Abstract 589P
Background
Resistance to enzalutamide and androgen signaling inhibitors (ARSI) is invariable and a major health concern. We hypothesized that tumor progression is associated with host-derived immune-evasion mechanisms that could be detected by changes in peripheral blood cells.
Methods
We analyzed dynamic changes in peripheral blood gene expression in mCRPC patients treated with enzalutamide in the prospective multi-center PREMIERE trial (NCT02288936). An independent single-center prospective cohort was used for validation. Whole-blood RNA was collected using PAXgene RNA tubes and analyzed using Affymetryx HTA 2.0 microarrays. Bioconductor packages and R software were used for gene expression analyses. A machine learning method, CIBERSORT X, was used for blood–cell type deconvolution including 22 human immune subsets.
Results
We analyzed 226 samples (basal (B)/progression (P)): 94/63 training; 54/15 validation. In the training set, we observed 629 genes differentially expressed at P compared to B. Pair-wise differential immune-cell profiling showed that tumor P was associated with expansion of monocytes (p < 0.002) and contraction of CD8 T-cell lymphocytes (p<0.005). We then analyzed the prognostic value for monocytes and CD8 T cell lymphocytes in B samples from the training cohort, and observed a worse survival outcome for patients with high monocytes (Q1) compared with normal values (Q2-4) with median overall survival of 30.8 vs 38.3 months (HR=2.30, 95%CI: 1.30-4.18; p<0.005). Association was also observed between low CD8 T-cell lymphocytes (Q4) compared with normal values (Q1-Q3) in B with median overall survival of 28.3 vs 38.1 months (HR=2.0, 95%CI:1.13-3.68; p<0.018). We then confirmed a numerical increase in monocytes and decrease in T-cell lymphocytes at P in the validation cohort and validated both conditions in B with worse survival for high monocytes (HR = 2.2, 95%CI: 1.06-4.23; p< 0.03) and low T-cell lymphocytes (HR = 3.9, 95%CI: 1.95-7.93; <0.001).
Conclusions
Prostate cancer progression is associated with changes in peripheral blood that compromise activation of immune-regulatory components, including the expansion of monocytes. These findings could offer biomarker and therapeutic opportunities to reverse resistance to enzalutamide.
Clinical trial identification
NCT02288936.
Editorial acknowledgement
Legal entity responsible for the study
Spanish Oncology Genitourinary Group (SOGUG).
Funding
This study was funded by the Instituto de Salud Carlos III (ISCIII) PI18/00883. SOGUG received a grant from Astellas to run the PREMIERE trial.
Disclosure
All authors have declared no conflicts of interest.