Utility of serial cfDNA NGS for prospective genomic analysis of patients on a phase I basket study Journal Article


Authors: Smyth, L. M.; Reichel, J. B.; Tang, J.; Patel, J. A. A.; Meng, F.; Selcuklu, D. S.; Houck-Loomis, B.; You, D.; Samoila, A.; Schiavon, G.; Li, B. T.; Razavi, P.; Piscuoglio, S.; Reis-Filho, J. S.; Taylor, B. S.; Baselga, J.; Solit, D. B.; Hyman, D. M.; Berger, M. F.; Chandarlapaty, S.
Article Title: Utility of serial cfDNA NGS for prospective genomic analysis of patients on a phase I basket study
Abstract: PURPOSE Cell-free DNA (cfDNA) analysis offers a noninvasive means to access the tumor genome. Despite limited sensitivity of broad-panel sequencing for detecting low-frequency mutations in cfDNA, it may enable more comprehensive genomic characterization in patients with sufficiently high disease burden. We investigated the utility of large-panel cfDNA sequencing in patients enrolled to a Phase I AKT1-mutant solid tumor basket study. METHODS Patients had AKT1 E17K-mutant solid tumors and were treated on the multicenter basket study (ClinicalTrials.gov identifier: NCT01226316) of capivasertib, an AKT inhibitor. Serial plasma samples were prospectively collected and sequenced using exon-capture next-generation sequencing (NGS) analysis of 410 genes (Memorial Sloan Kettering [MSK]-Integrated Molecular Profiling of Actionable Cancer Target [IMPACT]) and allele-specific droplet digital polymerase chain reaction (ddPCR) for AKT1 E17K. Tumor DNA (tDNA) NGS (MSK-IMPACT) was also performed on available pretreatment tissue biopsy specimens. RESULTS Among 25 patients, pretreatment plasma samples were sequenced to an average coverage of 504x. Somatic mutations were called in 20/25 (80%), with mutant allele fractions highly concordant with ddPCR of AKT1 E17K (r(2) = 0.976). Among 17 of 20 cfDNA-positive patients with available tDNA for comparison, mutational concordance was acceptable, with 82% of recurrent mutations shared between tissue and plasma. cfDNA NGS captured additional tumor heterogeneity, identifying mutations not observed in tDNA in 38% of patients, and revealed oncogenic mutations in patients without available baseline tDNA. Longitudinal cfDNA NGS (n = 98 samples) revealed distinct patterns of clonal dynamics in response to therapy. CONCLUSION Large gene panel cfDNA NGS is feasible for patients with high disease burden and is concordant with single-analyte approaches, providing a robust alternative to ddPCR with greater breadth. cfDNA NGS can identify heterogeneity and potentially biologically informative and clinically relevant alterations. (C) 2021 by American Society of Clinical Oncology
Journal Title: JCO Precision Oncology
Volume: 5
ISSN: 2473-4284
Publisher: American Society of Clinical Oncology  
Date Published: 2021-01-08
Start Page: 6
End Page: 16
Language: English
ACCESSION: WOS:000636553200002
DOI: 10.1200/po.20.00184
PROVIDER: wos
Notes: Sadan Duygu Selcuklu's name appears as Duygu S. Selcuklu on the original publication -- Article -- Source: Wos
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MSK Authors
  1. David Solit
    617 Solit
  2. David Hyman
    345 Hyman
  3. Michael Forman Berger
    557 Berger
  4. Barry Stephen Taylor
    222 Taylor
  5. Jorge Sergio Reis
    456 Reis
  6. Aliaksandra Samoila
    21 Samoila
  7. Jose T Baselga
    480 Baselga
  8. Daoqi You
    29 You
  9. Pedram Razavi
    99 Razavi
  10. Jonathan Brett Reichel
    14 Reichel
  11. Bob Tingkan Li
    146 Li
  12. Lillian   Smyth
    40 Smyth
  13. Jiabin   Tang
    5 Tang
  14. Fanli   Meng
    16 Meng
  15. Juber Ahamad Abdul Bari Patel
    16 Patel