Molecular profile and clinical impact of MDM2 amplification in patients with advanced biliary tract cancer.

BACKGROUND

MDM2, a negative regulator of p53, has emerged as a potential therapeutic target as its inhibition can restore p53 tumor suppressor activity in MDM2-amplified tumors, including subsets of biliary tract cancer (BTC). However, the genomic and clinical characteristics of MDM2-amplified BTC remain poorly understood.

MATERIALS AND METHODS

Patients with advanced BTC who underwent tissue-based targeted next-generation sequencing and received first-line gemcitabine plus cisplatin (GemCis)-based chemotherapy at Asan Medical Center, Seoul, Korea, between January 2016 and December 2023 were included. Clinicogenomic characteristics and survival outcomes were compared according to the presence of MDM2 amplification with wild-type TP53 (MDM2-amp/TP53-WT). Propensity score (PS) matching was carried out to balance baseline characteristics between patients with and without MDM2-amp/TP53-WT.

RESULTS

Among 813 patients, there were 41 patients (5.0%) with MDM2-amp/TP53-WT, demonstrating no significant association with the primary tumor site: intrahepatic cholangiocarcinoma (4.7%), extrahepatic cholangiocarcinoma (3.7%), and gall-bladder cancer (8.0%) (P = 0.111). Overall, clinical characteristics did not differ according to MDM2-amp/TP53-WT status. Actionable alterations, including ERBB2 amplification (2.4% versus 10.6%) and IDH1 mutation (2.4% versus 6.9%), were less common in MDM2-amp/TP53-WT tumors. In both unmatched and PS-matched populations, MDM2-amp/TP53-WT was associated with significantly longer progression-free survival with first-line GemCis-based therapy [in PS-matched analysis: median 9.6 versus 6.9 months, hazard ratio (HR) 0.63, P = 0.035] and longer, but not statistically significant, overall survival (in PS-matched analysis: median 20.3 versus 16.4 months, HR 0.81, P = 0.267).

CONCLUSIONS

In advanced BTC, tumors harboring MDM2-amp/TP53-WT exhibited distinct mutational patterns with limited other actionable alterations and were associated with better survival outcomes following first-line GemCis-containing chemotherapy. Further investigation of MDM2-targeted therapies for this subset is warranted.