RET rearrangements are actionable alterations in breast cancer

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.

S100 and CD34 positive spindle cell tumor with prominent perivascular hyalinization and a novel NCOA4‐RET fusion

“…RET gene fusions are exceedingly rare in soft tissue neoplasia and to our best knowledge, NCOA4‐RET fusion has not been reported in a mesenchymal neoplasm so far. NCOA4‐RET fusions occur most commonly in the thyroid cancer but have recently been reported in a variety of other carcinomas originating in the breast, colon, lungs, or salivary glands . However, the frequency of this alteration might be higher, but as illustrated in the current case as well as in other studies, both fusion partners are located very close to each other on the 10q11.2 locus to be reliably detected by the FISH break apart probe.…”

RET Gene Fusions in Malignancies of the Thyroid and Other Tissues

“…In a recent study based on targeted genomic profiling of 9693 cases, RET genomic alterations, including 16 rearrangements, were observed in 1.2% of breast cancers. These rearrangements featured the classical CCDC6-RET and NCOA4-RET fusions, the new uncharacterized RASGEF1A-RET and ZNF485-RET fusions, and rearrangements resulting in tandem duplications that involve exons 12-19 of RET [32].…”

RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies

“…RET fusion-positive NSCLC (1%-2%) and RET-mutant medullary thyroid cancer (MTC) (60% sporadic, >90% hereditary) represent the largest burden of RET-altered cancers; RET fusions have also been identified in 5% to 10% of diverse (nonmedullary) thyroid cancers and rarely in various other tumor types. [1][2][3][4][5][6] Although multikinase inhibitors (MKIs) that target RET and other kinases, such as vandetanib and cabozantinib, have been approved for MTC and investigated in RET fusion-positive NSCLC, their use is limited by substantial off-target toxicity and modest clinical activity. [7][8][9][10][11][12] Recently, registrational results of the phase 1 and 2 study of selpercatinib (LOXO-292, NCT03157128), a highly selective anti-RET tyrosine kinase inhibitor (TKI), reported durable responses in various tumor histologic diagnoses, against diverse RET gene alterations, after prior MKIs, and in the setting of the RET V804 "gatekeeper" mutation.…”