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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."xsd:string
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http://purl.uniprot.org/citations/37061618http://purl.uniprot.org/core/author"Kim H."xsd:string
http://purl.uniprot.org/citations/37061618http://purl.uniprot.org/core/author"Spanheimer P.M."xsd:string
http://purl.uniprot.org/citations/37061618http://purl.uniprot.org/core/author"Kakati R.T."xsd:string
http://purl.uniprot.org/citations/37061618http://purl.uniprot.org/core/author"Whitman A."xsd:string
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http://purl.uniprot.org/citations/37061618http://purl.uniprot.org/core/name"Breast Cancer Res Treat"xsd:string
http://purl.uniprot.org/citations/37061618http://purl.uniprot.org/core/pages"589-601"xsd:string
http://purl.uniprot.org/citations/37061618http://purl.uniprot.org/core/title"High expression of the RET receptor tyrosine kinase and its ligand GDNF identifies a high-risk subset of estrogen receptor positive breast cancer."xsd:string
http://purl.uniprot.org/citations/37061618http://purl.uniprot.org/core/volume"199"xsd:string
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