Clinical Utility of Plasma-Based Comprehensive Molecular Profiling in Advanced Non-Small-Cell Lung Cancer

Robert D Schouten, Daan C L Vessies, Linda J W Bosch, Nicole P Barlo, Anne S R van Lindert, Saskia A G M Cillessen, Daan van den Broek, Michel M van den Heuvel, Kim Monkhorst, Robert D Schouten, Daan C L Vessies, Linda J W Bosch, Nicole P Barlo, Anne S R van Lindert, Saskia A G M Cillessen, Daan van den Broek, Michel M van den Heuvel, Kim Monkhorst

Abstract

Comprehensive molecular profiling (CMP) plays an essential role in clinical decision making in metastatic non-small-cell lung cancer (mNSCLC). Circulating tumor DNA (ctDNA) analysis provides possibilities for molecular tumor profiling. In this study, we aim to explore the additional value of centralized ctDNA profiling next to current standard-of-care protocolled tissue-based molecular profiling (SoC-TMP) in the primary diagnostic setting of mNSCLC in the Netherlands.

Methods: Pretreatment plasma samples from 209 patients with confirmed mNSCLC were analyzed retrospectively using the NGS AVENIO ctDNA Targeted Kit (Roche Diagnostics, Basel, Switzerland) and compared with paired prospective pretreatment tissue-based molecular profiling from patient records. The AVENIO panel is designed to detect single-nucleotide variants, copy-number variations, insertions or deletions, and tyrosine kinase fusion in 17 genes.

Results: Potentially targetable drivers were detected with SoC-TMP alone in 34.4% of patients. Addition of clonal hematopoiesis of indeterminate potential-corrected, plasma-based CMP increased this to 39.7% (P < .001). Concordance between SoC-TMP and plasma-CMP was 86.6% for potentially targetable drivers. Clinical sensitivity of plasma-CMP was 75.2% for any oncogenic driver. Specificity and positive predictive value were more than 90% for all oncogenic drivers.

Conclusion: Plasma-CMP is a reliable tool in the primary diagnostic setting, although it cannot fully replace SoC-TMP. Complementary profiling by combined SoC-TMP and plasma-CMP increased the proportion of patients who are eligible for targeted treatment.

Conflict of interest statement

Kim Monkhorst Consulting or Advisory Role: Roche Molecular Diagnostics, MSD, AstraZeneca, AbbVie, Bristol Myers Squibb, Lilly, Boehringer Ingelheim, Bayer Speakers' Bureau: Quadia Research Funding: AstraZeneca, Roche Molecular Diagnostics, Personal Genome Diagnostics Travel, Accommodations, Expenses: Takeda No other potential conflicts of interest were reported. Kim Monkhorst Consulting or Advisory Role: Roche Molecular Diagnostics, MSD, AstraZeneca, AbbVie, Bristol Myers Squibb, Lilly, Boehringer Ingelheim, Bayer Speakers' Bureau: Quadia Research Funding: AstraZeneca, Roche Molecular Diagnostics, Personal Genome Diagnostics Travel, Accommodations, Expenses: Takeda No other potential conflicts of interest were reported.

© 2021 by American Society of Clinical Oncology.

Figures

FIG 1.
FIG 1.
Flow diagram of inclusion. In total, 209 patients had CMP, either tissue-based, plasma-based, or both. Fifteen of the initially selected 224 patients were ineligible. CMP, comprehensive molecular profiling; LEMA, Lung cancer Early Molecular Assessment; NGS, next-generation sequencing; NSCLC, non–small-cell lung cancer; SoC-TMP, standard-of-care protocolled tissue-based molecular profiling.

References

    1. Novello S, Barlesi F, Califano R, et al. : Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 27:v1-v27, 2016. (suppl 5)
    1. Planchard D, Popat S, Kerr K, et al. : Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 29:iv192-iv237, 2018. (suppl 4)
    1. IKNL IKN : Landelijke richtlijn niet kleincellig longcarcinoom.
    1. Rangachari D, VanderLaan PA, Le X, et al. : Experience with targeted next generation sequencing for the care of lung cancer: Insights into promises and limitations of genomic oncology in day-to-day practice. Cancer Treat Commun 4:174-181, 2015
    1. Lim C, Tsao MS, Le LW, et al. : Biomarker testing and time to treatment decision in patients with advanced nonsmall-cell lung cancer. Ann Oncol 26:1415-1421, 2015
    1. Kuijpers C, Heuvel MMvd, Overbeek LIH, et al. : Landelijke variatie in moleculaire diagnostiek bij gemetastaseerde longkanker. Ned Tijdschr Geneeskd 163:1-10, 2019
    1. Lovejoy A, Pati A, Muñoz A, et al. . In-depth assessment reveals powerful performance and flexibility of the AVENIO ctDNA Analysis Kits.
    1. Balaji SA, Shanmugam A, Chougule A, et al. : Analysis of solid tumor mutation profiles in liquid biopsy. Cancer Med 7:5439-5447, 2018
    1. Aggarwal C, Thompson JC, Black TA, et al. : Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non-small cell lung cancer. JAMA Oncol 5:173-180, 2019
    1. Leighl NB, Page RD, Raymond VM, et al. : Clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly diagnosed metastatic non–small cell lung cancer. Clin Cancer Res 25:4691-4700, 2019
    1. Newman AM, Lovejoy AF, Klass DM, et al. : Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol 34:547-555, 2016
    1. Solutions RS : AVENIO ctDNA Targeted Kit.
    1. Chakravarty D, Gao J, Phillips SM, et al. : OncoKB: A Precision Oncology Knowledge Base. JCO Precis Oncol 2017:PO.17.00011, 2017
    1. National Library of Medicine : Variation Viewer.
    1. Bouaoun L, Sonkin D, Ardin M, et al. : TP53 variations in human cancers: New lessons from the IARC TP53 database and genomics data. Hum Mutat 37:865-876, 2016
    1. Forbes SA, Beare D, Boutselakis H, et al. : COSMIC: Somatic cancer genetics at high-resolution. Nucleic Acids Res 45:D777-d83, 2017
    1. JaxCKB :
    1. Franklin Genoox :
    1. OncoKB : OncoKB Therapeutic Levels of Evidence V2.
    1. Razavi P, Li BT, Brown DN, et al. : High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants. Nat Med 25:1928-1937, 2019
    1. Hu Y, Ulrich BC, Supplee J, et al. : False-positive plasma genotyping due to clonal hematopoiesis. Clin Cancer Res 24:4437-4443, 2018
    1. MacConaill LE, Burns RT, Nag A, et al. : Unique, dual-indexed sequencing adapters with UMIs effectively eliminate index cross-talk and significantly improve sensitivity of massively parallel sequencing. BMC Genomics 19:30, 2018
    1. Kircher M, Sawyer S, Meyer M: Double indexing overcomes inaccuracies in multiplex sequencing on the Illumina platform. Nucleic Acids Res 40:e3, 2012
    1. Leal A, van Grieken NCT, Palsgrove DN, et al. : White blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer. Nat Commun 11:525, 2020
    1. Kloten V, Lampignano R, Krahn T, et al. : Circulating tumor cell PD-L1 expression as biomarker for therapeutic efficacy of immune checkpoint inhibition in NSCLC. Cells 8:809, 2019

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