Circulating DNA is a Useful Prognostic Factor in Patients with Advanced Non-small Cell Lung Cancer

Sirera, Rafael; Bremnes, Roy M.; Cabrera, A.; Jantus‐Lewintre, Eloísa; Sanmartín, Elena; Blasco, Ana; Pozo, Nieves del; Rosell, Rafael; Guijarro, Ricardo; Galbis, Jose M.; Sánchez, José Javier; Camps, Carlos

doi:10.1097/jto.0b013e31820189a5

Cited by 77 publications

(72 citation statements)

References 18 publications

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“…Camps et al managed to demonstrate a correlation between increased hTERT in serum and poor prognosis [13]. Similar results in plasma have also been reported, but the results have not been validated by other authors [14,15]. In this cohort of patients with known advanced lung cancer, we find the use of PPIA feasible, as it does not depend on tumor-related genes and therefore provides an estimate of the total cfDNA [16].…”

Section: Discussionsupporting

confidence: 68%

The Prognostic Value of Cell-Free DNA in Advanced Non-Small-Cell Lung Cancer

Nygaard¹,

Spindler²,

Pallisgaard³

et al. 2013

JCT

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Background: Cell-free DNA (cfDNA) holds promise as a tumor marker of clinical importance. We aimed to investigate the prognostic value of baseline cfDNA in non small-cell lung cancer (NSCLC). Material and Methods: During a three-year period, patients with newly diagnosed, previously untreated advanced NSCLC were included in a consecutive, prospective marker-trial. Plasma was isolated from a pre-treatment peripheral blood sample and the level of total cfDNA was measured by an in-house assay qPCR-method. The treatment comprised carboplatin (AUC 5) intravenously day 1), and vinorelbine (30 mg/m 2 intravenously day 1 and 60 mg/m 2 perorally day 8) q3w for a maximum of six cycles. The primary end-point was overall survival (OS). Secondary end-points were progression free survival (PFS) and overall response rate (ORR). Results: 245 patients were included and received a minimum of 1 cycle of chemotherapy (median 4). The median OS was 8.9 months, the median PFS by intention to treat 5.4 months and the ORR was 25%. The patients were divided into four groups based on quartiles of cfDNA and subsequently dichotomized by the 75th percentile revealing a significantly worse prognosis for patients in the upper 75th percentile (median OS 4.9 months) compared to patients with lower levels (10.0 months) (HR 2.1, 95%CI 1.4 -3.1, p < 0.0001). A multivariate analysis confirmed the independent prognostic value of cfDNA. A subgroup analysis of patients with high cfDNA and poor performance status (PS = 2) identified a group of patients with even worse prognosis (median OS 2.0 versus 9.1 months, HR 3.6, 95%CI 1.4 -9.2, p < 0.0001). Similar and significant results were found when comparing level of cfDNA and PFS. Conclusions: High pre-treatment level of cfDNA seems to have a strong prognostic impact in patients with newly diagnosed advanced NSCLC. Combined with PS it identifies a patient group with minimal or no benefit of chemotherapy.

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Section: Discussionsupporting

confidence: 68%

The Prognostic Value of Cell-Free DNA in Advanced Non-Small-Cell Lung Cancer

Nygaard¹,

Spindler²,

Pallisgaard³

et al. 2013

JCT

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“…In a recent large meta-analysis, a high correlation between ccfDNA concentration and mCRC patient survival was observed, revealing that patients with relatively low levels of ccfDNA lived significantly longer than patients with higher levels (6). The relevance of ccfDNA levels for the prognosis of other cancer types has also been described, including advanced breast cancer (10), lung cancer (11,12), prostate cancer (13), pancreatic cancer (14), and other cancer types (15).…”

Section: Introductionmentioning

confidence: 99%

Circulating DNA as a Strong Multimarker Prognostic Tool for Metastatic Colorectal Cancer Patient Management Care

Messaoudi

Moulière

Manoir

et al. 2016

Clinical Cancer Research

148

108

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Purpose: Circulating cell-free DNA (ccfDNA) is a valuable source of tumor material obtained from a simple blood sampling that enables noninvasive analysis of the tumor genome. Our goal was to carry out a multiparametric analysis of ccfDNA and evaluate its prognostic value by investigating the overall survival (OS) of 97 metastatic colorectal cancer patients (mCRC).Experimental Design: Qualitative parameters (determination of the main KRAS exon2 and BRAF V600E mutations) and quantitative parameters (total ccfDNA concentration, mutant ccfDNA concentration, the proportion of mutant ccfDNA, and ccfDNA integrity index) were determined simultaneously in a single run using a unique Q-PCR multimarker approach (100% success rate).Results: The median follow-up time was 36 months and median OS was 22 months. Patients showing high ccfDNA levels had significantly shorter OS (18.07 months vs. 28.5 months, P ¼ 0.0087). Moreover, multivariate analysis revealed that a high ccfDNA level is an independent prognostic factor (P ¼ 0.034). All ccfDNA parameters were of prognostic interest: patients with higher levels of mutant ccfDNA and higher mutation loads for the detected mutations had shorter OS (P ¼ 0.0089 and P ¼ 0.05, respectively). In addition, the level of ccfDNA fragmentation correlated positively with decreased OS in the exclusive KRAS/ BRAF-mutant cohort of patients (P ¼ 0.0052) and appeared as a strong independent prognostic factor (P ¼ 0.0072), whereas it was not significant in the exclusive KRAS/BRAF WT cohort of patients (P ¼ 0.67).Conclusions: Our data provide for the first time qualitative and quantitative evidence in favor of multiparametric ccfDNA analysis in mCRC patients for prognostic assessment.

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“…High cfDNA level has been proven to be a non-invasive biomarker of poor outcome in lung cancer patients [6][7][8], whereas other studies did not report such a relationship [9]. This is mostly explained by the lack of standardisation of the cfDNA test, with major differences regarding cfDNA extraction, quantification and cut-off points.…”

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confidence: 46%

Circulating free DNA, new dynamic marker in nonsmall cell lung cancer patients?

et al. 2015

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@ERSpublications cfDNA concentration might be a prognostic factor in NSCLC and could be a tool for detecting molecular alterations http://ow.ly/TF8TCPlatinum-based doublet chemotherapy prolongs survival and improves quality of life as first-line treatment for non-selected and good performance status patients with advanced nonsmall cell lung cancer (NSCLC) [1]. However, the survival benefit is limited, even if this combination is the standard of care for decades, no clinically relevant predictive biomarkers have been discovered so far. The identification of surrogates for survival is an important topic for cancer therapy selection. Indeed, overall survival is still the best criterion for predicting treatment efficacy in lung cancer but it can, of course, not be used in clinical practice. In a recent systematic review of the literature, some intermediate criteria have been shown to be potentially useful predictors such as time to progression, progression-free survival, objective response, local control after radiotherapy, downstaging in locally advanced NSCLC, complete resection and pathological TNM (tumour, node, metastases) in resected NSCLC or circulating molecular markers or cells. Retrospective studies have suggested that carcinoembryonic antigen, cytokeratin 19 fragments, pro-gastrin-releasing peptide and, to a lesser extent, neuron specific enolase, cancer antigen 125 and cancer antigen 19-9, used as single criterion to assess overall survival, could be adequate intermediate criteria for survival in lung cancer patients [2]. The use of more sophisticated molecular markers developed thanks to recent progresses in molecular biology has also so far not been successful for that purpose even if high throughput techniques are used such as transcriptomic analyses assessing multiple miRNAs and mRNAs [3].In the study reported in the present issue of the European Respiratory Journal, TISSOT et al. [4] have assessed circulating cell-free DNA (cfDNA), which comprises small fragments of nucleic acids that are released from normal cells and tumours by programmed cell death (apoptosis). cfDNA can be detected and monitored in plasma of blood in all patients [5]. Thus, cfDNA has emerged as an attractive tumour marker for its minimal invasive, convenient, and easily accepted properties.The purpose of the study was to determine if this biomarker can be used as a prognostic tool for tumour response assessment and for survival in NSCLC patients treated by platinum-based chemotherapy. The authors report that cfDNA concentration in plasma samples collected before (baseline) platinum-based chemotherapy in 218 locally advanced or metastatic NSCLC patients had an independent prognostic value. Patients with highest cfDNA concentration showed a significantly shorter progression-free survival ( p=0.034) and overall survival ( p=0.001) than patients with lower cfDNA concentrations. However, changes in total cfDNA concentration during treatment were not predictive to assess the effectiveness of chemotherapy in NSCLC patients. In terms o...

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Circulating DNA is a Useful Prognostic Factor in Patients with Advanced Non-small Cell Lung Cancer

Abstract: In advanced NSCLC, high pretreatment circulating hTERT level is an independent poor prognostic marker for TTP and OS. Circulating DNA is a noninvasive marker, which may help to improve the prognostic profile of these patients.

Cited by 77 publications

References 18 publications

The Prognostic Value of Cell-Free DNA in Advanced Non-Small-Cell Lung Cancer

The Prognostic Value of Cell-Free DNA in Advanced Non-Small-Cell Lung Cancer

Circulating DNA as a Strong Multimarker Prognostic Tool for Metastatic Colorectal Cancer Patient Management Care

Circulating free DNA, new dynamic marker in nonsmall cell lung cancer patients?

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