Biomarker analysis from a phase II multi-institutional study of nivolumab in patients with advanced refractory biliary tract cancer Journal Article
| Authors: | Kim, D. W.; Kim, Y. C.; Kovari, B. P.; Chung, V.; Alese, O. B.; El-Rayes, B. F.; Li, D.; Park, W.; Kim, R. D. |
| Article Title: | Biomarker analysis from a phase II multi-institutional study of nivolumab in patients with advanced refractory biliary tract cancer |
| Abstract: | Background: Our previous phase II study demonstrated that nivolumab provides modest but durable clinical efficacy in patients with refractory biliary tract cancer, suggesting the significant clinical benefit of nivolumab in selected patients and the necessity of predictive biomarkers. We evaluated clinicopathological characteristics and tumour microenvironment of the patients who were enrolled the trial to identify potential biomarkers. Methods: Baseline clinicopathological characteristics and pretreatment tumour samples were collected. The obtained tumour samples were assessed for whole exome sequencing, RNA sequencing and immunohistochemistry. Their correlations with clinical outcome were analysed. Results: Pretreatment tumour evaluation revealed PD-L1 expression on tumour, CD8 T cell infiltration and high ratio of CD8 T cell/regulatory T cell in tumour microenvironment were significantly associated with prolonged progression-free survival (PFS), while PD-1 expression on lymphocytes and CD68 macrophages infiltration in tumour microenvironment had no predictive role. Asian patients (N = 3) had improved PFS and disease control rate compared with non-Asian (N = 54). A six-gene predictive model was constructed by evaluation of total 23,550 candidate genes from RNA sequencing of baseline tumour samples using LASSO-Cox regression analysis, and high score of the six-gene prediction model was associated with prolonged PFS. Conclusion: This study suggests that PD-L1 expression on tumour, CD8 T cell infiltration and high ratio of CD8/regulatory T cells and six-gene expression profile in tumour microenvironment may be potential predictive biomarkers of nivolumab in biliary tract cancers. Further studies are needed to confirm these findings. © 2022 Elsevier Ltd |
| Keywords: | immunohistochemistry; signal transduction; protein kinase b; adult; cancer survival; controlled study; aged; unclassified drug; gene mutation; major clinical study; clinical feature; cisplatin; advanced cancer; cancer growth; drug efficacy; bone metastasis; cancer patient; comparative study; follow up; lymph node metastasis; dna replication; cd8 antigen; transcription factor foxp3; cd8+ t lymphocyte; lymphocyte proliferation; progression free survival; phase 2 clinical trial; gene expression profiling; cell infiltration; protein; phosphatidylinositol 3 kinase; tumor marker; prediction; liver metastasis; lung metastasis; regulatory t lymphocyte; antigen presentation; gamma interferon; biomarker; multicenter study; cell migration; cytokine production; down regulation; upregulation; cd4 antigen; cancer control; macrophage; peritoneum metastasis; biliary tract cancer; fibroblast growth factor receptor 2; predictive value; cd68 antigen; programmed death 1 ligand 1; programmed death 1 receptor; tumor microenvironment; asian; isocitrate dehydrogenase 1; clinical outcome; macrophage activation; pi3k/akt signaling; b lymphocyte activation; leukocyte activation; inositol phosphate; nivolumab; predictive model; g2 phase cell cycle checkpoint; human; male; female; article; rna sequencing; whole exome sequencing; tumor mutational burden; brpf3 protein; cdkl5 protein; kctd21 protein; methionyl aminopeptidase 2; mss51 protein; pappa2 protein; rnaseh2a protein; sbx24 protein; sngh12 protein; snhg3 protein; snora2c protein; snora3a protein; snora6 protein; advanced refractory biliary tract cancer |
| Journal Title: | European Journal of Cancer |
| Volume: | 176 |
| ISSN: | 0959-8049 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2022-11-01 |
| Start Page: | 171 |
| End Page: | 180 |
| Language: | English |
| DOI: | 10.1016/j.ejca.2022.09.014 |
| PUBMED: | 36252287 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2022 -- Source: Scopus |
