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

  • Original Laboratory Investigation
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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.

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Data availability

The datasets used and code generated during the current study are available on a public GitHub repository (www.github.com/rashatk/HighRETGDNF). The dataset obtained from Xia et al. can be accessed at https://doi.org/10.1158/1078-0432.CCR-21-3189.

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Acknowledgements

This work was presented, in part, as an oral presentation at the 18th Annual Academic Surgical Congress, February 8, 2023 in Houston, TX.

Funding

Dr Philip Spanheimer is supported by the National Institutes of Health grant P50CA058223. This work was supported by a UNC Lineberger Comprehensive Cancer Center Developmental Award which is supported in part by P30 CA016086 Cancer Center Core Support Grant.

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Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina, 170 Manning Drive, Suite 1149, Chapel Hill, NC, 27599-7213, USA

    Rasha T. Kakati, Hyunsoo Kim, Austin Whitman & Philip M. Spanheimer

  2. Department of Surgery, University of North Carolina, Chapel Hill, NC, USA

    Philip M. Spanheimer

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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by RTK. Project visualization and planning was performed by RTK and PMS. Writing of the original draft and editing the manuscript was performed by RTK, HK, AW, and PMS. Project supervision and funding management was performed by PMS. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Kakati, R.T., Kim, H., Whitman, A. et al. 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 199, 589–601 (2023). https://doi.org/10.1007/s10549-023-06937-9

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