Project description:Intrahepatic cholangiocarcinoma is an aggressive, often fatal, malignancy that arises from the bile ducts. As it often presents with metastatic disease, surgery has limited utility. However, in some cases, neoadjuvant chemotherapy has provided the necessary reduction in tumor burden to allow for adequate resection. Consequently, new advances in neoadjuvant chemoradiation and targeted therapy are of interest with numerous case reports and small series published routinely; it is challenging to present a large case series or study given the overall rare frequency with which this malignancy is seen. Herein, we aim to summarize the newest advances in both neoadjuvant chemotherapy and targeted immunotherapy.
Project description:Intrahepatic cholangiocarcinoma (CC) accounts for approximately 20% of all biliary tract cancer (BTC) cases and 10-15% of all primary liver cancer cases. Many patients are diagnosed with unresectable BTC, and, even among patients with resectable BTC, the 5-year survival rate is approximately 20%. The BTC incidence rate is high in Southeast and East Asia and has increased worldwide in recent years. Since 2010, cytotoxic chemotherapy, particularly combination gemcitabine + cisplatin (ABC-02 trial), has been the first-line therapy for patients with BTC. In 2022, a multicenter, double-blind, randomized phase 3 trial (TOPAZ-1 trial) examined the addition of programmed death-ligand 1 immunotherapy (durvalumab) to combination gemcitabine + cisplatin for BTC treatment, resulting in significantly improved survival without notable additional toxicity. As a result of this trial, this three-drug combination has become the new standard first-line therapy, leading to notable advances in BTC management for the first time since 2010. The molecular profiling of BTC has continued to drive the development of new targeted therapies for use when first-line therapies fail. Typically, second-line therapy decisions are based on identified genomic alterations in tumor tissue. Mutations in fibroblast growth factor receptor 1/2/3, isocitrate dehydrogenase 1/2, and neurotrophic tyrosine receptor kinase A/B/C are relatively frequent in intrahepatic CC, and precision medicines are available that can target associated pathways. In this review, we suggest strategies for systemic pharmacotherapy with a focus on intrahepatic CC, in addition to presenting the results and safety outcomes of clinical trials evaluating immune checkpoint inhibitor therapies in BTC.
Project description:Intrahepatic cholangiocarcinoma (iCCA) is a treatment-refractory primary liver cancer with an increasing incidence and mortality worldwide in recent years. Lack of a stereotyped genetic signature and limited understanding of genomic landscape make the development of effective targeted therapies challenging. Recent application of advanced technologies such as next-generation sequencing (NGS) has broadened our understanding of genetic heterogeneity in iCCA and many potentially actionable genetic alterations have been identified. This review explores the recent advances in defining genetic alterations in iCCAs, which may present potent therapeutic targets. Chromatin remodeling genes and genes encoding isocitrate dehydrogenase and tyrosine kinase receptors as well as their downstream effectors are among the most frequently altered genes. Clinical trials testing the effect of new targeted agents on iCCA patients, especially those with the above genetic markers are under way. However, the complex interplay of environmental and evolutionary factors contributing to the genetic variability in iCCA calls for a more cautionary use of NGS in tailoring targeted regimen to the patients. Next-generation functional testing may complement NGS to execute precision medicine in future.
Project description:ImportanceBRAF variants are associated with tumor progression; however, the prevalence of BRAF variant subtypes and their association with disease characteristics, prognosis, and targeted therapy response in patients with intrahepatic cholangiocarcinoma (ICC) are largely unknown.ObjectiveTo explore the association of BRAF variant subtypes with disease characteristics, prognosis, and targeted therapy response in patients with ICC.Design, setting, and participantsIn this cohort study, 1175 patients who underwent curative resection for ICC from January 1, 2009, through December 31, 2017, were evaluated at a single hospital in China. Whole-exome sequencing, targeted sequencing, and Sanger sequencing were performed to identify BRAF variants. The Kaplan-Meier method and log-rank test were used to compare overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analyses were performed using Cox proportional hazards regression. Associations between BRAF variants and targeted therapy response were tested in 6 BRAF-variant, patient-derived organoid lines and in 3 of the patient donors of those lines. Data were analyzed from June 1, 2021, to March 15, 2022.InterventionsHepatectomy in patients with ICC.Main outcomes and measuresThe association of BRAF variant subtypes with OS and DFS.ResultsOf 1175 patients with ICC, the mean (SD) age was 59.4 (10.4) years and 701 (59.7%) were men. A total of 20 different subtypes of BRAF somatic variance affecting 49 patients (4.2%) were identified; V600E was the most frequent allele in this cohort, accounting for 27% of the identified BRAF variants, followed by K601E (14%), D594G (12%), and N581S (6%). Compared with patients with non-V600E BRAF variants, patients with BRAF V600E variants were more likely to have large tumor size (10 of 13 [77%] vs 12 of 36 [33%]; P = .007), multiple tumors (7 of 13 [54%] vs 8 of 36 [22%]; P = .04), and more vascular/bile duct invasion (7 of 13 [54%] vs 8 of 36 [22%]; P = .04). Multivariate analysis revealed that BRAF V600E variants, but not overall BRAF variants or non-V600E BRAF variants, were associated with poor OS (hazard ratio [HR], 1.87; 95% CI, 1.05-3.33; P = .03) and DFS (HR, 1.66; 95% CI, 1.03-2.97; P = .04). There were also broad differences among organoids with different BRAF variant subtypes in sensitivity to BRAF or MEK inhibitors.Conclusions and relevanceThe findings of this cohort study suggest that there are broad differences among organoids with different BRAF variant subtypes in sensitivity to BRAF or MEK inhibitors. Identifying and classifying BRAF variants may be able to help guide precise treatment for patients with ICC.
Project description:Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and causes major economic and health burdens throughout the world. Although the incidence of ICC is relatively low, an upward trend has been seen over the past few decades. Owing to the lack of specific manifestations and tools for early diagnosis, most ICC patients have relatively advanced disease at diagnosis. Thus, neoadjuvant therapy is necessary to evaluate tumor biology and downstage these patients so that appropriate candidates can be selected for radical liver resection. However, even after radical resection, the recurrence rate is relatively high and is a main cause leading to death after surgery, which makes adjuvant therapy necessary. Because of its low incidence, studies in both neoadjuvant and adjuvant settings of ICC are lagging compared with other types of malignancy. While standard neoadjuvant and adjuvant regimens are not available in the current guidelines due to a lack of high-level evidence, some progress has been achieved in recent years. In this review, the available literature on advances in neoadjuvant and adjuvant strategies in ICC are evaluated, and possible challenges and opportunities for clinical and translational investigations in the near future are discussed.
Project description:Presentation of the Case A 37-year-old woman presented at 35 weeks of gestation with her third child with failure to adequately gain weight and was noted by her obstetrician to have delay in the growth of her baby. Ultrasound of the abdomen incidentally revealed the presence of a liver lesion. After additional evaluation, she ultimately delivered her daughter at 36 weeks uneventfully. She subsequently underwent additional evaluation. Liver magnetic resonance imaging (MRI) revealed a 5-cm solitary solid mass in segment 4A of the liver, concerning for malignancy. Serum α-fetoprotein, carcinoembryonic antigen, cancer antigen (CA)19-9, CA15-3, and CA125 were all normal. Liver biopsy was positive for adenocarcinoma. The tumor cells demonstrated a phenotype suggesting a possible breast primary, although the immunohistochemistry did not support that diagnosis and the tumor was negative for mammaglobin, gross cystic disease fluid protein (GCDFP)-15, estrogen receptor (ER), and progesterone receptor (PR) (Table 1). The tumor was also CDX2 and cardiotrophin-1 negative, but cytokeratin (CK) 19 positive. Her endoscopic retrograde cholangiopancreatography, upper endoscopy, colonoscopy, breast mammogram, and breast MRI were completely normal. A positron emission tomography-computed tomography scan showed a fluorodeoxyglucose-avid 5.8-cm × 6.0-cm hypoattenuating lesion with peripheral enhancement involving segment 4 and segment 8 at the dome. In addition, central necrosis within the lesion was noted. The left main portal vein was mildly attenuated by the mass. She eventually underwent a left hepatectomy en bloc with caudate resection, portal lymphadenectomy, cholecystectomy, and omental pedicle flap. On exploration of the abdomen, no additional disease was noted. The final pathology revealed a 9.4-cm moderately to poorly differentiated adenocarcinoma of the intrahepatic bile ducts. Venous invasion was present. Perineural invasion was absent. The margins were negative. Thirteen lymph nodes were obtained, all of which were negative, consistent with a stage T2, N0, MX intrahepatic cholangiocarcinoma. The tumor was positive for CK7, CK19, and CA19-9 and negative for CK20, CDX2, CA125, ER, PR, GCDFP-15, synaptophysin, and chromogranin (Table 1). The uninvolved liver was unremarkable and a trichrome stain showed no fibrosis. Following an uneventful postoperative recovery, she was referred for consideration of adjuvant therapy.
Project description:Although rare, intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy and the incidence of ICC has increased 14% per year in recent decades. Treatment of ICC remains difficult as most people present with advanced disease not amenable to curative-intent surgical resection. Even among patients with operable disease, margin-negative surgical resection can be difficult to achieve and the incidence of recurrence remains high. As such, there has been considerable interest in systemic chemotherapy and targeted therapy for ICC. Over the last decade, the understanding of the molecular and genetic foundations of ICC has reshaped treatment approaches and strategies. Next-generation sequencing has revealed that most ICC tumors have at least one targetable mutation. These advancements have led to multiple clinical trials to examine the safety and efficacy of novel therapeutics that target tumor-specific molecular and genetic aberrations. While these advancements have demonstrated survival benefit in early phase clinical trials, continued investigation in randomized larger-scale trials is needed to further define the potential clinical impact of such therapy.
Project description:BackgroundIntrahepatic cholangiocarcinoma (iCCA) is the second most common hepatic malignancy and has a poor prognosis. Surgical resection is the standard of care for patients with resectable disease, representing 30-40% of cases. Increasingly, neoadjuvant systemic therapy is being utilized in patients due to high-risk anatomic or biologic considerations. However, data on the clinical effect of this approach are limited. We performed a cohort study to evaluate the effect of neoadjuvant therapy in patients with oncologically high-risk iCCA.MethodsiCCA patients (n = 181) between the years 2014-2020 were reviewed for clinical, histopathologic, treatment, and outcome-related data. Tumor regression grade was scored per CAP criteria for gastrointestinal carcinomas.Results47 iCCA patients received neoadjuvant therapy and 72 did not. Neoadjuvant treatment led to objective response and tumor regression by CAP score. After adjustment for age, clinical stage, and tumor size, the outcomes of patients who had neoadjuvant therapy followed by surgery were not significantly different from those patients who had surgery first.DiscussionIn conclusion, neoadjuvant therapy in iCCA facilitated surgical care. The progression-free and overall survival for surgical patients with and without neoadjuvant therapy were not significantly different suggesting this approach needs further exploration as an effective treatment paradigm.
Project description:Intrahepatic cholangiocarcinoma (iCCA) is a malignant neoplasm of the biliary tract, the incidence of which has increased in recent years. The etiopathogenesis is not fully elucidated, but the greatest association has been shown with inflammatory changes within the biliary tract. Surgical treatment is the main therapeutic modality; however, less than 30% of its are resectable at diagnosis, with the majority of patients requiring systemic treatment. Chemotherapy with capecitabine is the standard adjuvant therapy. For patients with inoperable tumors or metastatic lesions, chemotherapy alone or in combination with immunotherapy (durvalumab, pembrolizumab) is used. There is a need to provide systemic treatment in patients with progression after first-line treatment in good performance status. New therapeutic pathways for the treatment of this tumor type are still being identified with new emerging potential targets such as isocitrate dehydrogenase (IDH), fibroblast growth factor receptor 2 (FGFR2), or BRAF mutation.