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).

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.

Genomics and translational precision oncology for 803 patients with biliary tract cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4589-4589
Author(s):  
Jianzhen Lin ◽  
Xu Yang ◽  
Yinghao Cao ◽  
Guangyu Li ◽  
Songhui Zhao ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Targeted Therapies ◽  
Objective Response ◽  
Disease Free Survival ◽  
Tumor Board ◽  
Precision Oncology ◽  
Free Survival ◽  
Tract Cancer ◽  
Incidence And Mortality

4589 Background: Both incidence and mortality of biliary tract cancer (BTC) are increasing, and BTCs are characterized by poor prognosis and limited antitumoral treatments. There is no well-received regimen as the non-first-line treatment in patients with advanced BTCs, leading to the urgency of umbrella-setting personalized therapies according to genomic alterations. Methods: We performed genomic sequencing in a total of 803 BTCs, including 160 patients with whole-exome sequencing and 643 patients with hybrid capture–based comprehensive genomic profiling. Our molecular tumor board developed precise targeted therapies for patients with actionable targets. Results: Overall, the median tumor mutation burden was 3.0 (IQR: 0.8-6.1) Mut/Mb, with 10.5% patients of hypermutated BTCs. The most frequently mutated genes included TP53 (51%), KRAS (23%), ARID1A (16%) and SMAD4 (11%). The most common genes with significantly amplified oncogenes were CCND1 (6.97%), MET (6.72%) and MDM2 (6.6%), while the frequently deleted tumor-suppressor genes are CDKN2A (5.73%) and CDKN2B (5.35%). The mutational map of BTCs highlighted pathways of receptor-tyrosine kinase (RTK)/RAS and p53 signaling were frequently altered. Somatic truncating mutations of mismatch repair genes were identified in 6.1% (49/803) of patients, and germline pathogenic mutations in DNA damage response genes occurred in 8% (64/803) of BTCs. In addition, we demonstrate the amplified chromosomal focal at 7q31.2 was an oncogenic factor and it independently predicts both disease-free survival and overall survival of BTC patients. When molecular screening was linked to targeted therapies, 25.4% (204/803) of patients could match biomarker-assigned drug treatment (BADT). The frequent actionable biomarkers included amplifications of ERBB2 and MET, FGFR2/3 fusions and IDH1 mutations. For 46 patients with refractory BTCs received BADT, the objective response rate was 26.1%, with a median progression-free survival (mPFS) of 5.0 (95%CI: 3.5-6.5) months, and 56.8% patients achieved a ≥1.3 ratio of PFS2/PFS1. 4 of 6 (67%) patients with high microsatellite instability (MSI-H) BTCs had a responsive status after immunotherapy of PD1 inhibitor, confirming that MSI-H status was a robust biomarker of anti-PD1 treatments. Conclusions: Our study established the largest cohort in Chinese BTC patients to investigate the tumor mutational profiling and its translational clinical applications. Clinical trial information: NCT02715089 .

scholarly journals A prospective feasibility study of one-year administration of adjuvant S-1 therapy for resected biliary tract cancer in a multi-institutional trial (Tokyo Study Group for Biliary Cancer: TOSBIC01)

2020 ◽  
Author(s):  
Osamu Itano ◽  
Yusuke Takemura ◽  
Norihiro Kishida ◽  
Eiji Tamagawa ◽  
Hiroharu Shinozaki ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Adverse Events ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Disease Free Survival ◽  
Completion Rate ◽  
Inclusion Criteria ◽  
Tract Cancer ◽  
Post Surgery ◽  
One Year

Abstract Background: Although surgery is the definitive curative treatment for biliary tract cancer (BTC), outcomes after surgery alone have not been satisfactory. Adjuvant therapy with S-1 may improve survival in patients with BTC. This study examined the safety and efficacy of 1 year adjuvant S-1 therapy for BTC in a multi-institutional trial.Methods: The inclusion criteria were as follows: histologically proven BTC, ECOG performance status 0 or 1, R0 or R1 surgery performed, cancer classified as Stage IB to III. Within 10 weeks post-surgery, a 42-day cycle of treatment with S-1 (80 mg/m2/day orally twice daily on days 1–28 of each cycle) was initiated and continued up to 1 year post surgery. The primary endpoint was adjuvant therapy completion rate. The secondary endpoints were toxicities, disease-free survival (DFS) and overall survival (OS).Results: Overall, 46 patients met the inclusion criteria of whom 19 had extrahepatic cholangiocarcinoma, 10 had gallbladder carcinoma, 9 had ampullary carcinoma, and 8 had intrahepatic cholangiocarcinoma. Overall, 25 patients completed adjuvant chemotherapy, with a 54.3% completion rate while the completion rate without recurrence during the 1 year administration was 62.5%. Seven patients (15%) experienced adverse events (grade 3/4). The median number of courses administered was 7.5. Thirteen patients needed dose reduction or temporal therapy withdrawal. OS and DFS rates at 1/2 years were 91.2/80.0% and 84.3/77.2%, respectively. Among patients who were administered S-1 more than 3 courses, only one case discontinued due to adverse events.Conclusions: One-year administration of adjuvant S-1 therapy for resected BTC was feasible and may be a promising treatment for those with resected BTC. Now, a randomized trial to determine the optimal duration of S-1 is ongoing.Trial registration: UMIN-CTR, UMIN000009029. Registered 5 October 2012-Retrospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009347)

scholarly journals Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes

2021 ◽  
Vol 9 (11) ◽  
pp. e003214
Author(s):  
Xiaofeng Chen ◽  
Deqiang Wang ◽  
Jing Liu ◽  
Jingrong Qiu ◽  
Jun Zhou ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Poor Prognosis ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Chinese Patients ◽  
Genomic Alterations ◽  
Early Stage Disease ◽  
Tract Cancer

BackgroundRecently, immunotherapy with immune checkpoint inhibitors (ICIs) has shown promising efficacy in biliary tract cancer (BTC), which includes gallbladder cancer (GBC) and cholangiocarcinoma (CHOL). Understanding the association between immunotherapy outcomes and the genomic profile of advanced BTC may further improve the clinical benefits from immunotherapy.MethodsGenomic tumor DNA was isolated from 98 Chinese patients with advanced BTC and used for targeted next-generation sequencing of 416 cancer-related genes to identify the genomic alterations common to advanced BTC. Thirty-four patients had received ICI camrelizumab plus gemcitabine and oxaliplatin (from the NCT03486678 trial) as a first-line treatment. Tumor-infiltrating immune cells were evaluated using immunofluorescence staining.ResultsKRAS and TP53 mutations were much more frequent in the advanced-stage BTC cohort than in other cohorts with mostly early stage disease. Specifically, KRAS-TP53 co-mutations were favored in advanced CHOL, with a favorable response to immunotherapy, while single KRAS mutations predicted poor prognosis and immunotherapy outcomes for CHOL. Compared with GBC, CHOL had more mutations in genes involved in KRAS signaling; a high mutation load in these genes correlated with poor immunotherapy outcomes and may subsequently cause inferior immunotherapy outcomes for CHOL relative to GBC. Furthermore, a genomic signature including 11 genes was developed; their mutated subtype was associated with poor prognosis and immunotherapy outcomes in both CHOL and GBC. Transcriptome analyses suggested immune dysfunction in the signature mutated subtype, which was validated by tumor microenvironment (TME) evaluation based on detection of immune cell infiltration. Importantly, the signature wild-type subtype with favorable TME may be an advantageous population of immunotherapy.ConclusionsGenomic alterations in advanced BTC were associated with specific prognosis and immunotherapy outcomes. Combining genomic classification with TME evaluation further improved the stratification of immunotherapy outcomes.

Feasibility and potential benefits of adjuvant chemotherapy with S-1 in patients with curative resected advanced biliary tract cancer: A multicenter trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15179-e15179
Author(s):  
Yoshikazu Toyoki ◽  
Keinosuke Ishido ◽  
Daisuke Kudo ◽  
Norihisa Kimura ◽  
Taiichi Wakiya ◽  
...  
Keyword(s):  
Adjuvant Chemotherapy ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Performance Status ◽  
Disease Free Survival ◽  
Radical Resection ◽  
Multicenter Trial ◽  
Eligibility Criteria ◽  
Tract Cancer ◽  
Grade 3

e15179 Background: S-1 chemotherapy is reported to be effective for treating metastatic and unresectable biliary tract cancer (BTC). We assessed the safety and feasibility of adjuvant S-1 chemotherapy in patients with curative resected advanced BTC. Methods: Patients with pathological stage II, III, or IVa BTC (according to JSBS) who underwent radical resection received oral S-1 (80 mg/m2/day) for 2 consecutive weeks every 3 weeks (1 cycle). Patients were aged 20–80 years, had a performance status of <1, and provided informed consent. The treatment was repeated until 1 year after surgery. The primary endpoint was feasibility of the adjuvant chemotherapy with S-1. The secondary endpoints were safety, disease-free survival (DFS), and overall survival (OS). Results: We enrolled 40 patients, but 5 patients were excluded on the basis of eligibility criteria (4 patients) or no drug administration (1 patient). We analyzed data from 35 patients (29 men and 6 women with a median age of 68 years) between January 2009 and November 2011. The feasibilities of 6-month and 12-month administration of S-1 were 65.7% (95% confidence interval [CI]: 47.8–80.9%) and 45.7% (95% CI 28.8–63.4%), respectively. Grade 3 neutropenia and anemia were observed in 2.9% and 5.7% of cases, respectively. Grade 3 non-hematological toxicities included anorexia in 14.3%, fatigue in 8.6%, and nausea in 2.9% of cases. No grade 4 hematological or non-hematological toxicities were observed, and no treatment-related deaths occurred. The 1-year OS was 91.4% (95% CI: 76.6–97.2%), and the 1-year DFS was 68.6% (95% CI: 51.7–81.7%). Conclusions: Adjuvant chemotherapy with S-1 for curative resected advanced BTC patients was both safe and feasible. Although the follow-up period was insufficient to evaluate OS and DFS, adjuvant chemotherapy with S-1 is believed to have improved the prognosis.

DNA-damage response-umbrella study of the combination of ceralasertib and olaparib, or ceralasertib and durvalumab in advanced biliary tract cancer: A phase 2 trial-in-progress.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS4166-TPS4166
Author(s):  
Jee Sun Yoon ◽  
Jin Won Kim ◽  
Ji-Won Kim ◽  
Tae-Yong Kim ◽  
Ah-Rong Nam ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Biliary Tract ◽  
Dna Damage Response ◽  
Biliary Tract Cancer ◽  
Phase 2 ◽  
Dna Breaks ◽  
Tumor Cell Death ◽  
Tract Cancer ◽  
Damage Response

TPS4166 Background: Ceralasertib (AZD6738) is a selective ATR inhibitor that causes stalled replication forks to collapse, leading to accumulation of double-strand DNA breaks, which is expected to have synergistic anti-tumor effects with immune checkpoint inhibitors (ICI) or PARP inhibitors. First, accumulation of DNA damage by ceralasertib induces tumor cell death, leads to the release of tumor-specific antigen, changing the tumor microenvironment to promote antigen presentation and enhances the anti-tumor effect of ICI. Second, by simultaneously inhibiting two DNA-damage response (DDR) pathways downstream of PARP and ATR, cancer cells are unable to repair damaged DNA, leading to cell death. Ceralasertib has demonstrated promising anti-tumor activity and manageable toxicity in combination with durvalumab or olaparib in solid tumors in a phase 1 study (NCT02264678). In preclinical studies, ceralasertib has shown potent anti-tumor effects in biliary tract cancer (BTC) as a monotherapy and in combination with chemotherapy (Nam, et al, 2019). Methods: This is an open-label, phase 2 umbrella study assessing the efficacy of ceralasertib in combination with durvalumab or olaparib in patients with advanced BTC. Eligible patients have histologically confirmed BTC (including intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer), have failed at least one chemotherapy and have ECOG performance status of 0-1. Patients who have received prior ICI, ATR or PARP inhibitor are excluded. Each cycle consists of 4 weeks. In ceralasertib /durvalumab cohort, 37 patients will receive durvalumab 1.5g on day 1 and ceralasertib 240mg twice daily on days 15-28. In ceralasertib /olaparib cohort, 37 patients receive ceralasertib 160mg once daily on days 1-7 and olaparib 300mg twice daily on days 1-28. The primary endpoint is disease control rate, with key secondary endpoints including overall response rate, progression-free survival, overall survival, and safety. Tissue and blood samples are being collected for translational biomarker studies. Clinical trial information: NCT04298021.

scholarly journals The efficacy of serum cell death biomarkers for diagnosing biliary tract cancer

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Mitsuru Sugimoto ◽  
Kazumichi Abe ◽  
Manabu Hayashi ◽  
Tadayuki Takagi ◽  
Rei Suzuki ◽  
...  
Keyword(s):  
Cell Death ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Tract Cancer

scholarly journals Prognostic value of the systemic immune-inflammation index in patients with biliary tract cancer: a systematic review and meta-analysis

2020 ◽  
Author(s):  
Faquan Zhou ◽  
Shi Chen ◽  
Yiquan Xiong ◽  
Xiaohui Yuan ◽  
Hongyu Sun ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Prognostic Value ◽  
Treatment Strategies ◽  
Disease Free Survival ◽  
Cochrane Library ◽  
Cancer Specific Survival ◽  
Free Survival ◽  
Tract Cancer ◽  
Immune Inflammation

Abstract Background: The systemic immune-inflammation index (SII) has been found to predict outcomes in many tumors. The purpose of this study was to determine the prognostic value of SII in biliary tract cancer.Methods: We searched PubMed, EMBASE, Web of Science, Cochrane Library, CNKI, CBM, Wanfang and VIP databases from its inception until May 18, 2020. Pooled hazard ratio and 95% confidence interval were calculated to assess the prognostic role of SII in patients with BTC. The main outcomes included the overall survival, cancer-specific survival, disease-free survival and recurrence-free survival. Stata 12.0 was used for statistical analysis.Results: A total of 8 studies involving 2249 patients were eventually included. The results showed that elevated SII was significantly associated with poorer OS (HR=1.56, 95% CI: 1.23–1.99, P<0.001, I2 = 68.1%), poorer DFS/RFS (HR=1.42, 95%CI:1.09–1.84, P =0.009) and poorer CSS (HR =1.55, 95% CI: 1.09–2.21, P<0.014). Subgroup analysis further verified the above results. Conclusions: Higher SII is a predictor of poor prognosis in BTC patients. SII can serve as a useful prognostic indicator and help to evaluate the prognosis and formulate treatment strategies.Registered in PROSPERO: CRD42020184556

Sign in / Sign up

Export Citation Format

Share Document