Comprehensive plasma metabolomic profiling of metastatic urothelial carcinoma (mUC) pre- and post-immune checkpoint inhibitor (ICI) or platinum-based chemotherapy (PBC).

Abstract

795 Background: Comprehensive plasma metabolomic profiling of mUC patients may identify mechanisms of resistance and new therapeutic targets. We analyzed metabolomic data from mUC patients prior to and following ICI and PBC. Methods: We retrospectively analyzed 648 metabolites in plasma from mUC patients who received ICI or PBC at Dana-Farber Cancer Institute. Paired plasma samples (0.2 mL) were obtained at baseline and after initiating therapy. Comprehensive metabolomic profiling was performed using 3 complementary liquid chromatography-mass spectrometry (LCMS) platforms at the Broad Institute. The metabolites that increased their mean values at least 1.5-fold in ≥1 platform were considered relevant. The paired sample t-test was used to assess the shifts in paired metabolites for significance (p <0.05). Results: 55 patients with mUC from the Dana-Farber Cancer Institute were evaluable: 48 received ICI and 9 received PBC, including 2 who received both. The ICIs administered were PD1/L1 inhibitor monotherapy (n=47) or PD/L1 + CTLA4 inhibitor therapy (n=1). The median age was 68 years, 45 (82%) patients were male and 32 (58%) were post-platinum. The median time between the pre- and post-therapy samples was 150 days. 5 (9.1%) patients had complete response, 17 (30.9%) had partial response, 13 (23.6%) had stable disease and 12 (21.8%) patients had progressive disease. Four metabolites exhibited >2-fold increase in mean fold change in ≥1 platform when comparing post vs. pre-therapy levels following ICI including taurodeoxycholic acid, taurocholic acid and α-carboxy-ethyl-hydroxy-chromans (CEHC) (Table 1). When examining 14 patients where the post-therapy timepoint was within 4 weeks before or after disease progression, the increase of taurocholic acid levels was further amplified to 9.7-fold. In the PBC cohort, 11 metabolites had a mean increase of >2-fold with the most prominent being N-acetylmethionine, which increased 8.29-fold. Conclusions: Taurocholic acid, a conjugated bile acid, exhibited >2-fold increase after ICI therapy, which was further amplified when measured close to disease progression, suggesting association with resistance and potential therapeutic utility of targeting taurine conjugation of bile acids. A greater number of metabolites demonstrated a >2-fold increase following PBC as opposed to ICI suggesting a broader range of resistance mechanisms, with most pronounced increase in N-acetylmethionine, a quencher that terminates oxidative reactions. Further validation from larger cohorts is required, given potential therapeutic relevance. Metabolite Mean fold change post-ICI Mean fold change in post-ICI progressors Mean fold change post-platinum Taurodeoxycholic acid 6.8 4.7 3.33 Taurocholic acid 4.61 9.74 3.55 alpha_CEHC 4.1 2.55 1.09 N-acetylmethionine 2.16 1.77 8.29