Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Prognostic utility of baseline neutrophil-to-lymphocyte ratio in patients receiving immune checkpoint inhibitors: a review and meta-analysis

Abstract

Introduction

Systemic inflammation is associated with prognosis in solid tumors. The neutrophil-to-lymphocyte ratio (NLR) is a marker for the general immune response to various stress stimuli. Studies have shown correlation of NLR to outcomes in immune checkpoint blockade, peripheral neutrophil count to intratumor neutrophil population, and NLR to intratumoral levels of myeloid-derived suppressor cells. Studies have shown elevated peripheral blood regulator T cells accompanied by elevated NLR are associated with poor outcomes further highlighting the importance of inflammation in the prognosis of cancer patients.

Methods

We performed a meta-analysis of published articles on the utility of baseline NLR in predicting outcomes in patients treated with immune checkpoint inhibitors (ICIs) using Review Manager, version 5.3. Seven studies on the prognostic utility of NLR in ICI treatment were included in this analysis. For outcomes of interest, the hazard ratios (HRs) were computed. Subgroup analyses were planned based on type of malignancy and type of immune checkpoint inhibitor.

Results/discussion

A high NLR resulted in worse overall survival (OS) (HR, 1.92; 95% CI, 1.29–2.87; p=0.001) and progression-free survival (PFS; HR, 1.66; 95% CI, 1.38–2.01; p<0.00001) across types of malignancies studied (melanoma, non-small-cell lung cancer, and genitourinary cancer). Subgroup analysis across different types of malignancies treated with ICI showed similar results for OS and PFS. The single study on genitourinary cancers also showed worse OS and PFS (OS: HR, 1.82; 95% CI, 1.29–2.87; p=0.001 and PFS: HR, 1.83; 95% CI, 0.97–3.44; p=0.06). A high NLR also showed worse OS and PFS across all ICIs (ipilimumab, nivolumab, and unspecified or pooled pembrolizumab and nivolumab; OS: HR, 1.92; 95% CI, 1.29–2.87; p=0.001 and PFS: HR, 1.66; 95% CI, 1.38–2.01; p<0.00001). Subgroup analysis by type of ICI showed similar results.

Conclusion

A high NLR is associated with poorer outcomes across studies. This shows that NLR has the potential as a readily available prognostic indicator for patients receiving ICI based on available studies. Studies utilizing more stringent design may serve to better determine the utility of this tool.

Keywords: neutrophil-to-lymphocyte ratio, immunotherapy, biomarkers, inflammation

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827677/

Cancer‐related circulating and tumor‐associated neutrophils – subtypes, sources and function



Abstract
In recent years, the role of neutrophils in cancer biology has been a matter of increasing interest. Many patients with advanced cancer show high levels of neutrophilia, tumor neutrophils are connected to dismal prognosis, and the neutrophil‐to‐lymphocyte ratio has been introduced as a significant prognostic factor for survival in many types of cancer. Neutrophils constitute an important portion of the infiltrating immune cells in the tumor microenvironment, but controversy has long surrounded the function of these cells in the context of cancer. Multiple evidences have shown that neutrophils recruited to the tumor can acquire either protumor or antitumor function. These findings have led to the identification of multiple and heterogeneous neutrophil subsets in the tumor and circulation. In addition, tumor‐associated neutrophils (TANs) were shown to demonstrate functional plasticity, driven by multiple factors present in the tumor microenvironment. In this review, we examine the current knowledge on cancer‐related circulating neutrophils, their source and the function of the different subtypes, both mature and immature. We then discuss the pro vs antitumor nature of TANs in cancer, their functional plasticity and the mechanisms that regulate neutrophil recruitment and polarization. Although the vast majority of the knowledge on neutrophils in cancer comes from murine studies, recent work has been done on human cancer‐related neutrophils. In the final paragraphs, we expand on the current knowledge regarding the role of neutrophils in human cancer and examine the question whether cancer‐related neutrophils (circulating or intratumoral) could be a new possible target for cancer immunotherapy.


https://febs.onlinelibrary.wiley.com/do ... febs.14524

I read that this dual nature of the pro vs antitumor nature of TANs in cancer might be the reason that sometimes there is a true hyperprogression under the ICI treatments, or a progression after the ablations or radio surgeries are used in attempt to create an abscopal effect - it is all about the timing and evolution of their role as the time goes and its interplay with the immune-checkpoint inhibitors. It seems that inhibiting the checkpoints in some situations can actually help the tumors to progress hence the hyperprogression or accrued resistance cases.

Olga
That’s interesting to hear .

“The good, the bad, and the ugly: hyperprogression in cancer patients following immune checkpoint therapy”

This article has some pretty great studies talking of hyper-progression research

https://genomemedicine.biomedcentral.co ... 019-0661-7

I thought this was an interesting thought on possible risk factors pertaining to hyper progression

“Risk factors
HPD has been shown to be associated with several putative risk factors, including age, genomic alterations, and metastasis burden, although the generalizability of these findings is currently unclear owing to limitations in cohort size and composition. “
Then further explained -

“For example, in a cohort of 131 patients across multiple tumor types, the 12 patients with HPD were significantly older, while age was correlated with tumor growth as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria [1]. To accurately assess patient risk and benefit, future studies that examine these preliminary findings need to control for tumor type, stage, and other clinical covariates, particularly in studies that examine these same covariates and their association with response or resistance to immunotherapy. In a similar study of 102 patients with multiple cancer types, alterations in EGFR were predominant while MDM2/MDM4 amplifications were exclusive to six patients with HPD [6]. While other studies have also noted MDM2/MDM4 alterations in select HPD patients [7, 8], this is not the case in non-small cell lung carcinoma (NSCLC) [9]. Some investigators have found that regional recurrence in head and neck squamous cell carcinoma (HNSCC) [4] or more than two metastatic sites in NSCLC [2] prior to therapy are associated with a higher incidence of HPD. Regional recurrence in HNSCC and metastatic disease in most other cancer types are associated with a poor prognosis, because the tumors have successfully acquired the necessary traits for survival in the primary lesion and metastasis to distant sites. Therefore, it can be difficult to disentangle the relative effects of prognostic versus predictive factors. Ultimately, while the prospect of identifying predictive correlates that potentially either spare or curtail disease progression in patients at risk for developing HPD is attractive, it is important to address, and control for, the degree to which these correlates are simply prognostic for the patients represented in an HPD subgroup. Additional studies are necessary to validate and determine the breadth of tumor histologies for which each risk factor is predictive.“

Whole genome sequence analysis links chromothripsis to EGFR, MDM2, MDM4, and CDK4 amplification in glioblastoma



Abstract

Background

Findings based on recent advances in next-generation sequence analysis suggest that, in some tumors, a single catastrophic event, termed chromothripsis, results in several simultaneous tumorigenic alterations. Previous studies have suggested that glioblastoma (GBM) may exhibit chromothripsis at a higher rate (39%) than other tumors (9%). Primary glioblastoma is an aggressive form of brain cancer that typically appears suddenly in older adults. With aggressive treatment, the median survival time is only 15 months. Their acute onset and widespread genomic instability indicates that chromothripsis may play a key role in their initiation and progression. GBMs are often characterized by EGFR amplification, CDKN2A and PTEN deletion, although approximately 20% of GBMs harbor additional amplifications in MDM2 or MDM4 with CDK4.




https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549359/

Abstract
In recent years, the paradigm that genomic abnormalities in cancer cells arise through progressive accumulation of mutational events has been challenged by the discovery of single catastrophic events. One such phenomenon termed chromothripsis, involving massive chromosomal rearrangements arising all at once, has emerged as a major mutational game changer. The strong interest in this process stems from its widespread association with a range of cancer types and its potential as a mutational driver.

In this review, we first describe chromothripsis detection and incidence in cancers. We then explore recently proposed underlying mechanistic origins, which explain the curious observations of the highly localised nature of the rearrangements on chromothriptic chromosomes. Detection of chromothriptic patterns following incorporation of single chromosomes into micronuclei or following telomere attrition have greatly contributed to our understanding of the reasons behind this chromosomal restriction. These underlying cellular events have been found to be participants in the tumourigenic process, strongly suggesting a potential role for chromothripsis in cancer development. Thus, we discuss potential implications of chromothripsis for cancer progression and therapy.
https://www.sciencedirect.com/science/a ... 4218300322

Abstract

Unbalanced translocations are a relatively common type of copy number variation and a major contributor to neurodevelopmental disorders. We analyzed the breakpoints of 57 unique unbalanced translocations to investigate the mechanisms of how they form. Fifty-one are simple unbalanced translocations between two different chromosome ends, and six rearrangements have more than three breakpoints involving two to five chromosomes. Sequencing 37 breakpoint junctions revealed that simple translocations have between 0 and 4 base pairs (bp) of microhomology (n = 26), short inserted sequences (n = 8), or paralogous repeats (n = 3) at the junctions, indicating that translocations do not arise primarily from nonallelic homologous recombination but instead form most often via nonhomologous end joining or microhomology-mediated break-induced replication. Three simple translocations fuse genes that are predicted to produce in-frame transcripts of SIRPG-WWOX, SMOC2-PROX1, and PIEZO2-MTA1, which may lead to gain of function. Three complex translocations have inversions, insertions, and multiple breakpoint junctions between only two chromosomes. Whole-genome sequencing and fluorescence in situ hybridization analysis of two de novo translocations revealed at least 18 and 33 breakpoints involving five different chromosomes. Breakpoint sequencing of one maternally inherited translocation involving four chromosomes uncovered multiple breakpoints with inversions and insertions. All of these breakpoint junctions had 0–4 bp of microhomology consistent with chromothripsis, and both de novo events occurred on paternal alleles. Together with other studies, these data suggest that germline chromothripsis arises in the paternal genome and may be transmitted maternally. Breakpoint sequencing of our large collection of chromosome rearrangements provides a comprehensive analysis of the molecular mechanisms behind translocation formation....


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484391


“Molecular Pathogenesis of Alveolar Soft Part Sarcoma. ASPS is characterized by an unbalanced translocation between the X chromosome and chromosome 17, first described in a seminal paper by Ladanyi et al. ... The t(X;17)(p11;25) translocation. (a) The ASPSCR-1 gene is located at chromosome 17q25 and the TFE3 gene at Xp11.Apr 8, 2012”


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337503/

/

Abstract
In 2011, a novel form of genome instability was reported by Stephens et al., characterized by tens to hundreds of locally clustered rearrangements affecting one or a few chromosome(s) in cancer cells. This phenomenon, termed chromothripsis, is likely due to a single catastrophic event leading to the simultaneous formation of multiple double-strand breaks, which are repaired by error-prone mechanisms. Since then, the occurrence of chromothripsis was detected in a wide range of tumor entities. In this review, we will discuss potential mechanisms of chromothripsis initiation in cancer and outline the prevalence of chromothripsis across entities. Furthermore, we will examine how chromothriptic events may promote cancer development and how they may affect cancer therapy.

© 2015 UICC.
PMID 26455580 [Indexed for MEDLINE]

https://www.ncbi.nlm.nih.gov/m/pubmed/26455580/

Full text -


https://onlinelibrary.wiley.com/doi/ful ... /ijc.29888

Chromothripsis is the phenomenon by which up to thousands of clustered chromosomal rearrangements occur in a single event in localised and confined genomic regions in one or a few chromosomes, and is known to be involved in both cancer and congenital diseases.

Chromoplexy refers to a class of complex DNA rearrangement observed in the genomes of cancer cells. ... Along with chromothripsis, and break-fusion-bridge cycles, chromoplexy is an example of chromoanagenesis, a catch-all term for events that generate complex structural chromosomal abnormalities.

https://en.m.wikipedia.org/wiki/Chromoplexy

D.ap wrote: ↑Wed Dec 18, 2019 1:32 pm Olga
That’s interesting to hear .

“The good, the bad, and the ugly: hyperprogression in cancer patients following immune checkpoint therapy”

This article has some pretty great studies talking of hyper-progression research

https://genomemedicine.biomedcentral.co ... 019-0661-7

I thought this was an interesting thought on possible risk factors pertaining to hyper progression

“Risk factors
HPD has been shown to be associated with several putative risk factors, including age, genomic alterations, and metastasis burden, although the generalizability of these findings is currently unclear owing to limitations in cohort size and composition. “
Then further explained -

“For example, in a cohort of 131 patients across multiple tumor types, the 12 patients with HPD were significantly older, while age was correlated with tumor growth as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria [1]. To accurately assess patient risk and benefit, future studies that examine these preliminary findings need to control for tumor type, stage, and other clinical covariates, particularly in studies that examine these same covariates and their association with response or resistance to immunotherapy. In a similar study of 102 patients with multiple cancer types, alterations in EGFR were predominant while MDM2/MDM4 amplifications were exclusive to six patients with HPD [6]. While other studies have also noted MDM2/MDM4 alterations in select HPD patients [7, 8], this is not the case in non-small cell lung carcinoma (NSCLC) [9]. Some investigators have found that regional recurrence in head and neck squamous cell carcinoma (HNSCC) [4] or more than two metastatic sites in NSCLC [2] prior to therapy are associated with a higher incidence of HPD. Regional recurrence in HNSCC and metastatic disease in most other cancer types are associated with a poor prognosis, because the tumors have successfully acquired the necessary traits for survival in the primary lesion and metastasis to distant sites. Therefore, it can be difficult to disentangle the relative effects of prognostic versus predictive factors. Ultimately, while the prospect of identifying predictive correlates that potentially either spare or curtail disease progression in patients at risk for developing HPD is attractive, it is important to address, and control for, the degree to which these correlates are simply prognostic for the patients represented in an HPD subgroup. Additional studies are necessary to validate and determine the breadth of tumor histologies for which each risk factor is predictive.“

Elevated preoperative neutrophil/lymphocyte ratio is associated with poor prognosis in soft-tissue sarcoma patients


Elevated preoperative neutrophil/lymphocyte ratio is associated with poor prognosis in soft-tissue sarcoma patients


Abstract
Background:
Recent data indicate that tumour microenvironment, which is influenced by inflammatory cells, has a crucial role in cancer progression and clinical outcome of patients. In the present study, we investigated the prognostic relevance of preoperative neutrophil/lymphocyte (N/L) ratio on time to tumour recurrence (TTR) and overall survival (OS) in soft-tissue sarcoma (STS) patients who underwent curative surgical resection.

https://www.nature.com/articles/bjc2013135#Tab2