Tumor transcriptomic proﬁling of patients (pts) with Metastatic Castration Sensitive Prostate Cancer (mCSPC) who do not achieve optimal PSA response to intensiﬁed androgen deprivation therapy (ADT-I)

Vinay M Thomas; Georges Gebrael; Nicolas Sayegh; Nishita Tripathi; Beverly Chigarira; Roberto Nussenzveig; Kamal K Sahu; Haoran Li; James Brundage; Benjamin Maughan; Umang Swami; Neeraj Agarwal

doi:10.53876/001c.90830

Background

Pts with mCSPC undergoing ADT-I and achieving a PSA nadir ≤0.2 ng/mL (PSA-L) any time after the start of therapy were associated with improved overall survival (OS) versus those with a PSA nadir >0.2 ng/mL (PSA-H) (HR: 0.17, P<0.0001) (Chi AUA 2021, Saad ASCO 2022). We hypothesized that tumor gene expression proﬁling in patients undergoing intensification therapy with an Androgen Receptor Axis Targeted Therapy (ARAT) would be different in PSA-L and PSA-H.

Methods

In this IRB-approved retrospective study, eligibility criteria included conﬁrmed mCSPC on ADT-I with ARAT and availability of RNAseq proﬁling performed by a CLIA-certiﬁed lab using primary prostate biopsies collected before treatment. 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. These results were subjected to Gene Set Enrichment software analysis (GSEA) to identify pathways enriched in each cohort. All bioinformatic analysis was undertaken using R v4.2.

Results

Seventy-eight were eligible, of which 55 were PSA-L, and 23 were PSA-H. The most significantly upregulated pathways in PSA-L were the TNFA signaling, androgen response (AR), estrogen response, and interferon-alpha response pathways. The most upregulated pathways in PSA-H were epithelial-mesenchymal transition, coagulation, and bile acid metabolism pathways.

Conclusion

Pts with PSA-L have tumors with increased dependence on AR signaling. In addition to overexpression of the androgen response pathway, PSA-L tumors showed an increased expression of genes such as DUSP1 and NR4A1 (TNFA signaling pathway) that promote apoptosis and slow down the growth of prostate cancer (PMIDs: 24080497, 956484). Furthermore, PSA-H tumors show an increased expression of pathways that increase migration and invasion of prostate cancer cells. These hypothesis-generating results, upon external validation, may provide the rationale for personalized therapy in men with metastatic prostatic adenocarcinoma.