Conference Abstracts
Vol. 3, Issue Supplement 2, 2023 · S1-1
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)
Georges Gebrael, MD,Nicolas Sayegh,Nishita Tripathi,Beverly Chigarira,Roberto Nussenzveig,Haoran Li, MD, PhD,James Brundage,Benjamin Maughan,Umang Swami, MD,Neeraj Agarwal, MD, FASCO
Submission received: 2023-12-02 / Published: 2023-12-07
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 hypothe-
sized that tumor gene expression profiling in patients un- dergoing intensification therapy with an Androgen Recep- tor 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 avail- ability of RNAseq profiling performed by a CLIA-certified lab using primary prostate biopsies collected before treat- ment. The DEseq2 pipeline was used to analyze differen- tially expressed genes between the groups. The data in- cluded the Log2 fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differen- tially expressed gene. These results were subjected to Gene Set Enrichment software analysis (GSEA) to identify path- ways 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 path- ways. The most upregulated pathways in PSA-H were ep- ithelial-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 andro- gen response pathway, PSA-L tumors showed an increased expression of genes such as DUSP1 and NR4A1 (TNFA sig- naling pathway) that promote apoptosis and slow down the growth of prostate cancer (PMIDs: 24080497, 956484). Fur- thermore, PSA-H tumors show an increased expression of pathways that increase migration and invasion of prostate cancer cells. These hypothesis-generating results, upon ex- ternal validation, may provide the rationale for personal- ized therapy in men with metastatic prostatic adenocarci- noma.