RET rearrangements are actionable alterations in breast cancer

Bhavna S. Paratala, Jon H. Chung, Casey B. Williams, Bahar Yilmazel, Whitney Petrosky, Kirstin Williams, Alexa B. Schrock, Laurie M. Gay, Ellen Lee, Sonia C. Dolfi, Kien Pham, Stephanie Lin, Ming Yao, Atul Kulkarni, Frances DiClemente, Chen Liu, Lorna Rodriguez-Rodriguez, Shridar Ganesan, Jeffrey S. Ross, Siraj M. Ali, Brian Leyland-Jones () and Kim M. Hirshfield ()
Additional contact information
Bhavna S. Paratala: Rutgers Cancer Institute of New Jersey
Jon H. Chung: Foundation Medicine
Casey B. Williams: Avera Cancer Institute Center for Precision Oncology
Bahar Yilmazel: Foundation Medicine
Whitney Petrosky: Rutgers Cancer Institute of New Jersey
Kirstin Williams: Avera Cancer Institute Center for Precision Oncology
Alexa B. Schrock: Foundation Medicine
Laurie M. Gay: Foundation Medicine
Ellen Lee: University Radiology Group
Sonia C. Dolfi: Rutgers Cancer Institute of New Jersey
Kien Pham: Rutgers New Jersey Medical School and Rutgers Robert Wood Johnson Medical School
Stephanie Lin: Rutgers Cancer Institute of New Jersey
Ming Yao: Rutgers Cancer Institute of New Jersey
Atul Kulkarni: Rutgers Cancer Institute of New Jersey
Frances DiClemente: Rutgers Cancer Institute of New Jersey
Chen Liu: Rutgers New Jersey Medical School and Rutgers Robert Wood Johnson Medical School
Lorna Rodriguez-Rodriguez: Rutgers University
Shridar Ganesan: Rutgers Cancer Institute of New Jersey
Jeffrey S. Ross: Foundation Medicine
Siraj M. Ali: Foundation Medicine
Brian Leyland-Jones: Avera Cancer Institute Center for Precision Oncology
Kim M. Hirshfield: Rutgers Cancer Institute of New Jersey

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07341-4

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