Abstract B144: Genomic characterization and clinical outcomes in MDM2-amplified biliary tract cancers

Abstract Background: Biliary tract cancers (BTCs), including intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), and gallbladder cancer (GBC), are molecularly heterogeneous malignancies with limited effective treatments. MDM2 may be a therapeutic vulnerability in a subset of BTC, although the frequency of MDM2 amplifications (MDM2amp) and their prognostic significance are poorly understood. Methods: Under an IRB-approved, prospective genotyping protocol (NCT01775072), patients with histologically confirmed BTC underwent next-generation sequencing using the FDA-authorized, MSK-IMPACT platform at Memorial Sloan Kettering Cancer Center. Clinicopathologic parameters were retrospectively extracted to (1) define the prevalence of MDM2 amplification and total copy number (TCN) in BTC; (2) characterize co-occurring genomic alterations; and (3) assess outcomes to cytotoxic chemotherapy in both first- and second-line settings. Results: As of the data lock in 07-2025, 2,903 BTC cases underwent prospective clinical sequencing, of which 123 (4.2%) had MDM2amp. Evaluable patients (N=94) had a median age of 65 (range 25–89); 50% were female. Anatomic subset distribution was GBC 36.2%, iCCA 33.0%, eCCA 29.8%, and CCA not otherwise specified 1.1%; 71.3% were Stage III/IV at diagnosis. MDM2amp TCN exhibited a median of 17.5 (4-70). The majority of MDM2amp occurred in TP53 wildtype tumors, though 12% exhibited co-occurrence with TP53 alterations. The most frequent co-occurring alterations included: CDK4 (23%), CDKN2A (17%), STK11 (12%), and KRAS (9%). OncoKB Level 1/2 alterations occurred in 10.6% of cases, including IDH1 (N=4), FGFR2 fusions (N=2), ERBB2 amplification (N=4), and NTRK1 fusions (N=1). Of the 93 evaluable patients, 81 received first-line therapy (74.1% gemcitabine plus platinum) and 62 received second-line treatment (53.2% Fluoropyridine doublet); the median line of systemic therapy was 2 (0-7). The median time on first-line treatment was 4.1 months, and the median time on second-line treatment was 3.7 months. From the time of diagnosis, the median follow-up and overall survival (OS) were 20.0 months (95% CI 18.0 - 27.9) and 29.5 months (95% CI 20.8 - 36.6). The median OS from first-line treatment and second-line treatment were 17.9 months (95% CI 15.8 - 25.0) and 11.2 months (95% CI 7.8-22.5 months). Conclusions: MDM2amp are infrequent but exhibit high TCN in a BTC subset. MDM2amp may co-occur with TP53 alterations and OncoKB level 1/2 drivers, potentially having implications for the investigational use of MDM2 inhibitors in BTC. Acknowledging the limitations of a small single-center study, outcomes appear no worse than historical controls. Ongoing work includes comprehensive copy number analysis (i.e., MDM2 TCN and TP53 biallelic status) as well as their correlations with genomic alterations and clinical features. Citation Format: Sundas F. Nasir, Fatema Nagib, Aruj Dhyani, Olivia Heffernan, Amin Yaqubie, Olca Basturk, Walid Chatila, James J. Harding. Genomic characterization and clinical outcomes in MDM2-amplified biliary tract cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B144.