Differences in Tumor Gene Expression Profiles Between De Novo Metastatic Castration-sensitive Prostate Cancer and Metastatic Relapse After Prior Localized Therapy

Vinay Mathew Thomas; Nicolas Sayegh; Beverly Chigarira; Georges Gebrael; Nishita Tripathi; Roberto Nussenzveig; Yeonjung Jo; Emre Dal; Gliceida Galarza Fortuna; Haoran Li; Kamal Kant Sahu; Ayana Srivastava; Benjamin L Maughan; Neeraj Agarwal; Umang Swami

doi:10.1016/j.euo.2024.04.013

Differences in Tumor Gene Expression Profiles Between De Novo Metastatic Castration-sensitive Prostate Cancer and Metastatic Relapse After Prior Localized Therapy

Eur Urol Oncol. 2024 May 11:S2588-9311(24)00105-6. doi: 10.1016/j.euo.2024.04.013. Online ahead of print.

Authors

Affiliations

¹ Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
² Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
³ Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Department of Internal Medicine, Detroit Medical Center Sinai Grace Hospital, Detroit, MI, USA.
⁴ Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; DDx Foundation, Lehi, UT, USA.
⁵ Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Division of Medical Oncology, Department of Internal Medicine, University of Kansas Cancer Center, Westwood, KS, USA.
⁶ Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. Electronic address: umang.swami@hci.utah.edu.

PMID: 38735779
DOI: 10.1016/j.euo.2024.04.013

Abstract

Background and objective: It has been reported that patients with de novo metastatic castration-sensitive prostate cancer (dn-mCSPC) have worse prognosis and outcomes than those whose cancer relapses after prior local therapy (PLT-mCSPC). Our aim was to interrogate and validate underlying differences in tumor gene expression profiles between dn-mCSPC and PLT-mCSPC.

Methods: The inclusion criteria were histologically confirmed prostate adenocarcinoma and the availability of RNA sequencing data for treatment-naïve primary prostate tissue. RNA sequencing was performed by Tempus or Caris Life Sciences, both of which have Clinical Laboratory Improvement Amendments certification. The Tempus cohort was used for interrogation, while the Caris cohort was used for validation. Differential gene expression analysis between the cohorts was conducted using the DEseq2 pipeline. The resulting gene expression profiles were further analyzed using Gene Set Enrichment software to identify pathways with enrichment in each cohort.

Key findings and limitations: Overall, 128 patients were eligible, of whom 78 were in the Tempus cohort (dn-mCSPC 37, PLT-mCSPC 41) and 50 were in the Caris cohort (dn-mCSPC 30, PLT-mCSPC 20). Tumor tissues from patients with dn-mCSPC had higher expression of genes associated with inflammation pathways, while tissues from patients with PLT-mCSPC had higher expression of genes involved in oxidative phosphorylation, fatty acid metabolism, and androgen response pathways.

Conclusions and clinical implications: Our study revealed upregulation of distinct genomic pathways in dn-mCSPC in comparison to PLT-mCSPC. These hypothesis-generating data could guide personalized therapy for men with prostate cancer and explain different survival outcomes for dn-mCSPC and PLT-mCSPC.

Patient summary: We measured gene expression levels in tumors from patients with metastatic castration-sensitive prostate cancer. In patients with metastatic disease at first diagnosis, inflammatory pathways were upregulated. In patients whose metastasis occurred on relapse after treatment, androgen response pathways were upregulated. These findings could help in personalizing therapy for prostate cancer and explaining differences in survival.

Keywords: Androgen response; Gene expression; Metastatic castration-sensitive prostate cancer; Precision medicine; Prostate cancer.