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Updated: Sep 13, 2025
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Molecular profile and clinical impact of MDM2 amplification in patients with advanced biliary tract cancer
1Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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.
Insights
MDM2-amplified biliary tract cancer (BTC) with wild-type TP53 (MDM2-amp/TP53-WT) shows unique mutations and better survival with gemcitabine plus cisplatin chemotherapy. Further research into MDM2-targeted therapies is recommended.
Area of Science:
- Oncology
- Genetics
- Cancer Therapeutics
Background:
- MDM2 is a negative regulator of p53, making it a therapeutic target in cancers with MDM2 amplification.
- Biliary tract cancer (BTC) can harbor MDM2 amplification, potentially restoring p53 tumor suppressor activity.
- The genomic and clinical features of MDM2-amplified BTC are not well understood.
Purpose of the Study:
- To investigate the clinicogenomic characteristics of MDM2-amplified BTC with wild-type TP53 (MDM2-amp/TP53-WT).
- To compare survival outcomes in patients with MDM2-amp/TP53-WT BTC receiving first-line chemotherapy.
- To identify potential therapeutic strategies for this specific BTC subset.
Main Methods:
- Retrospective analysis of 813 advanced BTC patients treated with gemcitabine plus cisplatin (GemCis) chemotherapy.
- Tissue-based targeted next-generation sequencing to identify MDM2 amplification and TP53 status.
- Propensity score matching to balance baseline characteristics between MDM2-amp/TP53-WT and non-amplified groups.
Main Results:
- MDM2-amp/TP53-WT was found in 5.0% of advanced BTC patients, with no significant difference in primary tumor site distribution.
- MDM2-amp/TP53-WT tumors had fewer actionable alterations like ERBB2 amplification and IDH1 mutations.
- Patients with MDM2-amp/TP53-WT exhibited significantly longer progression-free survival (PFS) with first-line GemCis therapy (median 9.6 vs. 6.9 months, P=0.035) in propensity score-matched analysis.
Conclusions:
- MDM2-amp/TP53-WT BTC presents distinct mutational profiles and limited other actionable targets.
- This subset of BTC demonstrates improved survival outcomes when treated with first-line GemCis-based chemotherapy.
- MDM2-targeted therapies warrant further investigation for advanced BTC patients with MDM2-amp/TP53-WT.
