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Non-invasive detection of EGFR and TP53 mutations through the combination of plasma, urine and sputum in advanced non-small cell lung cancer.

ABSTRACT: The sensitivity and utility of liquid biopsy in clinical practice requires some improvement. The aim of the present study was to improve the detection of epidermal growth factor (EGFR) and cellular tumor antigen p53 (TP53) mutations in liquid biopsies from patients with advanced non-small cell lung cancer (NSCLC) by combining plasma, sputum and urine samples under the same sequencing platform. Plasma, sputum and urine samples, and tumor tissues were obtained from 50 patients with NSCLC and were analyzed using next-generation sequencing. The sensitivity of EGFR-sensitive mutation detection was 84% in plasma, 63% in sputum, 28% in urine, and 91% when combining the three liquid samples (P<0.001). The sensitivity of TP53 mutation detection increased from 87% in plasma to 94% when the three samples were combined (P<0.001). The sensitivity of EGFR or TP53 mutations detection was higher in patients with multiple metastatic sites compared with patients ≤1 metastatic site. In addition, the progression free survival (PFS) rates obtained following analysis of the three samples independently in patients with EGFR sensitizing mutations were similar, and were 9.0 months in the tissue sample, 7.5 months in plasma, 7.9 months in the sputum and 7.3 months in urine (P=0.721). The PFS of patients with TP53 mutations was shorter compared with patients without TP53 mutations and was as follows: Tissue, 8.2 months compared with 10.2 months (P=0.412); plasma, 8.4 months compared with 10.2 months (P=0.466); sputum, 8.3 months compared with 9.1 months (P=0.904); and when combined, 8.8 months compared with 10.3 months (P=0.599). The combination of plasma, sputum and urine increased the detection of EGFR or TP53 mutation with higher sensitivity, and may improve the predictive value of personalized treatment.

SUBMITTER: Wu Z

PROVIDER: S-EPMC6732959 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundEpidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatments for advanced EGFR-mutated non-small cell lung cancer (NSCLC) patients. Osimertinib is an effective therapy for NSCLC patients with acquired resistance due to T790M mutation after first- and second-generation EGFR-TKI treatment. This study aimed to analyze the clinical outcomes of sequential therapy following first-line EGFR-TKIs and the predictive factors of an acquired T790M mutation.MethodsBetween January 2014 and December 2018, data from 2190 advanced NSCLC patients with common EGFR mutations (exon 19 deletion and L858R) receiving first- and second-generation EGFR-TKIs in Linkou, Kaohsiung, Chiayi and Keelung Chang Gung Memorial Hospitals were retrospectively retrieved and analyzed.ResultsUntil August 2021, among 1943 patients who experienced progressive disease, 526 underwent T790M mutation tests, and their T790M-positive rate was 53.6%. Exon 19 deletion mutation and progression-free survival (PFS) of >12 months were positively associated with secondary T790M mutation. Different first-line first- and second-generation EGFR-TKI therapies did not affect the appearance of acquired T790M mutations. The median overall survival (OS) was 58.3 [95% confidence interval (CI): 49.0-67.5] months among the patients with T790M mutation who received second-line osimertinib therapy compared with 31.0 (95% CI: 27.5-34.5) months among the patients without T790M mutation who received chemotherapy alone. The multivariate analysis showed that a poor performance status (score: >2), nonadenocarcinoma histology, stage IV cancer, liver metastasis, brain metastasis, PFS while on first-line EGFR-TKIs, and subsequent chemotherapy without third-generation EGFR-TKIs were significant independent unfavorable prognostic factors for OS.ConclusionThis study demonstrated the efficacy of first-line EGFR-TKIs and sequential osimertinib therapy. The results of our study suggest that T790M mutation tests are important for the use of subsequent osimertinib, which yielded favorable survival outcomes.

Project description:BackgroundThe prognostic significance of TP53 concurrent mutations in patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)- mutated advanced non-small-cell lung cancer (NSCLC) who received EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs based targeted therapy remains controversial. Therefore, the present meta-analysis was performed to investigate the association between TP53 concurrent mutations and prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK-TKIs treatments.MethodsEligible studies were identified by searching the online databases PubMed, Embase, Medline, The Cochrane library and Web of Science. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to clarify the correlation between TP53 mutation status and prognosis of patients. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.ResultsIn total, 15 studies with 1342 patients were included for final analysis. Overall, concurrent TP53 mutation was associated with unfavorable progression-free survival (PFS) (HR = 1.88, 95%CI: 1.59-2.23, p < 0.001, I2 = 0.0%, P = 0.792) and overall survival (OS) (HR = 1.92, 95%CI: 1.55-2.38, p < 0.001, I2 = 0.0%, P = 0.515). Subgroup analysis based on type of targeted therapy (EGFR-TKIs or ALK-TKIs, pathological type of cancer (adenocarcinoma only or all NSCLC subtypes) and line of treatment (first-line only or all lines) all showed that TP53 mutations was associated with shorter survivals of patients with EGFR-TKIs or ALK-TKIs treatments. Particularly, in patients with first-line EGFR-TKIs treatment, significantly poorer prognosis was observed in patients with TP53 concurrent mutations (pooled HR for PFS: 1.69, 95% CI 1.25-2.27, P < 0.001, I2 = 0.0%, P = 0.473; pooled HR for OS: 1.94, 95% CI 1.36-2.76, P < 0.001, I2 = 0.0%, P = 0.484). Begg's funnel plots and Egger's tests indicated no significant publication bias in this study.ConclusionsThis meta-analysis indicated that concurrent TP53 mutations was a negative prognostic factor and associated with poorer outcomes of patients with EGFR-TKIs or ALK-TKIs treatments in advanced NSCLC. In addition, our study provided evidence that TP53 mutations might be involved in primary resistance to EGFR-TKIs treatments in patients with sensitive EGFR mutations in advanced NSCLC.

Project description:PurposeThe analysis of exosome/microvesicle (extracellular vesicles (EVs)) and the RNA packaged within them (exoRNA) has the potential to provide a non-invasive platform to detect and monitor disease related gene expression potentially in lieu of more invasive procedures such as biopsy. However, few studies have tested the diagnostic potential of EV analysis in humans.Experimental designThe ability of EV analysis to accurately reflect prostate tissue mRNA expression was examined by comparing urinary EV TMPRSS2:ERG exoRNA from pre-radical prostatectomy (RP) patients versus corresponding RP tissue in 21 patients. To examine the differential expression of TMPRSS2:ERG across patient groups a random urine sample was taken without prostate massage from a cohort of 207 men including prostate biopsy negative (Bx Neg, n = 39), prostate biopsy positive (Bx Pos, n = 47), post-radical prostatectomy (post-RP, n = 37), un-biopsied healthy age-matched men (No Bx, n = 44), and young male controls (Cont, n = 40). The use of EVs was also examined as a potential platform to non-invasively differentiate Bx Pos versus Bx Neg patients via the detection of known prostate cancer genes TMPRSS2:ERG, BIRC5, ERG, PCA3 and TMPRSS2.ResultsIn this technical pilot study urinary EVs had a sensitivity: 81% (13/16), specificity: 80% (4/5) and an overall accuracy: 81% (17/21) for non-invasive detection of TMPRSS2:ERG versus RP tissue. The rate of TMPRSS2:ERG exoRNA detection was found to increase with age and the expression level correlated with Bx Pos status. Receiver operator characteristic analyses demonstrated that various cancer-related genes could differentiate Bx Pos from Bx Neg patients using exoRNA isolated from urinary EVs: BIRC5 (AUC 0.674 (CI:0.560-0.788), ERG (AUC 0.785 (CI:0.680-0.890), PCA3 (AUC 0.681 (CI:0.567-0.795), TMPRSS2:ERG (AUC 0.744 (CI:0.600-0.888), and TMPRSS2 (AUC 0.637 (CI:0.519-0.754).ConclusionThis pilot study suggests that urinary EVs have the potential to be used as a platform to non-invasively differentiate patients with prostate cancer with very good accuracy. Larger studies are needed to confirm the potential for clinical utility.

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Non-invasive detection of EGFR and TP53 mutations through the combination of plasma, urine and sputum in advanced non-small cell lung cancer.

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