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    The first circulating tumor cell-derived explant (CDX) model of a Merkel cell carcinoma

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    Authors
    Frizziero, Melissa
    Kilgour, Elaine
    Simpson, Kathryn L
    Rothwell, Dominic G
    Chen, Y.
    Kerr, Alastair
    Lamarca, Angela
    Hubner, Richard A
    Valle, Juan W
    McNamara, Mairead G
    Dive, Caroline
    Frese, Kristopher K
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    Affiliation
    Cancer Biomarker Centre, Cancer Research UK Manchester Institute, University of Manchester, Manchester,
    Issue Date
    2022
    
    Metadata
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    Abstract
    Introduction:Poorly differentiated ExtraPulmonary NeuroEndocrine Carcinomas (EP-NECs) have a median overall survival of <12 months and lack effective treatments; patient-relevant preclinical models are needed. Aim(s):In EP-NEC, to assess feasibility of liquid biopsy technologies used for the pulmonary-NEC counterpart Small Cell Lung Cancer (SCLC); circulating tumor cell (CTC) enumeration by CellSearch (CS) and CTC-Derived eXplants (CDX) which in SCLC mirror biology and chemo response of donor patients. Materials and methods:Serial CTC enumeration and attempt at CDX generation in a prospective cohort of patients with advanced EP-NEC undergoing palliative chemotherapy (chemo). Results:27 patients were recruited from Jun-19 to Nov-21. CS-CTCs were present in 70% of pre-chemo samples (mean 57, median 2, range 0-685 CTCs per 7.5mL of blood). A CDX was generated with a pre-chemo sample from a patient with a NEC of unknown origin. Whole-exome sequencing of the CDX and matched pre-chemo cell-free DNA from the donor revealed shared copy number changes and somatic mutations (e.g. PIK3CA). The CDX was sensitive to platinum/etoposide in vivo, mirroring the donor’s treatment response. Morphological and immunohistochemical (IHC) evaluation of the CDX showed a small cell NEC concordant withthe donor’s biopsy. Further IHC and RNA sequencing revealed expression of the neuroendocrine transcription factor atonal homolog 1 (ATOH1), CK20 and abundant Merkel cell polyomavirus transcripts; prompting reclassification of the diagnosis to Merkel cell carcinoma (MCC). Conclusion:This is the first reported MCC CDX and provides an avatar for in-depth molecular characterisation of the original tumor, with potential to inform future treatment for the donor (alive >24 months from diagnosis) and future patients.
    Citation
    Frizziero M, Kilgour E, Simpson KL, Rothwell D, Frese K, Chen Y, et al. The first circulating tumor cell-derived explant (CDX) model of a Merkel cell carcinoma. Journal of Neuroendocrinology. 2022;34:41.
    Journal
    Journal of Neuroendocrinology
    URI
    http://hdl.handle.net/10541/625209
    Type
    Meetings and Proceedings
    Language
    en
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