Extrahepatic Biliary Tract Cancer Research Articles

Combination anlotinib and toripalimab for an advanced biliary tract cancer patient with high Eastern Cooperative Oncology Group performance status: a case report.

Up to 80% of biliary tract cancer (BTC) patients relapse within 3 years after surgery and the efficacy of second-line treatment remains dismal for patients who progressed on gemcitabine and cisplatin chemotherapy. Median overall survival of patients with palliative chemotherapy is less than 1 year. The feasibility and safety of targeted therapies plus immunotherapies remain scanty currently, and patients with recurrent or advanced BTCs often experience a rapid decline in Eastern Cooperative Oncology Group (ECOG) performance status. This case report is the first report suggesting a 17-month progression-free survival (PFS), partial response, and another 11-month PFS after progressive disease of anlotinib plus toripalimab in advanced BTC with high ECOG performance status. We report a 67-year-old Chinese male with BTC. He was observed with progressive disease after surgical resection, adjuvant chemotherapy, palliative chemotherapy, and diagnosed with American Joint Committee on Cancer clinical stage IV (cT3N0M1) extrahepatic BTC. The patient experienced a rapid decline in performance status, and he received oral anlotinib and toripalimab with informed consent. MRI scans showed partial response on 22 June 2022. PET-CT showed that tumor activity has been inhibited on 8 March 2023. He achieved 17 months of PFS. Although the patient developed solitary lung metastasis, he had a continuous survival benefit from treatment of anlotinib plus toripalimab after lung radiotherapy. Until the writing of the case draft, he had achieved another 11 months of PFS. The present case suggests that anlotinib plus toripalimab might be a potential effective treatment for advanced BTCs patients with high ECOG performance status.

Practice guidelines for managing extrahepatic biliary tract cancers.

Reported incidence of extrahepatic bile duct cancer is higher in Asians than in Western populations. Korea, in particular, is one of the countries with the highest incidence rates of extrahepatic bile duct cancer in the world. Although research and innovative therapeutic modalities for extrahepatic bile duct cancer are emerging, clinical guidelines are currently unavailable in Korea. The Korean Society of Hepato-Biliary-Pancreatic Surgery in collaboration with related societies (Korean Pancreatic and Biliary Surgery Society, Korean Society of Abdominal Radiology, Korean Society of Medical Oncology, Korean Society of Radiation Oncology, Korean Society of Pathologists, and Korean Society of Nuclear Medicine) decided to establish clinical guideline for extrahepatic bile duct cancer in June 2021. Contents of the guidelines were developed through subgroup meetings for each key question and a preliminary draft was finalized through a Clinical Guidelines Committee workshop. In November 2021, the finalized draft was presented for public scrutiny during a formal hearing. The extrahepatic guideline committee believed that this guideline could be helpful in the treatment of patients.

Severity of Complications and Duration of Type 2 Diabetes and the Risk of Cancer: A Population-Based Study.

The literature on the association between diabetes severity and cancer risk is limited and inconclusive. The study aimed to evaluate the association between the adapted Diabetes Complications Severity Index (aDCSI) and the duration of type 2 diabetes and cancer risk. Patients ages 20 years or older with newly diagnosed type 2 diabetes between January 1, 2007, and December 31, 2011, were identified from Taiwan National Health Insurance claims data. Standardized incidence ratios (SIR) were calculated to compare cancer incidence in people with diabetes with that in the general population. Poisson regression was used to examine whether SIRs differed by age, sex, aDSCI, and duration of diabetes. A total of 756,547 patients were included, with a median follow-up of 8.8 years. Excluding the first year after diagnosis, the SIR for overall cancer was 1.18 [95% confidence interval (CI) 1.17-1.19]. Higher aDCSI was associated with increased SIRs for overall [SIR ratio 1.03 (1.02-1.03) per point increase], head and neck (1.03; 1.01-1.04), liver (1.04; 1.03-1.05), pancreas (1.03; 1.00-1.05), kidney (1.13; 1.10-1.15), and leukemia (1.09; 1.06-1.13). There was no association between aDCSI and colorectal, extrahepatic biliary tract, uterus and thyroid cancer, and a negative association with breast cancer (0.97; 0.95-0.98). Type 2 diabetes duration was associated with increased SIRs for overall [1.01 (1.00-1.02) per year increase], head and neck (1.03; 1.01-1.05), and liver cancer (1.04; 1.02-1.05). The heterogeneity in the association between diabetes severity and diabetes-related cancers suggests diverse underlying connections. Adopting distinct approaches in further research and prevention strategies for different kinds of diabetes-related cancers is important.

Osteosarcopenia is a significant predictor of recurrence and the prognosis after resection for extrahepatic bile duct cancer.

This study examined the impact of osteosarcopenia on recurrence and the prognosis after resection for extrahepatic biliary tract cancer (EBTC). We retrospectively analyzed 138 patients after resection for perihilar cholangiocarcinoma (11), distal cholangiocarcinoma (54), gallbladder carcinoma (30), or ampullary carcinoma (43). Osteosarcopenia is defined as the concomitant occurrence of osteopenia and sarcopenia. We investigated the relationship between osteosarcopenia and the overall survival (OS) and disease-free survival (DFS) in univariate and multivariate analyses. Osteosarcopenia was identified in 38 patients (27.5%) before propensity score (PS) matching. In the multivariate analysis, the independent recurrence factors were the prognostic nutrition index (p = 0.015), osteosarcopenia (p < 0.001), poorly differentiated adenocarcinoma (p = 0.004), perineural invasion (p = 0.002), and non-curability (p = 0.008), whereas the independent prognostic factors were prognostic nutrition index (p = 0.030), osteosarcopenia (p < 0.001), poorly differentiated adenocarcinoma (p = 0.007), lymphatic invasion (p = 0.018), and non-curability (p = 0.004). After PS matching, there was no significant difference in the variables between the patients with and without osteosarcopenia (n = 34 each). The 5-year DFS and OS after PS matching in patients with osteosarcopenia were significantly worse than in patients without osteosarcopenia (17.6% vs. 38.8%, p = 0.013 and 20.6% vs. 57.4%, p = 0.0005, respectively). Preoperative osteosarcopenia could predict the DFS and OS of patients after resection for EBTC.

PBRM1 mutations might render a subtype of biliary tract cancers sensitive to drugs targeting the DNA damage repair system

Polybromo-1 (PBRM1) loss of function mutations are present in a fraction of biliary tract cancers (BTCs). PBRM1, a subunit of the PBAF chromatin-remodeling complex, is involved in DNA damage repair. Herein, we aimed to decipher the molecular landscape of PBRM1 mutated (mut) BTCs and to define potential translational aspects. Totally, 1848 BTC samples were analyzed using next-generation DNA-sequencing and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). siRNA-mediated knockdown of PBRM1 was performed in the BTC cell line EGI1 to assess the therapeutic vulnerabilities of ATR and PARP inhibitors in vitro. PBRM1 mutations were identified in 8.1% (n = 150) of BTCs and were more prevalent in intrahepatic BTCs (9.9%) compared to gallbladder cancers (6.0%) or extrahepatic BTCs (4.5%). Higher rates of co-mutations in chromatin-remodeling genes (e.g., ARID1A 31% vs. 16%) and DNA damage repair genes (e.g., ATRX 4.4% vs. 0.3%) were detected in PBRM1-mutated (mut) vs. PBRM1-wildtype (wt) BTCs. No difference in real-world overall survival was observed between PBRM1-mut and PBRM1-wt patients (HR 1.043, 95% CI 0.821–1.325, p = 0.731). In vitro, experiments suggested that PARP ± ATR inhibitors induce synthetic lethality in the PBRM1 knockdown BTC model. Our findings served as the scientific rationale for PARP inhibition in a heavily pretreated PBRM1-mut BTC patient, which induced disease control. This study represents the largest and most extensive molecular profiling study of PBRM1-mut BTCs, which in vitro sensitizes to DNA damage repair inhibiting compounds. Our findings might serve as a rationale for future testing of PARP/ATR inhibitors in PBRM1-mut BTCs.

Proton beam therapy for extrahepatic biliary tract cancer: Analysis with prospective multi-institutional patients' registration database, Proton-Net.

To examine the role of proton beam therapy (PBT) in the treatment of extrahepatic biliary tract cancer (EBC). We analyzed the data accumulated in the Proton-Net database, which prospectively registered all individual patient data treated with PBT in all Japanese proton institutions from May 2016 to June 2019. The primary endpoint was overall survival (OS), and the secondary endpoints were local control (LC), progression-free survival (PFS), and toxicity. Ninety-three patients with unresectable and/or recurrent EBC were treated with PBT using a median prescribed dose of 67.5Gy (RBE) (range, 50-72.6Gy) in 25 (22-30 fractions). With a median follow-up of 16.3months, the median survival time was 20.1months and the 2-year OS was 37.8%. Two-year PFS and LC rates were 20.6% and 66.5%, respectively. Poor liver function (Child-Pugh B, C), a narrower distance between the tumor and digestive tract (2cm >), and a larger tumor diameter (2cm <) were identified as poor prognostic factors for OS. PBT-related grade 3 ≤ acute and late adverse events occurred in 5.4% and 4.3% of patients, respectively, including one gastrointestinal late toxicity (duodenal ulcer). This is the largest prospectively accumulated series of PBT for EBC, and PBT showed favorable outcomes with acceptable toxicity profiles.

Neoadjuvant Therapy for Extrahepatic Biliary Tract Cancer: A Propensity Score-Matched Survival Analysis

Background: Although surgery is the mainstay of curative-intent treatment for extrahepatic biliary tract cancer (EBTC), recurrence following surgery can be high and prognosis poor. The impact of neoadjuvant therapy (NAT) relative to upfront surgery (US) among patients with EBTC remains unclear. Methods: The Surveillance, Epidemiology, and End Results (SEER) databases was utilized to identify patients who underwent surgery from 2006 to 2017 for EBTC, including gallbladder cancer (GBC) and extrahepatic cholangiocarcinoma (ECC). Trends in NAT utilization were investigated, and the impact of NAT on prognosis was compared with US using a propensity score-matched (PSM) analysis. Results: Among 6582 EBTC patients (GBC, n = 4467, ECC, n = 2215), 1.6% received NAT; the utilization of NAT for EBTC increased over time (Ptrend = 0.03). Among patients with lymph node metastasis, the lymph node ratio was lower among patients with NAT (0.18 vs. 0.40, p < 0.01). After PSM, there was no difference in overall survival (OS) and cancer-specific survival (CSS) among patients treated with NAT versus US (5-year OS: 24.0% vs. 24.6%, p = 0.14, 5-year CSS: 38.0% vs. 36.1%, p = 0.21). A subgroup analysis revealed that NAT was associated with improved OS and CSS among patients with stages III-IVA of the disease (OS: HR 0.65, 95%CI 0.46-0.92, p = 0.02, CSS: HR 0.62, 95%CI 0.41-0.92, p = 0.01). Conclusions: While NAT did not provide an overall benefit to patients undergoing surgery for EBTC, individuals with advanced-stage disease had improved OS and CSS with NAT. An individualized approach to NAT use among patients with EBTC may provide a survival benefit.

Trial in progress: A phase 2/3 randomized, controlled study of CTX-009 in combination with paclitaxel versus paclitaxel alone in adult patients with unresectable advanced, metastatic or recurrent biliary tract cancers who have received one prior systemic chemotherapy regimen.

TPS640 Background: CTX-009 is a recombinant bispecific antibody that binds both delta-like ligand-4 (DLL4) and vascular endothelial growth factor A (VEGF-A). The antibody simultaneously inhibits the DLL4-Notch 1 and VEGF A-VEGF receptor signaling pathways. Presently, there is no consensus second-line therapy for patients with Biliary Tract Cancer (BTC) in whom first-line therapy has failed. In a Phase 1b study of CTX-009 in combination with paclitaxel, there were 4 patients with cholangiocarcinoma enrolled, and 2 of these 4 patients (both received CTX-009 at 10mg/kg + paclitaxel) had confirmed PRs with declines of 41.4% and 61.6% in their linear tumor burden from the baseline. Both of these patients had multiple prior therapies, and were on study for more than a year, with durable responses for more than 9 months each. Based on that observation, an adaptive Phase 2 cohort was added to the Phase 1b Study. There are currently 9 confirmed PRs among 24 patients treated for a 37.5% overall response rate in the ongoing Phase 2 Study of CTX-009 in combination with paclitaxel in patients with BTC treated in the second- or third-line setting. While there is anecdotal data suggesting that taxanes may have activity in BTC, the contribution of CTX-009 needs to be confirmed in a randomized study. Methods: CTX-009 is being evaluated in an open-label, randomized, controlled study in patients with previously treated, advanced or metastatic BTC. 120 patients will be randomized in a 2:1 ratio to receive either CTX-009 plus paclitaxel or paclitaxel alone. The stratification factors to be used at randomization include sex, presence of disease inside the liver only (intrahepatic cholangiocarcinoma) vs. outside the liver (all extrahepatic BTC or metastatic disease), and Eastern Cooperative Oncology Group (ECOG) Performance status (0 vs. 1). Patients will be treated in 28-day cycles, with CTX-009 administered at 10 mg/kg IV on Day 1 and 15, and paclitaxel administered at 80 mg/m2 on days 1, 8, and 15. The primary objective of the study is to assess the efficacy of CTX-009 in combination with paclitaxel vs. paclitaxel alone, as measured by Overall Response Rate (ORR) assessed by an Independent Central Radiology (ICR) review. Key secondary objectives include overall survival, progression-free survival, and duration of response. The study is currently activating sites with first patient in expected to be enrolled in 2022. Clinical trial information: NCT05506943 .

Preoperative Alkaline Phosphatase-adjusted CA19-9 as a Superior Prognosticator for Extrahepatic Biliary Tract Cancer With Jaundice.

The major limitation of carbohydrate antigen (CA)19-9 as a tumor marker is the high incidence of false-positive results during cholestasis. We evaluated preoperative CA19-9 and its adjusted values [ratios of CA19-9 to total-bilirubin (TB), direct-bilirubin (DB), and alkaline phosphatase (ALP)] to investigate the most suitable prognostic parameter in extrahepatic biliary tract cancer (eBTC) patients with or without jaundice. eBTC patients (n=140) who underwent resection were divided based on the absence (TB <2.0 mg/dl, n=90) or presence (TB ≥2.0 mg/dl, n=50) of preoperative jaundice. Within each group, the associations with overall survival (OS) were assessed for CA19-9, CA19-9/TB, CA19-9/DB and CA19-9/ALP ratios using Cox regression, receiver operating characteristic (ROC) analyses, and area under the curve (AUC) estimates. In univariate analysis in the group without jaundice, both high CA19-9 and high CA19-9/TB ratio were associated with poor OS, whereas other parameters were not. ROC-AUC for OS prediction was greater in CA19-9 than in the CA19-9/TB ratio, and CA19-9 was identified as an independent prognosticator in multivariate analysis. In the group with jaundice, CA19-9 was not significant; however, CA19-9/TB, CA19-9/DB, and CA19-9/ALP ratios were all associated with poor OS. In ROC-AUC analysis, CA19-9/ALP ratio showed the highest predictive value; furthermore, it was an independent prognosticator in multivariate analysis. Adjustment of the CA19-9 value was less useful as a predictor in the absence of jaundice. On the other hand, the CA19-9/ALP ratio showed superior prognostic value in jaundiced patients with eBTC.

Trends of the Extra-Hepatic Biliary Cancer and Its Surgical Management: A Cross-Sectional Study From the National Cancer Database.

IntroductionBiliary cancers are rare cancers with poor prognoses. In this study, we aimed to evaluate trends in early detection and surgical treatment and approaches in extra-hepatic biliary tract cancers (EBCs) over 13 years in the US.MethodsThe most recent data on patients diagnosed with EBC between 2004 and 2016 were extracted from the National Cancer Database (NCDB). The patients’ demographics (sex, age, race), primary tumor sites, tumor grades and stages, staging modalities, diagnostic confirmation, surgical treatment modalities and approaches, and 90-day mortality were analyzed to determine trends.ResultsBiopsy was the most common staging modality in 63.9% of total 60,291 patients. The bile duct was the primary tumor site (55.0%). Histologic examination was the most common confirmatory diagnostic modality (77.5%). The most common stage was stage II (23%). The most common surgical treatment modality was radical surgery (13.88%). The open surgical approach was used in 27.1% of patients, followed by a laparoscopic approach (4.3%).ConclusionEBC showed no significant change in the trends of the stage at diagnosis, treatment modality, and extent of surgical procedures despite advances in surgical diagnostic and therapeutic modalities; however, the total number of cases slightly increased between 2004 and 2016.

Preoperative cachexia index can predict the prognosis of extrahepatic biliary tract cancer after resection

IntroductionCachexia is associated with poor survival of patients with bile duct cancer. The cachexia index (CXI), which comprises skeletal muscle, inflammation, and nutritional status, has been proposed as a novel biomarker of cancer cachexia. In this study, we investigated the prognostic significance of the cachexia index after surgical resection of extrahepatic biliary tract cancer. MethodsBetween January 2008 and December 2020, 124 patients underwent radical resection of extrahepatic biliary tract cancer. The skeletal muscle index (SMI) was calculated as the area of the psoas muscle at the third lumbar vertebra/(height)2. CXI was calculated using as: SMI × serum albumin level/neutrophil-to-lymphocyte ratio. We performed univariate and multivariate analyses of the relationships between clinicopathological variables and disease-free and overall survival. ResultsThe CXI-low group included 57 patients. CXI-low was associated with poor disease-free (p < 0.01) and overall survival (p < 0.01) after curative resection. Preoperative bile duct drainage (p = 0.01), poor tumor differentiation (p = 0.04), advanced Tumor-Nodes-Metastasis (TNM) stage (II or III) (p < 0.01), and CXI-low (p = 0.03) were independent and significant predictors of disease-free survival. Age > 70 years (p = 0.03), preoperative bile duct drainage (p < 0.01), poor tumor differentiation (p = 0.01), advanced TNM stage (II or III) (p = 0.03), and CXI-low (p = 0.04) were independent and significant predictors of overall survival. ConclusionIn extrahepatic biliary tract cancer, preoperative CXI-low was an independent and significant risk factor for recurrence and poor prognosis, suggesting that cancer cachexia may progress to tumor development and recurrence.

Survival trends in hilar and extrahepatic cholangiocarcinoma based on Facility type: A National Cancer Database analysis.

e13536 Background: The diagnosis and treatment of Cholangiocarcinoma continues to pose a challenge. Due to their rarity, few studies have examined the impact of facility type on the survival of patients with extrahepatic cholangiocarcinoma. The hypothesis of this study was that differences in the outcome of patients at different facility types exist. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with hilar and extra-hepatic cholangiocarcinoma from 2004 to 2017 using ICD-O-3 histology codes. We used four different cohorts to assess survival amongst those at different facility types: academic/research programs, community cancer programs, comprehensive community center programs, and integrated network cancer programs. Data was analyzed and descriptive statistics and Kaplan Meier curves were produced using SPSS to measure survival in these patients with statistical significance set at α = 0.05. Results: Using the database, a total of 57,146 patients with hilar and extrahepatic cholangiocarcinoma were identified. Overall median survival in these patients was 11.2 months. Patients at Academic/research programs had a median survival of 14 months (95% CI 14.1-14.8 p &lt; 0.001). In comparison, median survival of 9.7 months (95%CI 9.3-10.2 p &lt; 0.001) and 8.7 months (95% CI 8.4-8.9 p &lt; 0.001) was noted in Integrated network and Comprehensive community cancer programs, respectively. Community cancer programs had the lowest median survival rate in patients with all extrahepatic biliary tract cancers included in our study was 6.9 months (95% CI 6.4-7.7 p &lt; 0.001). Specifically, patients with Klatskin tumors at Academic/Research programs had median survival of 10.3 months (95% CI 8.6-11.9 p &lt; 0.0010) compared to median survival of 3.6 months in patients treated at Community Cancer program. We also studied specific histology types such as papillary and mucinous adenocarcinomas. In papillary adenocarcinomas, there are no statistically significant differences in median survival in different facility types. In mucinous adenocarcinomas, median survival of 26.5 months was found in academic/research program patients compared to 16.2 months in Comprehensive Community Cancer program patients (p &lt; 0.001). Conclusions: Median overall survival in patients with hilar and extrahepatic cholangiocarcinoma was significantly higher in academic/research programs compared to other facility types. Further studies are needed to ascertain why academic/research programs have superior outcomes in these patients.

Treatment patterns and clinical outcomes among patients with biliary tract cancers in a large commercially insured US population.

398 Background: The American Cancer Society estimates 11,980 new cases of biliary tract cancers (BTCs), including gall bladder and nearby large bile ducts, to occur in the US in 2021. BTCs are characterized by poor prognosis and limited treatment choices. Gemcitabine (GEM) plus platinum chemotherapy is the standard of care. However, there are limited data regarding real-world treatment patterns and clinical outcomes for BTCs patients receiving systemic treatments (ST). Methods: A retrospective cohort study of BTCs patients who received first line (1L) ST, using US private payer Cancer Care Quality Program (CCQP) data and administrative claims from the HealthCore Integrated Research Database (HIRD) between 07/01/2014 - 03/31/2021, was performed. Index date was defined as first claim of ST within 60 days of documented 1L therapy in the CCQP from 01/01/2015 - 09/30/2020. Adult BTCs patients with ≥6 months pre-index enrollment were included. Patients with ampullary cancer, brain/ CNS metastases, other primary cancer before BTCs diagnosis were excluded. Treatment patterns and clinical outcomes were examined. Results: A total of 413 patients [Stage IV (n=315), III (n=44), II/I (n=54)] were identified. The mean (SD) age was 61 (10) years, 55% were female, and there were 67% intrahepatic, 22% gall bladder, and 11% extrahepatic BTCs. There were 150 (36%), 203 (49%), 27 (7%) patients with baseline ECOG scores of 0, 1, 2+, respectively. At pre-index, frequently observed conditions included non-alcoholic liver diseases (75%), hypertension (65%), dyslipidemia (48%), mental health conditions (47%), gallstones (41%), gastrointestinal disorders (39%), and obesity (32%). GEM was commonly used as monotherapy (6%) or in combinations (85%): GEM + Cisplatin (64%), GEM + Oxaliplatin (6%), GEM + Capecitabine (5%), GEM + others (10%). Median overall survival was 11.5 months. The table summarizes clinical outcomes by stage. Conclusions: Most patients with BTCs received 1L GEM-based therapies, experienced poor survival and had high hospitalization rates. These data indicate need for future innovative approaches for management of BTC.[Table: see text]

Conversion surgery for initially unresectable extrahepatic biliary tract cancer.

Backgrounds/AimsSurgical resection is the only curative treatment for biliary tract cancers; however, most patients undergo palliative chemotherapy because they are contraindicated for surgery. Conversion surgery, a treatment strategy for downsizing chemotherapy and subsequent surgical resection, is feasible for initially unresectable biliary tract cancers following the introduction of effective chemotherapeutic agents.MethodsPatients initially diagnosed with unresectable biliary tract cancers, and treated with conversion surgery after palliative chemotherapy between 2013 and 2019, were reviewed retrospectively.ResultsTwelve patients underwent conversion surgery after palliative chemotherapy for initially unresectable biliary tract cancers. The final pathological diagnosis included six perihilar cholangiocarcinomas, four distal common bile duct cancers, and two gallbladder cancers. Different chemotherapy regimens were used, but all the patients were treated with gemcitabine at some point during their treatment. The median overall survival was 28 months, which was longer than that of patients treated with isolated palliative chemotherapy in previous studies.ConclusionsConversion surgery represents a therapeutic alternative for specific cases of unresectable biliary tract cancers. Palliative chemotherapy for initially unresectable biliary tract cancers is recommended for downsizing the tumor and expanding the indications for surgery. Further studies and clinical trials are required to develop new and effective chemotherapeutic regimens.

ARID1A mutation to predict disease progression during first-line chemotherapy in biliary tract cancer patients.

4105 Background: Biliary tract cancer (BTC) is a retractable disease showing a dismal prognosis with therapeutic resistance. There are clinical unmet needs on predicting therapeutic response and precise strategy for the patient classification according to clinically relevant tumor biology in the patients with BTC. We aimed to identify clinically detectable genomic alteration predicting therapeutic response after first-line chemotherapy in BTC using real-world data. Methods: A comprehensive genomic analysis of multi-institutional cohorts of BTC cases was performed using next-generation sequencing (NGS) with targeted DNA panel and patients’ clinicopathologic data. Results: A total of 200 BTC patients with NGS panel tests from three cancer centers were included in this study. The genomic alteration of TP53 (55.5%), KRAS (23%), ARID1A (10%), and ERBB2 amplification (10%) were the most frequent alteration events in the BTC. Pathologically-proved BTC including extrahepatic (n = 52), ampulla of Vater (n = 4), gallbladder (n = 56), intrahepatic (n = 88) cancers showed a distinct pattern of genomic alterations in terms of ARID1A for extrahepatic BTC and ERBB2 amplification, RB1, ARID2 for GB cancer, and KRAS, IDH1, PBRM1, BAP1 for intrahepatic BTC respectively (chi-square test, P &lt; 0.05). The oncologic outcomes for progression-free and overall survival were significantly stratified according to the best response after the first-line chemotherapy (log-rank test, P &lt; 0.001). The logistic regression test revealed that ARID1A, BRCA2, and STK11 could significantly predict disease progression during first-line chemotherapy. ARID1A, especially, was the only independent predictive marker in the multivariate regression model in total BTC (OR 3.91, 95%CI 1.25-11.66, P = 0.015) and extrahepatic BTC (OR 5.71, 95%CI 1.23-28.98, P = 0.027). The predictive performance of significant genomic alteration was enhanced with the tumor marker CA19-9 (DeLong’s test, Z = 1.933, P = 0.053, AUC 0.73, 95%CI 0.623-0.837). Conclusions: Clinically available NGS test showed distinct genomic alterations in terms of different deterioration patterns for oncogenic molecular pathways according to the anatomic locations of BTC. Integrative analysis using the data for genomic alteration and therapeutic response for the first-line chemotherapy uncover that the patients with ARID1A mutation show a significant disease progression rate during initial treatment for BTC, especially in the extrahepatic BTC. Prospective translational studies revealing underlying biology and precision strategy should be followed to improve the therapeutic response of BTC.

Identification and prognostic impact of PBRM1 mutations in biliary tract cancers: Results of a comprehensive molecular profiling study.

4022 Background: The prognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. Polybromo-1 ( PBRM1) is a subunit of the PBF chromatin-remodeling complex and preclinical studies suggest induction of synthetic lethality by PARP inhibitors in PBRM1-mutated cancers. Therefore, we aimed to describe the molecular landscape in BTC harboring PBRM1 mutations. Methods: 1,848 BTC samples were included in this study. Specimens were analyzed using NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Pathway gene enrichment analyses were done using GSEA (Subramaniam 2015, PNAS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). Survival was calculated from time of tissue collection to last contact using Kaplan-Meier estimates. Results: PBRM1 mutations were identified in 8.1% (n = 150) of BTC tumors and were more prevalent in intrahepatic BTC (9.9%) than in gallbladder cancer (6%, p = 0.0141) and in extrahepatic BTC (4.5%, p = 0.008). In PBRM1-mutated tumors, we found a higher rate of MSI-H/dMMR (8.7% vs. 2.1%, p &lt; 0.0001) and a higher median TMB (4 vs. 3 mt/MB, p &lt; 0.0001). When compared to PBRM1-wildtype cancers higher rates of co-mutations in chromatin-remodeling genes (e.g. ARID1A, 31% vs. 16% , p &lt; 0.0001) and DNA damage repair pathway (e.g. ATRX, 4.4% vs. 0.3%, p &lt; 0.0001) were detected. Within PBRM1-mutated tumors, a significant higher frequency of infiltrating M1 macrophages was observed (p &lt; 0.0001). Gene set enrichment analysis revealed that genes associated with tumor inflammation (e.g. HLA-DRA, HLA-DRB1, IFNGR1) were enriched in PBRM1-mutated tumors (NES = 2.02, FDR = 1.3%, p &lt; 0.0001). Overall survival analysis showed that PBRM1 mutations were associated with a favorable outcome (HR 1.502, 95% CI [1.013-2.227], p = 0.041). This relationship was also present in MSS subgroup (HR: 1.667, [1.026-2.71], p = 0.037). Conclusions: This is the largest and most extensive molecular profiling study focusing on PBRM1-mutated BTC. Co-mutations in chromatin-remodelling and DNA damage repair genes might set the stage for clinical testing of PARP inhibitors in PBRM1-mutated BTC. Moreover, a distinct tumor microenvironment characterized by high M1 macrophages infiltration and an enrichment of inflammatory genes suggest a potential benefit of immunotherapy.

Epidemiologic trends and geographic distribution of patients with gallbladder and extrahepatic biliary tract cancers in Canada

BackgroundGallbladder and biliary tract cancers are rare malignancies that carry a poor prognosis. Research on their epidemiologic trends is scarce. MethodsWe performed a retrospective analysis of the data in Canada using population-based cancer registries from 1992 to 2010. The incidence and mortality of gallbladder and extrahepatic bile duct cancers were examined at the levels of provinces/territories, cities, and Forward Sortation Area (FSA) postal codes. ResultsThe incidence and mortality rates decreased over the study period. The average national incidence rate of gallbladder and biliary tract cancers was 30.92 cases per million individuals per year. Higher than average incidence rates were observed in Manitoba, Saskatchewan and Québec; there were contiguous regions with high incidence in Saskatchewan and Manitoba that suggest an area of putative case clustering. Higher incidence of gallbladder cancer was observed in women, whereas higher incidence of extrahepatic bile duct cancers was noted in men. Lower socioeconomic status and Hispanic race were found to be risk factors for gallbladder and biliary tract cancers. ConclusionThis is the first study to analyze the burden of gallbladder and biliary tract cancers in Canada. The geographic clustering trends present new avenues for research on environmental triggers.

Bacterial Gastroenteritis and the Risk of Biliary Tract Cancer: A Population-Based Study

Background: Salmonella has shown to have oncogenic transformative effects and thereby increase the risk of certain cancers. For Campylobacter, no comparable effects have been demonstrated. Risk factor identification may allow for timely diagnosis and preventive treatment. To substantiate the oncogenic potential of Salmonella, this epidemiological study compared the incidence of extrahepatic biliary tract cancer (ehBTC) in patients with diagnosed Salmonella or Campylobacter infection with the ehBTC incidence in the general population. Methods: National infectious diseases surveillance records for patients aged ≥20 years when diagnosed with Salmonella or Campylobacter infection during 1999-2016 in the Netherlands were linked to the Netherlands Cancer Registry. All infections were clinically severe infections confirmed by laboratory testing. Incidence of ehBTC in Salmonella and Campylobacter patients ≥1 year post-infection was compared to the incidence of ehBTC in the Dutch general population using Standardized Incidence Ratios (SIRs). Results: 16.252 patients were diagnosed with Salmonella and 27.668 with Campylobacter infection. Of those, nine developed ehBTC at a median of 46 months (range 13-67) after Salmonella infection and seven at median 60 months (range 18-138) after Campylobacter infection. Compared to the general population, the SIR of ehBTC in Salmonella patients was 1.53 (95%CI 0.70-2.91). In patients aged < 60 years, SIR was 1.74 (95%CI 0.36-5.04). For Campylobacter patients, SIR was 0.97 (95%CI 0.39-2.00). Conclusion: Although statistical significance was not reached, there was a tendency towards increased occurrence of ehBTC among salmonellosis patients, but not among campylobacteriosis patients. Further research is necessary to uncover putative oncogenic transformative effects of other enteropathogens.Tabled 1PB06-05: Incidence of biliary tract cancer in patients ≥1 year after confirmed infection with Salmonella or Campylobacter, stratified by age and genderObserved incidenceExpected incidenceSIR95% CIP-valueSalmonella, all patients95.881.530.70-2.910.28020-6031.741.720.36-5.040.507Male52.6651.880.61-4.380.264Female43.291.220.33-3.110.835Campylo-bacter, all patients77.220.970.39-2.000.86820-6022.130.940.11-3.400.715Male34.030.750.15-2.180.857Female42.231.240.34-3.170.810 Open table in a new tab

Severe Salmonella spp. or Campylobacter spp. Infection and the Risk of Biliary Tract Cancer: A Population-Based Study.

Simple SummaryAlthough it is known that bacterial infection may increase risk of cancer, the relationship between certain infections and cancer remains ill-quantified. To identify potential risk factors, this study compared the incidence of biliary tract cancer (BTC) in patients with Salmonella spp. or Campylobacter spp. infection to the general population in a large Western cohort of 16,252 salmonellosis and 27,668 campylobacteriosis patients. Standardized relative incidence ratio for BTC was 1.53 (95% CI 0.70–2.91) in salmonellosis patients and 0.97 (95% CI 0.39–2.00) in campylobacteriosis patients. Patients with Salmonella spp. infection and BTC were significantly younger than BTC patients without Salmonella spp. infection. Potentially, the study was underpowered to detect differences in cancer incidence, or cancer etiology in Western patients differs from those in non-Western countries and instead of bacterial infection, other factors contribute to cancer risk. Better understanding of cancer etiology is needed to identify risk factors and facilitate screening and early detection of cancer patients.Salmonella spp. infection has shown to have oncogenic transformative effects and thereby increases the risk of certain cancers. For Campylobacter spp., similar effects have been demonstrated. Risk factor identification may allow for timely diagnosis and preventive treatment. To substantiate the oncogenic potential of Salmonella and Campylobacter spp., this study compared the incidence of extrahepatic biliary tract cancer (BTC) in patients with diagnosed Salmonella or Campylobacter spp. infection with BTC incidence in the Netherlands. National infectious diseases surveillance records of patients diagnosed with a laboratory-confirmed Salmonella or Campylobacter spp. infection during 1999–2016 were linked to the Netherlands Cancer Registry. Incidence of BTC in Salmonella and Campylobacter spp. patients was compared to the incidence of BTC in the general population using Standardized Incidence Ratios (SIRs). In total, 16,252 patients were diagnosed with Salmonella spp. and 27,668 with Campylobacter spp. infection. Nine patients developed BTC at a median of 46 months (13–67) after Salmonella spp. infection and seven at a median of 60 months (18–138) after Campylobacter spp. infection. SIR of BTC in salmonellosis patients was 1.53 (95% CI 0.70–2.91). In patients aged <60 years, the SIR was 1.74 (95% CI 0.36–5.04). For campylobacteriosis patients, the SIR was 0.97 (95% CI 0.39–2.00). Even though Salmonella or Campylobacter spp. infection was not significantly associated with increased BTC risk in this cohort, it remains extremely important to study potential risk factors for cancer to facilitate screening and ultimately improve prognosis of cancer patients.

Survival of older patients with advanced biliary tract cancers by disease site.

e16598 Background: Biliary tract cancers (BTC) arise from the epithelial lining of the biliary tree and include intrahepatic and extrahepatic cholangiocarcinoma, gallbladder cancer, and sometimes cancer of the ampulla of Vater. Although this is a closely related group of diseases, comparisons of risk factors, treatment, and mortality by disease site are limited. Methods: This retrospective cohort study used Surveillance, Epidemiology, and End Results (SEER) cancer registry data linked with Medicare claims. Patients aged ≥66 years with a pathologically confirmed diagnosis of advanced (stage III or IV) BTC from 2010 to 2015 were included and followed up through 2016. Patients with any SEER-reported cancer in the prior 2 years were excluded. Any outpatient systemic treatment during follow-up was identified using Medicare claims. Patients were followed up until death, end of follow-up, subsequent primary cancer, or switch to managed care. The Kaplan-Meier estimator was used to estimate unadjusted median survival. A Cox proportional hazards model was used to identify factors associated with survival. Results: There were 2,891 patients in the cohort (Table). Factors significantly associated with worse survival included older age, presence of mobility limitations, living in an area with &gt; 30% of the people below poverty, higher comorbidity burden, and stage IV BTC (vs stage III). Factors significantly associated with better survival included history of cancer, intrahepatic BTC (vs extrahepatic), or ampulla of Vater BTC (vs extrahepatic). Conclusions: Survival in BTC is poor and many patients do not receive outpatient systemic therapy. Patients with gallbladder and extrahepatic BTC had worse median survival and were less likely to receive systemic therapy than those with intrahepatic or ampulla of Vater BTC. Fewer ampulla of Vater patients present with Stage IV disease which could be a contributing factor to the significantly longer survival. Prior work has demonstrated an association between history of some types of cancer and survival; additional research is needed to better understand this finding. [Table: see text]