20Characterizing genomic, transcriptomic and clinical landscape in CCNE/CCND amplified biliary tract cancer
Akhila Madulapalli Reddy, Mohamed Nuh, Monica Hsiang, Eiline Cai, Ian Hu, Funda Meric-Bernstam, Milind Javle, Sunyoung LeeAbstract
Background
The impact of cell cycle regulator amplifications in biliary tract cancer (BTC) remains undefined in the chemo-immunotherapy era. This study characterizes clinical outcomes alongside genomic and transcriptomic profiles in cyclin amplified BTC within the CCNE/CCND family.
Methods
263 BTC patients were analyzed with comprehensive genomic/transcriptomic sequencing. Cohorts were stratified into Cyclin-Amplified (Amp, N = 71, Copy Number ≥6) and non-amplified Control (N = 192), with comparison of demographics, DNA co-alteration and survival (Kaplan-Meier/Log-Rank). Transcriptomic profiling utilized 29 established gene signatures quantifying immune cell infiltration and stromal features. Differential gene expression assessed markers of chemotherapy resistance.
Results
The Amp cohort consisted of CCNE1 (N = 30), CCND1/2/3 (N = 29/2/7), and CCNE1/D1 co-amplification (N = 3). Amp patients had significantly inferior overall survival (OS) compared to control (median 21.2 vs 28.3 m, p = 0.009). Adding immunotherapy (IO) to chemotherapy significantly improved OS in the control group (36.1 vs 23.0 m, p = 0.001) but provided no OS benefit in the Amp group (median 19.2 m [Chemo + IO] vs 24.1 m [Chemo], p = 0.80). Amp tumors exhibited high genomic instability, dominated by TP53 (67%), IRS2 (13%), ARID1A (11%), KRAS (11%), and ATM (11%) mutations. Frequent co-amplifications included FGF19/4 (35%), MYC (23%) and ERBB2 (19%). Transcriptomic profiling in Amp tumors revealed an “immune desert” microenvironment characterized by depletion of adaptive and innate immunity: B-cells (p < 0.001), NK cells (p = 0.002), T-cells (p = 0.008), and Th1/Th2 signatures (p < 0.01) were significantly downregulated compared to control. Amp tumors exhibited intrinsic chemotherapy resistance via upregulation of gemcitabine targets (RRM1, = p = 0.04) and platinum efflux pumps (ABCC2, p = 0.04), alongside increased tumor proliferation (p = 0.053).
Conclusions
Cyclin amplification identifies an aggressive BTC subtype characterized by poor prognosis and intrinsic resistance mechanisms to standard chemo-immunotherapy. This resistance is driven by a profound “immune desert” microenvironment limiting immunotherapy efficacy and the upregulation of genes associated with chemotherapy resistance, illustrating the complex biological underpinnings of this high-risk population.