Clinical and mutational profiles of microsatellite instability (MSI-H) in intrahepatic cholangiocarcinoma (iCCA).
Authors: Eluri Madhulika , Danner De Armas Anaemy , Ross Jeffrey S. , Sharaf Radwa , Pavlick Dean C. , Chatterjee Deyali , Javle Milind M. 
Published: January 2023

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Background: Microsatellite instability (MSI-H) and increased tumor mutation burden (TMB) have been associated with clinical benefit from immunotherapy. A small subset of patients with intrahepatic cholangiocarcinoma (iCCA) have microsatellite instability (MSI-H). Understanding their clinical outcomes and genomic landscape has been limited. These patients may derive clinical benefit from immunotherapy compared to chemotherapy. Methods: 7565 cases of iCCA underwent comprehensive genomic profiling of 324 genes (FoundationOne CDx). Prevalence of genomic alterations in cases with MSI-H were compared with MSI-low and MSS iCCA using Fischer’s exact test with Bonferonni correction. Clinical and pathological data were collected by retrospective chart review for patients with MSI-H/dMMR iCCA. Results: Among 7565 iCCA cases identified, 137 (1.8%) were MSI-H. Compared to MSS/MSI-low cases, MSS-H patients were more likely to be male and have Lynch syndrome. Median TMB was 21.7 (muts/Mb). MSI-H cases were enriched for genomic alterations (GA) in APC (13.9%), TP53 (59.9%), ARID1A (13.9%), and PRBM1 (37.2%). MSI-H cases had lower frequencies of previously identified, actionable iCCA drivers such as FGFR2 fusions (0% v 9%, p=NS), IDH1 (3.7% v 14.5%, p<0.0001) and IDH2 (0% v 4.1%, p=0.007). Compared to MSS/MSI-low, MSI-H cases had higher GA in PIK3CA (16.8% v 6.6%, p=<0.0001), PTEN (10.9% v 2.8%, p=<0.0001), and BRCA2 (10.2% v 2%, p=<0.0001). MSI-H cases had lower GA in CDKN2A (24.1% v 30.9%, p=0.09) and MTAP loss (3.4% v. 15.5%, p<0.0001). Five patients were identified with dMMR/MSI-H iCCA out of 974 patients at a single institution (0.5%). Median age at diagnosis was 53 years (range 46-70) and 83% were male (n=4). Two patients had resectable disease at time of diagnosis. TMB range was 20-29 (muts/Mb). Patients had 4-6 co-mutations on average with the most common GA being TP53, ARID1A and CDKN2A. One patient had Lynch syndrome with germline alteration of MLH1 gene and one patient had a germline BRCA mutation. One patient was noted to have FGFR2 rearrangement. Gemcitabine/Cisplatin was given to 3 of 6 patients as first-line (1L) therapy, with median progression free survival of 4 months. One hundred percent of patients received immunotherapy (IO) as first or second-line (2L) therapies. Patients receiving IO in the 1L had responses ranging from 4 to 9 months. Three patients have ongoing responses. Median overall survival ranged from 12 months to >18 months. Two patients presented with CNS involvement and did not respond to immunotherapy-based regimens. Conclusions: MSI-H represents a small subset of patients with iCCA. High-TMB noted amongst MSI-H iCCA. Currently, MSI testing is not universally performed and may be necessary to identify and best treat these patients. These findings support the development of personalized immunotherapy treatment strategies for this distinct patient population.