Plasma ctDNA Analysis for Detection of the EGFR  T790M Mutation in Patients with Advanced Non–Small Cell Lung Cancer

Jenkins, Suzanne; Yang, James Chih‐Hsin; Ramalingam, Suresh S.; Yu, Karen; Patel, S.; Weston, Susie; Hodge, Rachel; Cantarini, Mireille; Jänne, Pasi A.; Mitsudomi, Tetsuya; Goss, Glenwood D.

doi:10.1016/j.jtho.2017.04.003

Cited by 243 publications

(213 citation statements)

References 33 publications

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“…Finally, 40% of patients with a mNSCLC diagnosis are eligible to receive the second-line treatment [3]; of them, 82% are eligible for the tissue re-biopsy [5] and 100% for the liquid one. Table II shows the percentages of sensitivity and specificity associated with the COBAS ® test performed on tissue (tissue biopsy) or plasma (liquid biopsy) samples and considered here [17,18]. In addition to these data, in the model -based on what is indicated in the literature -in the presence of a tissue biopsy, a 14% probability that the diagnostic investigation could determine the onset of a post-procedure complication (eg.…”

Section: Populationmentioning

confidence: 99%

“…Patients eligible for the second-line treatment (40.0%) 6,890 [3] Patients eligible for the tissue re-biopsy (82.0%) 5,650 [5] Patients eligible for the liquid biopsy (100.0%) 6,890 Assumption [17,18] determining the presence of DNA mutations, only the sampling of venous blood is provided for. Every single specialist outpatient service was then attributed a value, considering the respective fee refunded by the NHS [20].…”

Section: Second-line Treatmentmentioning

confidence: 99%

“…In particular, compared to the base case, the sensitivity and specificity of the liquid biopsy in determining EGFR mutations (T790M and exons 19 and 21) was varied, by simultaneously considering (multivariate analysis) the respective lower limits of the confidence interval [17], while leaving unchanged the values of sensitivity and specificity associated with the tissue biopsy. With regard to the presence of the post-tissue biopsy complications, conservatively with respect to the base case, a 50% reduction in complications (from 14% to 7%) was assumed.…”

Section: Sensitivity Analysismentioning

confidence: 99%

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Cost-Consequence Analysis of Three Different Diagnostic Strategies in the First- and Second-Line Treatment of Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

Gancitano

Ravasio²,

Dionisi

2018

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BACKGROUND: Unlike the tissue one, liquid biopsy is a less invasive diagnostic method for the assessment of possible mutations of the tumor, based on the analysis of circulating free DNA (cfDNA) present in the plasma component of the blood. Because blood samples are easily obtainable, plasma biopsy is a non-invasive method, supplementing the more traditional biopsy techniques.AIM: A cost-consequence analysis was conducted to compare the adoption of three different diagnostic strategies in the first- and second-line treatment of locally advanced or metastatic NSCLC: i) tissue strategy (only tissue biopsy for first and second line), ii) combined strategy (first line: tissue biopsy. If unknown, liquid biopsy; second line: liquid biopsy. If negative, tissue biopsy) and iii) potential strategy (first line: tissue biopsy. If unknown or tissue ineligible, liquid biopsy; secondline: liquid biopsy. If negative, tissue biopsy).METHODS: A decision-analytic model was developed considering the Italian NHS’s perspective. We only evaluated direct medical costs (tissue biopsy, management of complications associated with tissue and liquid biopsies) borne by the NHS. The CCA was conducted over a time horizon of 1 year, assuming that for each patient with mNSCLC the diagnosticpathway (first- and second-line treatment) ended within such period. Key variables were tested in the sensitivity analysis.RESULTS: Considering both the first and the second line of treatment, the potential strategy constitutes the cost-effective alternative, characterized by an average cost per correctly identified case (€ 685) lower than that estimated for the combined strategy (€ 732) or for the tissue strategy (€ 1,004). The potential strategy remains cost-effective, also considering the results referred to the first- or second-line treatment only.CONCLUSION: The choice of a correct diagnostic strategy is crucial in order to optimize cancer therapies in the first- and second-line treatment of locally advanced or metastasized NSCLC. The addition to the diagnostic pathway of the liquid biopsy would correctly identify a greater number of cases, supporting the prescription of the best oncological therapy.

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Section: Populationmentioning

confidence: 99%

Section: Second-line Treatmentmentioning

confidence: 99%

Section: Sensitivity Analysismentioning

confidence: 99%

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Cost-Consequence Analysis of Three Different Diagnostic Strategies in the First- and Second-Line Treatment of Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

Gancitano

Ravasio²,

Dionisi

2018

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“…Prior work has demonstrated the feasibility of using “hotspot” and comprehensive cfDNA profiling for identification of activating mutations and therapeutic resistance mechanisms in EGFR -mutated NSCLC. 18–24 However, its utility in evaluating ALK gene fusions has not been assessed on a large scale. Small studies, such as a recent report that identified two cfDNA ALK fusions in a cohort of 102 patients show that the detection of these alterations is feasible, albeit more technically challenging than somatic mutation detection, while a longitudinal evaluation of 22 patients was able to detect ALK fusions in 86% at progression.…”

Section: Introductionmentioning

confidence: 99%

Clinical Utility of Cell-Free DNA for the Detection of ALK Fusions and Genomic Mechanisms of ALK Inhibitor Resistance in Non–Small Cell Lung Cancer

McCoach

Blakely

Banks

et al. 2018

Clinical Cancer Research

143

124

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Purpose Patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase (ALK) gene fusions benefit from treatment with ALK inhibitors (ALKi). Analysis of cell-free circulating tumor DNA (cfDNA) may provide a non-invasive way to identify ALK fusions and actionable resistance mechanisms without an invasive biopsy. Experimental Design The Guardant360 (G360) de-identified database of NSCLC cases was queried to identify 88 consecutive patients with 96 plasma-detected ALK fusions. G360 is a clinical cfDNA next-generation sequencing (NGS) test that detects point mutations, select copy number gains, fusions, insertions, and deletions in plasma. Results Identified fusion partners included EML4 (85.4%), STRN (6%), and KCNQ, KLC1, KIF5B, PPM1B, and TGF (totaling 8.3%). Forty-two ALK positive patients had no history of targeted therapy (cohort 1) with tissue ALK molecular testing attempted in 21 (5 negative, 5 positive, 11 tissue insufficient). Follow-up of 3 of the 5 tissue negative patients showed responses to ALKi. Thirty-one patients were tested at known or presumed ALKi progression (cohort 2); 16 samples (53%) contained 1 – 3 ALK resistance mutations. In 13 patients, clinical status was unknown (cohort 3), and no resistance mutations or bypass pathways were identified. In 6 patients with known EGFR activating mutations, an ALK fusion was identified on progression (cohort 4) (4 STRN, 1 EML4; one both STRN and EML4), five harbored EGFR T790M. Conclusions In this cohort of cfDNA detected ALK fusions, we demonstrate that comprehensive cfDNA NGS provides a non-invasive means of detecting targetable alterations, and characterizing resistance mechanisms on progression.

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“…AURA extension and AURA2 phase II studies using COBAS RT platform have reported overall predictive agreement of T790M reported in tumor tissue and plasma samples to be 65%. [41] Ahsan et al . have reported concordance of around 77% on DdPCR for T790M.…”

Section: Discussionmentioning

confidence: 99%

The detection of primary and secondary EGFR mutations using droplet digital PCR in patients with nonsmall cell lung cancer

et al. 2018

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Background:We share our experience of using droplet digital polymerase chain reaction (DdPCR) in liquid biopsy specimens for detecting primary and secondary epidermal growth factor receptor (EGFR) mutations among patients with nonsmall-cell lung cancer who had tissue biopsy initially analyzed for del19, L858R and T790M.Materials and Methods:Three groups of patients were chosen: Group 1: patients positive for EGFR mutation (del 19 or L858R) by conventional tissue biopsy that were treatment naïve, Group 2: patients positive for EGFR mutation (del 19 or L858R) by conventional tissue biopsy with acquired resistance to tyrosine kinase inhibitor (TKI) therapy, documented by radiology, and Group 3: no known EGFR mutation detected on primary tissue biopsy and treatment naive.Results:One hundred and thirty-three patients were included in the study. Group 1 had 40 cases, of which 21 (52.5%) and 19 (47.5%) were positive for del19 and L858R mutations, respectively, by tissue biopsy. DdPCR detected primary mutation in all but 5 cases. DdPCR additionally found four patients to have T790M mutation. Group 2 had 73 cases and DdPCR detected T790M mutation in 39 (53.4%) cases. Liquid biopsy also picked the original primary mutation in 56/73 cases. Secondary tissue biopsy for T790M mutation status was performed in 11 patients and while it detected mutation in 2 out of 11 cases, DdPCR detected the same in 7 cases, thus providing significantly superior yield (46% difference, McNemar's test, P value 0.063). Tissue biopsy additionally detected c-MET amplification in a patient who had T790M mutation on liquid biopsy. Group 3 had 20 patients and none were falsely positive for EGFR mutation on liquid biopsy. Overall, DdPCR had a Cohen's kappa of 0.82 (standard error 0.074, 95% CI 0.68–0.97) indicating “very good agreement” with conventional tissue biopsy.Conclusion:DdPCR demonstrated 87.5% sensitivity and 100% specificity in detecting primary EGFR mutations in patients who were treatment naïve with overall positive and negative predictive value of 100% and 80%, respectively. DdPCR demonstrated T790M mutation postprogression on TKI therapy in 53.4% patients.

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Plasma ctDNA Analysis for Detection of the EGFR T790M Mutation in Patients with Advanced Non–Small Cell Lung Cancer

Abstract: The cobas plasma test detected the T790M mutation in 61% of tumor tissue T790M mutation-positive patients. To mitigate the risk of false-negative plasma results, patients with a negative plasma result should undergo a tissue test where feasible.

Cited by 243 publications

References 33 publications

Cost-Consequence Analysis of Three Different Diagnostic Strategies in the First- and Second-Line Treatment of Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

Cost-Consequence Analysis of Three Different Diagnostic Strategies in the First- and Second-Line Treatment of Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

Clinical Utility of Cell-Free DNA for the Detection of ALK Fusions and Genomic Mechanisms of ALK Inhibitor Resistance in Non–Small Cell Lung Cancer

The detection of primary and secondary EGFR mutations using droplet digital PCR in patients with nonsmall cell lung cancer

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