Tumor necrosis factor alpha signaling activity and NCCN risk, adverse pathology, and progression during active surveillance in prostate cancer.

415 Background: Elevated serum levels of tumor necrosis factor alpha (TNF-α) are characteristic of chronic inflammatory conditions and advanced prostate cancer (PCa). Local and systemic inflammation associated with TNF-α may enhance oncogenicity in the prostate. This study investigates the association between intra-tumoral TNF-α levels, NCCN risk, adverse pathology (AP) at radical prostatectomy (RP), and progression on active surveillance (AS). Methods: Intra-tumoral TNF-α pathway expression levels were assessed through TNF-α signaling via the NF-kB pathway. Transcriptomic profiles from 82,470 prospectively collected biopsy samples with the Decipher prostate genomic classifier (Veracyte, San Diego, CA) retrieved from the Decipher GRID registry (NCT02609269) were used to compare TNF-α levels by quartile across NCCN risk groups, Decipher score, and basal-luminal prostate subtype classifier (PSC). Transcriptomic data from a retrospective study of 647 patients with low or favorable intermediate risk (FIR) disease treated with RP were used in logistic regression to examine TNF-α levels with AP (any of Gleason grade group ≥3, SVI or LNI). A cohort of 28 favorable disease patients prospectively tested (2019-2024) with Decipher and managed with AS compared TNF-α levels with Wilcoxon for the binary endpoint of progression on AS. For progression, data from a retrospective study at a single academic center (2019-2024) were classified based on progression status (n=17 progressed, n=11 did not) following Decipher analysis of their initial biopsy specimens. Results: Among 82,470 PCa patients, the proportion of highest quartile TNF-α signature increased across NCCN low to very high risk prostate cancer and the lowest quartile decreased with increased NCCN risk group (Fisher’s exact test p < 2.2e-16). Median Decipher score was 0.57 (IQR 0.38-0.78) in the highest quartile TNF-α compared to 0.38 (IQR 0.24-0.58) for the lowest. The majority of samples with the highest TNF-α were PSC basal (73%) whereas the lowest were PSC luminal (76%) subtypes. Among 647 FIR disease patients treated with RP, higher TNF-α levels were significantly associated with AP (univariable OR 3.41, p=0.02; multivariate OR 2.93, p=0.05). In the AS cohort, elevated TNF-α signature correlated with a higher likelihood of progression. Conclusions: Increased TNF-α signaling levels are associated with increasingNCCN and Decipher risk groups and basal subtype. Elevated TNF-α levels in patients with FIR disease tumors had higher risk of AP at RP. In AS, higher TNF-α signaling was associated with progression and it may serve as a tool to guide treatment counseling. Uni- and multivariable analysis for pT3b+, GG 3-5, or LNI+. Univariable OR (95% CI) P-value Multivariable OR (95% CI) P-value TNF-α 3.41 (1.21 – 9.12) 0.02* 2.93 (1.01 – 8.02) 0.05* CAPRA - - 1.43 (1.08 – 1.91) 0.01* *p < 0.05 denotes significance.