Introduction
Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell dealth-1/program cell death ligand-1 (PD-1/PDL-1) proteins are able to augment host anti-tumor immune response (Kantarjian et al.
2016; Patel and Minn
2018). Despite the advent of new immunotherapies, there are few clinical prognostic tools available for patients who are offered treatment with ICIs. Previous studies have evaluated PD-L1 expression and tumor mutational burden (TMB) as potential biomarkers. These markers have shown great promise, but there are significant limitations due to cost, assay variability and tumor heterogeneity of PD-L1 expression (McLaughlin et al.
2016; Rimm et al.
2017), need for adequate tissue, requirement for invasive biopsy, and lack of standardization for interpretation of TMB (Rizvi et al.
2015; Carbone et al.
2017; Hellmann et al.
2018).
Cancer-associated inflammation leads to poor survival (Naqash et al.
2018; Hanahan and Weinberg
2011; Mantovani et al.
2008). Neutrophil to lymphocyte ratio (NLR) has been studied as a marker for systemic inflammation (Naqash et al.
2018). NLR has been demonstrated to be prognostic for cancer patients who have received ICI, with low baseline NLR at the start of ICIs being associated with favorable clinical outcomes (Naqash et al.
2018; Ameratunga et al.
2018; Lalani et al.
2018; Sacdalan et al.
2018; Lawati
2018; Park et al.
2018; Bagley et al.
2017; Zaragoza et al.
2015; Khoja et al.
2016). In past studies, the decrease in NLR during treatment was associated with improved survival. However, the decrease in NLR has not been quantitated. Instead, patients with decreasing NLR were combined into a single cohort with favorable OS. To evaluate whether there is any association between the degree of change and overall survival, we studied NLR at baseline and during ICI treatments in patients with advanced cancer at our institution.
Discussion
In the era of cancer immunotherapy, indications for ICI use in cancer care are expanding at a rapid pace (Antonia et al.
2017; Marin-Acevedo et al.
2018). Previous studies explored high PDL-1 expression and tumor mutation burden (TMB) as potential predictive biomarkers. Patients with high tumor expression of PD-L1 tend to have a better outcome (Garon et al.
2015; Gettinger et al.
2014; Reck et al.
2016). However, the durable benefit seen in some patients without PD-L1 expression limits its role as an exclusionary prognostic biomarker. TMB has also shown promise (Rizvi et al.
2015; Carbone et al.
2017; Hellmann et al.
2018). However, there is a lack of standardization for TMB calculation, a variety of assays available, and not all tumor mutations will lead to altered proteins that are measured by TMB (Rizvi et al.
2015; Carbone et al.
2017). Furthermore, both PDL-1 expression and TMB analysis require expensive and invasive biopsies to obtain tissue samples, which are impractical to use for frequent biomarker monitoring. Recent evidence has suggested the microbiome as an additional marker, though it has not been widely adopted (Routy et al.
2018).
In this study, we confirmed the prognostic value of NLR at the initiation of ICI treatment. Interestingly, the relationship between NLR and survival was non-linear. Only a moderate decrease in NLR was associated with the longest OS. An excessive decline in NLR was associated with reduced OS.
NLR is calculated from existing routine labs for patients who are receiving ICI and it is obtained with a routine peripheral blood draw. The inexpensive and readily available nature of NLR allows it to be conveniently monitored overtime. The change in NLR is a useful biomarker to the extent that it can be calculated in a timely manner in the clinic. Ideally, the baseline NLR value would stratify patients who will respond to ICI vs. those who are better suited to alternative treatments such as chemotherapy. More study is needed to validate this prediction, and if it holds, to identify the optimal time for repeat NLR.
The mechanism by which NLR relates to ICI activity and OS is unknown. Our results show that large increases or decreases are negatively associated with OS. Large increases in NLR may reflect increased tumor burden, lack of ICI efficacy and, therefore, decreased OS. Large decreases in NLR are more challenging to interpret. We observed that change in NLR is driven primarily by the decline in neutrophils and that the lymphocyte count remained relatively constant in our patient population. The common causes of decline in neutrophils can include decreased bone marrow activity, infection, and malnutrition, all of which have been shown to impact OS (Bouteloup et al.
2017). Agranulocytosis and neutropenia may also rarely occur as a result of auto-immune toxicity from ICI treatment (Barbacki et al.
2018).
This is the first study to demonstrate the non-linear relationship between change in NLR and OS during ICI treatment. There are several limitations in our study, including its retrospective nature, unknown mechanism of action, inclusion of a heterogeneous patient population, and the inability to evaluate variables with known predictive power in this context, notably the line of therapy and mutation status. Further studies looking into relationship between NLR and tumor micro-environment, medication interactions, infection, nutrition status, microbiota, line of therapy, and immune-related adverse events may help to delineate the mechanisms between the non-linear change in NLR and OS. Prospective studies with a larger patient cohort are needed for validation.
Conclusion
This is the first study to demonstrate the non-linear relationship between change in NLR and survival during ICI treatment for patients with advanced cancer. Further studies looking into the reasons for this non-linear relationship, including possibly the contributions of tumor micro-environment, infection, nutrition status, microbiota, and other immune-related adverse events to change in NLR may help to delineate the mechanisms between the non-linear change in NLR and clinical outcomes.
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