Circulating tumor DNA evaluated by Next-Generation Sequencing is predictive of tumor response and prolonged clinical benefit with nivolumab in advanced non-small cell lung cancer

Leprieur, Étienne Giroux; Herbretau, Guillaume; Duménil, Coraline; Julié, Catherine; Giraud, Violaine; Labrune, Sylvie; Dumoulin, Jennifer; Tisserand, Julie; Émile, Jean-François; Blons, Hélène; Chinet, Thierry

doi:10.1080/2162402x.2018.1424675

Cited by 72 publications

(56 citation statements)

References 22 publications

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“…We next investigated whether the early decrease in peripheral ctDNA could predict prolonged survival in response to immunotherapy, as reported in ICB‐treated cohorts with relatively large cohort sizes. [ 12,14,23 ] Surprisingly, even with a small sample size of nine patients (P10 was excluded) with baseline blood samples in our cohort, the substantial early decrease in ctDNA abundance (≥50% decrease at eight weeks) predicted prolonged progression‐free survival after ICB administration (Figure S6, Supporting Information, ** p = 0.003 and HR = 6.005 [0.879–41.010]). These observations strongly support the use of ICP‐based ctDNA sequencing to identify patients likely to have favorable outcomes following ICB treatment.…”

Section: Resultsmentioning

confidence: 99%

Tracking Neoantigens by Personalized Circulating Tumor DNA Sequencing during Checkpoint Blockade Immunotherapy in Non‐Small Cell Lung Cancer

Jia

Chiu

et al. 2020

Advanced Science

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The evolutionary dynamics of tumor-associated neoantigens carry information about drug sensitivity and resistance to the immune checkpoint blockade (ICB). However, the spectrum of somatic mutations is highly heterogeneous among patients, making it difficult to track neoantigens by circulating tumor DNA (ctDNA) sequencing using "one size fits all" commercial gene panels. Thus, individually customized panels (ICPs) are needed to track neoantigen evolution comprehensively during ICB treatment. Dominant neoantigens are predicted from whole exome sequencing data for treatment-naïve tumor tissues. Panels targeting predicted neoantigens are used for personalized ctDNA sequencing. Analyzing ten patients with nonsmall cell lung cancer, ICPs are effective for tracking most predicted dominant neoantigens (80-100%) in serial peripheral blood samples, and to detect substantially more genes (18-30) than the capacity of current commercial gene panels. A more than 50% decrease in ctDNA concentration after eight weeks of ICB administration is associated with favorable progressionfree survival. Furthermore, at the individual level, the magnitude of the early ctDNA response is correlated with the subsequent change in tumor burden. The application of ICP-based ctDNA sequencing is expected to improve the understanding of ICB-driven tumor evolution and to provide personalized management strategies that optimize the clinical benefits of immunotherapies.

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Section: Resultsmentioning

confidence: 99%

Tracking Neoantigens by Personalized Circulating Tumor DNA Sequencing during Checkpoint Blockade Immunotherapy in Non‐Small Cell Lung Cancer

Jia

Chiu

et al. 2020

Advanced Science

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“…The OAK and POPLAR trials, which evaluated the efficacy of atezolizumab, showed a relationship between PFS and TMB of plasma ctDNA with FoundationOne CDx [60,61]. Giroux Leprieur et al [62] also showed that TMB of ctDNA determined by an NCS gene panel approach can predict the efficacy of nivolumab in patients with advanced NSCLC. Patients with a ctDNA increase > 9% from baseline to the first tumor evaluation at 2 months had no longterm clinical benefit with nivolumab with a sensitivity of 71.4% and specificity of 100%.…”

Section: Future Perspectives On Circulating Tumor Dna Testing In Lungmentioning

confidence: 99%

Current status and future perspectives of liquid biopsy in non-small cell lung cancer

Chang

Hur

Choi

et al. 2020

J Pathol Transl Med

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Molecular analysis is traditionally performed on tumor tissue. Although the number of mandatory tests for treatment decisions increases in patients with advanced non-small cell lung cancer (NSCLC), it is difficult to secure adequate tumor tissue for this purpose [1]. Small biopsy specimens, cell blocks, or aspirates are often the only available samples in patients with advanced NSCLC [2,3]. It is difficult to repeat tissue biopsies because they are invasive. Liquid biopsy could be an alternative or a complementary minimally invasive method for detecting molecular changes in NSCLC [1,2,4,5]. The clinical use of liquid biopsy to select patients with advanced NSCLC who are candidates for third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy has been demonstrated in many clinical trials [6-10]. The United States Food and Drug Administration (FDA) approved Cobas EGFR Mutation Test v2 (Roche, Indianapolis, IN, USA) in 2018 as a companion diagnostic for third-generation EGFR TKI based on these results [11]. The Korea National Health Insurance Service (NHIS) has covered circulating cell-free tumor DNA (ctDNA) tests for EGFR mutations in advanced NSCLC since 2018. In this review, we present the current status and future perspectives of liquid biopsy in patients with NSCLC. BIOLOGY OF CIRCULATING TUMOR DNA Liquid biopsy refers to the collection and analysis of analytes from various body fluids such as blood, urine, sputum, and pleural fluid [12-14]. Different analytes can be present in a liquid biopsy including circulating tumor cells (CTCs), circulating cell-free DNAs (cfDNAs), circulating tumor RNAs (ctRNAs), circulating exosomes, tumor-educated platelets, proteins, and metabolites [15,16]. CTCs are intact, viable tumor cells circulating in the blood [12]. Cancer releases single or clusters of CTCs into the bloodstream during the course of hematogenous spread. cfDNA refers to all circulating DNA in body fluids. cfDNA can be derived from neoplastic as well as non-neoplastic cells [15,16]. cfDNA can be detected in other body fluids, including urine, saliva, or cerebrospinal fluid. ctDNA refers to a subgroup

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“…Circulating tumour DNA (ctDNA) has shown to be a good predictive marker of ICIs efficacy. [17][18][19] However, no study has been dedicated so far to other circulating biomarkers such as ICIrelated proteins or circulating microRNA (miRNA). The presence of soluble PD-L1 (sPD-L1) has already been established in patients with NSCLC with a prognostic impact of sPD-L1 concentrations.…”

Section: Introductionmentioning

confidence: 99%

Predictive role of plasmatic biomarkers in advanced non-small cell lung cancer treated by nivolumab

et al. 2018

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Immune checkpoint inhibitors, as nivolumab, are used in advanced non-small cell lung cancer (NSCLC). However, no associated biomarker is validated in clinical practice with this drug. We investigated herein immune-related blood markers in patients with advanced NSCLC treated with nivolumab. Plasma of 43 consecutive patients were prospectively collected at time of the diagnosis of cancer, at the initiation of nivolumab and at the first tumour evaluation (2 months). Concentrations of PD-L1 (sPD-L1), soluble PD-L2 (sPD-L2), Interleukine-2 (sIl-2), Interferon-gamma (sIFN-γ), and Granzyme B (sGranB) were quantified by ELISA. Cell free RNA was quantified by Reverse Transcriptase -PCR), and plasmatic microRNAs (miRNAs) were evaluated by targeted sequencing. Expression of PD-L1 on tumour biopsies was performed by immunohistochemistry using E13LN. High sPD-L1 at 2 months and increase of sPD-L1 concentrations were associated with poor response and absence of clinical benefit (nivolumab treatment less than 6 months). The variation of sPD-L1 concentrations were confirmed by RNA quantification. sPD-L1 concentrations were not correlated with PD-L1 expression on corresponding tumour samples. Low sGranB at nivolumab initiation was also associated with poor response. High sPD-L1 and low sGranB were associated with poor progression-free survival (PFS) and overall survival (OS). Low sPD-L2, low sIl-2 and high sIFN-γ were associated with grade 3-4 toxicities. Finally, miRNA screening showed that patients with clinical benefit (n = 9) had down-expression of miRNA-320b and -375 compared to patients with early progression at 2 months (n = 9). In conclusion, our results highlight the interest of circulating biomarkers in patients treated with nivolumab.

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Circulating tumor DNA evaluated by Next-Generation Sequencing is predictive of tumor response and prolonged clinical benefit with nivolumab in advanced non-small cell lung cancer

Cited by 72 publications

References 22 publications

Tracking Neoantigens by Personalized Circulating Tumor DNA Sequencing during Checkpoint Blockade Immunotherapy in Non‐Small Cell Lung Cancer

Tracking Neoantigens by Personalized Circulating Tumor DNA Sequencing during Checkpoint Blockade Immunotherapy in Non‐Small Cell Lung Cancer

Current status and future perspectives of liquid biopsy in non-small cell lung cancer

Predictive role of plasmatic biomarkers in advanced non-small cell lung cancer treated by nivolumab

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