Change in neutrophil to lymphocyte ratio during immunotherapy treatment is a non-linear predictor of patient outcomes in advanced cancers

Abstract

BackgroundThe neutrophil to lymphocyte ratio (NLR) is known to be prognostic for patients with advanced cancers treated with immune checkpoint inhibitors (ICI), but has generally been evaluated as a single threshold value at baseline. We evaluated NLR at baseline and within first month during treatment in patients who received ICI for advanced cancer to evaluate the prognostic value of baseline and of changes from baseline to on-treatment NLR.MethodsA retrospective review of patients with advanced cancer treated with ICI from 2011 to 2017 at the Ohio State University was performed. NLR was calculated at the initiation of ICI and repeated at median of 21 days. Overall survival (OS) was calculated from the initiation of ICI to date of death or censored at last follow-up. Significance of Cox proportional hazards models were evaluated by log-rank test. Calculations were performed using the survival and survminer packages in R, and SPSS.Results509 patients were identified and included in the analysis. Patients with baseline and on-treatment NLR < 5 had significantly longer OS (P < 0.001). The change in NLR overtime was a predictor of OS and was observed to be non-linear in nature. This property remained statistically significant with P < 0.05 after adjusting for age, body mass index, sex, cancer type, performance status, and days to repeat NLR measurement. Patients with a moderate decrease in NLR from baseline had the longest OS of 27.8 months (95% CI 21.8–33.8). Patients with significant NLR decrease had OS of 11.4 months (95% CI 6.1–16.7). Patients with a significant increase in NLR had the shortest OS of 5.0 months (95% CI 0.9–9.1).ConclusionsWe confirmed the prognostic value of NLR in patients with advanced cancer treated with ICIs. We found that change in NLR over time is a non-linear predictor of patient outcomes. Patients who had moderate decrease in NLR during treatment with ICI were found to have the longest survival, whereas a significant decrease or increase in NLR was associated with shorter survival. To our knowledge, this is the first study to demonstrate a non-linear change in NLR over time that correlates with survival.

Prognostic Value of the Lung Immune Prognostic Index May Differ in Patients Treated With Immune Checkpoint Inhibitor Monotherapy or Combined With Chemotherapy for Non-small Cell Lung Cancer

“…However, they did not assess changes in LIPI score over time with treatment. On the other hand, in previous studies, dynamic changes in the NLR during treatment were associated with survival ( 22 , 23 ). Patients with a high post-treatment NLR had significantly shorter progression-free survival (PFS) than those with a low post-treatment NLR.…”

Preoperative plus postoperative neutrophil‑lymphocyte ratio for predicting overall survival following partial hepatectomy for hepatocellular carcinoma

“…However, the preoperative NLR plus postoperative NLR was an independent prognostic factor for OS in patients with HCC. Certain studies have divided the postoperative NLR by the preoperative NLR or used the post NLR minus the preoperative NLR to define novel prognostic factors ( 3 , 13 , 14 , 16 – 20 ). Certain studies have hypothesized that an increase in the postoperative NLR relative to the preoperative NLR following treatment indicates that the balance has been tipped in favor of a pro-tumor inflammatory response ( 3 , 16 – 20 ).…”

“…In recent years, certain studies have focused on the effect of postoperative NLR on the prognosis of patients with malignant tumors ( 11 – 21 ) and have reported that an increased postoperative NLR was associated with poorer survival outcomes in patients with solid tumors ( 12 , 15 , 21 ). Certain studies have begun to focus on the association between preoperative NLR and postoperative NLR: Postoperative NLR changes for advanced tumors ( 13 , 14 ); the preoperative plus the postoperative NLR for gastric cancer ( 15 ); and the postoperative NLR minus preoperative NLR for HCC ( 3 , 16 ), colorectal ( 17 ), non-small-cell lung ( 18 ) and gastric cancer ( 19 , 20 ). Some of these studies were based on the hypothesis that the postoperative NLR is higher than the preoperative NLR following treatment, which may be due to a protumor inflammatory response, and they found that patients with a postoperative NLR higher than the preoperative NLR had a poorer prognosis ( 3 , 13 , 14 , 16 – 20 ).…”

“…Certain studies have begun to focus on the association between preoperative NLR and postoperative NLR: Postoperative NLR changes for advanced tumors ( 13 , 14 ); the preoperative plus the postoperative NLR for gastric cancer ( 15 ); and the postoperative NLR minus preoperative NLR for HCC ( 3 , 16 ), colorectal ( 17 ), non-small-cell lung ( 18 ) and gastric cancer ( 19 , 20 ). Some of these studies were based on the hypothesis that the postoperative NLR is higher than the preoperative NLR following treatment, which may be due to a protumor inflammatory response, and they found that patients with a postoperative NLR higher than the preoperative NLR had a poorer prognosis ( 3 , 13 , 14 , 16 – 20 ). However, the association between the preoperative NLR and postoperative NLR remains controversial, and it may not be appropriate to study the postoperative NLR in the context of the preoperative NLR.…”

The EGFR-HSF1 Axis Accelerates the Tumorigenesis of Pancreatic Cancer

“…Besides, to elucidate the effect of the certain single gene on the clinical and biological characteristics of pancreatic cancer, we rstly obtained a "The Cancer Genome Atlas (TCGA)" dataset corresponding to 182 pancreatic cancers patients' tissues (4 normal pancreas tissues and 178 tumor tissues) from the TCGA database (https://portal.gdc.cancer.gov/); besides, a "Genotype-Tissue Expression (GTEx)" dataset corresponding to 167 normal pancreas tissues was obtained from GTEx database (https://www.gtexportal.org/). Next, the R language package [16,17] limma, beeswarm, survival and survminer were used to: 1) merge the two datasets (171 normal vs 178 tumor), 2) extract the different expression of the certain single gene in normal tissues vs tumor tissues, 3) analyze the relationship between the certain single gene and survival or other clinical characteristics of pancreatic cancer patients (high-and low-expression groups were de ned by median values of samples), 4) build univariate and multivariate COX regression models towards the certain single gene in pancreatic cancer. Finally, the biological pathways and transcription factors' binding motifs/transcription factors' signature or target gen sets [18] related to the certain single gene (according to above TCGA datasets) and to the differentially expressed gene set GSE98399 (created by Bauer TW and colleagues [19], according to https://www.ncbi.nlm.nih.gov/geo/) were evaluated by using "Gene Set Enrichment Analysis software (GSEA)" [20], and the number of permutations was set at 1000.…”