1800P - Differential tumor gene-expression profiling of patients (pts) with de-novo metastatic castration-sensitive prostate cancer (dn-mCSPC) versus (vs.) mCSPC relapsing after prior localized therapy (PLT-mCSPC)

Background

Dn-mCSPC is markedly aggressive, with shorter time to castration resistance and poorer overall survival than PLT-mCSPC (PMID: 28899723). We interrogate and validate differences in tumor gene expression profiles of dn-mCSPC vs. PLT-mCSPC.

Methods

In this IRB-approved retrospective study, eligibility criteria included histologically confirmed prostate adenocarcinoma (PC) and available RNA sequencing results from treatment naïve primary prostate tissue from a CLIA-certified lab [either Tempus (T) or Caris (C)]. T cohort was used for interrogation and C for validation. Pts in each cohort were categorized into two groups: dn-mCSPC vs. PLT-mCSPC. The DEseq2 pipeline was used to analyze differentially expressed genes between the groups. The data included the Log2 fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. Results were subjected to Gene Set Enrichment Analysis (GSEA) to identify pathways enriched in each cohort. Bioinformatic analysis was performed using R v4.2.

Results

128 pts were eligible. T cohort: n=78 (dn-mCSPC=37, PLT-mCSPC=41); C cohort: n=50 (dn-mCSPC=30, PLT-mCSPC=20). Both T and C showed that dn-mCSPC had an increased expression of the TNFα signaling, hypoxia signaling, and inflammatory response pathway (PTW). PLT-mCSPC had higher expression of E2F target, G2M checkpoint, and MYC target PTW. Normalized enrichment scores (NES) are reported in the table.

Table: 1800P

Differential GSEA in dn-mCSPC vs. PLT-mCSPC (q value for each pathway <0.01)

Positive NES = upregulation in dn-mCSPC, negative NES = downregulation in dn-mCSPC

Conclusions

Pts with dn-mCSPC had PTW associated with tumor aggressiveness such as TNFα signaling, hypoxia, and inflammatory response. After external validation, these hypothesis-generating data may provide rationale for personalized therapy in men with PC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

B.L. Maughan: Financial Interests, Personal, Advisory Role: AbbVie, Pfizer, AVEO oncology, Janssen, Astellas, BMS, Clovis, Tempus, Merck, Exelixis, Bayer Oncology and Peloton Therapeutics; Financial Interests, Institutional, Funding: Exelixis (Inst), Bavarian-Nordic (Inst), Clovis (Inst), Genentech (Inst) and BMS (Inst). U. Swami: Financial Interests, Personal, Advisory Role: Seattle Genetics, Astellas Pharma, Exelixis, Imvax, and AstraZeneca; Financial Interests, Institutional, Funding: Janssen, Seattle Genetics/Astellas, and Exelixis. N. Agarwal: Financial Interests, Personal, Advisory Board, In the last two calendar years, I participated in the scientific advisory board of these pharma companies between February 2021 to April 2021. None after that: Merck, Aveo, Gilead, Lilly, Exelixis, Foundation Medicine; Financial Interests, Trial Chair, I am involved in the following phase 3 trials as the trial co-chair: TALAPRO-2, TALAPRO-3 (both Pfizer), and CONTACT-2 (Exelxis): Pfizer, Exelixis; Financial Interests, Institutional, Other, I serve in the leadership of my cancer center (Huntsman Cancer Institute, University of Utah. Salt Lake City, UT, USA). There are multiple research projects sponsored by these companies which pay money to my institution: Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, BMS, Calithera, Celldex, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, GSK, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon.; Financial Interests, Steering Committee Member, I am involved in the steering committee of the trials sponsored by these pharmas with no personal honorarium: AstraZeneca, Calithera, Clovis, Crispr, Eisai, Eli Lilly, Exelixis, Immunomedics, Janssen; Financial Interests, Steering Committee Member, I am involved in the steering committee of the trials sponsored by these pharma companies with no personal honorarium: Merck, Nektar, New Link Genetics, Oric, Pfizer, Prometheus, Rexahn, Takeda, and Tracon. All other authors have declared no conflicts of interest.