Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor-Positive Breast Cancer

Cancer Discov. 2018 Mar;8(3):336-353. doi: 10.1158/2159-8290.CD-17-0535. Epub 2017 Dec 14.

Abstract

We sought to uncover genetic drivers of hormone receptor-positive (HR+) breast cancer, using a targeted next-generation sequencing approach for detecting expressed gene rearrangements without prior knowledge of the fusion partners. We identified intergenic fusions involving driver genes, including PIK3CA, AKT3, RAF1, and ESR1, in 14% (24/173) of unselected patients with advanced HR+ breast cancer. FISH confirmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of novel kinase fusions in nontransformed cells deregulates phosphoprotein signaling, cell proliferation, and survival in three-dimensional culture, whereas expression in HR+ breast cancer models modulates estrogen-dependent growth and confers hormonal therapy resistance in vitro and in vivo Strikingly, shorter overall survival was observed in patients with rearrangement-positive versus rearrangement-negative tumors. Correspondingly, fusions were uncommon (<5%) among 300 patients presenting with primary HR+ breast cancer. Collectively, our findings identify expressed gene fusions as frequent and potentially actionable drivers in HR+ breast cancer.Significance: By using a powerful clinical molecular diagnostic assay, we identified expressed intergenic fusions as frequent contributors to treatment resistance and poor survival in advanced HR+ breast cancer. The prevalence and biological and prognostic significance of these alterations suggests that their detection may alter clinical management and bring to light new therapeutic opportunities. Cancer Discov; 8(3); 336-53. ©2017 AACR.See related commentary by Natrajan et al., p. 272See related article by Liu et al., p. 354This article is highlighted in the In This Issue feature, p. 253.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Estrogen Receptor alpha / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Fusion*
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Mice, Nude
  • Middle Aged
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-raf / genetics
  • Pyridones / pharmacology
  • Pyrimidinones / pharmacology
  • Receptors, Steroid / metabolism
  • Ribosomal Protein S6 Kinases / genetics
  • Ribosomal Protein S6 Kinases / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Estrogen Receptor alpha
  • Heterocyclic Compounds, 3-Ring
  • MK 2206
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidinones
  • Receptors, Steroid
  • estrogen receptor alpha, human
  • trametinib
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • AKT3 protein, human
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-raf
  • RPS6KC1 protein, human
  • Raf1 protein, human
  • Ribosomal Protein S6 Kinases