High expression of the RET receptor tyrosine kinase and its ligand GDNF identifies a high-risk subset of estrogen receptor positive breast cancer

Breast Cancer Res Treat. 2023 Jun;199(3):589-601. doi: 10.1007/s10549-023-06937-9. Epub 2023 Apr 15.

Abstract

Purpose: Resistance to endocrine therapy is the primary cause of treatment failure and death in patients with ER-positive (ER +)/luminal breast cancer. Expression and activation of the RET receptor tyrosine kinase may be driving poor outcomes. We aim to identify high-risk patients and druggable pathways for biomarker-based clinical trials.

Methods: We obtained batch-normalized mRNA expression data from Breast Invasive Carcinoma-The Cancer Genome Atlas, PanCancer Atlas (BRCA-TCGA). To determine clinically significant cutoffs for RET expression, patients were grouped at different thresholds for Kaplan-Meier plotting. Differential gene expression (DGE) analysis and enrichment for gene sets was performed. transcriptomic dataset of antiestrogen-treated ER + tumors stratified by clinical response was then analyzed.

Results: High RET expression was associated with worse outcomes in patients with ER + tumors, and stratification was enhanced by incorporating GDNF expression. High RET/GDNF patients had significantly lower overall survival (HR = 2.04, p = 0.012), progression-free survival (HR = 2.87, p < 0.001), disease-free survival (HR = 2.67, p < 0.001), and disease-specific survival (HR = 3.53, p < 0.001) than all other ER + patients. High RET/GDNF tumors were enriched for estrogen-independent signaling and targetable pathways including NTRK, PI3K, and KRAS. Tumors with adaptive resistance to endocrine therapy were enriched for gene expression signatures of high RET/GDNF primary tumors.

Conclusion: Expression and activation of the RET receptor tyrosine kinase may be driving poor outcomes in some patients with ER + breast cancer. ER + patients above the 75th percentile may benefit from clinical trials with tyrosine kinase inhibitors.

Keywords: Breast cancer; Estrogen receptor signaling; GDNF; MAPK; RET.

MeSH terms

  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / pathology
  • Female
  • Glial Cell Line-Derived Neurotrophic Factor / genetics
  • Glial Cell Line-Derived Neurotrophic Factor / therapeutic use
  • Humans
  • Ligands
  • Proto-Oncogene Proteins c-ret / genetics
  • Proto-Oncogene Proteins c-ret / metabolism
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism

Substances

  • Glial Cell Line-Derived Neurotrophic Factor
  • Ligands
  • Proto-Oncogene Proteins c-ret
  • Receptors, Estrogen
  • RET protein, human
  • GDNF protein, human