Practical considerations in screening for genetic alterations in cholangiocarcinoma

•CCA is a relatively rare, aggressive, heterogeneous malignancy associated with poor outcomes.•Comprehensive molecular profiling has revealed diverse landscape of oncogenic genomic alterations in CCA.•Advances NGS have allowed large gene panels to be assayed high sensitivity and specificity at reduced cost.•Large-scale found actionable targeted by therapies approved other indications.•Large-scale may allow precise diagnostics guide treatment decisions CCA. Cholangiocarcinoma (CCA) encompasses epithelial tumors historically outcomes due an aggressive disease course, late diagnosis, limited benefit standard chemotherapy for advanced disease. Comprehensive as drivers TP53 mutations, CDKN2A/B loss, KRAS mutations are the most common genetic However, intrahepatic CCA (iCCA) extrahepatic (eCCA) differ substantially frequency many alterations. This includes alterations, such isocitrate dehydrogenase 1 (IDH1) variety FGFR2 rearrangements, which up 29% ∼10% patients iCCA, respectively, but rare eCCA. rearrangements currently only alteration therapy, fibroblast growth factor receptor 1-3 inhibitor pemigatinib, been approved. favorable phase III results IDH1-targeted therapy ivosidenib iCCA published, numerous indications. Recent advances next-generation sequencing (NGS) led development assays that comprehensive within 2-3 weeks, including vitro diagnostic tests United States. These vary regarding acceptable source material (tumor tissue or peripheral whole blood), library construction (DNA RNA), target selection technology, panel size, type detectable While some commercial laboratories offer rapid services based on proprietary assay platforms, clinical centers use kits designed research develop their own customized laboratory-developed tests. Large-scale allows detailed diagnosis provides important opportunity improved plans tailored individual patient's signature. represents originating from cholangiocytes bile ducts. Depending anatomical location, classified (eCCA), eCCA further perihilar distal eCCA.1Rizvi S. Khan S.A. Hallemeier C.L. Kelley R.K. Gores G.J. Cholangiocarcinoma—evolving concepts therapeutic strategies.Nat Rev Clin Oncol. 2018; 15: 95-111Crossref PubMed Scopus (0) Google Scholar,2Louis C. Papoutsoglou P. Coulouarn Molecular classification cholangiocarcinoma.Curr Opin Gastroenterol. 2020; 36: 57-62PubMed Scholar cancer incidence rate States 1.20 per 100 000 person-years 2000 2015, data National Cancer Institute (NCI) Surveillance, Epidemiology, End Results (SEER) Program.3Gad M.M. Saad A.M. Faisaluddin M. et al.Epidemiology cholangiocarcinoma; mortality trends.Clin Res Hepatol 44: 885-893Crossref (1) Estimated rates during this period were 0.77 0.43 person-years, respectively.3Gad retrospective analyses suggest increased past decades both States3Gad Scholar, 4Mukkamalla S.K.R. Naseri H.M. Kim B.M. Katz S.C. Armenio V.A. Trends factors affecting survival cholangiocarcinoma States.J Natl Compr Canc Netw. 16: 370-376Crossref (12) 5Saha S.K. Zhu A.X. Fuchs C.S. Brooks G.A. Forty-year trends U.S.: rise.Oncologist. 2016; 21: 594-599Crossref (263) European countries,6Florio A.A. Ferlay J. Znaor A. al.Global 1993 2012.Cancer. 126: 2666-2678Crossref (23) particularly iCCA. In States, annual percentage increases 2003 2015 7.0 2.1, Western Central Europe, age-adjusted (per person-years) 2008 2012 highest UK (1.15), France (1.13), Germany (1.05), those (0.74), Netherlands (0.69), Ireland (0.68).6Florio Although essentially sporadic disease, risk CCA, duct cyst, Caroli's primary sclerosing cholangitis, cholelithiasis choledocholithiasis, parasitic liver infections, cirrhosis, hepatitis B C virus infection, hepatolithiasis (iCCA only).7Khan Tavolari Brandi G. Cholangiocarcinoma: epidemiology factors.Liver Int. 2019; 39: 19-31Crossref (99) The East Asian countries, South Korea Thailand,6Florio endemic presence Opisthorchis viverrini Clonorchis sinensis flukes7Khan vertical transmission.8Zhou H. Wang Zhou D. al.Hepatitis virus-associated hepatocellular carcinoma hold process carcinogenesis.Eur J Cancer. 2010; 46: 1056-1061Abstract Full Text PDF prognosis. SEER diagnosed between 1973 suggested estimated 5-year 70%-91%, depending age.4Mukkamalla Major contribute late-stage options. complete surgical resection potentially curative, about third qualify surgery.1Rizvi Approved treatments unresectable, largely regimens tested study populations biliary tract (BTC). first-line consists combination cisplatin gemcitabine, was median overall (OS) 11.7 months pivotal trial locally metastatic BTC, 60% whom had CCA.9Valle Wasan Palmer D.H. al.Cisplatin plus gemcitabine versus cancer.N Engl Med. 362: 1273-1281Crossref (2097) For who experience progression after available second-line chemotherapies provide modestly benefit. ABC-06 BTC (including 72% CCA) progressed addition modified FOLFOX active symptom control marginal improvement OS compared alone (6.2 5.3 months).10Lamarca H.S. al.ABC-06 | A randomised III, multi-centre, open-label (ASC) ASC oxaliplatin/5-FU (ASC+mFOLFOX) (pts) advanced/metastatic cancers (ABC) previously-treated cisplatin/gemcitabine (CisGem) [abstract 4003].J 37: 4003Google database analysis time initiation 13.4 6.8 eCCA.11Lowery M.A. Goff L.W. Keenan B.P. al.Second-line cancers: retrospective, multicenter outcomes.Cancer. 125: 4426-4434Crossref (14) Based histologic criteria, CCAs can well, moderately, poorly differentiated adenocarcinomas, variants.12Krasinskas Cholangiocarcinoma.Surg Pathol Clin. 11: 403-429Abstract histopathologic criteria proven insufficient tools guiding improve outcomes. integrative substantial heterogeneity even anatomically histologically defined subtypes, implications classification,13Jusakul Cutcutache I. Yong C.H. al.Whole-genome epigenomic landscapes etiologically distinct subtypes cholangiocarcinoma.Cancer Discov. 2017; 7: 1116-1135Crossref (268) 14Sia Hoshida Y. Villanueva al.Integrative reveals 2 classes different outcomes.Gastroenterology. 2013; 144: 829-840Abstract (278) 15Montal R. Sia Montironi al.Molecular targets cholangiocarcinoma.J Hepatol. 73: 315-327Abstract prognosis,13Jusakul Scholar,16Churi C.R. Shroff al.Mutation cholangiocarcinoma: prognostic implications.PLoS One. 2014; 9: e115383Crossref (244) treatment.16Churi Scholar,17Ross J.S. K. Gay L. al.New routes cholangiocarcinomas sequencing.Oncologist. 19: 235-242Crossref (252) International Genome Consortium (ICGC) project coordinating large-scale genome studies ∼50 cancers, two projects focusing systematically characterize community access data.18Hudson T.J. Anderson W. al.International ConsortiumInternational network projects.Nature. 464: 993-998Crossref (1483) 19Zhang Baran Cros Data Portal—a one-stop shop genomics data.Database (Oxford). 2011; 2011: bar026Crossref (321) 20International (ICGC)Cancer Projects.https://dcc.icgc.org/projectsGoogle Pan Analysis Whole major initiative ICGC US NCI's Atlas,21National InstituteThe Atlas Program.https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcgaGoogle involves collaboration >1300 scientists clinicians 37 countries. As February 2020, >2600 genomes 38 tumor types analyzed 16 working groups created multiple aspects development, progression, classification.20International light effectiveness complexity recent technological conducting include work-up staging suspected ‘Molecular diagnosis’ patient level useful information planning appropriate therapies, especially therapy. review, we overview platforms implication management number used determine prior eCCA.17Ross Scholar,22Farshidfar F. Zheng Gingras M.C. identifies IDH-mutant profiles.Cell Rep. 18: 2780-2794Abstract (178) 23Lee Johnson al.Comprehensive long tail targets.J Pathol. 69: 403-408Crossref (32) 24Lowery Ptashkin Jordan E. cholangiocarcinomas: potential intervention.Clin Res. 24: 4154-4161Crossref (111) 25Silverman I.M. Hollebecque Friboulet al.Clinicogenomic FGFR2-rearranged correlates response mechanisms resistance pemigatinib.Cancer 2021; 326-339Crossref (7) 26Xue Guo Zhang Chinese population practice.Hepatobiliary Surg Nutr. 8: 615-622Crossref 27Javle MM, Murugesan K, RT, al. Profiling identify mutational burden (TMB) loss heterozygosity (gLOH). Paper presented Annual Meeting American Society Clinical Oncology. May 31, 2019 June 4, Chicago, IL.Google 28Javle Bekaii-Saab T. Jain al.Biliary cancer: utility management.Cancer. 122: 3838-3847Crossref (137) these varied respect numbers genes analyzed, findings among profiles differences (Figure 1). largest reported date, Javle profiled samples 4371 exons select introns 404 (TMB), microsatellite instability (MSI), heterozygosity.27Javle 75% originated biopsies, location eCCA) not disclosed. commonly altered (in least 10% patients) (mostly truncations mutations), copy loss), ARID1A truncations), (mutations), BAP1 PBRM1 (85% fusions) 1A).27Javle >1000 carried out screening enrollment FIbroblast Growth oncology Hematology Trial (FIGHT)-202 (NCT02924376), II selective oral (FGFR) pemigatinib previously treated CCA.29Abou-Alfa G.K. Sahai V. al.Pemigatinib treated, multicentre, open-label, study.Lancet 671-684Abstract (201) Most (>80%) although could determined all (I Silverman, personal communication). Similar al.,27Javle TP53, CDKN2A/B, KRAS, CDKN2B, ARID1A, IDH1, SMAD4, BAP1, PBRM1; 7% 1A).25Silverman An similar distribution also observed 410 cancer-associated 195 158 (81%) 1A).24Lowery Several separately Scholar,24Lowery Scholar,28Javle small eCCA, they Lowery al.,24Lowery preferentially (n = 158; Figure 1B) 37) IDH1 (29% 5%), (19% 0%), (13% whereas eCCAs iCCAs (49% 18%), (38% 7%), SMAD4 (30% STK11 (11% <1%). Genomic 412 57 identified 16% 9%, 1B), failed detect eCCA.28Javle 73 150 1C).15Montal addition, recurrent chromosomal amplifications YEATS4 (6.0%), MDM2 (4.7%), CCNE1 (2.7%), CDK4 (1.3%), ERBB2 (1.3%).15Montal Lee 99 1C).23Lee Of note, (68%) 80 1C).26Xue Along apparent profile geographically heterogeneous, reflect divergent extrinsic etiologies.6Florio regard, located 283) China 164).30Cao Hu Liu al.Intrahepatic eastern western patients.JCO Precis 4: 557-569Crossref (8) Divergent signatures found: BRCA1/2, DDR, KMT2C, NF1, RB1, RBM10, SPTA1, TERT, TGFBR2, significantly more prevalent patients, IDH1/2 patients.30Cao Also, consistent this, Notably, clustering number, expression, mutation, epigenetic 489 spanning 10 countries yielded four clusters characterized clinicopathologic profiles.13Jusakul Clusters primarily encompassed fluke-positive enriched amplification mutation; 3 4 fluke-negative CCAs, cluster displaying immune checkpoint up-regulation (PD1, PD-L1, BTLA), exhibiting well FGFR alterations.13Jusakul Another significant -negative iCCA.31Chan-On Nairismagi M.L. Ong C.K. al.Exome patterns fluke-related non-infection-related cancers.Nat Genet. 45: 1474-1478Crossref (300) Elsewhere whole-exome (WES) 103 provided evidence association somatic surface antigen (HBV) seropositivity,32Zou Li al.Mutational cholangiocarcinoma.Nat Commun. 5: 5696Crossref (189) suggesting role p53-mediated signaling resulting HBV infection.8Zhou 201