scholarly journals Exploration of a Novel Prognostic Risk Signature and Its Effect on the Immune Response in Nasopharyngeal Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Shuang Zhao ◽  
Xin Dong ◽  
Xiaoguang Ni ◽  
Lin Li ◽  
Xin Lu ◽  
...  
Keyword(s):  
Immune Response ◽  
Nasopharyngeal Carcinoma ◽  
Risk Group ◽  
Progression Free Survival ◽  
Gene Signature ◽  
Metastatic Carcinoma ◽  
High Risk Group ◽  
Molecular Characteristics ◽  
Novel Gene ◽  
Kaplan Meier

Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic carcinoma with different molecular characteristics and clinical outcomes. In this work, we aimed to establish a novel gene signature that could predict the prognosis of NPC patients. A total of 13 significant genes between the recurrence/metastasis (RM) group and the no recurrence/metastasis (no-RM) group were identified by machine learning from RNA-Seq data including 60 NPC tumor biopsies. Based on these genes, a 4-mRNA signature (considering U2AF1L5, TMEM265, GLB1L and MLF1) was identified. Receiver operating characteristic (ROC) and Kaplan-Meier (K-M) analyses indicated that this signature had good prognostic value for NPC. The overall survival (OS) and progression-free survival (PFS) of the patients in the high-risk group were significantly shorter than those of the patients in the low-risk group (p = 0.00126 and p = 0.000059, respectively). The area under the ROC curve (AUC) values of the 4-mRNA signature were higher than those of T stage and N stage for OS (0.893 vs 0.619 and 0.582, respectively) and PFS (0.86 vs 0.538 and 0.622, respectively). Furthermore, the 4-mRNA signature was closely associated with cell proliferation and the immune response. The expression of GLB1L and TMEM265 was associated with the level of tumor-infiltrating immune cells (r > 0.4, p < 0.05). We have validated the model through measuring the expression levels of the 4-mRNA signature by qRT-PCR, in an independent cohort of NPC patients. Here, we report a novel gene signature that can serve as a new tool for predicting the prognosis of NPC patients.

scholarly journals Neoadjuvant or Adjuvant Chemotherapy Plus Concurrent CRT Versus Concurrent CRT Alone in the Treatment of Nasopharyngeal Carcinoma: A Study Based on EBV DNA

2019 ◽  
Vol 17 (6) ◽  
pp. 703-710 ◽  
Author(s):  
Li-Ting Liu ◽  
Qiu-Yan Chen ◽  
Lin-Quan Tang ◽  
Shan-Shan Guo ◽  
Ling Guo ◽  
...  
Keyword(s):  
Adjuvant Chemotherapy ◽  
Nasopharyngeal Carcinoma ◽  
Treatment Failure ◽  
Risk Group ◽  
Progression Free Survival ◽  
High Risk Group ◽  
Low Risk ◽  
Rank Test ◽  
Free Survival ◽  
Ebv Dna

Background: The goal of this study was to explore the value of adding neoadjuvant chemotherapy (NACT) or adjuvant chemotherapy (ACT) to concurrent chemoradiotherapy (CCRT) in patients with nasopharyngeal carcinoma (NPC) with different risks of treatment failure. Patients and Methods: A total of 2,263 eligible patients with stage III–IVb NPC treated with CCRT ± NACT or ACT were included in this retrospective study. Distant metastasis–free survival (DMFS), overall survival, and progression-free survival were calculated using the Kaplan-Meier method and differences were compared using the log-rank test. Results: Patients in the low-risk group (stage N0–1 disease and Epstein-Barr virus [EBV] DNA <4,000 copies/mL) who received NACT followed by CCRT achieved significantly better 5-year DMFS than those treated with CCRT alone (96.2% vs 91.3%; P= .008). Multivariate analyses also demonstrated that additional NACT was the only independent prognostic factor for DMFS (hazard ratio, 0.42; 95% CI, 0.22–0.80; P=.009). In both the intermediate-risk group (stage N0–1 disease and EBV DNA ≥4,000 copies/mL and stage N2–3 disease and EBV DNA <4,000 copies/mL) and the high-risk group (stage N2–3 disease and EBV DNA ≥4,000 copies/mL), comparison of NACT or ACT + CCRT versus CCRT alone indicated no significantly better survival for all end points. Conclusions: The addition of NACT to CCRT could reduce distant failure in patients with low risk of treatment failure.

scholarly journals A 5-Gene Signature Is Closely Related to Tumor Immune Microenvironment and Predicts the Prognosis of Patients with Non-Small Cell Lung Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Jia Li ◽  
Huiyu Wang ◽  
Zhaoyan Li ◽  
Chenyue Zhang ◽  
Chenxing Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Risk ◽  
Risk Group ◽  
Gene Signature ◽  
High Risk Group ◽  
Low Risk ◽  
Egfr Mutations ◽  
Kaplan Meier ◽  
Tumor Immune Microenvironment ◽  
Nsclc Patients

Purpose. Establishing prognostic gene signature to predict clinical outcomes and guide individualized adjuvant therapy is necessary. Here, we aim to establish the prognostic efficacy of a gene signature that is closely related to tumor immune microenvironment (TIME). Methods and Results. There are 13,035 gene expression profiles from 130 tumor samples of the non-small cell lung cancer (NSCLC) in the data set GSE103584. A 5-gene signature was identified by using univariate survival analysis and Least Absolute Shrinkage and Selection Operator (LASSO) to build risk models. Then, we used the CIBERSORT method to quantify the relative levels of different immune cell types in complex gene expression mixtures. It was found that the ratio of dendritic cells (DCs) activated and mast cells (MCs) resting in the low-risk group was higher than that in the high-risk group, and the difference was statistically significant (P<0.001 and P=0.03). Pathway enrichment results which were obtained by performing Gene Set Variation Analysis (GSVA) showed that the high-risk group identified by the 5-gene signature had metastatic-related gene expression, resulting in lower survival rates. Kaplan–Meier survival results showed that patients of the high-risk group had shorter disease-free survival (DFS) and overall survival (OS) than those of the low-risk group in the training set (P=0.0012 and P<0.001). The sensitivity and specificity of the gene signature were better and more sensitive to prognosis than TNM (tumor/lymph node/metastasis) staging, in spite of being not statistically significant (P=0.154). Furthermore, Kaplan–Meier survival showed that patients of the high-risk group had shorter OS and PFS than those of the low-risk group (P=0.0035, P<0.001, and P<0.001) in the validating set (GSE31210, GSE41271, and TCGA). At last, univariate and multivariate Cox proportional hazard regression analyses were used to evaluate independent prognostic factors associated with survival, and the gene signature, lymphovascular invasion, pleural invasion, chemotherapy, and radiation were employed as covariates. The 5-gene signature was identified as an independent predictor of patient survival in the presence of clinical parameters in univariate and multivariate analyses (P<0.001) (hazard ratio (HR): 3.93, 95% confidence interval CI (2.17–7.1), P=0.001, (HR) 5.18, 95% CI (2.6995–9.945), P<0.001), respectively. Our 5-gene signature was also related to EGFR mutations (P=0.0111), and EGFR mutations were mainly enriched in low-risk group, indicating that EGFR mutations affect the survival rate of patients. Conclusion. The 5-gene signature is a powerful and independent predictor that could predict the prognosis of NSCLC patients. In addition, our gene signature is correlated with TIME parameters, such as DCs activated and MCs resting. Our findings suggest that the 5-gene signature closely related to TIME could predict the prognosis of NSCLC patients and provide some reference for immunotherapy.

scholarly journals Development and Validation of a Seven-Gene Signature for Predicting the Prognosis of Lung Adenocarcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Yingqing Zhang ◽  
Xiaoping Zhang ◽  
Xiaodong Lv ◽  
Ming Zhang ◽  
Xixi Gao ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Risk Score ◽  
Cox Regression ◽  
Risk Group ◽  
Clinical Information ◽  
R Package ◽  
Tumor Stage ◽  
Gene Signature ◽  
High Risk Group ◽  
Kaplan Meier

Background. Prognosis is a main factor affecting the survival of patients with lung adenocarcinoma (LUAD), yet no robust prognostic model of high effectiveness has been developed. This study is aimed at constructing a stable and practicable gene signature-based model via bioinformatics methods for predicting the prognosis of LUAD sufferers. Methods. The mRNA expression data were accessed from the TCGA-LUAD dataset, and paired clinical information was collected from the GDC website. R package “edgeR” was employed to select the differentially expressed genes (DEGs), which were then used for the construction of a gene signature-based model via univariate COX, Lasso, and multivariate COX regression analyses. Kaplan-Meier and ROC survival analyses were conducted to comprehensively evaluate the performance of the model in predicting LUAD prognosis, and an independent dataset GSE26939 was accessed for further validation. Results. Totally, 1,655 DEGs were obtained, and a 7-gene signature-based risk score was developed and formulated as risk_score=0.000245∗NTSR1+7.13E−05∗RHOV+0.000505∗KLK8+7.01E−05∗TNS4+0.000288∗C1QTNF6+0.00044∗IVL+0.000161∗B4GALNT2. Kaplan-Meier survival curves revealed that the survival rate of patients in the high-risk group was lower in both the TCGA-LUAD dataset and GSE26939 relative to that of patients in the low-risk group. The relationship between the risk score and clinical characteristics was further investigated, finding that the model was effective in prognosis prediction in the patients with different age (age>65, age<65) and TNM stage (N0&N1, T1&T2, and tumor stage I/II). In sum, our study provides a robust predictive model for LUAD prognosis, which boosts the clinical research on LUAD and helps to explore the mechanism underlying the occurrence and progression of LUAD.

scholarly journals Dynamic serum biomarkers to predict the efficacy of PD-1 in patients with nasopharyngeal carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ao Zhang ◽  
Guanqing Zhong ◽  
Luocan Wang ◽  
Rongzeng Cai ◽  
Runkun Han ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Nasopharyngeal Carcinoma ◽  
Prediction Model ◽  
Risk Score ◽  
Validation Cohort ◽  
Risk Group ◽  
Dynamic Change ◽  
Progression Free Survival ◽  
High Risk Group ◽  
Prognostic Indicators

Abstract Background There is a lack of effective treatments for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). Furthermore, the response rate of NPC patients to programmed death 1 (PD-1) inhibitors is approximately 20% to 30%. Thus, we aimed to explore reliable and minimally invasive prognostic indicators to predict the efficacy of PD-1 inhibitors combination therapy in RM-NPC. Methods The serum markers of 160 RM-NPC patients were measured before and three weeks after the first anti-PD-1 treatment. The least absolute shrinkage and selection operator (LASSO) logistic regression was carried out to select dynamic serum indicators and construct a prediction model. Furthermore, we carried out univariate, multivariate, nomogram and survival analyses to identify independent prognostic factors that were associated with 1-year progression-free survival (PFS). Results Based on two markers that were screened by Lasso logistic regression, we constructed a risk score prediction model for the prediction of anti-PD-1 efficacy at 8–12 weeks with an AUC of 0.737 in the training cohort and 0.723 in the validation cohort. Risk score and metastases were included in the nomogram, and the Kaplan–Meier survival curves demonstrated that the high-risk group has shorter PFS compared to the low-risk group. The concordance index (C-index) of the nomogram for PFS is higher than that of the TNM stage in the training and validation cohort. Conclusion We proposed a strategy to monitor dynamic changes in the biochemistry markers and emphasized their importance as potential prognostic biomarkers for the treatment of advanced NPC treated with PD-1 inhibitors. Our risk score prediction model was based on the dynamic change of LDH and AST/ALT, which has predictive and prognostic value for NPC patients who were treated with PD-1 inhibitors.

scholarly journals SOX1 and PAX1 Are Hypermethylated in Cervical Adenocarcinoma and Associated with Better Prognosis

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Zitong Zhao ◽  
Xiaoye Zhang ◽  
Xueheng Zhao ◽  
Jingting Cai ◽  
Na-Yi Yuan Wu ◽  
...  
Keyword(s):  
Cox Regression ◽  
Risk Group ◽  
Methylation Status ◽  
Progression Free Survival ◽  
High Risk Group ◽  
Cervical Adenocarcinoma ◽  
Survival Prediction ◽  
Kaplan Meier ◽  
Increased Risk ◽  
Poor Survival Outcome

Background. The increased risk and poor survival outcome of cervical adenocarcinoma (CAC) demand for effective early diagnostic biomarkers that can predict the disease progression and outcome. The purpose of this study was to investigate the value of methylation status of SOX1 and PAX1 in the detection and prognosis of CAC. Methods. We performed a quantitative methylation-specific polymerase chain reaction in 205 cervical paraffin-embedded specimens (175 CACs, 30 noncancer cervical tissues). Overall and progression-free survival (OS and PFS, respectively) rates were calculated and compared using the Kaplan-Meier method. The prognostic value of SOX1m and PAX1m on CAC patients was assessed by the Cox regression model. A mathematical formula combining SOX1m, PAX1m, and age was constructed for survival prediction. Results. The methylation status of SOX1 and PAX1 was higher in CAC tissues than in noncancer cervical tissues. In addition, SOX1m-positive CAC patients showed a higher 5-year OS rate than SOX1m-negative patients. In CAC patients with smaller tumor size (<4 cm), the PAX1m-positive group showed a higher 5-year PFS rate than the PAX1m-negative group. In the algorithm combining SOX1m, PAX1m, and age, the low-risk group showed a better 5-year OS and PFS rate than the high-risk group. Conclusion. SOX1 and PAX1 methylation levels are higher in CAC than in normal cervical tissues and are potential biomarkers for monitoring CAC prognosis.

scholarly journals Clinical and Biological Prognostic Factors in Follicular Lymphoma Patients During Treatment

2021 ◽  
Author(s):  
Ádám Jóna ◽  
Anna Kenyeres ◽  
Sándor Barna ◽  
Árpád Illés ◽  
Zsófia Simon
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Follicular Lymphoma ◽  
Risk Group ◽  
Standardized Uptake Value ◽  
Progression Free Survival ◽  
High Risk Group ◽  
Pet Ct ◽  
Significant Difference ◽  
Biological Prognostic Factors

Abstract Introduction: Follicular lymphoma (FL) is an indolent yet heterogeneous B-cell lymphoproliferative disorder. Most people respond to treatment well. However, a particular group of patients has a poor prognosis, and these patients are difficult to define.Patients and methods: We retrospectively analyzed FL patients treated at the University of Debrecen in the past 20 years. We investigated prognostic factors that may influence the survival of FL patients.Results: We found a standardized uptake value (SUV)max cut-off value of 9.85 at the staging PET/CT to significantly separate FL patients’ progression-free survival (PFS) (p=0.0003, HR: 0.2560, 95%CI: 0.1232-0.5318). Lymphocyte/ monocyte (Ly/Mo) ratio of 3.45 drawn at diagnosis also significantly predicted PFS (p=0.0324, HR: 1.806, 95% CI: 1.051-3.104). Combining patients’ with staging SUVmax >9.85 and Ly/Mo < 3.45 a high-risk group of FL patients can be identified (p<0.0001, HR: 0.1033, 95%CI: 0.03719-0.2868). Similarly, a significant difference was shown with a SUVmax cut-off of 3.15 at the interim PET/CT (p<0.0001, HR: 0.1535, 95%CI: 0.06329-0.3720). Combining patients with staging SUVmax >9.85 and interim SUVmax >3.15, a high-risk group of FL patients can be identified (p<0.0001, HR: 0.1037, 95%CI: 0.03811-0.2824). The PFS difference is translated into overall survival advantage (p=0.0506, HR: 0.1187, 95%CI: 0.01401-1.005).Discussion: Biological prognostic factors, such as the Ly/ Mo ratio, may improve the prognostic assessment of staging PET/CT. Nevertheless, PFS difference is translated into OS when using a combination of staging and interim SUVmax. We consider investigating additional biological prognostic factors while currently highlighting PET/CT's role in FL.

scholarly journals A Novel Ferroptosis-Related Gene Signature Robustly Predicts Clinical Prognosis And Tumor Immunity in Patients With Kidney Renal Clear Cell Carcinoma

2021 ◽  
Author(s):  
Wei Song ◽  
Weiting Kang ◽  
Qi Zhang
Keyword(s):  
High Risk ◽  
Clear Cell ◽  
Risk Group ◽  
Gene Signature ◽  
Renal Clear Cell Carcinoma ◽  
High Risk Group ◽  
Risk Scores ◽  
Related Gene ◽  
Clinical Prognosis ◽  
Validation Set

Abstract Objective: This study aimed to construct a ferroptosis-related gene signature to predict clinical prognosis and tumor immunity in patients with kidney renal clear cell carcinoma (KIRC).Methods: The mRNA expression profiles and corresponding clinical data of KIRC patients were downloaded from The Cancer Genome Atlas (TCGA), which were randomly divided into training (398 patients) and validation set (132 patients). The iron death related (IDR) prediction model was constructed based on training set and 60 ferroptosis-related genes from previous literatures, followed by prognostic performance evaluation and verification using the validation set. Moreover, functional enrichment, immune cell infiltration, metagene clusters correlation, and TIDE scoring analyses were performed. Results: In total, 23 ferroptosis-related genes were significantly associated with overall survival (OS). The IDR prediction model (a 10-gene signature) was then constructed to stratify patients into two risk groups. The OS of KIRC patients with high-risk scores was significantly shorter than those with low-risk scores. Moreover, the risk score was confirmed as an independent prognostic predictor for OS. The positive and negative correlated genes with this model were significantly enriched in p53 signaling pathway, and cGMP-PKG signaling pathway. The patients in the high-risk group had higher ratios of plasma cells, T cells CD8, and T cells regulatory Tregs. Furthermore, IgG, HCK, LCK, and Interferson metagenes were significantly correlated with risk score. By TIDE score analysis, patients in the high-risk group could benefit from immunotherapy.Conclusions: The identified ferroptosis-related gene signature is significantly correlated with clinical prognosis and immune immunity in KIRC patients.

Integrated Analysis of Immune-Related Genes in High-Risk Neuroblastoma

2020 ◽  
Author(s):  
FengLing Shao ◽  
Zhenni Wang ◽  
Shan Wang
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Clinical Characteristics ◽  
Roc Analysis ◽  
Risk Group ◽  
High Risk Group ◽  
Data Sets ◽  
Qrt Pcr ◽  
Kaplan Meier ◽  
Immune Related Genes

Abstract BackgroundDue to the extremely high mortality rate of children with high-risk Neuroblastoma (NB), there is an urgent need for new indicators to further classify children in the high-risk group for more precise treatment. The purpose of our research is to explore the immune-related genes in NB in the high-risk group, and to further identify and develop a prognostic nomogram based on immune IRG signatures. MethodsThrough bioinformatics analysis to explore the abnormal expression of immune-related genes in the high-risk group. Cox regression and the least absolute shrinkage and selection operator (LASSO) analysis were conducted to identify the immune and overall survival (OS) related mRNA. The accuracy of the risk score is evaluated by Kaplan-Meier method and receiver operating characteristics (ROC) analysis, which is used to build a nomogram in combination with other clinical characteristics.. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the accuracy of our results. ResultsA total of 127 common differentially expressed immune genes were found between the high-risk group and the non-high-risk group of the two data sets. Four immune-related genes (IRG) related to prognosis were identified and a risk score was established. Kaplan–Meier survival analysis and time-dependent ROC analysis showed that the 4-IRG risk score has satisfactory predictive potential and achieved consistency in the verification of external data sets. Subsequently, the risk score combined with clinical characteristics draws a nomogram. The reliability of the results was verified on 29 cases of NB tissues by qRT-PCR. ConclusionsOverall, we have developed a powerful multi-gene classifier that can effectively classify NB patients into low- and high-risk groups with poor prognosis, and draw a nomogram for children in the high-risk group. This feature can help select high-risk patients who need more aggressive adjuvant target therapy or immunotherapy.

scholarly journals Pharmacogenetic score predicts overall survival, progression-free survival and platinum sensitivity in ovarian cancer

2020 ◽  
Vol 21 (14) ◽  
pp. 995-1010
Author(s):  
Sara Gagno ◽  
Michele Bartoletti ◽  
Chiara Romualdi ◽  
Elena Poletto ◽  
Simona Scalone ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Germ Line ◽  
Risk Group ◽  
Prognostic Score ◽  
Progression Free Survival ◽  
High Risk Group ◽  
Free Survival ◽  
Estrogen Activity ◽  
The Impact

Aim: To define the impact of polymorphisms in genes involved in platinum-taxane and estrogen activity in the outcome of platinum-based treated ovarian cancer patients (OCP). Patients & Methods: Two hundred and thirty OCP were analyzed for 124 germ-line polymorphisms to generate a prognostic score for overall survival (OS), progression-free survival (PFS) and platinum-free interval (PFI). Results: ABCG2 rs3219191D>I, UGT1A rs10929302G>A and UGT1A rs2741045T>C polymorphisms were significantly associated with all three parameters (OS, PFS and PFI) and were used to generate a score. Patients in high-risk group had a poorer OS (hazard ratio [HR]: 1.8; 95% CI: 1.3–2.7; p = 0.0019), PFS (HR: 2.0; 95% CI: 1.4–2.9; p < 0.0001) and PFI (HR: 1.9; 95% CI: 1.4–2.8; p = 0.0002) compared with those in low-risk group. Conclusion: The prognostic-score including polymorphisms involved in drug and estrogen pathways stratifies OCP according to OS, PFS and PFI.

Clinical and molecular characteristics of advanced non-small cell lung cancer (NSCLC) patients (pts) with rapid progressive disease (RPD) on gefitinib therapy (G)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7592-7592
Author(s):  
M. J. Fidler ◽  
L. Buckingham ◽  
M. Gale ◽  
J. Coon ◽  
A. Mauer ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Objective Response ◽  
Gene Copy Number ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
Gene Copy ◽  
Molecular Characteristics ◽  
Kaplan Meier ◽  
G 12 ◽  
Nsclc Patients

7592 Background: Prognostic factors associated with better outcomes (EGFR mutations (mut), high EGFR gene copy number, never smoking) can be used to select pts for EGFR tyrosine kinase inhibitor (TKI) combination trials, but would exclude the majority of NSCLC pts. Excluding pts with the worst likely outcomes is another strategy that may result in more pts who could benefit from the combination of a TKI with other agents. Our objective was to identify clinical and molecular characteristics associated with RPD (=70 days) and shorter progression-free survival (PFS) in previously treated NSCLC pts receiving G. Methods: Consecutive Expanded Access Trial pts with >1 week G were included for analysis. Tissue from 87 pts was evaluated for EGFR, pAKT and PTEN protein expression by immunohistochemistry; 58 tumors were analyzed for mut and sum of CA dinucliotide repeats (ΣCA rpts) by SSCP, PCR and sequencing. Results: There were 150 pts; 77 female, median (md) age 67. Md follow-up was 5.8 months (mo). Objective response was 8% (2CR, 10PR, 56 SD, 82 RPD). Md Kaplan-Meier PFS and survival were 2.0 and 5.8 mo, respectively. See table for univariate results. Smoking, Mut-PTEN-, EGFR-PTEN- and EGFR-pAKT- tumors were associated with shorter PFS. Separate clinical and molecular multivariate models were developed. In logistic regressions, non-adenocarcinoma histology (N- A), p=0.004, =12 mo from diagnosis to G (dx-G =12 mo), p=0.0009, lack of mut (p=0.0298) and ΣCA rpts <34 (p=0.0622) were associated with RPD. In Cox regressions, N-A (p=0.0256), dx-G =12 mo (p=0.0166) and lack of mut (p=0.0298) were associated with shorter PFS. Conclusions: N-A, dx-G =12 mo and lack of mut were associated with RPD and shorter PFS in univariate and multivariate analyses. ΣCA rpts <34 and double-negative molecular combinations were also related to worse outcome. These clinical and molecular characteristics may warrant further study as exclusion criteria for TKI combination clinical trials. [Table: see text] [Table: see text]

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