Hepatocellular Carcinoma Diagnosis and Management in 2021: A National Veterans Affairs Quality Improvement Project.

BACKGROUND & AIMS: The coronavirus disease-2019 pandemic profoundly disrupted preventative health care services including cancer screening. As the largest provider of cirrhosis care in the United States, the Department of Veterans Affairs (VA) National Gastroenterology and Hepatology Program aimed to assess factors associated with hepatocellular carcinoma (HCC) stage at diagnosis, treatment, and survival. METHODS: Veterans with a new diagnosis of HCC in 2021 were identified from electronic health records (N = 2306). Structured medical record extraction was performed by expert reviewers in a 10% random subsample of Veterans with new HCC diagnoses. Factors associated with stage at diagnosis, receipt of treatment, and survival were assessed using multivariable models. RESULTS: Among 199 patients with confirmed HCC, the average age was 71 years and most (72%) had underlying cirrhosis. More than half (54%) were at an early stage (T1 or T2) at diagnosis. Less-advanced liver disease, number of imaging tests adequate for HCC screening, HCC diagnosis in the VA, and receipt of VA primary care were associated significantly with early stage diagnosis. HCC-directed treatments were administered to 145 (73%) patients after a median of 37 days (interquartile range, 19-54 d) from diagnosis, including 70 (35%) patients who received potentially curative treatments. Factors associated with potentially curative (vs no) treatments included HCC screening, early stage at diagnosis, and better performance status. Having fewer comorbidities and better performance status were associated significantly with noncurative (vs no) treatment. Early stage diagnosis, diagnosis in the VA system, and receipt of curative treatment were associated significantly with survival. CONCLUSIONS: These results highlight the importance of HCC screening and engagement in care for HCC diagnosis, treatment, and survival while demonstrating the feasibility of developing a national quality improvement agenda for HCC screening, diagnosis, and treatment.

Clinical Characteristics and Adverse Impact of Hepatotoxicity due to Immune Checkpoint Inhibitors.

INTRODUCTION: We conducted this study to characterize the incidence, clinical features, treatment, and outcomes of immune checkpoint inhibitor (ICI) hepatotoxicity. METHODS: Patients who received ICIs (with either single-agent or combination regimens) from January 1, 2010, to March 31, 2018, were identified. Hepatotoxicity was defined as alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN), in the absence of an alternate cause, and categorized as grade 3 (ALT 5-20× ULN) or grade 4 (ALT >20× ULN), according to Common Terminology Criteria for Adverse Events 4.03. RESULTS: Among 5,762 patients, 100 (2%) developed hepatotoxicity, occurring in a higher proportion of recipients of combination therapy (9.2%) compared with monotherapy (up to 1.7%, P < 0.001). ICIs were discontinued permanently in 69 and temporarily in 31 patients. Sixty-seven patients received steroids, 10 of whom (14%) had recurrent hepatotoxicity after the steroid taper. Thirty-one patients resumed ICIs after ALT improvement, 8 of whom (26%) developed recurrent hepatotoxicity. Characteristics of liver injury, response to steroids, and outcomes were similar between 38 individuals with and 62 without possible pre-existing liver disease. The severity and outcome of hepatotoxicity due to combination therapy were not significantly different from monotherapy. There were 36 deaths. Two had liver failure at the time of death, both with progression of liver metastases and grade 3 hepatotoxicity. DISCUSSION: Clinically significant ICI-related hepatotoxicity was uncommon but led to permanent ICI discontinuation in the majority. ICIs were restarted in a sizable proportion of patients, most of whom did not experience recurrent hepatotoxicity.

Quality of endoscopy reporting at index colonoscopy significantly impacts outcome of subsequent EMR in patients with > 20 mm colon polyps.

Background and study aims Endoscopic mucosal resection (EMR) is safe and cost-effective in management of patients with colon polyps. However, very little is known about the actions of the referring endoscopist following identification of these lesions at index colonoscopy, and the impact of those actions on the outcome of subsequent referral for EMR. The aim of this study was to identify practices at index colonoscopy that lead to failure of subsequent EMR. Patients and methods Two hundred and eighty-nine consecutive patients with biopsy-proven non-malignant colon polyps (> 20 mm) referred for EMR were analyzed to identify practices that could be improved from the time of identifying the lesion at index colonoscopy until completion of therapy. Results EMR was abandoned at colonoscopy at the EMR center in 71 of 289 patients (24.6 %). Reasons for abandoning EMR included diagnosis of invasive carcinoma (n = 9; 12.7 %), tethered lesions (n = 21; 29.6 %) from prior endoscopic interventions, and overly large (n = 22; 31 %) and inaccessible lesions (n = 17; 24 %) for complete and safe resection whose details were not recorded in the referring endoscopy report, or polyposis syndromes (n = 2; 2.8 %) that were not recognized. Conclusions In our practice, one in four EMR attempts were abandoned as a result of inadequate diagnosis or management by the referring endoscopist, which could be improved by education on optical diagnosis of polyps, comprehensive documentation of the procedure and avoidance of interventions that preclude resection.

Sofosbuvir-Based Therapy in Hepatitis C Virus-Infected Cancer Patients: A Prospective Observational Study.

BACKGROUND: Data are sparse on treatment of chronic hepatitis C virus (HCV) in cancer patients. We evaluated the efficacy and safety of sofosbuvir-based therapy (SOFBT) in cancer patients. METHODS: Patients treated with SOFBT at our center during 2014-2017 were included in a prospective observational study. Efficacy [sustained virologic response at 12 weeks after the end of treatment (SVR12)], cancer-related outcomes and adverse events (AEs) were assessed. RESULTS: We included 153 patients. Most were men (109; 71%), white (92; 60%), non-cirrhotic (105; 69%), and with HCV genotype 1 (110; 72%). The most common cancers were hepatocellular carcinoma (HCC) (27; 18%) and multiple myeloma (14; 9%). The overall SVR12 rate was 91% (128/141). SVR12 was 100% in patients treated with ledipasvir/sofosbuvir for 8 weeks. Of the 32 patients initially excluded from cancer clinical trials because of HCV, 27 (84%) were granted cancer therapy access after starting SOFBT. Six patients with indolent non-Hodgkin's lymphoma (NHL) received SOFBT without cancer treatment. Two achieved complete remission, one had partial remission, and two had stable cancer. Within 6 months after SOFBT, 5% (6/121) of patients in remission or with stable cancer, had progression or recurrence (two with HCC and one each with esophageal cancer, cholangiocarcinoma, NHL, and tonsillar cancer). No de novo HCCs occurred. AEs were most commonly grade 1-2 (90%). CONCLUSIONS: SOFBT in HCV-infected cancer patients is effective and safe, may permit access to investigational cancer therapy expanding treatment options, may induce remission of NHL, and may be used for 8 weeks.

Endoscopic and Histologic Features of Immune Checkpoint Inhibitor-Related Colitis.

Background: Diarrhea and colitis are the second most common immune checkpoint inhibitor (ICPI)-induced adverse events. However, a comprehensive characterization of the endoscopic and histologic features of ICPI-induced diarrhea and colitis is lacking. Therefore, we aimed to describe endoscopic and histologic features of ICPI-induced gastrointestinal toxicities and to assess their association with patients' clinical characteristics and outcomes. Methods: We retrospectively reviewed records of 53 patients with ICPI-related diarrhea/colitis between 2011 and 2017. We collected data on demographics, diarrhea/colitis grade, treatment, and endoscopic and histologic findings. Long-term follow-up included repeat endoscopy findings, diarrhea recurrence, and overall survival. We compared groups by treatment, endoscopic and histologic findings, and constructed Kaplan-Meier survival curves. Results: Most patients had grade 2 or higher diarrhea (87%) and colitis (60%). Thirty-one patients were successfully treated with corticosteroids, and 22 additionally required infliximab. On endoscopy, 21 (40%) patients had ulcerations and 22 (42%) had nonulcerative inflammation. Patients with ulcerations had more steroid-refractory disease (P = 0.044) and high-grade diarrhea (P = 0.033). Histology showed mostly acute (23%) or chronic (60%) inflammation. During mean follow-up duration of 18.9 months, 19 (36%) developed recurrent diarrhea. Most patients had persistent endoscopic (8/13, 62%) and histologic (9/11, 82%) inflammation. Patients with higher-grade adverse events had improved survival. Higher-grade colitis was associated with endoscopic inflammation (P = 0.039), but grade of diarrhea was not associated with endoscopic inflammation or grade of colitis. Conclusion: 10.1093/ibd/izy104_video1izy104.video15808053084001.

Analysis of the c-KIT Ligand Promoter Using Chromatin Immunoprecipitation.

Multiple cellular processes, including DNA replication and repair, DNA recombination, and gene expression, require interactions between proteins and DNA. Therefore, DNA-protein interactions regulate multiple physiological, pathophysiological, and biological functions, such as cell differentiation, cell proliferation, cell cycle control, chromosome stability, epigenetic gene regulation, and cell transformation. In eukaryotic cells, the DNA interacts with histone and nonhistone proteins and is condensed into chromatin. Several technical tools can be used to analyze DNA-protein interactions, such as the Electrophoresis (gel) Mobility Shift Assay (EMSA) and DNase I footprinting. However, these techniques analyze the protein-DNA interaction in vitro, not within the cellular context. Chromatin immunoprecipitation (ChIP) is a technique that captures proteins at their specific DNA binding sites, thereby allowing for the identification of DNA-protein interactions within their chromatin context. It is done by fixation of the DNA-protein interaction, followed by immunoprecipitation of the protein of interest. Subsequently, the genomic site that the protein was bound to is characterized. Here, we describe and discuss ChIP and demonstrate its analytical value for the identification of the Transforming Growth Factor-ß (TGF-ß)-induced binding of the transcription factor SMAD2 to SMAD Binding Elements (SBE) within the promoter region of the tyrosine-protein kinase Kit (c-KIT) receptor ligand Stem Cell Factor (SCF).

A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune activation and dysregulation resulting in extreme and often life-threatening inflammation. HLH has been well recognized in pediatric populations, and most current diagnostic and therapeutic guidelines are based on pediatric HLH. Recently there has been recognition of HLH in adults, especially secondary to immune deregulation by an underlying rheumatologic, infectious, or malignant condition. This review is focused on malignancy-associated HLH (M-HLH), in which possible mechanisms of pathogenesis include severe inflammation, persistent antigen stimulation by the tumor cells, and loss of immune homeostasis because of chemotherapy, hematopoietic stem cell transplantation, or infection. Previously considered rare, M-HLH may occur in up to 1% of patients with hematologic malignancies. M-HLH is often missed or diagnosed late in most published studies, and it has been associated with a poor median survival of less than 2 months. Identification of the clinical and laboratory features specific to M-HLH in adults may allow early detection, consultation with HLH experts, and intervention. Improved management of adult M-HLH with optimal combinations of T-lympholytic and immunosuppressive agents and the incorporation of novel agents based on the pediatric experience hopefully will improve outcomes in adults with M-HLH. Cancer 2017;123:3229-40. © 2017 American Cancer Society.

Adult cancer-related hemophagocytic lymphohistiocytosis - a challenging diagnosis: a case report.

BACKGROUND: Adult hemophagocytic lymphohistiocytosis is a secondary immunopathologic phenomenon, mainly secondary to malignancy, infection, or autoimmune disorders. The performance of diagnostic criteria, studied in the pediatric population, is yet to be validated in the adult population. Some of the criteria include cytopenias and organomegaly that are inherent features to malignant processes, thus making the diagnosis of hemophagocytic lymphohistiocytosis a challenge in patients with cancer. CASE PRESENTATION: We describe the case of a 54-year-old white man with history of metastatic maxillary sinus adenoid cystic carcinoma who had severe liver injury and cytopenias with progressive clinical deterioration. We performed an evaluation, by flow cytometry, of the expression of surface markers in his natural killer cells that revealed remarkable abnormalities. His syndrome eventually fulfilled criteria for hemophagocytic lymphohistiocytosis and he received therapy with steroids with interval clinical improvement. Unfortunately, he refused further cytotoxic treatment and died 2 weeks later. CONCLUSIONS: The conventional criteria for the diagnosis of hemophagocytic lymphohistiocytosis are suboptimal for adult patients with cancer resulting in delays in diagnosis and timely initiation of treatment. The diagnostic criteria have to be re-evaluated in patients with cancer; novel, easily available, and accurate diagnostic methods are needed.

Loss of the transforming growth factor-ß effector ß2-Spectrin promotes genomic instability.

Exposure to genotoxins such as ethanol-derived acetaldehyde leads to DNA damage and liver injury and promotes the development of cancer. We report here a major role for the transforming growth factor ß/mothers against decapentaplegic homolog 3 adaptor ß2-Spectrin (ß2SP, gene Sptbn1) in maintaining genomic stability following alcohol-induced DNA damage. ß2SP supports DNA repair through ß2SP-dependent activation of Fanconi anemia complementation group D2 (Fancd2), a core component of the Fanconi anemia complex. Loss of ß2SP leads to decreased Fancd2 levels and sensitizes ß2SP mutants to DNA damage by ethanol treatment, leading to phenotypes that closely resemble those observed in animals lacking both aldehyde dehydrogenase 2 and Fancd2 and resemble human fetal alcohol syndrome. Sptbn1-deficient cells are hypersensitive to DNA crosslinking agents and have defective DNA double-strand break repair that is rescued by ectopic Fancd2 expression. Moreover, Fancd2 transcription in response to DNA damage/transforming growth factor ß stimulation is regulated by the ß2SP/mothers against decapentaplegic homolog 3 complex. CONCLUSION: Dysfunctional transforming growth factor ß/ß2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway. (Hepatology 2017;65:678-693).

Cholangiocarcinoma: Current Knowledge and New Developments.

Cholangiocarcinoma (CCA) is the second most common primary malignancy. Although it is more common in Asia, its incidence in Europe and North America has significantly increased in recent decades. The prognosis of CCA is dismal. Surgery is the only potentially curative treatment, but the majority of patients present with advanced stage disease, and recurrence after resection is common. Over the last two decades, our understanding of the molecular biology of this malignancy has increased tremendously, diagnostic techniques have evolved, and novel therapeutic approaches have been established. This review discusses the changing epidemiologic trends and provides an overview of newly identified etiologic risk factors for CCA. Furthermore, the molecular pathogenesis is discussed as well as the influence of etiology and biliary location on the mutational landscape of CCA. This review provides an overview of the diagnostic evaluation of CCA and its staging systems. Finally, new therapeutic options are critically reviewed, and future therapeutic strategies discussed.

A Positive TGF-ß/c-KIT Feedback Loop Drives Tumor Progression in Advanced Primary Liver Cancer.

UNLABELLED: Hepatocellular carcinoma (HCC) is globally the second most common cause of cancer mortality. The majority of HCC patients are diagnosed at advanced stage disease for which no curative treatments exist. TGF-ß has been identified as a potential therapeutic target. However, the molecular mechanisms mediating its functional switch from a tumor suppressor to tumor promoter in HCC and its interactions with other signaling pathways are poorly understood. Here, we demonstrate an aberrant molecular network between the TGF-ß and c-KIT pathway that mediates the functional switch of TGF-ß to a driver of tumor progression in HCC. TGF-ß/SMAD2 signaling transcriptionally regulates expression of the c-KIT receptor ligand (stem cell factor [SCF]) with subsequent auto- and paracrine activation of c-KIT/JAK1/STAT3 signaling. SCF induces TGF-ß1 ligand expression via STAT3, thereby forming a positive feedback loop between TGF-ß/SMAD and SCF/c-KIT signaling. This network neutralizes TGF-ß-mediated cell cycle inhibition and induces tumor cell proliferation, epithelial-to-mesenchymal-transition, migration, and invasion. Disruption of this feedback loop inhibits TGF-ß tumor-promoting effects and restores its antiproliferative functions. Consistent with our in vitro data, we demonstrate SCF overexpression and its correlation to SMAD2 and STAT3 activation in human HCC tumors, advanced tumor-node-metastasis stages, and shorter survival. CONCLUSIONS: Canonical TGF-ß and c-KIT signaling forms a positive, tumor-promoting feedback loop. Disruption of this loop restores TGF-ß tumor suppressor function and provides the rationale for targeting the TGF-ß/SCF axis as a novel therapeutic strategy for HCC.

Natural language processing as an alternative to manual reporting of colonoscopy quality metrics.

BACKGROUND AND AIMS: The adenoma detection rate (ADR) is a quality metric tied to interval colon cancer occurrence. However, manual extraction of data to calculate and track the ADR in clinical practice is labor-intensive. To overcome this difficulty, we developed a natural language processing (NLP) method to identify adenomas and sessile serrated adenomas (SSAs) in patients undergoing their first screening colonoscopy. We compared the NLP-generated results with that of manual data extraction to test the accuracy of NLP and report on colonoscopy quality metrics using NLP. METHODS: Identification of screening colonoscopies using NLP was compared with that using the manual method for 12,748 patients who underwent colonoscopies from July 2010 to February 2013. Also, identification of adenomas and SSAs using NLP was compared with that using the manual method with 2259 matched patient records. Colonoscopy ADRs using these methods were generated for each physician. RESULTS: NLP correctly identified 91.3% of the screening examinations, whereas the manual method identified 87.8% of them. Both the manual method and NLP correctly identified examinations of patients with adenomas and SSAs in the matched records almost perfectly. Both NLP and the manual method produced comparable values for ADRs for each endoscopist and for the group as a whole. CONCLUSIONS: NLP can correctly identify screening colonoscopies, accurately identify adenomas and SSAs in a pathology database, and provide real-time quality metrics for colonoscopy.

Cancer review: Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is the most common biliary tract malignancy. CCA is classified as intrahepatic, perihilar or distal extrahepatic; the individual subtypes differ in their biologic behavior, clinical presentation, and management. Throughout the last decades, CCA incidence rates had significantly increased. In addition to known established risk factors, novel possible risk factors (i.e. obesity, hepatitis C virus) have been identified that are of high importance in developed countries where CCA prevalence rates have been low. CCA tends to develop on the background of inflammation and cholestasis. In recent years, our understanding of the molecular mechanisms of cholangiocarcinogenesis has increased, thereby, providing the basis for molecularly targeted therapies. In its diagnostic evaluation, imaging techniques have improved, and the role of complementary techniques has been defined. There is a need for improved CCA biomarkers as currently used ones are suboptimal. Multiple staging systems have been developed, but none of these is optimal. The prognosis of CCA is considered dismal. However, treatment options have improved throughout the last two decades for carefully selected subgroups of CCA patients. Perihilar CCA can now be treated with orthotopic liver transplantation with neoadjuvant chemoradiation achieving 5-year survival rates of 68%. Classically considered chemotherapy-resistant, the ABC-02 trial has shown the therapeutic benefit of combination therapy with gemcitabine and cisplatin. The benefits of adjuvant treatments for resectable CCA, local ablative therapies and molecularly targeted therapies still need to be defined. In this article, we will provide the reader with an overview over CCA, and discuss the latest developments and controversies.

HuR Suppresses Fas Expression and Correlates with Patient Outcome in Liver Cancer.

UNLABELLED: Hepatocellular carcinomas (HCC) show resistance to chemotherapy and have blunt response to apoptotic stimuli. HCC cell lines express low levels of the Fas death receptor and are resistant to FasL stimulation, whereas immortalized hepatocytes are sensitive. The variable Fas transcript levels and consistently low Fas protein in HCC cells suggest posttranscriptional regulation of Fas expression. The 3'-untranslated region (UTR) of Fas mRNA was found to interact with the ribonucleoprotein Human Antigen R (HuR) to block mRNA translation. Silencing of HuR in HCC cells increased the levels of cell surface Fas and sensitized HCC cells to FasL. Two AU-rich domains within the 3'-UTR of Fas mRNA were identified as putative HuR-binding sites and were found to mediate the translational regulation in reporter assay. Hydrodynamic transfection of HuR plasmid into mice induced downregulation of Fas expression in livers and established functional resistance to the killing effects of Fas agonist. Human HCC tumor tissues showed significantly higher overall and cytoplasmic HuR staining compared with normal liver tissues, and the high HuR staining score correlated with worse survival of patients with early-stage HCC. Combined, the protumorigenic ribonucleoprotein HuR blocks the translation of Fas mRNA and effectively prevents Fas-mediated apoptosis in HCC, suggesting that targeting HuR would sensitize cells to apoptotic stimuli and reverse tumorigenic properties. IMPLICATIONS: Demonstrating how death receptor signaling pathways are altered during progression of HCC will enable the development of better methods to restore this potent apoptosis mechanism.

Effect of hepatitis C virus infection in patients with cancer: addressing a neglected population.

BACKGROUND: Hepatitis C virus (HCV) infection is a neglected disease in patients with cancer. Therefore, this study examined the impact of HCV infections in these patients. METHODS: The records of HCV-infected patients with cancer seen at The University of Texas MD Anderson Cancer Center (2008-2011) were reviewed. The outcomes of those who underwent HCV treatment were analyzed. RESULTS: Of 1291 patients who had positive test results for an antibody to HCV (anti-HCV), 744 (58%) were tested for HCV-RNA; 642 (86%) of which had chronic HCV infections. Most had solid tumors (72%) and genotype-1 (G-1) infections (66%). HCV therapy was administered in 348 patients (98 of them after cancer diagnosis). Sustained virologic response (SVR) occurred in 27 (35%) of the 78 patients treated for whom outcome data were available. Compared with patients who experienced an SVR, more patients who did not were black (29% vs 4%; P=.007), had G-1 infections (72% vs 6%; P<.0001), and had higher baseline aspartate aminotransferase (78 vs 47 IU/L; P=.006) and alanine aminotransferase levels (71.1 vs 43.3 IU/L; P=.009). Overall, progression to cirrhosis (hazard ratio [HR], 0.38; P=.03) and portal hypertension (HR, 0.19; P=.009) was less common in those treated, irrespective of the treatment outcome (SVR or non-SVR). Hepatocellular carcinoma (HCC) developed as a second primary malignancy in 7% of patients with non-HCC cancer. CONCLUSIONS: This is the largest series to analyze HCV infections in patients with cancer. HCV therapy is feasible and prevents liver disease progression in this forgotten population. A treatment algorithm is provided.

Impact of hepatitis E virus seropositivity on chronic liver disease in cancer patients with hepatitis C virus infection.

AIM: Immunocompromised patients can develop chronic hepatitis E virus (HEV) infection and progress to cirrhosis. Hepatitis C virus (HCV)-infected cancer patients who have received chemotherapeutic agents experience accelerated liver fibrosis progression. Our aim was to investigate the prevalence and impact of HEV seropositivity on liver-related outcomes in HCV-infected cancer patients. METHODS: As part of a prospective study of HCV-infected cancer patients conducted at our center, we investigate the characteristics associated with progression of their liver disease. RESULTS: Of the 115 patients tested, 13 (11%) were positive for HEV immunoglobulin G. HEV seropositivity was associated with advanced age (P = 0.004), race (P = 0.02), place of birth outside the USA (P = 0.021), cirrhosis (P = 0.027), history of reused needles/syringes during massive vaccination campaigns (P = 0.015) and coronary artery disease (P = 0.039). Overall, 47 (41%) of the patients had cirrhosis. Factors independently associated with cirrhosis were male sex (odds ratio [OR], 2.8; P = 0.028) and HEV seropositivity (OR, 4.1; P = 0.032). CONCLUSION: HEV seropositivity is present in 11% of HCV-infected cancer patients and seems to be associated with cirrhosis. Our results suggest that HEV screening should be implemented in HCV-infected patients with cancer.

Hepatocellular carcinoma biology.

Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy. Its incidence and prevalence is globally heterogeneous with the highest rates in Southeast Asia and Sub-Saharan Africa. In Western Industry nations, its incidence has significantly increased throughout the previous three decades. Its global heterogeneity is in part a reflection of the global distribution of its risk factors. Its prognosis is dismal with a 5-year survival of 11 %. The only potentially curative treatment is surgical with either resection or orthotopic liver transplantation. However, the majority of HCC patients are diagnosed at an advanced stage at which surgical therapies are not feasible. HCC is considered chemotherapy-resistant-a characteristic thought to be mediated in part through stem-like tumor initiating cells (STICs). Recent studies have provided significant insights in the hepatocarcinogenesis and the molecular signaling pathways of this malignancy resulting in the development of novel, molecular targeted therapies with modest therapeutic benefit. Our growing understanding of the biology of this malignancy will help in the development of novel, molecular-targeted therapies.

Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors.

BACKGROUND & AIMS: Cholangiocarcinoma is a heterogeneous disease with a poor outcome that accounts for 5%-10% of primary liver cancers. We characterized its genomic and genetic features and associated these with patient responses to therapy. METHODS: We profiled the transcriptomes from 104 surgically resected cholangiocarcinoma samples collected from patients in Australia, Europe, and the United States; epithelial and stromal compartments from 23 tumors were laser capture microdissected. We analyzed mutations in KRAS, epidermal growth factor receptor (EGFR), and BRAF in samples from 69 tumors. Changes in gene expression were validated by immunoblotting and immunohistochemistry; integrative genomics combined data from the patients with data from 7 human cholangiocarcinoma cell lines, which were then exposed to trastuzumab and lapatinib. RESULTS: Patients were classified into 2 subclasses, based on 5-year survival rate (72% vs 30%; χ(2) = 11.61; P < .0007), time to recurrence (13.7 vs 22.7 months; P < .001), and the absence or presence of KRAS mutations (24.6%), respectively. Class comparison identified 4 survival subgroups (SGI-IV; χ(2) = 8.34; P < .03); SGIII was characterized by genes associated with proteasomal activity and the worst prognosis. The tumor epithelium was defined by deregulation of the HER2 network and frequent overexpression of EGFR, the hepatocyte growth factor receptor (MET), pRPS6, and Ki67, whereas stroma was enriched in inflammatory cytokines. Lapatinib, an inhibitor of HER2 and EGFR, was more effective in inhibiting growth of cholangiocarcinoma cell lines than trastuzumab. CONCLUSIONS: We provide insight into the pathogenesis of cholangiocarcinoma and identify previously unrecognized subclasses of patients, based on KRAS mutations and increased levels of EGFR and HER2 signaling, who might benefit from dual-target tyrosine kinase inhibitors. The group of patients with the worst prognosis was characterized by transcriptional enrichment of genes that regulate proteasome activity, indicating new therapeutic targets.