Fusion-associated carcinomas of the breast: Diagnostic, prognostic, and therapeutic significance

Genes Chromosomes Cancer. 2022 May;61(5):261-273. doi: 10.1002/gcc.23029. Epub 2022 Feb 17.


Recurrent gene fusions comprise a class of viable genetic targets in solid tumors that have culminated several recent breakthrough cancer therapies. Their role in breast cancer, however, remains largely underappreciated due to the complexity of genomic rearrangements in breast malignancy. Just recently, we and others have identified several recurrent gene fusions in breast cancer with important clinical and biological implications. Examples of the most significant recurrent gene fusions to date include (1) ESR1::CCDC170 gene fusions in luminal B and endocrine-resistant breast cancer that exert oncogenic function via modulating the HER2/HER3/SRC Proto-Oncogene (SRC) complex, (2) ESR1 exon 6 fusions in metastatic disease that drive estrogen-independent estrogen-receptor transcriptional activity, (3) BCL2L14::ETV6 fusions in a more aggressive form of the triple-negative subtype that prime epithelial-mesenchymal transition and endow paclitaxel resistance, (4) the ETV6::NTRK3 fusion in secretory breast carcinoma that constitutively activates NTRK3 kinase, (5) the oncogenic MYB-NFIB fusion as a genetic driver underpinning adenoid cystic carcinomas of the breast that activates MYB Proto-Oncogene (MYB) pathway, and (6) the NOTCH/microtubule-associated serine-threonine (MAST) kinase gene fusions that activate NOTCH and MAST signaling. Importantly, these fusions are enriched in more aggressive and lethal breast cancer presentations and appear to confer therapeutic resistance. Thus, these gene fusions could be utilized as genetic biomarkers to identify patients who require more intensive treatment and surveillance. In addition, kinase fusions are currently being evaluated in breast cancer clinical trials and ongoing mechanistic investigation is exposing therapeutic vulnerabilities in patients with fusion-positive disease.

Keywords: breast cancer; breast carcinoma; diagnostic significance; gene fusions; prognostic significance; therapeutic significance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Breast Neoplasms* / diagnosis
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Carcinoma, Adenoid Cystic* / genetics
  • Carcinoma, Adenoid Cystic* / metabolism
  • Carcinoma, Adenoid Cystic* / pathology
  • Estrogens / therapeutic use
  • Female
  • Gene Fusion
  • Humans
  • Neoplasm Recurrence, Local
  • Oncogene Proteins, Fusion / genetics
  • Prognosis
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / therapeutic use


  • BCL2L14 protein, human
  • Estrogens
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins c-bcl-2