Monitoring Therapeutic Response and Resistance: Analysis of Circulating Tumor DNA in Patients With ALK+ Lung Cancer

Horn, Leora; Whisenant, Jennifer G.; Wakelee, Heather A.; Reckamp, Karen L.; Qiao, Huan; Leal, Ticiana; Du, Liping; Hernández, Jennifer; Huang, Vincent; Blumenschein, George R.; Waqar, Saiama N.; Patel, Sandip Pravin; Nieva, Jorgé; Oxnard, Geoffrey R.; Sanborn, Rachel E.; Shaffer, Tristan; Garg, Kavita D.; Holzhausen, Allison; Harrow, Kimberly; Liang, Chris; Lim, Lee P.; Li, Mark; Lovly, Christine M.

doi:10.1016/j.jtho.2019.08.003

Cited by 137 publications

(149 citation statements)

References 33 publications

(48 reference statements)

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“…Our descriptive findings of the correlation between longitudinal ctDNA mutant allele concentrations and treatment response are in agreement with previous studies that mostly investigated EGFR-mutated NSCLC patients [14,15,24,25], while only few studies have been performed in ALK-positive patients [26][27][28]. In our study, we assessed not only the ALK rearrangement driving the cancer but also other somatic aberrations.…”

Section: Discussionsupporting

confidence: 90%

“…We identified genomic alterations in the majority of patients (17 out of 24), though ALK rearrangements were only identified in plasma samples from 9 patients (39%). This is lower than what was found by other studies with ALK-positive patients [26][27][28]. However, recent studies have elucidated the discrepancies in the detection of SNVs and rearrangements in plasma, comparing different commercial NGS assays [33,34].…”

Section: Discussioncontrasting

confidence: 56%

“…As is often the case when studying ALK-positive patients, the current study is limited by the number of included patients, which mainly renders it hypothesis-generating [26][27][28]. Thus, our results should be validated in a larger cohort of ALK-positive patients.…”

Section: Discussionmentioning

confidence: 89%

“…The majority of patients (19 of 24) had stage IV adenocarcinoma and was treatment naïve (14 of 24). The median follow-up time was 21 months (95% CI: [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. At the last follow-up date, 14 patients had experienced disease progression on at least one ALK TKI, and six patients were deceased.…”

Section: Patient Characteristicsmentioning

confidence: 99%

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Genomic Profiling of Circulating Tumor DNA Predicts Outcome and Demonstrates Tumor Evolution in ALK-Positive Non-Small Cell Lung Cancer Patients

Madsen

Winther‐Larsen

McCulloch

et al. 2020

Cancers

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With the rapid development of targeted therapies for the treatment of cancer, methods for predicting response and outcome are in high demand. Non-small cell lung cancer driven by genomic rearrangements of the anaplastic lymphoma kinase (ALK) gene can be successfully treated with ALK-targeted therapy. Unfortunately, a subset of patients does not respond, and all patients ultimately acquire resistance, highlighting the need for better clinical tools to manage these patients. Here, we performed targeted next-generation sequencing on plasma circulating tumor DNA (ctDNA) from 24 patients to assess the clinical utility of ctDNA genomic profiling. Patients with detectable ctDNA prior to treatment had worse progression-free survival (PFS) than those without (median 8.7 vs. 15.2 months, p = 0.028). In addition, the presence of ctDNA within two months after treatment initiation predicted inferior PFS (median 4.6 vs. 14.5 months, p = 0.028). Longitudinal monitoring of ctDNA with droplet digital PCR during treatment reflected the radiological response and revealed potential acquired resistance mutations. Interestingly, an increase in the ctDNA concentration was evident prior to the determination of progressive disease by conventional radiological imaging, with a median lead time of 69 days (range 30–113). Genomic profiling of ctDNA is a promising tool for predicting outcome and monitoring response to targeted therapy.

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Section: Discussionsupporting

confidence: 90%

Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 89%

Section: Patient Characteristicsmentioning

confidence: 99%

See 2 more Smart Citations

Genomic Profiling of Circulating Tumor DNA Predicts Outcome and Demonstrates Tumor Evolution in ALK-Positive Non-Small Cell Lung Cancer Patients

Madsen

Winther‐Larsen

McCulloch

et al. 2020

Cancers

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“…Hence, the serial mutation profiling based on cfDNA over the duration of the diseas, may permit the real-time appreciation of the efficacy of systemic therapy and detection of disease resistance. In multiple studies, cfDNA has been utilised for monitoring of resistance mutations including EGFR T790M, BRAF, ALK, ERBB2 amplification in NSCLC patients receiving therapy [15,37,41,73,109,128,161,162]. In a study by Sung et al, longitudinal cfDNA analysis lead to the detection of EGFR T790M mutation emergence in 28.6% of NSCLC patients receiving EGFR TKI treatment [36].…”

Section: The Future Of Cfdna In Precision Oncologymentioning

confidence: 99%

Assessing the Concordance of Genomic Alterations between Circulating-Free DNA and Tumour Tissue in Cancer Patients

Jahangiri

Hurst

2019

Cancers

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Somatic alterations to the genomes of solid tumours, which in some cases represent actionable drivers, provide diagnostic and prognostic insight into these complex diseases. Spatial and longitudinal tracking of somatic genomic alterations (SGAs) in patient tumours has emerged as a new avenue of investigation, not only as a disease monitoring strategy, but also to improve our understanding of heterogeneity and clonal evolution from diagnosis through disease progression. Furthermore, analysis of circulating-free DNA (cfDNA) in the so-called “liquid biopsy” has emerged as a non-invasive method to identify genomic information to inform targeted therapy and may also capture the heterogeneity of the primary and metastatic tumours. Considering the potential of cfDNA analysis as a translational laboratory tool in clinical practice, establishing the extent to which cfDNA represents the SGAs of tumours, particularly actionable driver alterations, becomes a matter of importance, warranting standardisation of methods and practices. Here, we assess the utilisation of cfDNA for molecular profiling of SGAs in tumour tissue across a broad range of solid tumours. Moreover, we examine the underlying factors contributing to discordance of detected SGAs between cfDNA and tumour tissue.

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NGS‐based liquid biopsy profiling identifies mechanisms of resistance to ALK inhibitors: a step toward personalized NSCLC treatment

et al. 2021

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Despite impressive and durable responses, non-small cell lung cancer (NSCLC) patients treated with anaplastic lymphoma kinase inhibitors (ALK-Is) ultimately progress due to development of resistance. Here, we have evaluated the clinical utility of circulating tumor DNA (ctDNA) profiling by next-generation sequencing (NGS) upon disease progression. We collected26 plasma and two cerebrospinal fluid samples from 24 advanced ALK-positive NSCLC patients at disease progression to an ALK-I. These samples were analyzed by NGS and digital PCR. A tool to retrieve variants at the ALK locus was developed (VALK tool).We identified at least one resistance mutation in the ALK locus in ten (38.5%) plasma samples; the G1269A and G1202R mutations were the most prevalent among patients progressing to first-and secondgeneration ALK-Is, respectively. Overall, 61 somatic mutations were detected in 14 genes: TP53, ALK,

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Monitoring Therapeutic Response and Resistance: Analysis of Circulating Tumor DNA in Patients With ALK+ Lung Cancer

Cited by 137 publications

References 33 publications

Genomic Profiling of Circulating Tumor DNA Predicts Outcome and Demonstrates Tumor Evolution in ALK-Positive Non-Small Cell Lung Cancer Patients

Genomic Profiling of Circulating Tumor DNA Predicts Outcome and Demonstrates Tumor Evolution in ALK-Positive Non-Small Cell Lung Cancer Patients

Assessing the Concordance of Genomic Alterations between Circulating-Free DNA and Tumour Tissue in Cancer Patients

NGS‐based liquid biopsy profiling identifies mechanisms of resistance to ALK inhibitors: a step toward personalized NSCLC treatment

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