Microsatellite Instability Occurs Rarely in Patients with Cholangiocarcinoma: A Retrospective Study from a German Tertiary Care Hospital

Winkelmann, Ria; Schneider, Markus; Hartmann, Sven; Schnitzbauer, Andreas A.; Zeuzem, Stefan; Peveling‐Oberhag, Jan; Hansmann, Martin Leo; Walter, Dirk

doi:10.3390/ijms19051421

Cited by 51 publications

(43 citation statements)

References 23 publications

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“…While cancers with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) are likely to benefit from anti-PD-1 inhibitor (eg, pembrolizumab [Keytruda]), BTCs are infrequently MSI-H or dMMR. 9 In the KEYNOTE-028 phase Ib basket trials across 20 advanced solid tumor types that include advanced BTCs, patients with high tumor mutation burden (TMB) and/or PD-L1 expression demonstrated higher response rates and better progression-free survival (PFS). 10 Follow-up studies on patients with advanced BTCs treated with immunotherapy in the KEYNOTE-158 (phase II) and KEYNOTE-028 (phase Ib) trials present preliminary evidence showing durable clinical outcome regardless of PD-L1 expression.…”

Section: Introductionmentioning

confidence: 99%

Integrative clinical and molecular analysis of advanced biliary tract cancers on immune checkpoint blockade reveals potential markers of response

Wei

Wu³

et al. 2020

Clinical & Translational Med

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Background While there have been encouraging preliminary clinical results for immune checkpoint inhibitors (ICIs) in BTCs, it remains a challenge to identify the subset of patients who may benefit. In this study, we evaluated the efficacy of ICI treatment in patients with advanced BTCs, and explored potential biomarkers that are predictive of response. Methods The study enrolled 26 patients with advanced microsatellite stable BTCs (15 with gallbladder cancers [GCs] and 11 with intrahepatic cholangiocarcinoma [ICCs]) who received ICI treatment. Targeted next‐generation sequencing (NGS) was performed on tumor tissue samples collected from 17 patients. Clinical and genomic characteristics were assessed for the correlation with clinical outcome. Results Analysis of the baseline clinical characteristics showed that performance score (PS) of 0 was associated with a better prognosis than PS of 1 (HR = 1.08 × 109; 95% CI, 0∼Inf; P = .002). No significant correlations were found between clinical outcome and inflammation‐related indicators. NGS profiling of the available tumor tissues, revealed largely non‐overlapping somatic alterations between GCs and ICCs. Mutations in LRP1B (HR = 0.26; 95% CI, 0.06‐1.21; P = .067), ERBB2 (HR = 0.15; 95% CI, 0.02‐1.19; P = .04), or PKHD1 (HR < 0.01; 95% CI, 0‐Inf; P = .04) showed strong association with increased progression‐free survival (PFS) benefit. Subsequent analysis showed that alterations in the RTK‐RAS pathway were associated with improved outcomes (HR = 0.12; 95% CI, 0.02‐0.63; P = .003). Tumor mutation burden (TMB) was higher in patients with GC than those with ICC, and was associated with LRP1B mutations (P = .032). We found that patients with 19q amplification (19q Amp) and 9p deletion (9p Del) had poor PFS outcome (19q Amp, HR = 15.4; 95% CI, 2.7‐88.5; P < .001; 9p Del; HR = 4.88 × 109; 95% CI, 0‐Inf; P < .001), while those with chromosomal instability derived PFS benefit (HR = 0.24; 95% CI, 0.05‐1.17; P = .057). Conclusion Our study identified several potential clinical and genomic features that may serve as biomarkers of clinical response to ICIs in advanced BTCs patients. A larger sample size is required for further verification.

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Section: Introductionmentioning

confidence: 99%

Integrative clinical and molecular analysis of advanced biliary tract cancers on immune checkpoint blockade reveals potential markers of response

Wei

Wu³

et al. 2020

Clinical & Translational Med

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“…In another recent German study performed in surgical specimens of CCA derived from resection, including 102 patients (35 iCCA, 42 pCCA, 25 dCCA), the prevalence of MSI was examined not only by IHC for the expression of MLH1, PMS2, MSH2, and MSH6, but also by pentaplex PCR for five quasimonomorphic mononucleotide repeats (BAT-25, BAT-26, NR-21, NR-22, and NR-24). Whereas in the IHC-based analysis, no loss of expression of DNA repair enzymes was observed, by PCR the authors found only 1% of MSI-high and 1% of MSI-low (99). Thus, in addition to highlight discrepancy between different techniques aimed at investigating MSI, this study argues against the actual relevance of MSI in CCA.…”

Section: Immunotherapymentioning

confidence: 56%

Precision medicine in cholangiocarcinoma

Pellino

Loupakis

Cadamuro

et al. 2018

Transl. Gastroenterol. Hepatol.

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Cholangiocarcinoma is one of the epithelial cancers with the poorest prognosis and the narrowest therapeutic choice in humans. Compared with other cancer types, cholangiocarcinoma has been often neglected by oncology and liver research studies, thereby leaving many issues unsolved. Apart from the early and marked aggressiveness, one of the main reasons of the still unsatisfying clinical management of cholangiocarcinoma is its wide tumor heterogeneity needing more than other diseases a 'precision medicine' approach. In this regard, in the last few years there has been an awakening of interest aimed at dissecting the complex molecular and genomic profile of cholangiocarcinoma. Thus, a range of molecular players have been recently identified as putative mechanistic determinants of cholangiocarcinoma invasiveness, encompassing tyrosine kinase receptors, metabolic enzymes, transcription factors, small GTPases, ubiquitin ligases, and chromatin-remodelling proteins, whose aberrant expression may derive from stochastic mutations as well as from pro-oncogenic paracrine signals released by the stromal microenvironment, which is particularly exuberant in cholangiocarcinoma. Herein, we sought to overview the most relevant observations unravelling the genomic landscape of cholangiocarcinoma, and the prognostic and predictive biomarkers that consequently have been emerging. Then, we will discuss innovative treatment approaches derived from conventional chemotherapy, targeted therapies, antiangiogenic therapies and immunotherapy, and how they are opening new avenues towards a precision medicine in cholangiocarcinoma.

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“…Microsatellite status was analyzed based on five commonly used markers of microsatellite sequence: BAT-25, BAT-26, NR-21, NR-22, and NR-24 using a fluorescencebased pentaplex polymerase chain reaction technique and capillary electrophoresis. 26,27…”

Section: Microsatellite Analysismentioning

confidence: 99%

<p>Nomograms for Prediction of Molecular Phenotypes in Colorectal Cancer</p>

Zou

et al. 2020

OTT

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Background: Colorectal cancer (CRC) patients with different molecular phenotypes, including microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS gene, vary in treatment response and prognosis. However, molecular phenotyping under adequate quality control in a community-based setting may be difficult. We aimed to build the nomograms based on easily accessible clinicopathological characteristics to predict molecular phenotypes. Methods: Three hundred and six patients with pathologically confirmed stage I-IV CRC were included in the cohort. The assays for MSI, CIMP, and mutations in BRAF and KRAS gene were performed using resected tumor samples. The candidate predictors were identified from clinicopathological variables using multivariate Logistic regression analyses to construct the nomograms that could predict each molecular phenotype. Results: The incidences of MSI, CIMP, BRAF mutation and KRAS mutation were 25.3% (72/285), 2.5% (7/270), 3.4% (10/293), and 34.8% (96/276) respectively. In the multivariate Logistic analysis, poor differentiation and high neutrophil/lymphocyte ratio (NLR) were independently associated with MSI; poor differentiation, high NLR and high carcinoembryonic antigen/tumor size ratio (CSR) were independently associated with CIMP; poor differentiation, lymphovascular invasion and high CSR were independently associated with BRAF mutation; poor differentiation, proximal tumor, mucinous tumor and high NLR were independently associated with KRAS mutation. Four nomograms for MSI, CIMP, BRAF mutation and KRAS mutation were developed based on these independent predictors, the C-indexes of which were 61.22% (95% CI: 60.28-62.16%), 95.57% (95% CI: 95.20-95.94%), 83.56% (95% CI: 81.54-85.58%), and 69.12% (95% CI: 68.30-69.94%) respectively. Conclusion: We established four nomograms using easily accessible variables that could well predict the presence of MSI, CIMP, BRAF mutation and KRAS mutation in CRC patients.

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Microsatellite Instability Occurs Rarely in Patients with Cholangiocarcinoma: A Retrospective Study from a German Tertiary Care Hospital

Cited by 51 publications

References 23 publications

Integrative clinical and molecular analysis of advanced biliary tract cancers on immune checkpoint blockade reveals potential markers of response

Integrative clinical and molecular analysis of advanced biliary tract cancers on immune checkpoint blockade reveals potential markers of response

Precision medicine in cholangiocarcinoma

<p>Nomograms for Prediction of Molecular Phenotypes in Colorectal Cancer</p>

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