Cancer-elicited inflammation attenuates response and outcome in tyrosine kinase inhibitor naive patients with advanced NSCLC

Objective: Cancer elicited inflammation is the main environmental cause leading to carcinogenesis and metastasis of non-small cell lung cancer (NSCLC). Roles of the inflammatory biomarker in predicting the clinical efficacy of tyrosine kinase inhibitor (TKI) and prognosis of naive patients with advanced NSCLC need to be determined, and the best inflammatory predicted biomarker remains unknown. Methods: A total of 178 eligible advanced NSCLC patients (124 and 54 cases within discovery and validation cohorts, respectively) who received first-line EGFR-TKI between July of 2014 and October of 2020 were enrolled in the present study. We detected circulating immune cell counting, albumin (Alb), pre-albumin (pAlb), ALP, AST, LDH, GGT, HDL-c, and fibrinogen (Fib) concentrations, and calculated 22 inflammatory ratios and scores. Logistic regression and Cox proportional hazards models were used to assess the impact of these ratios and scores on objective response and disease control rate (ORR and DCR) as well as progression-free survival (PFS) in these patients. Results: Twenty-five percentage and 24.07% of NSCLC patients were observed objective response to the treatment of first-line EGFR-TKI in discovery and validation cohort, respectively. Univariate and multivariate Cox regression showed that high PLR, NPS, SII, SIS, mSIS, GLR and FPR as well as low PNI were significantly associated with poor PFS in discovery cohort. However, only high SII and FPR were found to be associated with unsatisfactory outcome in validation cohort. Time-dependent areas under ROC of FPR were 0.702 (0.517-0.888) in discovery cohort, and 0.767 (0.613-0.921) in validation cohort, which were extremely higher than the other biomarkers. The patients with FPR-SII combined score 2 harbored worse prognosis compared to the combined score 0 in discovery (p(log-rank) = 0.003, adjusted HR = 2.888, 95%CI = 1.500-5.560) and validation cohort (p(log-rank) = 0.001, adjusted HR = 3.769, 95%CI = 1.676-8.478) as well as overall population (p(log-rank) = 0.001, adjusted HR = 3.109, 95%CI = 1.878-5.147), and its time-dependent AUCs were 0.747 (0.594-0.900) and 0.815 (0.688-0.942) in the two cohorts, respectively, which were significantly higher than the single biomarker in the two cohorts. The patients with high FPR and FPR-SII score harbored worse DCR than the low patients in the two cohorts and overall population, respectively. Moreover, the similar poor survival was observed in advanced high-FPR NSCLC patients with different treatment options, however, the survival of low-FPR patients with treatment of single TKI, radiotherapy or chemotherapy or radio-chemotherapy combined TKI was good compared to the high-FPR patients with radio-chemotherapy combined TKI, and the survival differences were observed between TKI (p(log-rank) < 0.001) or radiotherapy combined TKI (p(log-rank) = 0.014) treated low-FPR patients and the high FPR patients. Additionally, FPR-SII combined score could monitor the progression of the disease in real-time, and the median month of the positive score appearance was significantly earlier than CT/MRI detection (p < 0.001 for 3 months vs. 13 months). Conclusions: High-grade cancer elicited inflammation could attenuates response and outcome in tyrosine kinase inhibitor naive patients with advanced NSCLC. FPR-SII combined score was the best inflammatory biomarker to monitor and predict the progression of advanced NSCLC patients with treatment of TKI.