < 0.001), or ALK fusion (45.0 m vs 31.4 m, HR 0.57, 95% CI 0.39-0.85, p = 0.005). In those treated with pembrolizumab (N=2685) or osimertinib (N=721), low LIF expression was associated with 4 (20.4 m vs 16.3 m, 0.85 HR, 95% CI 0.77-0.94, p = 0.001) and 9.4 months of improved OS (36.1 m vs 26.7 m, HR 0.69, 95% CI 0.55-0.86, p < 0.001), respectively. High LIFR expressors had superior OS vs low LIFR expressors (27.9 m vs 14.0 m, HR 0.63, 95% CI 0.59-0.66, p < 0.001), as well as among pembrolizumab treated (20.7 m vs 15.0 m, HR 0.78, 95% CI 0.71-0.86, p < 0.001) and osimertinib-treated patients (35.8 m vs 31.6 m, HR 0.75, 95% CI 0.59-0.96, p < 0.05). EGFR mutation was more frequent in LIFR Q4 vs Q1 (27.2% vs 7.6%, p < 0.001), while KRAS mutation was less frequent (27.4% vs 42.5%, p < 0.001). In those with KRAS mutations, high LIFR expression was associated with improved OS (27.1 m vs 10.6 m, HR 0.54, 95% CI 0.49-0.60, p < 0.001), with a similar trend among those with EGFR mutation (34.6 m vs 28.2 m, HR 0.86, 95% CI 0.73-1.01, p = 0.058). Conclusions: Superior survival outcomes were seen in low LIF expressors and high LIFR expressors, with augmented survival benefits in patients with key oncogenic driver mutations, namely EGFR, KRAS , and ALK fusion, and those receiving pembrolizumab. These findings highlight the biomarker role of LIF and LIFR expression in LUAD and warrant investigation for clinical application.