MDM2 amplification in patients with biliary tract cancer in RETUD registry.
Authors: Muñoz Martín Andrés J. , Castet Florian , Soto Alsar Javier , Adeva Jorge , Peinado Paloma , Graña Begoña , Alés Diaz Inmaculada , Rodriguez-Alonso Rosa Maria , Lobo Miriam , Vera Ruth , Ruiz de Mena Inmaculada , Aguilar-Izquierdo Susana , Vega Sharela , Ortega Morán Laura , Macarulla Teresa 
Published: January 2025

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Background:
Antagonism of Mouse double minute 2 homolog (
MDM2
) can restore p53 activity and represents a novel therapeutic strategy in biliary tract cancer (BTC). We aimed to characterize the epidemiology of total population versus that harbouring
MDM2
amplifications; potential associations of
MDM2
to other genetic alterations and survival outcomes.
Methods:
We evaluated a large real-world cohort of patients (pt) diagnosed with BTC from 1st January 2017 to 31st December 2022 from the Spanish RETUD registry. Next generation sequencing (NGS) test was performed in all patients. Data collected included demographic and clinical characteristics, molecular profile, systemic oncologic treatment and effectiveness (best response and survival outcomes). Progression free survival (PFS) outcomes and best response were calculated for pts who received first line therapy. Descriptive statistic was used to analyse sociodemographic data, tumor characterization, molecular analysis, and best response. PFS and overall survival (OS) were estimated by the Kaplan-Meier method.
Results:
A total of 301 evaluable pt were included in 24 sites.
MDM2
amplifications were reported in 19 pt (6.3%) and 2 pt (10.5%) had TP53 mutations. At primary diagnosis, in the
MDM2
amplified population the tumour was mostly intrahepatic (63.2%); followed by gallbladder cancer (21.0%). Half of the pt had advanced disease at diagnosis (52.6%) and 21.0% resectable disease. No significant differences were observed in clinical characteristics (age, sex, tumor location, stage, ECOG performance status and metastasis location) and most common actionable genomic alterations (BRAF, HER2, IDH, FGFR2) in pt with
MDM2
amplification compared to overall population. Median overall survival (95% Confidence Interval [CI]) in pt with
MDM2
amplification was 18.4 months (12.3-19.9), and 17.8 months (95% CI, 12.3-19.9, p=0.247 in pt without amplification. Median PFS in first-line was 5.3 months (95% CI, 2.7-8.9) in
MDM2
amplified group, as compared with 6.0 months in non-
MDM2
amplified group (95% CI, 5.3-6.8; p=0.4233. The objective response rate in first-line was 21.4% in the
MDM2
amplified group versus 29.6% in non-amplified group. The proportion of pt who received systemic therapy in first, second and third line was similar in both groups. The main first-line regimen in
MDM2
amplified pt was cisplatin/gemcitabine (n=9, 47.4%), followed by clinical trial (n=3, 15.8%), GEMOX (n=2, 10.5%) and gemcitabine (n=2, 10.5%). The median OS and PFS of patients treated with cisplatin/gemcitabine in first line was similar in both groups.
Conclusions:
This analysis provides insights into the characterization of
MDM2
amplified BTC pt. Similar incidence of
MDM2
amplification was observed compared to other cohorts of BTC. No significant differences were observed in clinical characteristics, molecular profile and survival in
MDM2
amplified pt compared to non-amplified pt.