KRAS mutations disrupt interactions between CD8+ T cells and antigen-presenting cells in the tumor microenvironment of biliary tract cancer.

Proteomic and single-cell landscape reveals novel pathogenic mechanisms of HBV-infected intrahepatic cholangiocarcinoma

BackgroundAlthough 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.MethodsThe inclusion criteria were as follows: histologically proven BTC, Eastern Cooperative Oncology Group (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).ResultsForty-six 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 temporary 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 more than 3 courses of S-1, only one patient discontinued because of adverse events.ConclusionsOne-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 registrationUMIN-CTR, UMIN000009029. Registered 5 October 2012-Retrospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009347

Introduction: Although the safety of biliary tract cancer resection has improved over the years, the recurrence rate is still high, and the postoperative prognosis remains low after biliary tract cancer resection. Therefore, the development of effective adjuvant therapy is essential to improve treatment outcomes. Because biliary tract cancer is rare compared with other gastrointestinal cancers, there have been only a small number of clinical trials of adjuvant therapy. However, in recent years, the results of several large-scale randomized controlled trials have been published, and clinical trials investigating the efficacy of new regimens are currently ongoing. Areas covered: This review presents the results of previously published important phase II and III clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer and discusses their interpretation. The future direction of new research on resectable biliary tract cancer treatment is also discussed. Expert opinion: The foundations of large-scale clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer are underway, and new trials will establish evidence of their effectiveness. Additionally, breakthroughs in treatment through genetic and molecular research are expected.

Ultrasensitive Detection of KRAS2 Mutations in Bile and Serum from Patients with Biliary Tract Carcinoma Using LigAmp Technology

Purpose: Biliary tract cancers (BTCs), including intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC), are rare malignancies which frequently present at advanced stage and have a poor survival. Incorporation of next-generation sequencing into clinical care has provided an avenue for the development of targeted therapies in BTCs which are rich in actionable mutations. However, clinically relevant models for BTC are limited, representing a major challenge in the field. We sought to develop a catalog of BTC patient-derived xenograft (PDX) models and representing diverse molecular profiles to create a resource for the modeling of precision oncology. Methods: Tumor tissue from surgical specimens or image-guided biopsies was collected from consenting patients at MD Anderson Cancer Center with histologically-confirmed BTCs for PDX development. Tumor fragments were implanted in the flank of NSG mice and passaged into nude mice. Whole-exome sequencing (WES) was performed on tumors from early-passage (P1-P2) PDXs and matching patient blood to determine somatic mutations/indels and copy number variations. Functional alterations in cancer-related genes that are targetable directly or indirectly with approved or investigational agents were considered “actionable”. Results: Samples were obtained from 97 patients undergoing image-guided biopsy (86/97, 89%) or surgical resection (11/97, 11%). Out of 97 tumors implanted, 33 (34%) PDXs from 30 patients were successfully established: 74% (24/33) ICC, 15% (5/33) ECC, and 12% (4/33) GBC. Relative take rates for PDX development were 34% (29/86) for those developed from biopsy samples and 36% (4/11) for those developed from surgical samples. In two patients, multiple PDXs were developed from biopsies at different time points during their care. WES demonstrated that the PDXs captured several key actionable alterations including alterations in ERRB2, FGFR2, IDH1, ATM, PIK3CA, PTEN and KRAS. Conclusion: Here, we describe a unique collection of clinically and molecularly annotated BTC PDX models which reflect the genomic heterogeneity present in ICC, ECC, and GBC. WES of early-passage PDXs provides evidence that these models capture the variety of actionable alterations harbored in the parental tumor and may enable the development of novel, biomarker-driven treatment strategies and rational combination therapies. To date, this is one of the largest collections of BTC PDX models available and will serve as an invaluable resource to guide the development of personalized treatments for patients with these aggressive malignancies. Citation Format: Timothy Philip DiPeri, Kurt W. Evans, Ching-Wei D. Tzeng, Lawrence Kwong, Michael P. Kahle, Xiaofeng Zheng, Dali Li, Hop S. Tran Cao, Thuy Vu, Sunhee Kim, Fei Su, Bryce Kirby, Chetna Wathoo, Gabriela Raso, Yasmin Rizvi, Huamin Wang, Filip Janku, Kenna Shaw, Timothy Yap, Milind Javle, Jordi Rodon, Funda Meric-Bernstam. The MD Anderson patient-derived xenograft series for modeling precision oncology in biliary tract cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2710.

Cancer originating in the biliary tract can be classified as bile duct cancer (cholangiocarcinoma), gallbladder cancer, or ampullary cancer. Bile duct cancer is further divided to intrahepatic, perihilar and distal bile duct subtypes according to the anatomical location of the tumor. The biological characteristics of each tumor are heterogeneous. However, because of the rarity of each disease, the efficacy of new drugs has been tested in groups of patients with different biliary tract cancers. In patients with metastatic or recurrent biliary tract cancer, recent randomized clinical trials revealed the non-inferiority of gemcitabine + S-1 and the superiority of gemcitabine + cisplatin + S-1 compared with gemcitabine + cisplatin in terms of overall survival, thereby establishing a new standard treatment. In the field of adjuvant therapy for biliary tract cancer, the British BILCAP (capecitabine compared with observation in resected biliary tract cancer) study revealed longer median overall survival in the capecitabine group than in the observation group in the per-protocol analysis (but not in the intention-to-treat analysis), bringing a shift toward postoperative management. Several other studies of adjuvant therapy are ongoing, and they may lead to reforms in treatment strategy for resectable biliary tract cancer in the future. The use of neoadjuvant therapy for biliary tract cancer is in its infancy, but it is expected to overcome the limitations of adjuvant therapy for this malignancy. In this review, we summarized the evidence available from clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer and described ongoing clinical trials.

It is necessary to establish effective chemotherapy to improve the survival of patients with biliary tract cancer, because most of these patients are unsuitable candidates for surgery, and even patients undergoing curative surgery often have recurrence. Recently, the combination of cisplatin plus gemcitabine was reported to show survival benefits over gemcitabine alone in randomized clinical trials conducted in the United Kingdom and Japan. Thus, the combination of cisplatin plus gemcitabine is now recognized as the standard therapy for unresectable biliary tract cancer. One of the next issues that need to be addressed is whether molecular targeted agents might also be effective against biliary tract cancer. Although some targeted agents have been investigated as monotherapy for first-line chemotherapy, none were found to exert satisfactory efficacy. On the other hand, monoclonal antibodies such as bevacizumab and cetuximab have also been investigated in combination with a gemcitabine-based regimen and have been demonstrated to show promising activity. Furthermore, clinical trials using new targeted agents for biliary tract cancer are also proposed. This cancer is a relatively rare and heterogeneous tumor consisting of cholangiocarcinoma and gallbladder carcinoma. Therefore, a large randomized clinical trial is necessary to confirm the efficacy of chemotherapy, and international collaboration is important.

Genetic Alteration of Keap1 Confers Constitutive Nrf2 Activation and Resistance to Chemotherapy in Gallbladder Cancer

Biliary tract cancers (BTCs), which encompass intra- and extrahepatic cholangiocarcinomas as well as gallbladder carcinomas, are a genetically diverse collection of cancers. Most patients with BTC will present with unresectable or metastatic disease. Although the standard systemic chemotherapy approaches are emerging, the prognosis remains poor. Development of molecularly targeted therapies in advanced BTC remains challenging. Recent early-stage clinical trials with targeted therapies appear promising, although the relationships between subsets of patients with positive responses to therapy and tumor genetics remain unexplored. Here we summarize the relevant molecular pathogenesis, recent and ongoing clinical trials with targeted agents, and the key issues in clinical trial design in BTC.

599 Background: Biliary tract cancers (BTC) are a rare type of gastrointestinal malignancy, often presenting in advanced stages and associated with a dismal prognosis. BTC are frequently resistant to conventional chemotherapy, with novel targeted therapies playing a pivotal role in overcoming this challenge. HER2 has recently emerged as an important actionable target in patients with BTC. We aim to evaluate the efficacy and safety of HER2 -directed monoclonal antibodies (MOAs), bispecific antibodies, antibody-drug conjugates (ADCs), and their combinations in BTC. Methods: A systematic literature search was conducted on PubMed, Embase, and Cochrane Central Register of Controlled Trials for clinical trials investigating HER2 -directed MOAs, bispecific antibodies, ADCs, and their combinations in BTC. The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. A random effects model was used to pool the outcomes along with 95% confidence intervals (CI). Statistical analyses were performed using program R version 4.4.1. Results: We included 12 clinical trials with three Phase I and nine Phase II trials. The pooled ORR (objective/overall response rate) was 35.5% (95% CI: 26.2-45.3, I 2 : 69%), and the DCR (disease control rate) was 72.2% (95% CI: 65.3-78.8, I 2 : 37%). The median follow-up period for DCR was four months. Trastuzumab, in combination with gemcitabine-cisplatin as first-line therapy, had the highest median progression-free survival of 7 months (95% CI: 6.2-7.8), whereas the combination of trastuzumab and tucatinib had the longest median overall survival 15.5 months (90% CI: 6.5-16.7) reported. The most common treatment-related ≥grade 3 adverse events reported across the cohort were anemia and neutropenia. Three cases of confirmed grade 5 interstitial lung disease were reported in patients who received trastuzumab deruxtecan. Clinical trials included in this study are summarized in the table. Conclusions: Advances in precision oncology and the emergence of novel targeted therapies have revolutionized cancer management. HER2 -directed therapies have shown promising results for patients inflicted with BTC having HER2 alterations in the early phase clinical trials. Further larger studies are awaited to explore the efficacy of HER2 -directed therapies in BTC. Clinical trials of HER2 -directed therapies in BTC. HER2-directed therapy Number of clinical trials Total number of BTC participants ORR, in % (95% CI) DCR, in % (95% CI) Trastuzumab + chemo 2 124 43.2 (19.4-68.8) 80 (72.3-86.7) Trastuzumab + pertuzumab 2 45 20.9 (9.1-35.3) 53.4 (37.8-68.8) Trastuzumab deruxtecan 4 84 27.2 (6.9-52.6) 71.9 (58.4-84) Trastuzumab + tucatinib 1 30 46.7 (28.5-65.5) 76.7 (57.7-89.7) Zanidatamab 2 101 40.5 (30.9-50.4) 67.6 (57.9-76.6) SHR-A1811 1 16 56.3 (29.9-80.2) 81.3 (54.4-96)

Background: BTCs are an uncommon malignancy with poor prognosis. ADCs have efficacy in several solid tumors with antigen surface expression serving as a potential biomarker in some instances. Herein, we evaluate the protein expression and heterogeneity of ADC target antigens and their prognostic implications in BTC. Methods: Utilizing an IRB-approved, retrospective biospecimen protocol, we constructed tissue microarrays (TMA) from resected, early staged intrahepatic cholangiocarcinoma (IHC), extrahepatic cholangiocarcinoma (EHC) and gallbladder cancer (GB). IHC for Nectin-4, TROP2, c-MET, CLDN18.2 was assessed. Positivity defined as ≥10% weakly stained tumor cells and quantified by H-score (intensity × percentage). HER2 IHC scored per standard colon criteria. Clinicopathological factors and outcomes were associated with ADC target expression. Results: N=65 resected cases were selected (median age 72 years (range 36-92); 55% males, anatomical subtype 40% IHC, 43% EHC, 17% GB; 84% moderately differentiated adenocarcinoma. c-MET and TROP2 were expressed in 75% and 83% of cases with differential expression based on anatomic site (c-MET: IHC: 62%, EHC: 89% vs GB: 73%, p=0.049; TROP2: IHC: 65%, EHC: 93% vs GB: 100%, p=0.010, Table). HER2, CLDN18.2, and Nectin-4 were expressed in 7.7%, 46%, and 66% of cases, and did not differ based on anatomic site. Median RFS and OS were 20 (95%CI 10-NR) and 40 (95%CI 27-NR) months respectively and outcomes were not impacted by expression of HER2, Nectin-4, TROP2, c-MET, or CLDN18.2. Conclusion: Modest to high expression of Nectin-4, TROP2, c-MET and CLDN18.2 was identified across BTC anatomic subtypes, suggesting a potential role for ADCs to these antigens in patients with BTC. Preclinical validation is ongoing in BTC patient derived xenografts with trastuzumab deruxtecan (HER2 sensitive and HER2 resistant models), enfortumab vendotin (Nectin-4 positive model), and sacituzumab govitecan and these results will be presented at the meeting. Citation Format: Aruj Dhyani, Zeynep Tarcan, Joanne Chou, Rohit Thummalapalli, Walid Chatila, Sharanya Nag, Ezra Rosen, Sydney Bowker, Wungki Park, Elisa De Stanchina, Sarat Chandarlapaty, David Solit, William Jarnagin, Marinela Capanu, Eileen M O'Reilly, Ghassan K Abou-Alfa, Olca Basturk, James Harding. Target identification for antibody-drug-conjugate (ADC) therapy in biliary tract cancers (BTC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 724.

Simple SummaryA new era has emerged in oncology in the last ten years with the development of immune therapies. However, single-agent immune therapy such as immune checkpoint inhibitors seems to have a limited clinical activity in biliary tract cancers and are still largely investigational, except for the few patients with microsatellite-instable tumors. Here, we review: (i) the molecular and immune landscape of biliary tract cancers, (ii) the existing results of immune therapies in biliary tract cancers, and (iii) the future of immune therapies in biliary tract cancers, with the identification of predictive biomarkers for response to these therapies, and the ongoing therapeutic trials.Biliary tract cancers are rare tumors with a poor prognosis. Two-thirds of these primary liver malignancies are diagnosed at advanced stages where therapeutic options are limited. Whereas several molecular targeted therapies emerge in biliary tract cancers, immunotherapy is still investigational, the only approved immunotherapy to date being the immune checkpoint inhibitor pembrolizumab for the small fraction of patients with microsatellite-instable tumors. In microsatellite-stable, pre-treated biliary tract cancers, single-agent immune checkpoint blockade has a limited albeit often long-lasting clinical activity in a still ill-defined subgroup of patients. The identification of predictive biomarkers will allow a better selection of patients that may benefit from immunotherapy. Combinations of immunotherapies with each other, with chemotherapy or targeted molecular therapies are being investigated in early lines of therapy, including first-line.

With a 15% incidence, KRAS is one of the most common mutations in biliary tract cancer (BTC) and is a poor prognostic factor. Immune checkpoint inhibitors (ICIs) as salvage therapy have modest activity in BTC. There are limited data on the efficacy of ICIs according to KRAS mutation in BTC. We evaluated the efficacy of ICIs in BTC patients with or without KRAS mutations. Retrospective observational study. We conducted molecular profiling in BTC patients who received ICIs as salvage therapy. The expression of programmed death ligand 1 (PD-L1) on tumor cells was assessed using immunohistochemistry. The TruSightTM Oncology 500 assay from Illumina was used as a cancer panel. We analyzed overall survival (OS) and progression-free survival (PFS) of ICI in BTC patients according to KRAS mutation and PD-L1 expression. A total of 62 patients were included in this analysis. The median age was 68.0 years; 47 patients (75.8%) received pembrolizumab and 15 (24.2%) received nivolumab as salvage therapy. All patients received gemcitabine plus cisplatin as the frontline therapy, and 53.2% received fluoropyrimidine plus oxaliplatin (FOLFOX) before ICI. The median number of lines of prior chemotherapy was 2.5. The KRAS mutation was found in 13 patients (19.1%), and 28 patients (45.2%) showed 1% or more of tumor cells out of visible tumor cells positive for PD-L1. There was no statistical correlation between KRAS mutation and PD-L1 expression. The median OS and PFS with ICI were 5.6 [interquartile range (IQR): 3.3-8.0] and 3.8 (IQR: 3.0-4.5) months, respectively. There were no statistically significant differences in PFS with ICIs according to KRAS mutation (mutant type versus wild type) and PD-L1 expression (positive versus negative). In subgroup analysis, patients with both KRAS mutation and PD-L1 positivity had longer PFS compared with patients with KRAS mutation and PD-L1 negativity (10.1 versus 2.6 months, p = 0.047). This finding was not shown in patients with wild-type KRAS. Our analysis suggested that PD-L1 expression might be a useful biomarker for ICIs in BTC patients with KRAS mutation but not in those with wild-type KRAS.

Introduction: Biliary tract cancers (BTCs) constitute a heterogeneous group of poor-prognosis solid tumors with limited treatment options. In the last decade, global efforts have tried to identify therapeutic targets by genomic profiling of BTC, unveiling several genetic aberrations that could play a prognostic and/or a predictive role in these malignancies. Areas covered: In this review, we will present an overview regarding the role of HER2 targeted therapies in BTC, with a particular focus on clinical studies carried out in this field to date and ongoing trials. A literature search was conducted in August 2020 of Pubmed/Medline, Cochrane library and Scopus databases for published preclinical and clinical studies; moreover, abstract of international cancer meetings (AACR, ASCO, and ESMO) were reviewed. Expert opinion: Despite recent advances in medical oncology, the overall survival of BTC patients remains low and there is an urgent need for novel and more effective treatments. Although HER2 blockade has been suggested to induce durable tumor responses in selected subjects with BTC, controversial results have been reported so far and data from ongoing prospective clinical trials are awaited to further clarify the role of anti-HER2 therapies in BTC.

Biliary tract cancers (BTCs) are heterogeneous cancers that include cancers of the bile duct and gallbladder. Although they are relatively uncommon, most patients with BTC are diagnosed at advanced-stage disease with high mortality rates. Recently, systemic therapy options for patients with BTC have evolved. This paper reviews recent advancements in systemic therapy and the results of key clinical trials in BTC. A literature search in PubMed and Google Scholar was performed using keywords related to BTC and systemic therapy. Studies that were presented in major international cancer research conferences were also included. The evidence shows that adjuvant capecitabine has been associated with a lower relapse rate in early-stage BTC. In unselected patients with advanced BTC, combination chemotherapy is a standard treatment option. However, with a better understanding of the molecular profile of BTC, there has been a shift toward targeted agents in BTC that have shown promising responses. The evolving data also support the evolving role of immunotherapy in patients with deficient DNA mismatch repair or PD-L1-positive BTC. Systemic treatment options for BTC have improved. The future identification of new targets, novel compounds, and predictive markers is a key step toward the use of personalized medicine in BTC.