Biomarkers For Cancer Prediction Research Articles

Tumour Mutational Burden and Immune Checkpoint Inhibitor Response in Non-small Cell Lung Cancer: A Continuous Modelling Approach.

Tumour mutational burden (TMB) is an established biomarker for patients treated with immune checkpoint inhibitors (ICIs). The optimal TMB cut-off is uncertain. It is also uncertain whether there is a sharp TMB threshold or a more graduated change in clinical outcomes as TMB increases. We aimed to determine the relationship between TMB and ICI treatment outcomes using alternative statistical approaches in patients with non-small cell lung cancer. Tumour mutational burden was evaluated as a prognostic and predictive biomarker in advanced non-small cell lung cancer utilising data from two real-world cohorts of ICI use (n = 968) and three randomised controlled trials evaluating ICIs (n = 1588). The non-linear relationship between continuous TMB and response/survival/efficacy outcomes was evaluated using statistical methods that do not require specifying a TMB cut-off. Median TMB for all cohorts was seven mutations/megabase, excluding MYSTIC, where the median was 13 mutations/megabase. Progressively higher TMB was significantly associated with a progressively higher objective response rate and progression-free survival in ICI-treated patients in Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] (objective response rate: p < 0.001, progression-free survival: p < 0.001), Strata Clinical Molecular Database [SCMD] (progression-free survival: p = 0.023) and OAK/POPLAR (objective response rate: p = 0.017, progression-free survival: p < 0.001) This relationship was not apparent for patients treated with chemotherapy. There was no obvious TMB threshold for ICI response. The relationship between TMB and overall survival was more complex and heterogeneous. Using a single cut-off to analyse a continuous biomarker may hide important information. Methods that provide more nuance to the underlying relationship between TMB and outcomes enable readers to judge for themselves the value and limitations of TMB cut-offs proposed for clinical practice.

Electrochemical immunosensor for the predictive cancer biomarker SLFN11 using reduced graphene oxide/MIL-101(Cr)-NH2 composite

SLFN11 is a predictive cancer biomarker essential for identifying tumors that are sensitive to DNA-damaging agents, facilitating more personalized and effective treatment approaches. Detecting this biomarker can guide therapeutic decisions and improve outcomes for cancer patients. However, existing detection methods for SLFN11 are complex and require advanced techniques. In this study, we introduce the first immunosensor designed for on-site detection of SLFN11. An advanced electrochemical immunosensor platform utilizing a composite of graphene oxide (GO) and chromium-based metal organic framework (MIL-101 (Cr)-NH2) was developed. The integration of GO and MIL-101(Cr)-NH2 was characterized through FT-IR, XRD, SEM, and XPS, affirming the formation of the composite. The subsequent electrochemical reduction to rGO/MIL-101(Cr)-NH2 significantly improved the electrochemical performance and stability. A glutaraldehyde cross-linker was then utilized to attach the SLFN11-specific antibody to the amine groups of the MOF-modified electrodes. This led to the development of rapid, sensitive, portable, and cost-effective immunosensor for SLFN11 at concentrations as low as 8.9 pg/mL which holds promise for early cancer diagnosis. High specificity was achieved, with minimal cross-reactivity observed with other cancer biomarkers such as pepsinogen I, claudin 18.2 and Programmed cell death protein 1. Demonstrating practical applicability, the electrochemical immunosensor validated by commercial ELISA kit showed successful detection in serum samples with high recovery rates and reproducibility. This research highlights the potential of rGO/MOFs composites in electrochemical biosensors developments for early cancer diagnostics and personalized medicine.

Agreement between Ki-67 Proliferative Index in Breast Cancer by Conventional Hotspot Method and International Ki-67 in Breast Cancer Working Group Global Scoring Method: A Cross-sectional Study

Introduction: The role of the Ki-67 Proliferative Index (PI) in the molecular classification and as a predictive and prognostic biomarker in breast cancer is definitive. To address the inconsistency in Ki-67 interpretation and scoring, the International Ki-67 in Breast Cancer Working Group (IKWG) introduced the visual scoring Android Application (APP) and proposed a standardised scoring method. Aim: To determine Ki-67 proliferative indices by both the Global Method (GW) with the Ki-67 visual scoring app recommended by IKWG and conventional institutional Hotspot Method (HM), and to analyse the agreement between the indices obtained by these two methods. Materials and Methods: A cross-sectional study involving 71 Ki-67 immunostained hormone receptor-positive trucut biopsies of breast cancers from January 2022 to January 2024 were retrospectively collected. Two observers independently scored the biopsies using HM and GW by an app in the Department of Pathology of a tertiary care centre. The GW scores of Ki-67 PI obtained were categorised into low, intermediate and high groups based on 2015 St. Gallen guidelines. A two-way random Intraclass Correlation Coefficient (ICC) was used to assess the absolute agreement between two scorers. Results: The overall intraclass correlation between interobserver values by HM was 0.819 (good), while it was 0.971 (excellent) by GW. The overall interobserver mean difference was five times greater (p-value=0.008, statistically significant) than the overall interobserver global weighted scores (p-value=0.901, not statistically significant). Conclusion: The study highlighted the significant interobserver variability in HM compared to GW scores by the app. The standardised app scoring method has the potential to broaden the prognostic role of Ki-67 as a companion diagnostic tool.

Pan-cancer analysis of biallelic inactivation in tumor suppressor genes identifies KEAP1 zygosity as a predictive biomarker in lung cancer.

The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis posits that loss of both alleles is necessary for inactivation. Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. TSGs largely assort into distinct classes associated with either pan-cancer (Class 1) or lineage-specific (Class 2) patterns of selection for biallelic loss, although some TSGs are predominantly monoallelically inactivated (Class 3/4). We demonstrate that selection for biallelic inactivation can be utilized to identify driver genes in non-canonical contexts, including among variants of unknown significance (VUSs) of several TSGs such as KEAP1. Genomic, functional, and clinical data collectively indicate that KEAP1 VUSs phenocopy established KEAP1 oncogenic alleles and that zygosity, rather than variant classification, is predictive of therapeutic response. TSG zygosity is therefore a fundamental determinant of disease etiology and therapeutic sensitivity.

Prognostic significance of soluble forms of the PD-1 receptor and its ligand PD-L1 in gastric cancer

Introduction. Despite advances in the diagnosis and drug therapy of some cancers over the past decade, solid tumors, particularly gastric cancer, still have a poor prognosis and remain a leading cause of death worldwide. Therefore, the development of methods for timely diagnosis, identification of new targets for therapy and biochemical prognosis factors is an urgent problem in clinical oncology. In recent years, the focus of clinical attention has been on immune checkpoint receptors and ligands that can identify patients for immunotherapy. The clinical and prognostic significance of the levels of soluble forms of the programmed cell death receptor PD-1 and its ligand PD-L1 in the blood of patients with gastric cancer is currently not fully determined.Aim. Comparative study of the levels of sPD-1 and sPD-L1 in the blood plasma of healthy donors and patients with gastric cancer, taking into account the prevalence of the tumor process and the prognosis of overall survival.Materials and methods. The study included 100 patients with stomach cancer aged from 25 to 81 years (57 men, 43 women), who underwent examination and treatment at the N. N. Blokhin National Medical Research Center for Oncology. The concentration of sPD-L1 and sPD-1 was determined in blood plasma obtained according to standard methods before the start of specific treatment, using reagent kits for enzyme-linked immunosorbent assay “Human PD-L1 Platinum ELISA” and “Human PD-1 ELISA kit” (Affimetrix, eBioscience, USA) in accordance with the manufacturer’s instructions. The content of markers was expressed in picograms (pg) per 1 ml of blood plasma. To compare indicators and analyze their relationships, the nonparametric Mann–Whitney test was used. Overall survival analysis was performed using the Kaplan–Meier method. For all statistical tests, p values &lt;0.05 were considered statistically significant.Results. The analysis did not reveal a connection at a threshold level of sPD-1 of 8.0 pg / ml in the blood plasma of patients with gastric cancer with overall survival rates (p = 0.59). However, an additional analysis conducted in a group of patients with gastric cancer with stages I–II demonstrated that a marker level ≥8.0 pg / ml is a favorable prognostic factor (p = 0.0039), while in advanced stages III–IV the disease it has no prognostic significance. There was no significant correlation between sPD-L1 concentrations in the blood plasma of patients with gastric cancer and overall survival rates (p = 0.35), however, the best long-term results were found at a threshold level of marker concentrations in blood plasma &lt;35 pg / ml.Conclusion. An sPD-1 level ≥8.0 pg / ml can serve as a favorable prognostic factor in stages I–II of gastric cancer, while in advanced stages III–IV of the disease it has no prognostic significance. The prognostic role of sPD-L1 in patients with gastric cancer has not been identified. The study needs to be continued in combination with additional predictive biomarkers for gastric cancer.

Predictive and prognostic biomarkers in cancer: towards the precision medicine era

Predictive and prognostic biomarkers in cancer: towards the precision medicine era

087. Relationship Between Neutrophil-Lymphocyte Ratio and Serum Thyroid Stimulating Hormone Preoperative Thyroidectomy as Predictors of Papillary Thyroid Cancer

Background: Thyroid cancer is the most common endocrine malignancy. The incidence of papillary thyroid cancer has been increasing. Early diagnosis and management are crucial for thyroid cancer. Therefore, the availability of predictive biomarkers for papillary thyroid cancer is important. This study aims to determine whether the preoperative Neutrophil-Lymphocyte Ratio (NLR) and Thyroid Stimulating Hormones (TSH) levels can be used as predictors of papillary thyroid cancer. Methods: Ninety-one patients with thyroid nodules who underwent thyroidectomy surgery at RSUP Prof. DR. R.D. Kandou were retrospectively analyzed. Complete blood count with differential count and serum TSH levels were taken before thyroidectomy. Results: The relationship between TSH levels and papillary thyroid cancer was significant, with a p-value of 0.025, sensitivity of 51.1%, and specificity of 73.9%. The relationship between NLR and papillary thyroid cancer was also significant, with a p-value of &lt;0.001, sensitivity of 68.9%, and specificity of 100%. However, the combination of NLR and TSH did not show a synergistic effect as predictors of papillary thyroid cancer due to several unstudied factors, such as IL-6, IL-37, ROS, NO, and NK cells, which may play a role in the pathogenesis of thyroid cancer. The limitations of this study include its retrospective cross-sectional design and the lack of further investigation into other factors, such as IL-6, IL-37, ROS, NO, and NK cells, due to limited facilities and time. Conclusion: Both NLR and TSH can be used as predictors of papillary thyroid cancer. NLR is more potent than TSH as a predictor.

Metabolomics: A Tool to Envisage Biomarkers in Clinical Interpretation of Cancer.

Cancer is amongst the most dreadful ailments of modern times, and its impact continuously worsens global health systems. Early diagnosis and suitable therapeutic agents are the prime keys to managing this disease. Metabolomics deals with the complete profiling of cells and physiological phenomena in their organelles, thus helping in keen knowledge of the pathological status of the disease. It has been proven to be one of the best strategies in the early screening of cancer. This review has covered the recent updates on the promising role of metabolomics in the identification of significant biochemical markers in cancer-prone individuals that could lead to the identification of cancer in the early stages. The literature was collected through various databases, like Scopus, PubMed, and Google Scholar, with stress laid on the last ten years' publications. It was assessed in this review that early recognition of cancerous growth could be achieved via complete metabolic profiling in association with transcriptomics and proteomics. The outcomes are rooted in various clinical studies that anticipated various biomarkers like tryptophan, phenylalanine, lactates, and different metabolic pathways associated with the Warburg effect. This metabolite imaging has been a fundamental step for the target acquisition, evaluation of predictive cancer biomarkers for early detection, and outlooks into cancer therapy along with critical evaluation. Significant efforts should be made to make this technique most reliable and easy.

Tumorspheres as In Vitro Model for Identifying Predictive Chemoresistance and Tumor Aggressiveness Biomarkers in Breast and Colorectal Cancer.

Chemoresistance remains a major challenge in the treatment of breast and colorectal cancer. For this reason, finding reliable predictive biomarkers of response to chemotherapy has become a significant research focus in recent years. However, validating in vitro results may be problematic due to the outcome heterogeneity. In this study, we evaluate the use of tumorspheres as an in vitro model for validating biomarkers of chemoresistance in breast and colorectal cancer. Our investigation highlights the crucial role of inflammation-related pathways in modulating the response to chemotherapy. Using in silico approaches, we identified specific markers elevated in responders versus non-responders patients. These markers were consistently higher in three-dimensional (3D) tumorsphere models compared to traditional adherent cell culture models. Furthermore, the number of tumorspheres from breast and colorectal cancer cells increased in response to cisplatin and oxaliplatin treatment, respectively, whereas cell viability decreased in adherent cell culture. This differential response underscores the importance of the 3D tumorsphere model in mimicking the tumor microenvironment more accurately than adherent cell culture. The enhanced chemoresistance observed in the 3D tumorspheres model and their correlation of data with the in silico study suggest that 3D culture models are a better option to approach the in vivo model and also to validate in silico data. Our findings indicate that tumorspheres are an ideal model for validating chemoresistance biomarkers and exploring the interplay between inflammation and chemoresistance in breast and colon cancer.

Plasma miR-122-5p and miR-142-5p and their role in chemoresistance of colon cancer patients.

Chemoresistance represents a major issue affecting cancer therapy efficacy. Because microRNAs (miRNAs) regulate gene expression on multiple levels, their role in chemoresistance development is reasonably certain. In our previous study, miR-122-5p and miR-142-5p were identified as diagnostic, prognostic, and predictive biomarkers for primary and metastatic rectal cancer. The aim of the present study was to investigate whether these miRNAs can also reflect the disease course of colon cancer (CC) patients. Further, we focused on a deeper understanding of their involvement in 5-fluorouracil (5-FU) chemoresistance development. The expression analysis of both miRNAs was analysed in repeated whole plasma samplings (n=3, approximately every 6 months) of CC patients (n=49) by RT-qPCR. Expression levels of both miRNAs were determined in the 5-FU sensitive and resistant CC cell lines. From RNA-seq profiles of both sensitive and 5-FU resistant DLD-1 cell lines, the expression levels of miR-122-5p and miR-142-5p validated target genes were detected and compared. Significant differences in the expression levels of both miRNAs between T0 and T1 or T2 samplings were observed. Further, an association between the occurrence of relapse and miR-122-5p expression levels was noticed. Patients who did not relapse had higher expression of miR-122-5p at T1 (p=0.01; 3.16-fold change) and T2 (p=0.04; 2.79-fold change) samplings in comparison with T0 sampling. Out of all miR-122-5p validated targets (n=102), 25 genes were significantly differentially expressed between sensitive and 5-FU-resistant cell lines. Our data suggest that miR-122-5p may represent a predictive marker of tumour relapse in CC patients. In vitro data suggests that this aspect may be linked to the potential therapeutic targets of miR-122-5p related to 5-FU-based chemoresistance. However, deeper mechanistic studies are still needed for progress toward personalized medicine.

Circulating miRNA panels as a novel non-invasive diagnostic, prognostic, and potential predictive biomarkers in non-small cell lung cancer (NSCLC)

BackgroundNon-small cell lung cancer (NSCLC) is characterised by its aggressiveness and poor prognosis. Early detection and accurate prediction of therapeutic responses remain critical for improving patient outcomes. In the present study, we investigated the potential of circulating microRNA (miRNA) as non-invasive biomarkers in patients with NSCLC.MethodsWe quantified miRNA expression in plasma from 122 participants (78 NSCLC; 44 healthy controls). Bioinformatic tools were employed to identify miRNA panels for accurate NSCLC diagnosis. Validation was performed using an independent publicly available dataset of more than 4000 NSCLC patients. Next, we correlated miRNA expression with clinicopathological information to identify independent prognostic miRNAs and those predictive of anti-PD-1 treatment response.ResultsWe identified miRNA panels for lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) diagnosis. The LUAD panel consists of seven circulating miRNAs (miR-9-3p, miR-96-5p, miR-147b-3p, miR-196a-5p, miR-708-3p, miR-708-5p, miR-4652-5p), while the LUSC panel comprises nine miRNAs (miR-130b-3p, miR-269-3p, miR-301a-5p, miR-301b-5p, miR-744-3p, miR-760, miR-767-5p, miR-4652-5p, miR-6499-3p). Additionally, miR-135b-5p, miR-196a-5p, miR-31-5p (LUAD), and miR-205 (LUSC) serve as independent prognostic markers for survival. Furthermore, two miRNA clusters, namely miR-183/96/182 and miR-767/105, exhibit predictive potential in anti-PD-1-treated LUAD patients.ConclusionsCirculating miRNA signatures demonstrate diagnostic and prognostic value for NSCLC and may guide treatment decisions in clinical practice.

Effects of exosomes and inflammatory response on tumor: a bibliometrics study and visualization analysis via CiteSpace and VOSviewer

BackgroundTumor is a new organism formed by abnormal hyperplasia of local tissue cells under the action of various tumorigenic factors. Inflammation plays a decisive role in inducing tumorigenesis, promoting tumor development, invasion and migration. More and more evidence indicate that exosomes are involved in regulating the formation of tumor microenvironment in the process of proinflammatory carcinogenesis, leading to the stimulation of anti-tumor immune response or systemic immunosuppression, and exosomes play a crucial role in the development of tumor.MethodsThe articles on tumor-derived exosomes and inflammatory responses from January 2005 to January 2024 were collected through Web of Science (WOS), and the inclusion criteria were “Article”, “Review Article” and “Early Access”. Articles obtained after excluding “Book Chapters”, “Editorial Material”, “Proceeding Paper”, “Meeting ” and “Retracted Publication”. Bibliometrics and visualization analysis were carried out on the obtained articles using CiteSpace6.2.R6 and VOSviewer1.6.20.ResultsTotal of 703 articles were included. The number of published documents showed a fluctuating growth trend year by year. A total of 61 countries have participated in the research on the effects of exosomes and inflammatory responses on tumors, among which China and the United States have the largest influence in this field. The obtained articles have been published in 60 journals around the world, among which PLOS ONE and NAT REV IMMUNOL are the journals with the most published articles and the highest co-citations respectively. The article from French author THERY C was cited the most (202 times). As a major researcher on the basic function of exosomes, THERY C established the gold standard for extraction, separation and identification of exosomes, and found that exosomes promote tumor metastasis through direct regulation of miRNA. Her research has had a huge impact on the field. Keyword co-occurrence analysis indicate that extracellular vesicles, inflammation, cancer, miRNAs, mesenchymal stem cells, drug delivery, gastric cancer and circulating endothelial microparticles are the research hotspot at present stage. The main keywords of the cluster analysis show that extracellular vesicles, human papilloma virus, myeloid cells, tumor macro-environment are the current research hotspots and frontier. The research hotspots have developed over time from the time chart of keywords and clustering, especially after 2016, exosomes have established extensive links with drug delivery, cancer treatment, inflammatory response and other fields. Tumor-derived exosomes stimulate receptor cells to secrete pro-inflammatory cytokines and growth factors, enabling immune and inflammatory cells to perceive the intracellular environment of cancer cells even when cancer cells do not express any tumor-specific antigens. For example, in anoxic environment, cancer cells can secrete exosomes containing pro-inflammatory factors to promote the invasion and metastasis of cancer cells. In the complex tumor microenvironment, both tumor cells and various stromal cells will secrete specific exosomes, and promote the development of tumors through various ways, so that tumor cells have drug resistance, and bring adverse effects on the clinical treatment of tumor patients. MicroRNAs and long noncoding RNA as hot keywords play important roles in regulating and mediating tumor development, and their specificity makes them important biomarkers for cancer prediction and diagnosis. Highlighting word analysis shows that microRNAs secreted by leukemia patients can effectively promote the proliferation of malignant cells and the development of cardiovascular diseases. At the same time, exosomes can induce the secretion of some microRNAs in patients, leading to cardiac repair and regeneration. Therefore, the detection and screening of microRNAs plays a crucial role in predicting the incidence of cardiovascular diseases in patients.ConclusionExosomes have attracted increasing attention due to their significant heterogeneity and ability to regulate the tumor immune microenvironment. However, tumor cell-derived exosomes accelerate tumor progression by enhancing immunosuppression and inflammation, increasing oxidative stress, and promoting angiogenesis, which may lead to poor prognosis.Graphical abstract

Exploring Predictive and Prognostic Biomarkers in Colorectal Cancer: A Comprehensive Review.

Colorectal cancer (CRC) remains the second leading cause of cancer-related mortality worldwide. While immune checkpoint inhibitors have significantly improved patient outcomes, their effectiveness is mostly limited to tumors with microsatellite instability (MSI-H/dMMR) or an increased tumor mutational burden, which comprise 10% of cases. Advancing personalized medicine in CRC hinges on identifying predictive biomarkers to guide treatment decisions. This comprehensive review examines established tissue markers such as KRAS and HER2, highlighting their roles in resistance to anti-EGFR agents and discussing advances in targeted therapies for these markers. Additionally, this review summarizes encouraging data on promising therapeutic targets and highlights the clinical utility of liquid biopsies. By synthesizing current evidence and identifying knowledge gaps, this review provides clinicians and researchers with a contemporary understanding of the biomarker landscape in CRC. Finally, the review examines future directions and challenges in translating promising biomarkers into clinical practice, with the goal of enhancing personalized medicine approaches for colorectal cancer patients.

ABCC2 induces metabolic vulnerability and cellular ferroptosis via enhanced glutathione efflux in gastric cancer.

Although it is traditionally believed that ATP binding cassette subfamily C member 2 (ABCC2) is a multidrug resistance-associated protein correlated with a worse prognosis, our previous and several other studies demonstrated the contrary to be true in gastric cancer (GC). We aim to explore the underlying mechanism of this discovery. Our study utilized whole-exome sequencing (WES), RNA sequencing, and droplet digital PCR (ddPCR) analysis of 80 gastric cancer samples, along with comprehensive immunohistochemical (IHC) analysis of 1044 human GC tissue samples.By utilizing CRISPRCas9 to genetically modify cell lines with the ABCC2-24C > T (rs717620) point mutation and conducting dual-luciferase reporter assays, we identified that transcription factors SOX9 and ETS1 serve as negative regulators of ABCC2 expression. Seahorse assay and mass spectrometry were used to discover altered metabolic patterns. Gain and loss-of-function experiments in GC cell lines and preclinical models were carried out to validate ABCC2 biological function. ABCC2 high expression correlated with better prognosis, and rs717620 can influence ABCC2 expression by disrupting the binding of ETS1 and SOX9. Gain and loss-of-function experiments in GC cell lines demonstrated amino acid deprivation reduces proliferation, migration, and drug resistance in ABCC2-high GC cells. ABCC2 leads to reduced intracellular amino acid pools and disruption of cellular energy metabolism. This phenomenon depended on ABCC2-mediated GSH extrusion, resulting in alterations in redox status, thereby increasing the cell's susceptibility to ferroptosis. Furthermore, patient-derived organoids and patient-derived tumor-like cell clusters were used to observe impact of ABCC2 on therapeutic effect. In the xenograft model with high ABCC2 expression, we observed that constricting amino acid intake in conjunction with GPX4 inactivation resulted in notable tumor regression. Our findings demonstrate a significant role of ABCC2 in amino acid metabolism and ferroptosis by mediating GSH efflux in GC. This discovery underlines the potential of combining multiple ferroptosis targets as a promising therapeutic strategy for GC with high ABCC2 expression. ABCC2 plays a crucial role in inducing metabolic vulnerability and ferroptosis in gastric cancer through enhanced glutathione efflux. The ABCC2 24C > T polymorphism is a key factor influencing its expression. These results highlight the potential of ABCC2 as a predictive biomarker and therapeutic target in gastric cancer.

Molecular Mechanisms and Potential Predictive Biomarkers in Advanced Non-small Cell Lung Cancer: A Summary of Current and Future Trends

Non-small-cell lung cancer (NSCLC) accounts for 85% of lung cancer cases and is associated with different risk factors (smoking habits, gender, and age). In this scenario, many studies have been conducted to pursue improvement of survival, faster and better therapy response, reduced adverse events, and expanded available therapies and treatments against tumor resistance to drugs. These studies have focused on defining the most prevalent NSCLC biomarkers (EGFR, HER2, ALK, MET, ROS1, BRAF, KRAS G12C, HER3, NTRK, and NRG1) and their actionability. It is noteworthy that expressed kinase receptors can have overlapping mechanisms of activation of different pathways (JAK-STAT, MAPK, PI3K-AKT-mTOR, and PLC-c), which can lead to the same outcome of cell proliferation, migration, and survival resulting in increased tumor resistance to treatment. This review provides an overview of the latest findings regarding NSCLC treatment, emphasizing particular biomarkers and potential molecularly altered pathways implicated as targeted therapies. Additionally, it explores the clinical significance of the proposed treatments, their implication on progression-free survival, ongoing clinical trials, and their perspective of evolution so far.

Lung Microbiome in Lung Cancer: A New Horizon in Cancer Study.

Lung cancer is the second most prevalent cancer worldwide and a leading cause of cancer-related deaths. Recent technological advancements have revealed that the lung microbiome, previously thought to be sterile, is host to various microorganisms. The association between the lung microbiome and lung cancer initiation, progression, and metastasis is complex and contradictory. However, disruption in the homeostasis of microbiome compositions correlated with the increased risk of lung cancer. This review summarizes current knowledge about the most recent developments and trends in lung cancer-related microbiota or microbial components. This article aims to provide information on this rapidly evolving field while giving context to the general role of the lung microbiome in lung cancer. In addition, this review briefly discussed the causative association of lung microbiome with lung cancer. We will review the mechanisms by which lung microbiota influence carcinogenesis, focusing on microbiota dysbiosis. Moreover, we will also discuss the host-microbiome interaction as it plays a crucial role in stimulating and regulating the immune response. Finally, we will provide information on the diagnostic role of the microbiome in lung cancer. This article aims to offer an overview of the lung microbiome as a predictive and diagnostic biomarker in lung cancer.

Predictive biomarkers for pathological complete response in early-stage triple negative breast cancer following neoadjuvant chemotherapy.

598 Background: Identifying predictive biomarkers for early-stage triple negative breast cancer (TNBC) is essential for tailoring neoadjuvant chemotherapy (NACT) strategies effectively. Methods: We investigated potential clinical and pathological biomarkers in early-stage TNBC patients who underwent NACT regimens with anthracyclines and taxanes at a single cancer center. Medical records were scrutinized for clinical and laboratory data, with categorical variables analyzed using Fisher’s exact test. Logistic regression assessed factors associated with pathological complete response (pCR). Sensitivity and specificity of the biomarkers were explored using receiver operating characteristics (ROC) curve analyses. Results: Among 110 TNBC patients receiving anthracycline- and taxane-based NACT with complete pathology data, the median age was 48 years, 60% had stage III tumors, and 30.9% achieved pCR. Stromal tumor infiltrating lymphocytes (TILs) &gt; 10% were observed in 54.5%, 32.7% had TILs ≥30%, and 90.9% had Ki67 ≥ 50%. Univariate analysis showed no association between pCR and TILs &gt;10% (p=0.5), Ki67 ≥ 50% (p=0.4), anatomic stage (p=0.06), eosinophil-to-lymphocyte ratio (p=0.3), platelet-to-lymphocyte ratio (p=0.08), age (p=0.5), grade (p=0.6), or HER2 status (p=0.6). Neutrophil-to-lymphocyte ratio (NLR) was significantly associated with pCR in both univariate (OR 3.92; 95% CI 1.67 - 9.57; p=0.002) and multivariable analyses (Table). No association was observed between NLR ≤ 1.76 and TILs, anatomic stage, or Ki67. The optimal NLR cutoff using ROC curve was 1.76, yielding 60.6% sensitivity and 71.8% specificity for pCR. NLR cutoffs of ≤ 1.43 had specificities higher than 85%. Although TILs value was not associated with pCR in the regression model, high TILs value (≥50%) yielded a specificity of 89.4% for pCR. Conclusions: NLR emerged as a significant and independent predictor of pCR in early-stage TNBC. Prospective studies should explore this readily available biomarker in assessing neoadjuvant strategy responses. Moreover, high specificities for pCR were observed with NLR ≤ 1.43 and TILs ≥ 50%, representing cutoff values that could be explored for treatment de-escalation. [Table: see text]

Abstract PO5-06-08: Real-world analysis of efficacy, adverse events and predictive biomarkers for advanced triple negative breast cancer (TNBC) treated with immune check point Inhibitors (ICI): A single center experience

Abstract Introduction KEYNOTE-355 investigated the addition of pembrolizumab to chemotherapy in advanced TNBC patients (pts) with PD-L1 positive tumors showing median overall survival (OS) of 23.0 months (mos) and median progression-free survival (PFS) of 16.1 mos. Given significant OS benefit with pembrolizumab, it is the current standard of care while the indication of atezolizumab has been withdrawn due to lack of OS benefit in IMPASSION-130. Clinical efficacy and adverse events in pts on this treatment regimen in clinical practice is unknown and understanding the real-world outcomes of this regimen is critical. Methods We conducted a retrospective, single-center observational study among TNBC pts treated with ICI (Pembrolizumab or Atezolizumab) at Roswell Park Comprehensive Cancer Center from January 2017 to May 2023. Demographics and clinicopathological variables were collected including comorbidities, laboratory data, sites of metastases (mets), treatment received, immune related adverse events (irAEs), and clinical outcomes. Adverse events were reported using the Common Terminology Criteria for Adverse Events v5.0. Serial CT scans were reviewed and response rate was determined using RECIST v1.1. Patient demographic, clinical and outcome characteristics were summarized by treatment and survival outcomes were obtained using standard Kaplan-Meier methods. Associations between survival outcomes and baseline or treatment characteristics were evaluated using Cox regression models using Firth’s method. All analyses were conducted in SAS v9.4 at a significance level of 0.05. Results A total of 44 pts with advanced TNBC treated with ICI were included (23 received pembrolizumab and 21 received Atezolizumab). The study population consisted of all female pts with stage IV disease, median age 53.7 years (IQR 30.4-85.2), 68.2 % (30/44) White, 25.0% (11/44) Black, 34.1% (15/44) obese (BMI≥30). 27.3% (12/44) pts developed any grade irAEs which included myocarditis (4.5%), rash (9.1%), hyperthyroidism (6.8%), hypothyroidism (4.5%), adrenal insufficiency (2.3%), diabetes mellitus (2.4%), colitis (2.3%), and transaminitis (2.3%). Distribution of reported irAE was 25% grade 1 (3/12), 66.7% grade 2 (8/12) and 8.3% grade 3 (1/12). 75% pts (33/44) received standard treatment (ICI+ chemotherapy) of which 72.7 % (24/33) received it in the first-line setting. Median OS in pts treated in first line was 16.2 mos (95% CI, 10.7-NR) and median PFS was 4.4 mos (95% CI, 2.7-8.4). Overall response rate (ORR) was 29.1% (7/24) of which 8.3% (2/24) had complete response and 20.8% (5/24) had partial response. ORR was 22.2 % (2/9) in pembrolizumab cohort and 33.3 % (5/15) in atezolizumab cohort. Among pts with first line treatment, obese pts were found to have improved PFS compared to non-obese (11.5 vs 3.8 mos, univariate hazard ratio (HR) 0.46, 95% CI 0.23-0.93, p= 0.031), and this difference was maintained in multivariable analysis even after adjusting for age (adjusted HR (aHR) 0.40, 95% CI 0.17-0.98, p= 0.044). Pts with brain mets had poor extracranial PFS compared to those without brain mets (2.8 vs. 5.2 mos, HR 2.25, 95% CI 1.08-4.68, p= 0.036), however this difference was not observed when further adjusted for age (aHR 2.27, 95% CI= 0.91-5.68, p= 0.08). Conclusion Clinical outcomes in our study were inferior to KEYNOTE-355 where median PFS was 16.1 mos and OS was 23.0 mos and ORR was 52.7% for PD-L1 positive population. This may reflect a more heterogeneous population of pts treated in routine clinical practice who are typically less fit than pts on clinical trials. Our study found improved outcomes among obese patients, similar to data reported in other disease settings. These data warrant multi-center validation with larger number of patients. Citation Format: Archit Patel, Arya Mariam Roy, Malak Alharbi, Kristopher Attwood, Chi-Chen Hong, Song Yao, Thaer Khoury, Amy Early, Tracey O'Connor, Ellis Levine, Shipra Gandhi. Real-world analysis of efficacy, adverse events and predictive biomarkers for advanced triple negative breast cancer (TNBC) treated with immune check point Inhibitors (ICI): A single center experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-06-08.

AB071. SOH24AB_184. Evaluating preoperative neutrophil-lymphocyte ratio as a predictive biomarker in primary breast cancer

AB071. SOH24AB_184. Evaluating preoperative neutrophil-lymphocyte ratio as a predictive biomarker in primary breast cancer

Absence of ATM leads to altered NK cell function in mice

Ataxia-telangiectasia (A-T) is a rare disorder caused by genetic defects of A-T mutated (ATM) kinase, a key regulator of stress response, and characterized by neurodegeneration, immunodeficiency, and high incidence of cancer. Here we investigated NK cells in a mouse model of A-T (Atm−/−) showing that they are strongly impaired at killing tumor cells due to a block of early signaling events. On the other hand, in Atm−/− littermates with thymic lymphoma NK cell cytotoxicity is enhanced as compared with ATM-proficient mice, possibly via tumor-produced TNF-α. Results also suggest that expansion of exhausted NKG2D+ NK cells in Atm−/− mice is driven by low-level expression of stress-inducible NKG2D ligands, whereas development of thymoma expressing the high-affinity MULT1 ligand is associated with NKG2D down-regulation on NK cells.These results expand our understanding of immunodeficiency in A-T and encourage exploring NK cell biology in A-T patients in the attempt to identify cancer predictive biomarkers and novel therapeutic targets.