Clinical implication of MDM2 amplification in advanced biliary tract cancer (BTC): A propensity score-matched, retrospective cohort study of 813 patients.

4078 Background: Restoring p53 tumor suppressor activity by blocking the interaction between p53 and MDM2, its endogenous negative regulator, has emerged as a potential therapeutic target for several tumors including BTC. However, the frequence and clinical implication of MDM2 amplification (amp) has not been investigated for BTC. Methods: Patients with unresectable or metastatic BTC who had available tissue-based targeted next generation sequencing (NGS) data and were treated with first-line gemcitabine plus cisplatin (GemCis)-containing chemotherapy at Asan Medical Center, Seoul, Korea between January 1, 2016, and December 31, 2023, were included. MDM2 -amp was defined 5 or greater copies per tumor cell. Baseline characteristics and clinical outcomes to GemCis-containing therapy were compared according to the presence of MDM2 -amp/ TP53 wild-type (WT). Propensity score matching (PSM) with a 1:4 ratio was performed to balance the baseline characteristics between the patients with and without MDM2 -amp/ TP53 -WT. Results: Among 813 patients, 41 (5.0%) had MDM2 -amp/ TP53 -WT and there was no significant association with primary tumor sites: 4.7% in intrahepatic cholangiocarcinoma, 3.7% in extrahepatic cholangiocarcinoma, and 8.0% in gallbladder cancer (p=0.111). Patients with MDM2 -amp/ TP53 -WT significantly had less frequent viral hepatitis B infection (2.4% vs. 18.4%, p=0.009) and lung metastasis (2.4% vs. 13.2%, p=0.043); otherwise, no significant association with baseline characteristics was noted. After PSM (40 for MDM2 -amp/ TP53 -WT vs. 155 for non- MDM2 -amp/ TP53 -WT), patients with MDM2 -amp/ TP53 -WT showed significantly longer progression-free survival compared to those in the matched group (median, 9.6 vs. 6.9 months; p=0.034) and non-significant tendency toward longer overall survival (median, 20.3 vs. 16.4 months; p=0.103). Conclusions: In patients with unresectable or metastatic BTC, MDM2 -amp/ TP53 -WT occurred in 5% and it was associated with better survival outcomes of first-line GemCis-containing chemotherapy. Our findings suggest that MDM2 -amp/ TP53 -WT serves as a biomarker for a distinct subgroup of BTC, warranting active investigation into MDM2 inhibitors.