scholarly journals Efficacy and Safety of Pembrolizumab for Gemcitabine/Cisplatin-Refractory Biliary Tract Cancer: A Multicenter Retrospective Study

2020 ◽  
Vol 9 (6) ◽  
pp. 1769 ◽  
Author(s):  
Sang Hoon Lee ◽  
Hee Seung Lee ◽  
Sang Hyub Lee ◽  
Sang Myung Woo ◽  
Dong Uk Kim ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Progression Free Survival ◽  
Cancer Type ◽  
Extrahepatic Cholangiocarcinoma ◽  
Tract Cancer ◽  
Tertiary Hospitals ◽  
Melanoma Treatment

Pembrolizumab, an anti-programmed cell death (PD)-1 monoclonal antibody, is an anticancer agent showing substantial benefit in lung cancer and melanoma treatment. Biliary tract cancer (BTC) has been shown to respond to pembrolizumab; however, no credible data of such treatment outcomes exist. Therefore, we assessed the clinical outcomes and safety of pembrolizumab in patients with gemcitabine/cisplatin-refractory BTC. In this multicenter study, we retrospectively analyzed 51 patients with programmed cell death 1-ligand 1 (PD-L1)-positive gemcitabine/cisplatin-refractory BTC treated with pembrolizumab in four tertiary hospitals in Korea. PD-L1 positivity was defined as the expression of PD-L1 in ≥1% of tumor cells based on immunohistochemical staining (22C3, SP263, and E1L3N assays). The median age of the patients was 66 (range, 43–83) years and 29 (56.9%) were male. Extrahepatic cholangiocarcinoma was the most common cancer type (n = 30, 58.8%). Partial response and stable disease were achieved in 5 (9.8%) and 13 (25.5%) patients, respectively. Median progression-free survival and overall survival were 2.1 (95% CI, 1.7–2.4) and 6.9 (95% CI, 5.4–8.3) months, respectively. Overall, 30 (58.8%) patients experienced treatment-related adverse events (AEs). Only four (7.8%) patients experienced grades 3 and 4 AEs. In PD-L1-positive gemcitabine/cisplatin-refractory BTC, pembrolizumab presented durable efficacy, with a 9.8% response rate and manageable toxicity.

scholarly journals A Combined TLR7/TLR9/GATA3 Score Can Predict Prognosis in Biliary Tract Cancer

Diagnostics ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1597
Author(s):  
Vittorio Branchi ◽  
Laura Esser ◽  
Corinna Boden ◽  
Azin Jafari ◽  
Jonas Henn ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Survival Data ◽  
Immune Cell ◽  
Disease Free Survival ◽  
Cox Proportional Hazards Model ◽  
Tract Cancer ◽  
Dismal Prognosis

Biliary tract cancer (BTC) refers to a heterogenous group of epithelial malignancies arising along the biliary tree. The highly aggressive nature combined with its silent presentation contribute to the dismal prognosis of this tumor. Tumor-infiltrating immune cells (TIICs) are frequently present in BTC and there is growing evidence regarding their role as therapeutic targets. In this study, we analyzed the immune cell infiltration in BTC and developed a promising immune signature score to predict prognosis in BTC. Immunohistochemistry (IHC) was carried out on tissue microarray sections from 45 patients with resectable cholangiocarcinoma for the detection of 6-sulfoLacNAc+ monocytes (slanMo), BDCA-2+ plasmacytoid dendritic cells (pDC), CD8+ or CD4+T-lymphocytes, CD103+ cells, GATA3+ cells, Toll-like receptor (TLR) 3, 7 and 9-expressing cells as well as programmed cell death protein 1 and programmed cell death ligand 1 positive cells. Data from the IHC staining were analyzed and correlated with clinicopathological and survival data. High expression of TLR7, TLR9, and GATA3 was associated with improved overall survival (OS, Log-rank p< 0.05). In addition, TLR9 was associated with better disease-free survival (Log-rank p< 0.05). In the multivariate Cox proportional-hazards model for OS, the TLR/TLR9/GATA3 score was found to be an independent prognostic factor for OS (“Score 2” vs. “Score 0”: HR 11.17 95% CI 2.27–54.95, p < 0.01).

Programmed Death Ligand 1 Expression as a Prognostic Marker in Patients with Advanced Biliary Tract Cancer

Oncology ◽  
2021 ◽  
pp. 1-8
Author(s):  
Hyera Kim ◽  
Jinchul Kim ◽  
Seonggyu Byeon ◽  
Kee-Taek Jang ◽  
Jung Yong Hong ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Tumor Location ◽  
Extrahepatic Cholangiocarcinoma ◽  
Programmed Death Ligand 1 ◽  
Tract Cancer ◽  
Programmed Death ◽  
Combined Positive Score

Background: Biliary tract cancer (BTC) is associated with poor prognosis because of its aggressive and heterogeneous nature. Programmed death ligand 1 (PD-L1) has been considered a novel biomarker for prognosis and response of immune checkpoint inhibitors in various tumors. However, there are limited data reporting on the role of PD-L1 in advanced BTC patients. Patients and Methods: We analyzed 186 patients with advanced BTC who received palliative gemcitabine and platinum between May 2010 and December 2019. All patients were evaluated for PD-L1 expression by combined positive score positivity. Results: Of the 186 patients, the primary tumor location was intrahepatic cholangiocarcinoma (IHCC) in 72 (38.7%), extrahepatic cholangiocarcinoma (EHCC) in 90 (48.4%), and gallbladder (GB) cancer in 24 (12.9%). Among all the patients, 53 (28.5%) had PD-L1 positivity. The median overall survival (OS) of patients with PD-L1 positivity or negativity was 12.1 and 15.4 months, respectively. The median progression-free survival (PFS) in patients with PD-L1 positivity or negativity was 5.7 and 7.1 months, respectively. OS and PFS were not statistically different between groups. In subgroup analysis, EHCC patients with PD-L1 negativity had more favorable OS (17.2 vs. 11.6 months, p = 0.002) and PFS (7.8 vs. 5.4 months, p = 0.005) than those who were PD-L1-positive. However, this finding was not reproduced in patients with IHCC or GB cancer. Conclusion: This study demonstrated that PD-L1 expression might be a novel prognostic biomarker in patients with EHCC but not in patients with IHCC or GB cancer.

scholarly journals Dual HER2 Blockade: An Emerging Option in Metastatic Biliary Tract Cancer?

Medicina ◽  
2021 ◽  
Vol 57 (12) ◽  
pp. 1301
Author(s):  
Angela Dalia Ricci ◽  
Alessandro Rizzo
Keyword(s):  
Gallbladder Cancer ◽  
Biliary Tract ◽  
Intrahepatic Cholangiocarcinoma ◽  
Biliary Tract Cancer ◽  
Heterogeneous Group ◽  
Perihilar Cholangiocarcinoma ◽  
Extrahepatic Cholangiocarcinoma ◽  
Tract Cancer ◽  
Hepatobiliary Malignancies

Biliary tract cancer (BTC) includes a heterogeneous group of aggressive and rare hepatobiliary malignancies, including gallbladder cancer, ampullary carcinomas, intrahepatic cholangiocarcinoma (iCCA), and extrahepatic cholangiocarcinoma, further subclassified into distal (dCCA) and perihilar cholangiocarcinoma (pCCA) [...]

Clinical benefit of maintenance therapy for patients with advanced biliary tract cancer without progression on first-line gemcitabine plus cisplatin.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 357-357
Author(s):  
Jaewon Hyung ◽  
Changhoon Yoo ◽  
Kyu-Pyo Kim ◽  
Bum Jun Kim ◽  
Jae Ho Jeong ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Clinical Benefit ◽  
Medical Center ◽  
Progression Free Survival ◽  
Observation Group ◽  
First Line ◽  
Tract Cancer ◽  
Maintenance Group

357 Background: Gemcitabine plus cisplatin (GP) is the standard first line chemotherapy for patients with advanced biliary tract cancer (BTC). In the pivotal ABC-02 study, patients received up to 24 weeks (6-8 cycles) of three-weekly GP. In daily practice setting, however, patients without progression often receive GP more than 6-8 cycles. It is uncertain whether maintenance treatment has clinical benefit in patients without progression on GP. Methods: Advanced BTC patients treated with GP between April 2010 and February 2015 in Asan Medical Center, Seoul, Korea, were retrospectively analyzed. Among the patients who did not progressed and stopped GP after 6-8 cycles, patients were stratified according to the further treatment; those with or without further cycles of GP (maintenance group vs observation group). Primary endpoint was overall survival (OS). Results: Among 740 patients, 231 patients (31.2%) were eligible for this analysis; 111 for observation group, 120 for maintenance group. In observation group, 76 patients (68.5%) stopped GP due to completion of scheduled chemotherapy and 27 patients (24.3%) due to the patients’ request or toxicity. There were no statistically significant differences in baseline characteristics between two groups. Median OS from the initiation of GP was 20.5 months [95% CI 15.4-25.6] and 22.4 months [95% CI 17.0-27.8] in the observation and maintenance group, respectively (p = 0.32). Median progression-free survival (PFS) was 10.4 months [95% CI 7.0-13.8] and 13.2 months [95% CI 11.3-15.2], respectively (p = 0.22). These were consistent in the multivariate analyses for OS and PFS after the adjustment of prognostic factors. Conclusions: In our analysis, maintenance therapy of GP was not associated with improved survival outcomes. Considering the potential disadvantages such as cumulative toxicities, maintenance therapy may not be beneficial in patients who did not progressed on 6-8 cycles of GP.

Frequency of BRCA mutation in biliary tract cancer and its correlation with tumor mutational burden (TMB) and microsatellite instability (MSI).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4085-4085 ◽  
Author(s):  
Gilbert Spizzo ◽  
Alberto Puccini ◽  
Joanne Xiu ◽  
Richard M. Goldberg ◽  
Axel Grothey ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Brca Mutation ◽  
Treatment Strategies ◽  
Missense Mutations ◽  
Brca Mutations ◽  
Extrahepatic Cholangiocarcinoma ◽  
Similar Frequency ◽  
Biliary Tract Cancers ◽  
Tract Cancer

4085 Background: Biliary tract cancers constitute ~3% of cancers worldwide with incidence increasing, especially for intrahepatic cholangiocarcinoma (IHC). The prognosis of these tumors remains dismal and novel treatment strategies are needed to improve overall survival. BRCA mutations occur in biliary tract cancers but their frequency in distinct sites of biliary tract cancer is unknown. Moreover, no data are available correlating BRCA mutation with immunogenic markers such as TMB, MSI, or PD-L1 expression. Methods: Tumor samples from 1288 primary biliary tract cancers, comprising IHC (n = 746), extrahepatic cholangiocarcinoma (EHC) (n = 189), gallbladder (GBC) (n=353) were profiled at Caris Life Sciences, Phoenix, AZ. Testing included NextGen SEQ (MiSeq on 47 genes, NextSeq on 592 genes) and PD-L1 IHC (SP142). TMB was calculated based on somatic nonsynonymous missense mutations, and MSI was evaluated by NGS of known MSI loci. Results: BRCA mutations were detected in 3.6% (N = 46) of samples ( BRCA1 0.6%, BRCA2 3%), no differences were seen based on the site of the tumor. In GBC and IHC BRCA2 mutations (4.0% and 2.7%) were more frequent than BRCA1 (0.3% and 0.4, p < 0.05) while in EHC, similar frequency was observed ( BRCA1: 2.1%; BRCA2: 2.6%). There was no significant association with gender or age. In BRCA-mutant biliary tract cancer the most frequently mutated genes were TP53 (55.6%), ARID1A (52.2%) and KRAS (26.1%), KMT2D/C (20%, 13%) and CDKN2A(13%). Overall, BRCA mutations were associated with a higher rate of MSI-H (19.5% vs 1.7%, p = 0.001) and higher TMB in both MSI-H and MSS tumors (p<0.05). When investigated separately, BRCA association with elevated TMB was seen in IHC and EHC, but not in GBC. No correlation was seen with PD-L1 expression. TP53, KMT2D/C, RB1, PTEN, KDM6A mutations and FGFR1 amplifications were significantly higher in BRCA mutated tumors (p < 0.05). Conclusions: BRCA mutations are found in a significant subgroup of biliary tract tumors and are associated with an immunogenic tumor profile. These data provide rationale for trials testing PARP inhibitors in combination with immunotherapy and targeted therapies in patients with BRCA-mutant biliary tract cancers that are MSS.

PD-L1 expression as a prognostic marker in patients with advanced biliary tract cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16679-e16679
Author(s):  
Hyera Kim ◽  
Jung Yong Hong ◽  
Jeeyun Lee ◽  
Se Hoon Park ◽  
Joon Oh Park ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Checkpoint Inhibitors ◽  
Univariate Analysis ◽  
Group Analysis ◽  
Progression Free Survival ◽  
Tumor Location ◽  
Tract Cancer ◽  
Positive Score ◽  
Combined Positive Score

e16679 Background: Biliary tract cancer (BTC) is associated with poor prognosis because of its aggressive and heterogeneous nature. Programmed death ligand 1 (PD-L1) has been considered as a novel biomarker for prognosis and response of immune checkpoint inhibitors in various tumors. However, there are limited data reporting on the role of PD-L1 in advanced BTC patients. Methods: We analyzed 186 patients with advanced BTC who received palliative gemcitabine and platinum between May 2010 and December 2019. All patients were evaluated for PD-L1 expression by combined positive score (CPS) positivity. Results: In all 186 patients, the median age was 62 years (range 38-82), and the primary tumor location was intrahepatic cholangiocarcinoma (IH-CCC) in 72 patients (38.7%), extrahepatic (EH)-CCC in 90 (48.4%), and gallbladder (GB) cancer in 24 (12.9%). There were 158 (84.9%) patients with recurrent disease and 28 (15.1%) with metastatic disease. Among the 186 patients, 53 (28.5%) had PD-L1 CPS positivity, and 133 were CPS negative. The median overall survival (OS) of patients with PD-L1 CPS positivity or negativity was 12.1 and 15.4 months, respectively. The median progression-free survival (PFS) in patients with PD-L1 positivity or negativity was 5.7 and 7.1 months, respectively. The OS and PFS were not statistically different between groups. In sub-group analysis, EH-CCC patients with PD-L1 negativity had more favorable OS (17.2 vs. 11.6 months, p= 0.002) and PFS (7.8 vs. 5.4 months, p= 0.005) than those that were PD-L1 negative. However, this finding was not reproduced in patients with IH-CCC or GB cancer. Univariate analysis of the association between PD-L1 expression and OS in patients with advanced BTC indicated that PD-L1 CPS positivity has a prognostic role in sub-populations older than 60 years (HR 1.743, CI 1.001-3.034, p = 0.050), those with EH-CCC (HR 2.449, CI 1.355-4.426, p = 0.003), and those with liver metastasis (HR 2.511, CI 1.362-4.626, p = 0.003). Conclusions: This study demonstrated that PD-L1 expression might be a novel prognostic biomarker in patients with EH-CCC but not for patients with IH-CCC or GB cancer.

scholarly journals Intrahepatic Cholangiocarcinoma: Evolving Concepts and Medical Treatment

2021 ◽  
Vol 26 (1) ◽  
pp. 33-42
Author(s):  
Hong Ja Kim
Keyword(s):  
Biliary Tract ◽  
Intrahepatic Cholangiocarcinoma ◽  
Biliary Tract Cancer ◽  
Chemotherapeutic Agents ◽  
Growth Patterns ◽  
Classification Systems ◽  
Anatomical Location ◽  
Extrahepatic Cholangiocarcinoma ◽  
Distal Cholangiocarcinoma ◽  
Tract Cancer

Cholangiocarcinoma (bile duct cancer) is classified into intrahepatic and extrahepatic cholangiocarcinoma (perihilar and distal cholangiocarcinoma) according to the anatomical location of the lesion. The incidence of extrahepatic cholangiocarcinoma has been relatively stagnant in recent decades, but intrahepatic cholangiocarcinoma is steadily increasing worldwide, requiring attention. Various classification systems based on gross growth patterns, histological findings, and tumor-derived cells, as well as classification based on existing anatomical location, have been proposed, however, the consensus has not been established yet. Intrahepatic cholangiocarcinoma is a carcinoma with an extremely poor prognosis. Complete tumor resection is the only curative treatment. The overall survival rate for 5 years after surgery is 15% to 40%, but recurrence after surgery is observed in 2/3 patients. Therefore, determining the right stage before surgery and selecting an appropriate treatment method through a multidisciplinary approach is a very important process in determining proper treatment. Systemic therapy may be used for locally advanced biliary tract cancer or metastatic biliary tract cancer where surgery is not possible. However, the effectiveness of traditional anticancer chemotherapeutic agents is rather pessimistic, therefore treatments using molecular biological properties have recently been attempted. Finding a way to increase the number of resectable cases through early diagnosis is one of the main challenges. In addition, it is also hoped that the selection of new therapeutic targets and therapeutics will be possible as a result of advanced research on gene expression profiles and mutations in cholangiocarcinoma.

scholarly journals Tumor Mutational Burden as a Biomarker for Advanced Biliary Tract Cancer

2021 ◽  
Vol 20 ◽  
pp. 153303382110623
Author(s):  
Hongsik Kim ◽  
Hana Kim ◽  
Ryul Kim ◽  
Hyunji Jo ◽  
Hye Ryeon Kim ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Objective Response ◽  
Progression Free Survival ◽  
Line Treatment ◽  
First Line ◽  
Tract Cancer ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
First Line Treatment

Background: High tumor mutational burden (TMB-H) has been reported as a predictive marker to immunotherapy or prognostic marker in various tumor types. However, there has been little study of the role of TMB-H in advanced biliary tract cancer (BTC). Methods: We analyzed 119 advanced BTC patients who received Gemcitabine/Cisplatin (GP) as a first-line treatment between November 2019 and April 2021. Next-generation sequencing (NGS), including TMB analysis, as a routine clinical practice was performed in 119 patients. The TruSightTM Oncology 500 assay from Illumina was used as a cancer panel. Results: Among 119 patients, 18 (18.5%) had a tumor with high TMB (≥ 10 Muts/Mb). There were no significant differences between the status of TMB and clinical outcomes with GP, including objective response rate (ORR) ( P = .126), disease control rate (DCR) ( p = .454), and median progression-free survival (PFS) ( p = .599). The median overall survival (OS) was not different between patients with TMB-H and no TMB-H ( p = .430). In subgroup analysis of 32 patients receiving immune checkpoint inhibitor (ICIs), there were significant differences in ORR ( p = .034) and median PFS ( p  = .025) with ICIs between patients with and without TMB-H. Conclusions: This study revealed that TMB-H in advanced BTCs did not have a prognostic or role in the standard first-line treatment. However, TMB-H might be a predictive biomarker for response to ICIs in advanced BTC.

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