Metaplastic breast cancer is a particularly aggressive form of TNBC affecting mesenchymal breast cells. Because it does not respond to standard therapies, the prognosis is worse for patients with this breast cancer subtype as compared to other TNBCs. Characterization of a small cohort (n = 17) revealed the presence of nine in-frame fusions, eg, TBL1XR1-PIK3CA, although none were reported as recurrent in this cohort.98 The therapeutic actionability of TBL1XR1-PIK3CA with PI3K inhibitors, AKT inhibitors, or mTOR inhibitors is yet to be evaluated.

ETV6-NTRK3 is the first recurrent fusion to be identified in a rare breast cancer subtype known as secretory breast carcinoma. These cancers have a good prognosis and rarely metastasize.68 With >90% occurrence in this subtype, the fusion was reported to transform mammary epithelial cells and promote tumor formation in mice, strongly suggesting its role as the dominant acting oncogene in this tumor type.68NTRK3 is a protein kinase that is normally activated by ligand binding, dimerization, and autophosphorylation. The ETV6-NTRK3 fusion transcripts encode the oligomerization domain of the transcription factor, ETV6, fused to the C-terminal protein kinase domain of NTRK3 (Figure 1C), leading to ligand-independent dimerization and constitutive autophosphorylation of NTRK3.99,100 Therapeutic targeting of this fusion has been reported with broad-spectrum kinase inhibitors101,102 as well as more specific and mechanism-based IGF1R/INSR inhibitors.103 A phase II clinical trial investigating a selective NTRK1/2/3 inhibitor, LOXO-101, for patients with advanced solid tumors harboring NTRK fusions is ongoing ( Interestingly, ETV6-NTRK3 was also the first fusion reported to occur in tumors from multiple tissue origins, including epithelial, mesenchymal,104–106 and hematopoietic origins.107,108 With massively parallel sequencing, it has become evident that many such recurrent fusions are prevalent across tumor and tissue types, indicating that different cell types may share similar mechanisms of tumorigenesis.

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An analysis of relapsed invasive lobular breast cancers reported the presence of a novel ERBB2 fusion,ERBB2-GRB7 (Table 4).109 Presence of ERBB2 amplifications in breast cancer is well known and routinely evaluated in diagnostic specimens. However, fusions will not be detected by routine IHC and FISH techniques that are currently used for HER2 or ERBB2 evaluation. Considering the impact of HER2-directed therapy in breast cancer, detection and functional testing of such rearrangements offers the potential for treating such tumors with clinically available HER2-targeting agents.

As this is a rapidly evolving field and new information is cataloged daily, some useful websites and data portals for gene fusions in breast cancer include those through the National Cancer Institute,110 Wellcome Trust Sanger Institute,111 and TCGA fusion gene data portal.34

Therapeutic Implications of Fusions in Breast Cancer

Adaptation of trial design has become more important, given the growing knowledge of genotype–drug response associations. Tumor-specific trials still have relevance; however, many recurrent genomic alterations, including rearrangements, identified in one cancer subtype are also seen in other cancers. This underscores the need for expanded eligibility criteria for enrolling patients in clinical trials. ALK and RETfusions are examples of kinase fusions that were initially found in lung and thyroid cancers, respectively, but have also been reported in other cancers, including breast cancers.3,112,113

As more pan-cancer studies are revealing recurrent fusions across tumor types, the concept of basket clinical trials is now being evaluated where patients are matched based on their genomic alteration rather than solely on the basis of tumor type. Basket trials that expand eligibility of cancers with novel genomic alterations would allow investigation of efficacy of targeted agents for previously unreported alterations. Singh et al56 reported the discovery of a highly oncogenic fusion protein, FGFR3-TACC3, in 3% of glioblastoma multiforme patients and demonstrated a high efficacy of FGFR inhibitors against this fusion protein. This fusion was later identified and found to be active in bladder,57 lung,55 and cervical cancers.114 Similarly, fusions involving other FGFR tyrosine kinases, eg, FGFR1/2, present at either the 5′ or 3′ end and retaining the tyrosine kinase domains have also been reported in breast cancer and other cancers.3,34,115 As a result, these fusions provide a therapeutic opportunity for FGFR inhibitors in multiple cancer patient subpopulations.