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Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors.

ABSTRACT: Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR?=?3.22; 95% CI, 2.26-4.58; P?

SUBMITTER: Valero C

PROVIDER: S-EPMC7851155 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors.

Valero Cristina C Lee Mark M Hoen Douglas D Weiss Kate K Kelly Daniel W DW Adusumilli Prasad S PS Paik Paul K PK Plitas George G Ladanyi Marc M Postow Michael A MA Ariyan Charlotte E CE Shoushtari Alexander N AN Balachandran Vinod P VP Hakimi A Ari AA Crago Aimee M AM Long Roche Kara C KC Smith J Joshua JJ Ganly Ian I Wong Richard J RJ Patel Snehal G SG Shah Jatin P JP Lee Nancy Y NY Riaz Nadeem N Wang Jingming J Zehir Ahmet A Berger Michael F MF Chan Timothy A TA Seshan Venkatraman E VE Morris Luc G T LGT

Nature communications 20210201 1

Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progres ...[more]

PMID: 33526794

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Project description:BACKGROUND:There is an unmet need to determine factors predictive of clinical benefit, to guide therapeutic sequencing and selection in metastatic RCC (mRCC). We evaluated clinical factors such as the neutrophil lymphocyte ratio (NLR) and duration of prior anti-vascular endothelial growth factor (VEGF) inhibitors, as predictors of response rate, progression free survival (PFS) and overall survival (OS) in mRCC patients treated with immune checkpoint inhibitor (ICI). METHODS:Regulatory approval was obtained. A single center retrospective chart review of mRCC patients at Karmanos Cancer Institute, treated with ICI based therapy (PD-1/PD-L1 inhibitors) was conducted. Data were collected on demographics, smoking status, prognostic scoring (Memorial Sloan Kettering and Heng criteria), NLR pretherapy, post 1 and 4 doses of ICI, and duration of prior anti-VEGF therapy ?6 months or <6. RESULTS:42 patients were evaluated with median age of 61 years (range, 24-85). Pretherapy NLR < 3 and ?3 was seen in 19 (45%) and 23 (55%) patients, respectively. 24 (57%) and 18 (43%) patients had prior anti-VEGF inhibitors for a duration of ?6 months and <6 months, respectively. 12 (29%), 22 (52%) and 8 (19%) patients had favorable, intermediate and poor risk disease based on Heng criteria, respectively. Multivariable analysis showed pretherapy NLR ?3 was predictive of shorter PFS and OS when treated with ICI with median 3.08 months and 13.50 months, respectively, versus 15.57 months and not reached for NLR < 3 (adjusted p-values =0.003 and 0.025, respectively). Prior anti-VEGF therapy <6 months was predictive of increased likelihood of benefit from ICI therapies (adjusted p = 0.028). The median PFS was 3.72 months and 14.33 months, respectively, in cases with prior anti-VEGF therapy for ?6 months and <6 months. CONCLUSION:Pretherapy NLR <3 and duration of prior anti-VEGF therapy of <6 months, are independent statistically significant predictors of longer PFS and OS with ICI therapy in mRCC. Validation is required in a larger sample size with multi-institutional collaboration.

Project description:BackgroundThe role of platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) as independent prognostic markers in different tumors is well established. However, there is a limited review of the potential of NLR and PLR as predictors of treatment outcomes from immune checkpoint inhibitors (ICIs).ObjectiveTo establish a correlation between NLR and PLR and the potential of clinical benefit from ICIs.MethodsThe literature search was performed for studies that reported the association between NLR, PLR, and treatment outcomes among cancer patients treated with ICIs. The outcomes of interest were objective response rate (ORR), disease control rate (DCR), and progressive disease (PD). ORR was the summation of patients who achieved complete response and partial response. DCR included patients who achieved stable disease. PD was the proportion of patients who progressed, relapsed, or discontinued the treatment. Statistical analysis was performed using the STATA 12.0 package. Heterogeneity was determined by the I2 value. Quality assessment was performed using the Newcastle-Ottawa Scale. Egger's test was used to establish publication bias and sensitivity analysis.ResultsA total of 40 papers that met the inclusion criteria were included in the systematic review. However, only 17 studies were used in the meta-analysis to determine the correlation between NLR, PLR, and treatment response. We found that treatment with ICIs and monitoring of outcomes and adverse events using PLR and NLR parameters have been studied in different tumors. Our analysis showed that low NLR correlated with higher ORR (OR = 0.62 (95% CI 0.47-0.81, p = 0.001) and higher DCR (OR = 0.23, 95% CI 0.14-0.36, p < 0.001). Higher NLR predicted a higher probability of PD (OR = 3.12, 95% CI 1.44, 6.77, p = 0.004). Similarly, low PLR correlated with higher ORR (OR = 0.69, 95% CI 0.5, 0.95, p = 0.025). Generally, patients with low NLR and PLR were more likely to achieve clinical benefit and better response (p-value < 0.001). Meanwhile, patients with high ratios were more likely to progress (p-value < 0.005), although there was significant heterogeneity among studies. There was no significant publication bias observed.ConclusionThe study showed that high NLR and PLR either at baseline or during treatment is associated with poorer treatment outcome. Therefore, these ratios can be utilized in clinical practice with other markers to determine treatment efficacy from immunotherapy.

Project description:AimNeutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), or monocyte-lymphocyte ratio (MLR) has been shown to be related to the poor prognosis of cervical cancer, ovarian cancer, breast cancer, and other malignant tumors, but their role in predicting the prognosis of endometrial cancer is still controversial. Therefore, we conducted this meta-analysis to evaluate the effectiveness of NLR more accurately, PLR, or MLR in predicting the prognosis of endometrial cancer (EC).MethodsThis review systematically searched for relevant publications in databases of the Cochrane Library, PubMed, EMBASE, CNKI, WanFang, VIP, and CBM. Pooled hazard ratios (HR) with 95% confidence intervals (95% CI) were determined and used to explore the association between inflammatory biomarkers (NLR, PLR, and MLR) and overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) in a random-effects model. We also conducted subgroup analysis and publication bias in this meta-analysis. Stata 12.0 was used for statistical analysis.ResultsThis meta-analysis contained 14 eligible studies including 5,274 patients. Our results showed that NLR or PLR was associated with OS [NLR: HR, 2.51; 95% CI, 1.70-3.71; p <0.001 in univariate analysis (Ua); HR, 1.87; 95% CI, 1.34-2.60; p <0.001 in multivariate analysis (Ma); PLR: HR, 2.50; 95% CI, 1.82-3.43; p <0.001 in Ua; HR, 1.86; 95% CI, 1.22-2.83; p = 0.004 in Ma], but MLR was not associated with OS (HR, 1.44; 95% CI, 0.70-2.95; p = 0.325 in Ua; HR, 1.01; 95% CI, 0.39-2.60; p =0.987 in Ma). A further subgroup analysis found that the correlations were not affected by race, cutoff value, sample size, or treatment. Our meta-analysis showed that NLR or PLR was associated with DFS (NLR: HR, 2.50; 95% CI, 1.38-4.56; p =0.003 in Ua; HR, 2.06; 95% CI, 1.26-3.37, P =0.004 in Ma; PLR: HR, 1.91; 95% CI, 1.30-2.81; p = 0.001 in Ua), and NLR was associated with PFS only in the univariate analysis (HR, 1.71; 95% CI, 1.04-2.81; p =0.035 in Ua; HR, 1.79; 95% CI, 0.65-4.89; P =0.257 in Ma), but MLR was not associated with DFS (HR, 0.36; 95% CI, 0.03-4.13; p =0.409 in Ua).ConclusionsOur results indicated that pretreatment NLR and PLR were biomarkers of poor prognosis in patients with endometrial cancer. The results indicated that NLR or PLR was associated with OS and disease-free survival DFS, and NLR was associated with PFS only in univariate analysis, but MLR was not associated with OS or DFS.

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Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors.

Publications

Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors.

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