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Circulating Cell-Free DNA and Circulating Tumor Cells as Prognostic and Predictive Biomarkers in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Chemotherapy.

ABSTRACT: Cell-free DNA (cfDNA) and circulating tumor cells (CTCs) are promising prognostic and predictive biomarkers in non-small cell lung cancer (NSCLC). In this study, we examined the prognostic role of cfDNA and CTCs, in separate and joint analyses, in NSCLC patients receiving first line chemotherapy. Seventy-three patients with advanced NSCLC were enrolled in this study. CfDNA and CTC were analyzed at baseline and after two cycles of chemotherapy. Plasma cfDNA quantification was performed by quantitative PCR (qPCR) whereas CTCs were isolated by the ScreenCell Cyto (ScreenCell, Paris, France) device and enumerated according to malignant features. Patients with baseline cfDNA higher than the median value (96.3 hTERT copy number) had a significantly worse overall survival (OS) and double the risk of death (hazard ratio (HR): 2.14; 95% confidence limits (CL) = 1.24-3.68; p-value = 0.006). Conversely, an inverse relationship between CTC median baseline number (6 CTC/3 mL of blood) and OS was observed. In addition, we found that in patients reporting stable disease (SD), the baseline cfDNA and CTCs were able to discriminate patients at high risk of poor survival. cfDNA demonstrated a more reliable biomarker than CTCs in the overall population. In the subgroup of SD patients, both biomarkers identified patients at high risk of poor prognosis who might deserve additional/alternative therapeutic interventions.

SUBMITTER: Coco S

PROVIDER: S-EPMC5454947 | biostudies-other | 2017 May

REPOSITORIES: biostudies-other

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Circulating Cell-Free DNA and Circulating Tumor Cells as Prognostic and Predictive Biomarkers in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Chemotherapy.

Coco Simona S Alama Angela A Vanni Irene I Fontana Vincenzo V Genova Carlo C Dal Bello Maria Giovanna MG Truini Anna A Rijavec Erika E Biello Federica F Sini Claudio C Burrafato Giovanni G Maggioni Claudia C Barletta Giulia G Grossi Francesco F

International journal of molecular sciences 20170511 5

Cell-free DNA (cfDNA) and circulating tumor cells (CTCs) are promising prognostic and predictive biomarkers in non-small cell lung cancer (NSCLC). In this study, we examined the prognostic role of cfDNA and CTCs, in separate and joint analyses, in NSCLC patients receiving first line chemotherapy. Seventy-three patients with advanced NSCLC were enrolled in this study. CfDNA and CTC were analyzed at baseline and after two cycles of chemotherapy. Plasma cfDNA quantification was performed by quantit ...[more]

PMID: 28492516

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Project description:Rationale: Platinum-based chemotherapy is one of treatment mainstay for patients with advanced lung squamous cell carcinoma (LUSC) but it is still a "one-size fits all" approach. Here, we aimed to investigate the predictive and monitoring role of circulating cell-free DNA (cfDNA) profiling for the outcome of first-line chemotherapy in patients with advanced LUSC. Methods: Peripheral blood samples of 155 patients from a phase IV trial and 42 cases from an external real-world cohort were prospectively collected. We generated a copy number variations-based classifier via machine learning algorithm to integrate molecular profiling of cfDNA, named RESPONSE SCORE (RS) to predict the treatment outcome. To monitor the treatment efficacy, cfDNA samples collected at different time points were subjected to an ultra-deep sequencing platform. Results: The results showed that patients with high RS showed substantially higher objective response rate than those with low RS in training set (P < 0.001), validation set (P < 0.001) and real-world cohort (P = 0.019). Furthermore, a significant difference was observed in both progression-free survival (training set, P < 0.001; validation set: P < 0.001; real-world cohort: P = 0.019) and overall survival (training set, P < 0.001; validation set: P = 0.037) between high and low RS group. Notably, variant allele frequency (VAF) calculated from an ultra-deep sequencing platform significantly reduced in patients experienced a complete or partial response after 2 cycles of chemotherapy (P < 0.001), while it significantly increased in these of non-responder (P < 0.001). Moreover, VAF undetectable after 2 cycles of chemotherapy was correlated with markedly better objective response rate (P < 0.001) and progression-free survival (P < 0.001) than those with detectable VAF. Conclusions: These findings indicated that the RS, a circulating cfDNA sequencing-based stratification index, could help to guide first-line chemotherapy in advanced LUSC. The change of VAF is valuable to monitor the treatment response.

Project description:BackgroundPeritoneal metastasis from colorectal cancer (CRC) carries a poor prognosis in most studies. The majority of those studies used either a single-agent or doublet chemotherapy regimen in the first-line setting.AimTo investigate the prognostic significance of peritoneal metastasis in a cohort of patients treated with triplet chemotherapy in the first-line setting.MethodsWe retrospectively evaluated progression-free survival (PFS) and overall survival (OS) in 51 patients with metastatic CRC treated in a prospective clinical trial with capecitabine, oxaliplatin, irinotecan, and bevacizumab in the first-line setting according to the presence and absence of peritoneal metastasis. Furthermore, univariate and multivariate analyses for PFS and OS were performed to assess the prognostic significance of peritoneal metastasis at the multivariate level.ResultsFifty-one patients were treated with the above triplet therapy. Fifteen had peritoneal metastasis. The patient characteristics of both groups showed a significant difference in the sidedness of the primary tumor (left-sided primary tumor in 60% of the peritoneal group vs 86% in the nonperitoneal group, P = 0.03) and the presence of liver metastasis (40% for the peritoneal group vs 75% for the nonperitoneal group, P = 0.01). Univariate analysis for PFS showed a statistically significant difference for age less than 65 years (P = 0.034), presence of liver metastasis (P = 0.046), lung metastasis (P = 0.011), and those who underwent metastasectomy (P = 0.001). Only liver metastasis and metastasectomy were statistically significant for OS, with P values of 0.001 and 0.002, respectively. Multivariate analysis showed that age (less than 65 years) and metastasectomy were statistically significant for PFS, with P values of 0.002 and 0.001, respectively. On the other hand, the absence of liver metastasis and metastasectomy were statistically significant for OS, with P values of 0.003 and 0.005, respectively.ConclusionPeritoneal metastasis in patients with metastatic CRC treated with first-line triple chemotherapy does not carry prognostic significance at univariate and multivariate levels. Confirmatory larger studies are warranted.

Project description:IntroductionIncreasing evidence has shown that immune surveillance is compromised in a tumor-promoting microenvironment for patients with non-small cell lung cancer (NSCLC), and can be restored by appropriate chemotherapy.MethodsTo test this hypothesis, we analyzed microarray gene expression profiles of peripheral blood mononuclear cells from 30 patients with newly-diagnosed advanced stage NSCLC, and 20 age-, sex-, and co-morbidity-matched healthy controls. All the patients received a median of four courses of chemotherapy with cisplatin and gemcitabine for a 28-day cycle as first line treatment.ResultsSixty-nine differentially expressed genes between the patients and controls, and 59 differentially expressed genes before and after chemotherapy were identified. The IL4 pathway was significantly enriched in both tumor progression and chemotherapy signatures. CXCR4 and IL2RG were down-regulated, while DOK2 and S100A15 were up-regulated in the patients, and expressions of all four genes were partially or totally reversed after chemotherapy. Real-time quantitative RT-PCR for the four up-regulated (S100A15, DOK2) and down-regulated (TLR7, TOP1MT) genes in the patients, and the six up-regulated (TLR7, CRISP3, TOP1MT) and down-regulated (S100A15, DOK2, IL2RG) genes after chemotherapy confirmed the validity of the microarray results. Further immunohistochemical analysis of the paraffin-embedded lung cancer tissues identified strong S100A15 nuclear staining not only in stage IV NSCLC as compared to stage IIIB NSCLC (p?=?0.005), but also in patients with stable or progressive disease as compared to those with a partial response (p?=?0.032). A high percentage of S100A15 nuclear stained cells (HR 1.028, p?=?0.01) was the only independent factor associated with three-year overall mortality.ConclusionsOur results suggest a potential role of the IL4 pathway in immune surveillance of advanced stage NSCLC, and immune potentiation of combination chemotherapy. S100A15 may serve as a potential biomarker for tumor staging, and a predictor of poor prognosis in NSCLC.

Dataset Information

Circulating Cell-Free DNA and Circulating Tumor Cells as Prognostic and Predictive Biomarkers in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Chemotherapy.

Publications

Circulating Cell-Free DNA and Circulating Tumor Cells as Prognostic and Predictive Biomarkers in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Chemotherapy.

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