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    Monitoring circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) genomic alterations in ER positive (POS)/HER2 negative (NEG) advanced breast cancer during endocrine therapy: correlative study of AZD9496 oral SERD phase I trial

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    Authors
    Cani, A. K.
    Dolce, E. M.
    Darga, E. P.
    Hu, K.
    Brown, M.
    Liu, C. J.
    Pierce, Jackie
    Bradbury, Kieran
    Aung, K.
    Schiavon, G.
    Carroll, D.
    Carr, T. H.
    Klinowska, T.
    Lindemann, J.
    Marshall, G.
    Rowlands, V.
    Harrington, E. A.
    Barrett, J.
    Armstrong, Anne C
    Baird, R.
    Hamilton, E.
    Im, S. A.
    Jhaveri, K.
    Patel, M. R.
    Dive, Caroline
    Tomlins, S. A.
    Udager, A. M.
    Hayes, D. F.
    Paoletti, C.
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    Affiliation
    University of Michigan, Ann Arbor, MI
    Issue Date
    2021
    
    Metadata
    Show full item record
    Abstract
    Purpose: The vast majority of advanced ER POS breast cancers eventually cease responding to endocrine (ET) and other therapies leading to evolution of lethal disease. However, timely monitoring of the molecular events associated with response/progression in tissue biopsies is logistically difficult. The use of liquid biopsies, such as CTC and ctDNA, in this context has been of recent interest. Patients and Methods: Individual CTC and ctDNA were obtained at different time points from patients with advanced ER POS/HER2 NEG breast cancer enrolled in a Phase I trial of AZD9496, an oral selective estrogen receptor degrader (SERD) ET. The CTC, purified using tandem CellSearch®/DepArray™ technologies, were genomically profiled by DNA single cell next generation sequencing (scNGS). Plasma ctDNA was isolated from blood collected in Streck BCT tubes. Genomic profiling was performed by targeted gene panel scNGS for CTC and ddPCR for ERα gene (ESR1) mutations in ctDNA. Results: 123 high-quality CTCs from 12 patients profiled by scNGS showed 100% concordance with ctDNA in detection of driver ESR1 somatic mutations. CTC scNGS additionally revealed extensive intra-patient heterogeneity of driver alterations, that would have been unresolvable by bulk ctDNA profiling, including separate subclonal CTC populations emerging within the same patient. ScNGS revealed potential opportunities for targeted therapies in 73% of patients, directed at alterations in PIK3CA, FGFR2, KIT and BRAF, at times present as 2 or more targets in the same or different cell populations. In one patient, an emergent, distinct, BRAF p.V600E targetable alteration was detected in a subpopulation of CTCs collected at the progression time point but not at baseline. Conclusion: Serial monitoring of CTC and ctDNA genomic alterations is feasible and should enable real-time tracking of response/progression, tumor evolution and opportunities for precision medicine interventions.
    Citation
    Cani AK, Dolce EM, Darga EP, Hu K, Brown M, Liu C-J, et al. Abstract 3143: Monitoring circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) genomic alterations in ER positive (POS)/HER2 negative (NEG) advanced breast cancer during endocrine therapy: correlative study of AZD9496 oral SERD phase I trial. In: Tumor Biology. American Association for Cancer Research; 2021.
    Journal
    Cancer Research
    URI
    http://hdl.handle.net/10541/624581
    DOI
    10.1158/1538-7445.AM2021-3143
    Additional Links
    https://dx.doi.org/ 10.1158/1538-7445.AM2021-3143
    Type
    Other
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1158/1538-7445.AM2021-3143
    Scopus Count
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