Genomic characterization and translational immunotherapy of microsatellite instability-high (MSI-H) in cholangiocarcinoma.

Abstract

4101 Background: Microsatellite instability-high (MSI-H) status is a unique genomic state with encouraging effects of PD-1-based therapy in patients with advanced cancer. Cholangiocarcinoma is often driven by genetic mutations. However, the genomic characterization and translational medicine of MSI-H are not clear. Methods: In this study, 881 Chinese patients with cholangiocarcinoma (582 intrahepatic cholangiocarcinoma and 299 extrahepatic cholangiocarcinoma) were enrolled and their genomes were investigated using panel sequencing or whole-exome sequencing. Clinicopathological and genomic features as well as PD-1 inhibitor-based immunotherapy were analyzed by MSI status in patients with cholangiocarcinoma. Results: Overall, 47 (5.3%) cholangiocarcinoma patients were identified as MSI-H patients after enrichment enrollment. Intrahepatic cholangiocarcinoma (ICC) accounted for 74.47% (35/47) of MSI-H patients. Clinicopathological parameters showed younger, ICC-dominated, and more positive PD-L1 expression in MSI-H patients. In the genome of MSI-H cholangiocarcinoma, ACVR2A (75.00%), ARID1A (75.0%), KMT2D (72.2%), TGFBR2 (63.9%), PBRM1 (58.3%), RNF43 (55.6%), TP53 (52.8%) ), ARID1B (47.2%) had a higher mutation frequency. Comparing the SNV and INDEL mutation in the genome, the differential genes between MSI-H and MSS were ARID1A, ACVR2A, KMT2D, TGFBR2, PBRM1, RNF43, LRP1B, ARID1B, etc., respectively. In addition, the differential mutation pathways of MSI-H showed that the mutation rate of DDR, SWI/SNF CellCycle, HRD and other pathways was significantly higher than that of MSS samples. The tumor mutation burden (TMB) in MSI-H patients was significantly higher than that in MSS (P<0.001). In a cohort of 151 CCA patients who received PD-1 inhibitor-based immunotherapy, 19 patients with MSI-H cholangiocarcinoma were found to have a favorable prognosis (1-year survival rate 68.4%). Compared with 132 MSS cholangiocarcinoma patients, Patients with MSI-H cholangiocarcinoma had significantly prolonged OS (Not reach vs. 13.4m, P<0.001, HR=0.17, P <0.001) and high clinical benefit (CBR) (OR=8.16, P <0.001). In this immunotherapy cohort, ≥2 DDR pathway genes and ≥2 SWI/SNF pathway genes mutations, positive PD-L1 expression and TMB-H were also associated with better OS and CBR (both P<0.05). Conclusions: MSI-H cholangiocarcinoma has distinct genomic features, and the effect of PD-1 inhibitors immunotherapy is excellent to these patients. Clinical trial information: NCT03892577.

Efficacy and biomarker analysis of second‐line nab‐paclitaxel plus sintilimab in patients with advanced biliary tract cancer

“…It is widely recognized that patients with MSI‐H status are an effective population for ICIs, but unfortunately, these patients account for less than 5% of all advanced BTC patients, which limits the clinical application of MSI‐H status in predicting ICI efficacy. Similarly, high TMB is a widely used immunotherapy predictive biomarker, but the majority of BTC patients show low TMB, with a median value of approximately 3.7 Muts/Mb 34 . In the present trial, there was only one patient with high TMB/MSI‐H status who obtained PR and is still receiving maintenance sintilimab treatment.…”

Overcoming Resistance to Immune Checkpoint Blockade in Liver Cancer with Combination Therapy: Stronger Together?

“…66 Interestingly, CCA patients with microsatellite-instability high showed a higher TMB and longer survival after ICI treatment, suggesting that while the TMB should not be used as a sole predictive biomarker its impact should be considered for treatment. 67 In addition, CCA tumors are known to have a predominantly cold phenotype and show downregulation of genes responsible for antigen presentation, 68 which greatly impairs the priming function of APC. 69 Excess lipid accumulation and a subsequent overload of DC in HCC are additional reasons for dysfunctional antigen presentation in liver cancer.…”