Abstract
BackgroundThe lack of non-invasive methods for detection of early micro-metastasis is a major cause of the poor prognosis of non-small cell lung cancer (NSCLC) brain metastasis (BM) patients. Herein, we aimed to identify circulating biomarkers based on proteomics for the early diagnosis and monitoring of patients with NSCLC BM.MethodsUpregulated proteins were detected by secretory proteomics in the animal-derived high brain metastatic lung cancer cell line. A well-designed study composed of three independent cohorts was then performed to verify these blood-based protein biomarkers: the serum discovery and verification cohorts (n = 80; n = 459), and the tissue verification cohort (n = 76). Logistic regression was used to develop a diagnostic biomarker panel. Model validation cohort (n = 160) was used to verify the stability of the constructed predictive model. Changes in serum Cathepsin F (CTSF) levels of patients were tracked to monitor the treatment response. Progression-free survival (PFS) and overall survival (OS) were analysed to assess their prognostic relevance.ResultsCTSF and Fibulin-1 (FBLN1) levels were specifically upregulated in sera and tissues of patients with NSCLC BM compared with NSCLC without BM and primary brain tumour. The combined diagnostic performance of CTSF and FBLN1 was superior to their individual ones. CTSF serum changes were found to reflect the therapeutic response of patients with NSCLC BM and the trends of progression were detected earlier than the magnetic resonance imaging changes. Elevated expression of CTSF in NSCLC BM tissues was associated with poor PFS, and was found to be an independent prognostic factor.ConclusionsWe report a novel blood-based biomarker panel for early diagnosis, monitoring of therapeutic response, and prognostic evaluation of patients with NSCLC BM.
Highlights
Lung cancer is one of the most common causes of cancer-related deaths worldwide [1]
brain metastasis (BM), their Cathepsin F (CTSF), FBLN1 and Aldo-keto reductase family 1 member B10 (AKR1B10) levels were not related to RESULTS Proteomics identified potential diagnostic candidates for non-small cell lung cancer (NSCLC) BM In order to explore secretory proteins that are highly expressed during the process of BM of NSCLC, we collected the supernatant of the parental cells PC9 and its derived highly BM subgroup PC9BrM3, which was established by injecting PC9 into the leftventricle of immunodeficient mice and isolating the metastatic cells from harvested brain metastases three times repeatedly in our previous work, for proteomics [20]
We further evaluated the role of serum CTSF and FBLN1 in NSCLC BM through multivariable logistic regression analysis in three serum cohorts
Summary
Lung cancer is one of the most common causes of cancer-related deaths worldwide [1]. It shows a high propensity for brain metastasis (BM). The lack of methods for detection of early micro-metastasis is a major cause of poor prognosis [4]. Routine contrast-enhanced brain magnetic resonance imaging (MRI) for detection of BM is recommended for patients with stage II–IV NSCLC; the high cost and low predictive ability for long-term recurrence is a major limitation of MRI [5, 6]. The lack of non-invasive methods for detection of early micro-metastasis is a major cause of the poor prognosis of non-small cell lung cancer (NSCLC) brain metastasis (BM) patients. CTSF serum changes were found to reflect the therapeutic response of patients with NSCLC BM and the trends of progression were detected earlier than the magnetic resonance imaging changes. CONCLUSIONS: We report a novel blood-based biomarker panel for early diagnosis, monitoring of therapeutic response, and prognostic evaluation of patients with NSCLC BM
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