{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T20:55:59Z","timestamp":1783976159588,"version":"3.55.0"},"reference-count":56,"publisher":"Harborside Press, LLC","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,6]]},"abstract":"<jats:p>Management of advanced intrahepatic cholangiocarcinoma (iCCA) is challenging and overall survival is poor. Progress in the development of new therapeutic options for metastatic cholangiocarcinoma (CCA) has been slow; hence, to date, there are no approved second-line agents in this setting. Although the development of immune checkpoint inhibitors has significantly improved overall survival in a variety of malignancies, there has not been a clinically important impact in CCA. This report presents a 66-year-old patient with chemotherapy-refractory iCCA who experienced a prolonged response to immunotherapy. Tumor genome profiling revealed a high tumor mutation burden of 17 mutations per megabase in the absence of microsatellite instability. He was started on immunotherapy with nivolumab and has experienced an ongoing response for 16 months without clinical symptoms and only minimal radiologic disease.<\/jats:p>","DOI":"10.6004\/jnccn.2019.7304","type":"journal-article","created":{"date-parts":[[2019,6,17]],"date-time":"2019-06-17T18:23:09Z","timestamp":1560795789000},"page":"644-648","source":"Crossref","is-referenced-by-count":15,"title":["Prolonged Response to Anti\u2013PD-1 Antibody Therapy in Chemotherapy-Refractory Cholangiocarcinoma With High Tumor Mutational Burden"],"prefix":"10.6004","volume":"17","author":[{"given":"Olumide","family":"Gbolahan","sequence":"first","affiliation":[{"name":"aUniversity of Alabama at Birmingham School of Medicine, Birmingham, Alabama;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neda","family":"Hashemi-Sadraei","sequence":"additional","affiliation":[{"name":"bUniversity of New Mexico School of Medicine, Albuquerque, New Mexico; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bert","family":"O\u2019Neil","sequence":"additional","affiliation":[{"name":"cIndiana University School of Medicine, Indianapolis, Indiana."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4047","reference":[{"key":"ref461","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1056\/NEJMoa1801946","article-title":"Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden","volume":"378","author":"Hellmann","year":"2018","journal-title":"N Engl J Med"},{"key":"ref361","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s40425-016-0153-x","article-title":"PD-L1 biomarker testing for non-small cell lung cancer: truth or fiction?","volume":"4","author":"Grigg","year":"2016","journal-title":"J Immunother Cancer"},{"key":"ref101","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1056\/NEJMoa1500596","article-title":"PD-1 blockade in tumors with mismatch-repair deficiency","volume":"372","author":"Le","year":"2015","journal-title":"N Engl J Med"},{"key":"ref421","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1200\/JCO.2017.75.3384","article-title":"Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing","volume":"36","author":"Rizvi","year":"2018","journal-title":"J Clin Oncol"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1200\/JCO.2014.56.2736","article-title":"Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma","volume":"33","author":"Schadendorf","year":"2015","journal-title":"J Clin Oncol"},{"key":"ref221","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1002\/cncr.24019","article-title":"Microsatellite instability, MLH1 promoter methylation, and BRAF mutation analysis in sporadic colorectal cancers of different ethnic groups in Israel","volume":"115","author":"Vilkin","year":"2009","journal-title":"Cancer"},{"key":"ref331","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1038\/nbt.2696","article-title":"Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing","volume":"31","author":"Frampton","year":"2013","journal-title":"Nat Biotechnol"},{"key":"ref501","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1002\/cncr.24019","article-title":"Microsatellite instability, MLH1 promoter methylation, and BRAF mutation analysis in sporadic colorectal cancers of different ethnic groups in Israel","volume":"115","author":"Vilkin","year":"2009","journal-title":"Cancer"},{"key":"ref311","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1634\/theoncologist.2015-0446","article-title":"Forty-year trends in cholangiocarcinoma incidence in the U.S.: intrahepatic disease on the rise","volume":"21","author":"Saha","year":"2016","journal-title":"Oncologist"},{"key":"ref371","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1001\/jamaoncol.2015.3638","article-title":"Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer","volume":"2","author":"McLaughlin","year":"2016","journal-title":"JAMA Oncol"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"Abstract 525","DOI":"10.1016\/S0959-8049(16)30326-4","article-title":"Safety and efficacy of pembrolizumab (MK-3475) in patients (pts) with advanced biliary tract cancer: interim results of KEYNOTE-028 [abstract]","volume":"51","author":"Bang","year":"2015","journal-title":"Eur J Cancer"},{"key":"ref321","doi-asserted-by":"crossref","first-page":"Abstract 525","DOI":"10.1016\/S0959-8049(16)30326-4","article-title":"Safety and efficacy of pembrolizumab (MK-3475) in patients (pts) with advanced biliary tract cancer: interim results of KEYNOTE-028 [abstract]","volume":"51","author":"Bang","year":"2015","journal-title":"Eur J Cancer"},{"key":"ref471","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1158\/1940-6207.CAPR-11-0288","article-title":"Identification of cancer patients with Lynch syndrome: clinically significant discordances and problems in tissue-based mismatch repair testing","volume":"5","author":"Bartley","year":"2012","journal-title":"Cancer Prev Res (Phila)"},{"key":"ref401","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1158\/1535-7163.MCT-17-0386","article-title":"Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers","volume":"16","author":"Goodman","year":"2017","journal-title":"Mol Cancer Ther"},{"key":"ref541","doi-asserted-by":"crossref","first-page":"e80023","DOI":"10.1371\/journal.pone.0080023","article-title":"Tumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations","volume":"8","author":"Birkbak","year":"2013","journal-title":"PLoS One"},{"key":"ref381","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1056\/NEJMoa1500596","article-title":"PD-1 blockade in tumors with mismatch-repair deficiency","volume":"372","author":"Le","year":"2015","journal-title":"N Engl J Med"},{"key":"ref91","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1001\/jamaoncol.2015.3638","article-title":"Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer","volume":"2","author":"McLaughlin","year":"2016","journal-title":"JAMA Oncol"},{"key":"ref171","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13073-017-0424-2","article-title":"Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden","volume":"9","author":"Chalmers","year":"2017","journal-title":"Genome Med"},{"key":"ref81","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s40425-016-0153-x","article-title":"PD-L1 biomarker testing for non-small cell lung cancer: truth or fiction?","volume":"4","author":"Grigg","year":"2016","journal-title":"J Immunother Cancer"},{"key":"ref291","doi-asserted-by":"crossref","first-page":"3140","DOI":"10.1200\/JCO.2011.35.6519","article-title":"Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment","volume":"29","author":"de Jong","year":"2011","journal-title":"J Clin Oncol"},{"key":"ref351","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1056\/NEJMoa1606774","article-title":"Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer","volume":"375","author":"Reck","year":"2016","journal-title":"N Engl J Med"},{"key":"ref71","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1056\/NEJMoa1606774","article-title":"Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer","volume":"375","author":"Reck","year":"2016","journal-title":"N Engl J Med"},{"key":"ref261","doi-asserted-by":"crossref","first-page":"e80023","DOI":"10.1371\/journal.pone.0080023","article-title":"Tumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations","volume":"8","author":"Birkbak","year":"2013","journal-title":"PLoS One"},{"key":"ref01","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1097\/SLA.0b013e318176c4d3","article-title":"Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection","volume":"248","author":"Endo","year":"2008","journal-title":"Ann Surg"},{"key":"ref281","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1097\/SLA.0b013e318176c4d3","article-title":"Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection","volume":"248","author":"Endo","year":"2008","journal-title":"Ann Surg"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1038\/nbt.2696","article-title":"Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing","volume":"31","author":"Frampton","year":"2013","journal-title":"Nat Biotechnol"},{"key":"ref521","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1634\/theoncologist.2016-0415","article-title":"Overall survival and clinical characteristics of BRCA-associated cholangiocarcinoma: a multicenter retrospective study","volume":"22","author":"Golan","year":"2017","journal-title":"Oncologist"},{"key":"ref251","doi-asserted-by":"crossref","first-page":"5696","DOI":"10.1038\/ncomms6696","article-title":"Mutational landscape of intrahepatic cholangiocarcinoma","volume":"5","author":"Zou","year":"2014","journal-title":"Nat Commun"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1634\/theoncologist.2015-0446","article-title":"Forty-year trends in cholangiocarcinoma incidence in the U.S.: intrahepatic disease on the rise","volume":"21","author":"Saha","year":"2016","journal-title":"Oncologist"},{"key":"ref551","doi-asserted-by":"crossref","first-page":"13587","DOI":"10.18632\/oncotarget.7277","article-title":"Association and prognostic significance of BRCA1\/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1\/PD-L1 in high grade serous ovarian cancer","volume":"7","author":"Strickland","year":"2016","journal-title":"Oncotarget"},{"key":"ref111","doi-asserted-by":"crossref","first-page":"264","DOI":"10.21037\/atm.2016.07.11","article-title":"DNA damage, tumor mutational load and their impact on immune responses against cancer","volume":"4","author":"Liontos","year":"2016","journal-title":"Ann Transl Med"},{"key":"ref161","doi-asserted-by":"crossref","first-page":"Abstract 4086","DOI":"10.1200\/JCO.2017.35.15_suppl.4086","article-title":"Tumor mutational burden (TMB) and co-existing actionable mutations in biliary tract cancers (BTC) [abstract]","volume":"35","author":"Jain","year":"2017","journal-title":"J Clin Oncol"},{"key":"ref181","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1056\/NEJMoa1801946","article-title":"Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden","volume":"378","author":"Hellmann","year":"2018","journal-title":"N Engl J Med"},{"key":"ref341","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1200\/JCO.2014.56.2736","article-title":"Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma","volume":"33","author":"Schadendorf","year":"2015","journal-title":"J Clin Oncol"},{"key":"ref241","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1634\/theoncologist.2016-0415","article-title":"Overall survival and clinical characteristics of BRCA-associated cholangiocarcinoma: a multicenter retrospective study","volume":"22","author":"Golan","year":"2017","journal-title":"Oncologist"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"3140","DOI":"10.1200\/JCO.2011.35.6519","article-title":"Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment","volume":"29","author":"de Jong","year":"2011","journal-title":"J Clin Oncol"},{"key":"ref491","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1089\/gtmb.2013.0393","article-title":"Association between IHC and MSI testing to identify mismatch repair-deficient patients with ovarian cancer","volume":"18","author":"Lee","year":"2014","journal-title":"Genet Test Mol Biomarkers"},{"key":"ref441","doi-asserted-by":"crossref","first-page":"Abstract 4086","DOI":"10.1200\/JCO.2017.35.15_suppl.4086","article-title":"Tumor mutational burden (TMB) and co-existing actionable mutations in biliary tract cancers (BTC) [abstract]","volume":"35","author":"Jain","year":"2017","journal-title":"J Clin Oncol"},{"key":"ref231","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.1002\/1097-0142(20011201)92:11<2829::AID-CNCR10094>3.0.CO;2-3","article-title":"Microsatellite instability, MLH-1 promoter hypermethylation, and frameshift mutations at coding mononucleotide repeat microsatellites in ovarian tumors","volume":"92","author":"Gras","year":"2001","journal-title":"Cancer"},{"key":"ref411","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1056\/NEJMoa1406498","article-title":"Genetic basis for clinical response to CTLA-4 blockade in melanoma","volume":"371","author":"Snyder","year":"2014","journal-title":"N Engl J Med"},{"key":"ref191","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1158\/1940-6207.CAPR-11-0288","article-title":"Identification of cancer patients with Lynch syndrome: clinically significant discordances and problems in tissue-based mismatch repair testing","volume":"5","author":"Bartley","year":"2012","journal-title":"Cancer Prev Res (Phila)"},{"key":"ref431","doi-asserted-by":"crossref","first-page":"Abstract 530","DOI":"10.1200\/JCO.2017.35.4_suppl.530","article-title":"Characterization of tumor mutation burden (TMB) in gastrointestinal (GI) cancers [abstract]","volume":"35","author":"Salem","year":"2017","journal-title":"J Clin Oncol"},{"key":"ref201","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.jmoldx.2010.12.004","article-title":"Quality assessment and correlation of microsatellite instability and immunohistochemical markers among population- and clinic-based colorectal tumors results from the Colon Cancer Family Registry","volume":"13","author":"Cicek","year":"2011","journal-title":"J Mol Diagn"},{"key":"ref271","doi-asserted-by":"crossref","first-page":"13587","DOI":"10.18632\/oncotarget.7277","article-title":"Association and prognostic significance of BRCA1\/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1\/PD-L1 in high grade serous ovarian cancer","volume":"7","author":"Strickland","year":"2016","journal-title":"Oncotarget"},{"key":"ref131","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1056\/NEJMoa1406498","article-title":"Genetic basis for clinical response to CTLA-4 blockade in melanoma","volume":"371","author":"Snyder","year":"2014","journal-title":"N Engl J Med"},{"key":"ref511","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.1002\/1097-0142(20011201)92:11<2829::AID-CNCR10094>3.0.CO;2-3","article-title":"Microsatellite instability, MLH-1 promoter hypermethylation, and frameshift mutations at coding mononucleotide repeat microsatellites in ovarian tumors","volume":"92","author":"Gras","year":"2001","journal-title":"Cancer"},{"key":"ref391","doi-asserted-by":"crossref","first-page":"264","DOI":"10.21037\/atm.2016.07.11","article-title":"DNA damage, tumor mutational load and their impact on immune responses against cancer","volume":"4","author":"Liontos","year":"2016","journal-title":"Ann Transl Med"},{"key":"ref141","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1200\/JCO.2017.75.3384","article-title":"Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing","volume":"36","author":"Rizvi","year":"2018","journal-title":"J Clin Oncol"},{"key":"ref451","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13073-017-0424-2","article-title":"Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden","volume":"9","author":"Chalmers","year":"2017","journal-title":"Genome Med"},{"key":"ref481","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.jmoldx.2010.12.004","article-title":"Quality assessment and correlation of microsatellite instability and immunohistochemical markers among population- and clinic-based colorectal tumors results from the Colon Cancer Family Registry","volume":"13","author":"Cicek","year":"2011","journal-title":"J Mol Diagn"},{"key":"ref211","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1089\/gtmb.2013.0393","article-title":"Association between IHC and MSI testing to identify mismatch repair-deficient patients with ovarian cancer","volume":"18","author":"Lee","year":"2014","journal-title":"Genet Test Mol Biomarkers"},{"key":"ref151","doi-asserted-by":"crossref","first-page":"Abstract 530","DOI":"10.1200\/JCO.2017.35.4_suppl.530","article-title":"Characterization of tumor mutation burden (TMB) in gastrointestinal (GI) cancers [abstract]","volume":"35","author":"Salem","year":"2017","journal-title":"J Clin Oncol"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1056\/NEJMoa0908721","article-title":"Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer","volume":"362","author":"Valle","year":"2010","journal-title":"N Engl J Med"},{"key":"ref121","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1158\/1535-7163.MCT-17-0386","article-title":"Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers","volume":"16","author":"Goodman","year":"2017","journal-title":"Mol Cancer Ther"},{"key":"ref531","doi-asserted-by":"crossref","first-page":"5696","DOI":"10.1038\/ncomms6696","article-title":"Mutational landscape of intrahepatic cholangiocarcinoma","volume":"5","author":"Zou","year":"2014","journal-title":"Nat Commun"},{"key":"ref301","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1056\/NEJMoa0908721","article-title":"Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer","volume":"362","author":"Valle","year":"2010","journal-title":"N Engl J Med"}],"container-title":["Journal of the National Comprehensive Cancer Network"],"original-title":[],"link":[{"URL":"https:\/\/jnccn.org\/view\/journals\/jnccn\/17\/6\/article-p644.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2019,8,4]],"date-time":"2019-08-04T03:54:33Z","timestamp":1564890873000},"score":1,"resource":{"primary":{"URL":"https:\/\/jnccn.org\/view\/journals\/jnccn\/17\/6\/article-p644.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6]]},"references-count":56,"journal-issue":{"issue":"6"},"URL":"https:\/\/doi.org\/10.6004\/jnccn.2019.7304","relation":{},"ISSN":["1540-1405","1540-1413"],"issn-type":[{"value":"1540-1405","type":"print"},{"value":"1540-1413","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6]]}}}