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Nat Commun. 2018 Nov 16;9(1):4821. doi: 10.1038/s41467-018-07341-4.

RET rearrangements are actionable alterations in breast cancer.

Author information

1
Department of Medicine, Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA.
2
Rutgers University, Piscataway, NJ, 08854, USA.
3
Foundation Medicine, Cambridge, MA, 02139, USA.
4
Avera Cancer Institute Center for Precision Oncology, Sioux Falls, SD, 57105, USA.
5
University Radiology Group, New Brunswick, NJ, 08901, USA.
6
Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School and Rutgers Robert Wood Johnson Medical School, Newark, NJ, 07103, USA.
7
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA.
8
Avera Cancer Institute Center for Precision Oncology, Sioux Falls, SD, 57105, USA. brian.leylandjones@avera.org.
9
Department of Medicine, Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA. kim.hirshfield@merck.com.
10
Rutgers University, Piscataway, NJ, 08854, USA. kim.hirshfield@merck.com.

Abstract

Fusions involving the oncogenic gene RET have been observed in thyroid and lung cancers. Here we report RET gene alterations, including amplification, missense mutations, known fusions, novel fusions, and rearrangements in breast cancer. Their frequency, oncogenic potential, and actionability in breast cancer are described. Two out of eight RET fusions (NCOA4-RET and a novel RASGEF1A-RET fusion) and RET amplification were functionally characterized and shown to activate RET kinase and drive signaling through MAPK and PI3K pathways. These fusions and RET amplification can induce transformation of non-tumorigenic cells, support xenograft tumor formation, and render sensitivity to RET inhibition. An index case of metastatic breast cancer progressing on HER2-targeted therapy was found to have the NCOA4-RET fusion. Subsequent treatment with the RET inhibitor cabozantinib led to a rapid clinical and radiographic response. RET alterations, identified by genomic profiling, are promising therapeutic targets and are present in a subset of breast cancers.

PMID:
30446652
PMCID:
PMC6240119
DOI:
10.1038/s41467-018-07341-4
[Indexed for MEDLINE]
Free PMC Article

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