The first circulating tumor cell-derived explant (CDX) model of a Merkel cell carcinoma
Frizziero, Melissa Kilgour, Elaine Simpson, Kathryn L Rothwell, Dominic G Chen, Y. Kerr, Alastair Lamarca, Angela McNamara, Mairead G
Frizziero, Melissa
Kilgour, Elaine
Simpson, Kathryn L
Rothwell, Dominic G
Chen, Y.
Kerr, Alastair
Lamarca, Angela
McNamara, Mairead G
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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.
Description
Date
2022
Publisher
Collections
Keywords
Type
Meetings and Proceedings
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.