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

Valero, Cristina; Lee, Mark; Hoen, Douglas R.; Weiss, Kate; Kelly, Daniel; Adusumilli, Prasad S.; Paik, Paul K.; Plitas, George; Ladanyi, Marc; Postow, Michael A.; Ariyan, Charlotte E.; Shoushtari, Alexander N.; Balachandran, Vinod P.; Hakimi, A. Ari; Crago, Aimeé M.; Roche, Kara C. Long; Smith, J. Joshua; Ganly, Ian; Wong, Richard J.; Patel, Snehal G.; Shah, Jatin P.; Lee, Nancy Y.; Riaz, Nadeem; Wang, Jingming; Zehir, Ahmet; Berger, Michael F.; Chan, Timothy A.; Seshan, Venkatraman; Morris, Luc G.T.

doi:10.1038/s41467-021-20935-9

Cited by 285 publications

(252 citation statements)

References 57 publications

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“…This suggests that increased neutrophils counts in the peripheral blood were associated with less benefit from ICI. Another retrospective cohort study with 1714 patients examined the association between pretreatment NLR and TMB levels and survival among patients treated with ICI, and found that the patients with NLR-high/TMB-low had the worst prognosis, while those in the NLR-low/TMB-high group had the best prognosis (23). Other studies also found that patients with advanced NSCLC receiving immunotherapy with high NLR or PLR value (i.e., markers of chronic inflammation) usually showed poor prognosis (24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

Association of Dynamic Changes in Peripheral Blood Indexes With Response to PD-1 Inhibitor-Based Combination Therapy and Survival Among Patients With Advanced Non-Small Cell Lung Cancer

et al. 2021

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BackgroundPD-1 inhibitors have been routinely used in the treatment of advanced non-small cell lung cancer (NSCLC), and have demonstrated to significantly improve survivorship when combining with other conventional therapies, such as chemotherapy and anti-angiogenesis therapy. PD-L1 is the most commonly used biomarker to select benefiting groups, while not all patients with high PD-L1 expression benefit from immunotherapy. Therefore, identifying other prognostic and predictive biomarkers, including peripheral blood indexes, is essential.MethodsWe retrospectively collected medical records and hematological data of 151 patients with advanced NSCLC treated with PD-1 inhibitor-based combination therapy in our hospital. The peripheral blood indexes of interest were NLR, PLR, PAR, Hb, LDH, CEA, and NSE. The association between peripheral blood indexes and treatment responses or survival outcomes was examined by multivariable logistic regression and Cox regression, respectively.ResultsThe decreased CEA at week 6 (OR = 4.209, 95%CI: 1.287-13.758) or 12 (OR = 7.267, 95%CI: 1.508-35.006) post-treatment was related to a higher disease control rate. The decrease or NLR at week 6 (OR = 3.081, 95%CI: 1.464-6.483) or 12 (OR = 3.304, 95%CI: 1.560-7.001) post-treatment, or CEA at week 12 post-treatment (OR = 2.469, 95%CI: 1.134-5.375), was associated with a higher objective response rate. Patients whose NLR (HR = 0.610, 95%CI: 0.411-0.907) or CEA (HR = 0.477, 95%CI: 0.320-0.710) decreased at week 6 post-treatment tended to have longer progression-free survival, and similar results were found in those with decreased NLR (HR = 0.587, 95%CI: 0.388-0.886) or CEA (HR = 0.406, 95%CI: 0.270-0.609) at week 12 post-treatment. Patients whose CEA (HR = 0.543, 95%CI: 0.339-0.871) or NSE (HR = 0.619, 95%CI: 0.386-0.994) decreased after 6 weeks post-treatment appeared to have longer overall survival, and the same was found for those whoseCEA (HR = 0.620, 95%CI: 0.390-0.986) or NSE (HR = 0.578, 95%CI: 0.353-0.947) was decreased at 12 weeks after treatment.ConclusionPost-treatment NLR, CEA and NSE changes are suggestive indicators for the prognosis of NSCLC patients after immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Association of Dynamic Changes in Peripheral Blood Indexes With Response to PD-1 Inhibitor-Based Combination Therapy and Survival Among Patients With Advanced Non-Small Cell Lung Cancer

et al. 2021

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“…In recent years, immunotherapy based on immune checkpoint inhibitors has been successful in treating NSCLC, especially in patients with a high tumour mutation burden (TMB), CD8 + tumour cell infiltration, and programmed death-ligand 1 (PD-L1) expression (14). In a retrospective study, Valero et al showed that neutrophil-to-lymphocyte ratio (NLR) is a suitable and promising biomarker for immunotherapy (15). They suggested that higher NLR is associated with poor prognosis after immune checkpoint inhibitors (ICI) therapy.…”

Section: Progress In Immunotherapy Of Kras-mutant Nsclcmentioning

confidence: 99%

“…In a retrospective study, Valero et al. showed that neutrophil-to-lymphocyte ratio (NLR) is a suitable and promising biomarker for immunotherapy ( 15 ). They suggested that higher NLR is associated with poor prognosis after immune checkpoint inhibitors (ICI) therapy.…”

Section: Progress In Immunotherapy Of Kras-mutant Nsclcmentioning

confidence: 99%

KRAS-Mutant Non-Small Cell Lung Cancer: An Emerging Promisingly Treatable Subgroup

Xie

Fan

2021

Front. Oncol.

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Lung cancer, the leading cause of cancer-related deaths worldwide, can be classified into small cell lung cancer and non-small cell lung cancer (NSCLC). NSCLC is the most common histological type, accounting for 85% of all lung cancers. Kirsten rat sarcoma viral oncogene (KRAS) mutations, common in NSCLC, are associated with poor prognosis, likely due to poor responses to most systemic therapies and lack of targeted drugs. The latest published clinical trial data on new small-molecule KRAS G12C inhibitors, AMG510 and MRTX849, indicate that these molecules may potentially help treat KRAS-mutant NSCLC. Simultaneously, within the immuno-therapeutic process, immune efficacy has been observed in those patients who have KRAS mutations. In this article, the pathogenesis, treatment status, progress of immunotherapy, and targeted therapy of KRAS-mutant NSCLC are reviewed.

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“…To study this hypothesis, we first collated the largest publicly available cohort of ICItreated (anti-PD1/anti-PDL1) patient's responses with TMB and demographic information, comprising 1959 patients [4,5,7,8] together with an additional new cohort of 318 patients, comprising a total of 2277 patients across 14 cancer types. Analyzing this combined cohort, we first aimed to depict the association between TMB-H and patients' response to ICI in each cancer type.…”

Section: Mainmentioning

confidence: 99%

Immune determinants of the association between tumor mutational burden and immunotherapy response across cancer types

Sinha

Valero

et al. 2021

Preprint

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The FDA has recently approved high tumor mutational burden (TMB), defined by ≥10 mutations/Mb, as a biomarker for the treatment of solid tumors with pembrolizumab, an immune checkpoint inhibitor (ICI) that targets PD1. However, recent studies testify that high TMB levels are only able to stratify ICI responders in a subset of cancer types, where the mechanisms underlying this observation have remained unknown. We hypothesized that the tumor immune microenvironment (TME) may modulate the stratification power of TMB (termed TMB power) in a cancer type, leading to this observation. To systematically study this hypothesis, we analyzed TCGA expression data to infer the levels of 31 immune-related factors characteristic of the TME of different cancer types. We integrated this information with TMB and response data of 2,277 patients treated with anti-PD1 or anti-PD-L1 ICI to identify the key immune factors that can determine TMB power across 14 different cancer types. We find that high levels of M1 macrophages and low resting dendritic cells in the TME characterize cancer types with high TMB power. A model based on these two immune factors is strongly predictive of the TMB power in a given cancer type (Spearman Rho=0.76, P<3.6x10-04). Using this model, we provide predictions of the TMB power in nine additional cancer types, including rare cancers, for which TMB and ICI response data are not yet publicly available on a large scale. Our analysis indicates that TMB-High may be highly predictive of ICI response in cervical squamous cell carcinoma, suggesting that such a study should be prioritized.

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

Cited by 285 publications

References 57 publications

Association of Dynamic Changes in Peripheral Blood Indexes With Response to PD-1 Inhibitor-Based Combination Therapy and Survival Among Patients With Advanced Non-Small Cell Lung Cancer

Association of Dynamic Changes in Peripheral Blood Indexes With Response to PD-1 Inhibitor-Based Combination Therapy and Survival Among Patients With Advanced Non-Small Cell Lung Cancer

KRAS-Mutant Non-Small Cell Lung Cancer: An Emerging Promisingly Treatable Subgroup

Immune determinants of the association between tumor mutational burden and immunotherapy response across cancer types

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