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Circulating metabolite profiles to predict overall survival in advanced non-small cell lung cancer patients receiving first-line chemotherapy.

ABSTRACT: The prognosis for advanced-stage non-small cell lung cancer (NSCLC) is usually poor. However, survival may be variable and difficult to predict. In the current study, we aimed to identify circulating metabolites as potential predictive biomarkers for overall survival of advanced-stage (III/IV) NSCLC patients treated with first-line platinum-based chemotherapy.Using two-stage study design, we performed global metabolomic profiling in blood of 220 advanced-stage NSCLC patients, including 110 with poor survival and 110 with good survival. Metabolomic profiling was conducted using Metabolon platform. The association of each metabolite with survival was assessed by Cox proportional hazard regression model with adjustment for covariates.We found levels of 4 metabolites, caffeine, paraxanthine, stachydrine, and methyl glucopyranoside (alpha+beta), differed significantly between NSCLC patients with poor and good survival in both discovery and validation phases (P<0.05). Interestingly, majority of the identified metabolites are involved in caffeine metabolism, and 2 metabolites are related to coffee intake. In fact, caffeine metabolism pathway was the only significant pathway identified which significantly differed between NSCLC patients with poor and good survival (P=1.48E-07) in the pathway analysis. We also found 4 metabolites whose levels were significantly associated with good survival in both discovery and validation phases. Strong cumulative effects on overall survival were observed for these 4 metabolites. In conclusion, we identified a panel of metabolites including metabolites in caffeine metabolism pathway that may predict survival outcome in advanced-stage NSCLC patients. The identified small metabolites may be useful biomarker candidates to help identify patients who may benefit from platinum-based chemotherapy.

SUBMITTER: Shen J

PROVIDER: S-EPMC5715727 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Circulating metabolite profiles to predict overall survival in advanced non-small cell lung cancer patients receiving first-line chemotherapy.

Shen Jie J Ye Yuanqing Y Chang David W DW Huang Maosheng M Heymach John V JV Roth Jack A JA Wu Xifeng X Zhao Hua H

Lung cancer (Amsterdam, Netherlands) 20171102

<h4>Objectives</h4>The prognosis for advanced-stage non-small cell lung cancer (NSCLC) is usually poor. However, survival may be variable and difficult to predict. In the current study, we aimed to identify circulating metabolites as potential predictive biomarkers for overall survival of advanced-stage (III/IV) NSCLC patients treated with first-line platinum-based chemotherapy.<h4>Materials and methods</h4>Using two-stage study design, we performed global metabolomic profiling in blood of 220 a ...[more]

PMID: 29173770

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Project description:Bevacizumab, combined with platinum-based chemotherapy, has been widely used in the treatment of advanced-stage lung adenocarcinoma (LADC). Although KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation is the most common genetic alteration in human LADC and its role in promoting angiogenesis has been well established, its prognostic and predictive role in the above setting remains unclear. The association between KRAS exon 2 mutational status and clinicopathological variables including progression-free survival and overall survival (PFS and OS, respectively) was retrospectively analyzed in 501 Caucasian stage IIIB-IV LADC patients receiving first-line platinum-based chemotherapy (CHT) with or without bevacizumab (BEV). EGFR (epidermal growth factor receptor)-mutant cases were excluded. Of 247 BEV/CHT and 254 CHT patients, 95 (38.5%) and 75 (29.5%) had mutations in KRAS, respectively. KRAS mutation was associated with smoking (p = 0.008) and female gender (p = 0.002) in the BEV/CHT group. We found no difference in OS between patients with KRAS-mutant versus KRAS wild-type tumors in the CHT-alone group (p = 0.6771). Notably, patients with KRAS-mutant tumors demonstrated significantly shorter PFS (p = 0.0255) and OS (p = 0.0186) in response to BEV/CHT compared to KRAS wild-type patients. KRAS mutation was an independent predictor of shorter PFS (hazard ratio, 0.597; p = 0.011) and OS (hazard ratio, 0.645; p = 0.012) in the BEV/CHT group. G12D KRAS-mutant patients receiving BEV/CHT showed significantly shorter PFS (3.7 months versus 8.27 months in the G12/13x group; p = 0.0032) and OS (7.2 months versus 16.1 months in the G12/13x group; p = 0.0144). In this single-center, retrospective study, KRAS-mutant LADC patients receiving BEV/CHT treatment exhibited inferior PFS and OS compared to those with KRAS wild-type advanced LADC. G12D mutations may define a subset of KRAS-mutant LADC patients unsuitable for antiangiogenic therapy with BEV.

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Project description:BackgroundThe available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients.ObjectiveTo develop a new model based on real-world patients.Design, setting, and participantsIndividual patient-level data from 29 centers were collected, including metastatic UC and first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011.InterventionFirst-line, platinum-based, combination chemotherapy.Outcome measurements and statistical analysisThe population was randomly split into a development and a validation cohort. Generalized boosted regression modelling was used to screen out irrelevant variables and address multivariable analyses. Two nomograms were built to estimate OS probability, the first based on baseline factors and platinum agent, the second incorporating objective response (OR). The performance of the above nomograms and that of other available models was assessed. We plotted decision curves to evaluate the clinical usefulness of the two nomograms.Results and limitationsA total of 1020 patients were analyzed (development: 687, validation: 333). In a platinum-stratified Cox model, significant variables for OS were performance status (p<0.001), white blood cell count (p=0.013), body mass index (p=0.003), ethnicity (p=0.012), lung, liver, or bone metastases (p<0.001), and prior perioperative chemotherapy (p=0.012). The c-index was 0.660. The distribution of the nomogram scores was associated with OR (p<0.001), and incorporating OR into the model further improved the c-index in the validation cohort (0.670).ConclusionsWe developed and validated two nomograms for OS to be used before and after completion of first-line chemotherapy for metastatic UC.Patient summaryWe proposed two models for estimating overall survival of patients with metastatic urothelial carcinoma receiving first-line, platinum-based chemotherapy. These nomograms have been developed on real-world patients who were treated outside of clinical trials and may be used irrespective of the chemotherapeutic platinum agent used.

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Circulating metabolite profiles to predict overall survival in advanced non-small cell lung cancer patients receiving first-line chemotherapy.

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Circulating metabolite profiles to predict overall survival in advanced non-small cell lung cancer patients receiving first-line chemotherapy.

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