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MSI-High Status Linked With PD-1 Therapy Response in Cholangiocarcinoma


Just 5% of patients in a cholangiocarcinoma cohort were categorized as microsatellite instability high (MSI-high), but those patients tended to have “excellent” responses to therapy.

A new analysis of patients with cholangiocarcinoma has found that microsatellite instability status appears to correlate with a positive response to programmed cell death protein-1 (PD-1)–based therapies.

The report, presented at the 2022 American Society of Clinical Oncology Annual Meeting, pertains to patients with microsatellite instability high (MSI-H) status.

The authors explained, MSI-H status has become a useful biomarker in advanced cancers, in part because the genomic state has been associated with therapeutic response. Yet, its relation to cholangiocarcinoma outcomes has not been extensively studied.

“Cholangiocarcinoma is often driven by genetic mutations,” they wrote. “However, the genomic characterization and translational medicine of MSI-H status are not clear.”

The investigators decided to analyze the cases of patients with cholangiocarcinoma and compare the genetic characteristics and outcomes of patients with MSI-H status to those with microsatellite stable (MSS) status. They recruited 881 Chinese patients with cholangiocarcinoma, 582 of whom had intrahepatic cholangiocarcinoma (iCCA). The subjects underwent clinicopathological and genomic evaluation, and their responses to PD-1 inhibitor immunotherapy were analyzed.

The study confirmed that MSI-H status is uncommon; just 47 patients (5.3%) were categorized as having the status. However, in the overall cohort, 66% of patients had iCCA vs 74.47% of those with MSI-H status. Patients with MSI-H status also tended to be younger and were more likely to have positive programmed death-ligand 1 (PD-L1) expression.

In a genomic analysis, the investigators found a higher mutation frequency for several genes in patients with MSI-H cancers: ACVR2A, ARID1A, KMT2D, TGFBR2, PBRM1, RNF43, TP53, and ARID1B.

“Comparing the [single nucleotide variant] and [insertion/deletion] mutation in the genome, the differential genes between MSI-H and MSS [disease] were ARID1A, ACVR2A, KMT2D, TGFBR2, PBRM1, RNF43, LRP1B, ARID1B, etc, respectively,” the authors said.

They added that several differential mutation pathways, including the DNA damage response and switch/sucrose nonfermentable pathways, had significantly higher mutation rates in patients with MSI-H status compared with those with MSS status. Patients with MSI-H status had higher tumor mutational burden, on average.

Those differences seemed to translate into superior PD-1 inhibitor outcomes. Of the 151 patients in the group that received PD-1–based therapies, 19 had MSI-H cases. Those patients had a 68.4% 1-year survival rate and a longer overall survival (OS) horizon vs patients with MSS disease (not reached vs 13.4 months; HR, 0.17; P < .001), the authors reported. Patients with MSI-H disease also had a much higher clinical benefit rate (odds ratio, 8.16; P < .001).

The investigators concluded that these data show that in cholangiocarcinoma, as in other advanced cancers, MSI-H status can be a useful biomarker when it comes to predicting PD-1 inhibitor response.

“MSI-H cholangiocarcinoma has distinct genomic features, and the effect of PD-1 inhibitor immunotherapy is excellent [in] these patients,” they wrote.


Xu Yang, Baofeng Lian, Yiran Li, et al. Genomic characterization and translational immunotherapy of microsatellite instability-high (MSI-H) in cholangiocarcinoma. J Clin Oncol. Published online June 2, 2022. doi:10.1200/JCO.2022.40.16_suppl.4101

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