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

ABSTRACT: 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.

SUBMITTER: Li J

PROVIDER: S-EPMC7423188 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Li Jingjing J Wei Qing Q Wu Xiaoying X Sima Jun J Xu Qi Q Wu Mengmeng M Wang Fufeng F Mou Haibo H Hu Hanguang H Zhao Jianguo J Li Da D Hu Jinlin J Zhang Lingnan L Zhu Xiu X Chen Lei L Luo Cong C Yan Junrong J He Jiachen J Ma Yutong Y Shao Yang Y Wu Wei W Ying Jieer J

Clinical and translational medicine 20200801 4

<h4>Background</h4>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.<h4>Methods</h4>The study enrolled 26 patients with advanced microsatellite stable BTCs (15 with gallbladder cancers [GCs] and 11 with int ...[more]

PMID: 32898339

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Project description:Cancers acquire multiple somatic mutations that can lead to the generation of immunogenic mutation-induced neoantigens. These neoantigens can be recognized by the host's immune system. However, continuous stimulation of immune cells against tumor antigens can lead to immune cell exhaustion, which allows uncontrolled outgrowth of tumor cells. Recently, immune checkpoint inhibitors have emerged as a novel approach to overcome immune cell exhaustion and reactivate antitumor immune responses. In particular, antibodies blocking the exhaustion-mediating programmed death receptor (PD-1)/programmed death receptor ligand (PD-L1) pathway have shown clinical efficacy. The effects were particularly pronounced in tumors with DNA mismatch repair (MMR) deficiency and a high mutational load, which typically occur in the colon and endometrium. Here, we report on a 24-yr-old woman diagnosed with extrahepatic cholangiocarcinoma who showed strong and durable response to the immune checkpoint inhibitor pembrolizumab, although treatment was initiated at an advanced stage of disease. The patient's tumor displayed DNA MMR deficiency and microsatellite instability (MSI) but lacked other features commonly discussed as predictors of response toward checkpoint blockade, such as PD-L1 expression or dense infiltration with cytotoxic T cells. Notably, high levels of HLA class I and II antigen expression were detected in the tumor, suggesting a potential causal relation between functionality of the tumor's antigen presentation machinery and the success of immune checkpoint blockade. We suggest determining MSI status in combination with HLA class I and II antigen expression in tumors potentially eligible for immune checkpoint blockade even in the absence of conventional markers predictive for anti-PD-1/PD-L1 therapy and in entities not commonly linked to the MSI phenotype. Further studies are required to determine the value of these markers for predicting the success of immune checkpoint blockade.

Project description:ImportanceThere are a limited number of predictive biomarkers for hyperprogressive disease (HPD), which is induced by immune checkpoint blockade (ICB) therapy.ObjectiveTo evaluate the association of biomarkers in serum with the response to ICB therapy in patients with metastatic gastrointestinal tract cancer.Design, setting, and participantsCohort study in which patients with metastatic gastrointestinal tract cancer treated with ICB were enrolled at the Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China, from August 1, 2015, to July 31, 2017, with the last follow-up date on January 1, 2018. Serum samples were collected at baseline and during the first visit to the clinic after starting treatment. Data analysis was conducted from January 16, 2018, to September 1, 2018.ExposuresA total of 59 factors, including cytokines/chemokines, growth factors, and soluble checkpoint-related proteins in serum, were examined by multiplexed bead immunoassays.Main outcomes and measuresTree-based estimators were used to evaluate the importance of serum protein levels to ICB treatment response. Progression-free survival and overall survival analyses were conducted with the Kaplan-Meier method and log-rank test.ResultsIn total, 56 patients were examined. All patients with HPD (5 [8.9%]) had significantly lower mean (SD) levels of serum monocyte chemoattractant protein 1 than patients without HPD at baseline (53.4 [17.3] pg/mL vs 106.4 [48.4] pg/mL; P = .02). All patients with HPD were also identified by lower leukemia inhibitory factor levels (<13.28 pg/mL) and higher cluster of differentiation 152 levels (≥31.81 pg/mL). Among the remaining 51 patients, responders with esophageal squamous cell carcinoma (ESCC) or colorectal cancer (CRC) showed larger decreases in interleukin 1 receptor antagonist levels than nonresponders (ESCC: -55.02% [95% CI, -86.52% to -23.51%] vs 43.44% [95% CI, 11.93% to 74.96%]; P < .001; CRC: -35.82% [95% CI, -67.38% to -4.26%] vs 59.14% [95% CI, -72.34% to 190.6%]; P = .04). Responders with gastric cancer (GC) had larger increases in brain-derived neurotrophic factor levels than nonresponders (44.77% [95% CI, 10.76% to 78.79%] vs -26.2% [95% CI, -58.53% to 6.12%]; P = .003). Furthermore, early decreases in serum interleukin 1 receptor antagonist in patients with metastatic ESCC and CRC were associated with longer progression-free survival (ESCC: not reached vs 2.1 months; hazard ratio, 0.19; 95% CI, 0.04 to 0.95; P = .04; CRC: not reached vs 2.1 months; hazard ratio, 0.06; 95% CI, 0.01 to 0.38; P < .001). Early increases in brain-derived neurotrophic factor levels in patients with metastatic GC were associated with longer progression-free survival (not reached vs 4.2 months; hazard ratio, 0.15; 95% CI, 0.03 to 0.84; P = .03).Conclusions and relevanceIn this study, baseline serum levels of monocyte chemoattractant protein 1, leukemia inhibitory factor, and cluster of differentiation 152 were associated with hyperprogressive metastatic gastrointestinal cancer among patients receiving ICB. An early decrease in serum interleukin 1 receptor antagonist levels in patients with metastatic ESCC or CRC and an early increase in serum brain-derived neurotrophic factor levels in patients with metastatic GC were better able to identify who would respond to ICB compared with microsatellite stability status or programmed cell death ligand 1 expression.

Project description:It is difficult to detect pancreatic cancer or biliary-tract cancer at an early stage using current diagnostic technology. Utilizing microRNA (miRNA) markers that are stably present in peripheral blood, we aimed to identify pancreatic and biliary-tract cancers in patients. With "3D-Gene", a highly sensitive microarray, we examined comprehensive miRNA expression profiles in 571 serum samples obtained from healthy patients, patients with pancreatic, biliary-tract, or other digestive cancers, and patients with non-malignant abnormalities in the pancreas or biliary tract. The samples were randomly divided into training and test cohorts, and candidate miRNA markers were independently evaluated. We found 81 miRNAs for pancreatic cancer and 66 miRNAs for biliary-tract cancer that showed statistically different expression compared with healthy controls. Among those markers, 55 miRNAs were common in both the pancreatic and biliary-tract cancer samples. The previously reported miR-125a-3p was one of the common markers; however, it was also expressed in other types of digestive-tract cancers, suggesting that it is not specific to cancer types. In order to discriminate the pancreato-biliary cancers from all other clinical conditions including the healthy controls, non-malignant abnormalities, and other types of cancers, we developed a diagnostic index using expression profiles of the 10 most significant miRNAs. A combination of eight miRNAs (miR-6075, miR-4294, miR-6880-5p, miR-6799-5p, miR-125a-3p, miR-4530, miR-6836-3p, and miR-4476) achieved a sensitivity, specificity, accuracy and AUC of 80.3%, 97.6%, 91.6% and 0.953, respectively. In contrast, CA19-9 and CEA gave sensitivities of 65.6% and 40.0%, specificities of 92.9% and 88.6%, and accuracies of 82.1% and 71.8%, respectively, in the same test cohort. This diagnostic index identified 18/21 operable pancreatic cancers and 38/48 operable biliary-tract cancers in the entire cohort. Our results suggest that the assessment of these miRNA markers is clinically valuable to identify patients with pancreato-biliary cancers who could benefit from surgical intervention.

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

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

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