{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:52:58Z","timestamp":1787032378360,"version":"build-2736575974"},"reference-count":58,"publisher":"Harborside Press, LLC","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:p>\n                    <jats:bold>Background:<\/jats:bold>\n                    Carcinoma of unknown primary (CUP) represents a heterogeneous group of cancers with unidentified primary tumor sites, accounting for 3% to 5% of all cancers. CUP is characterized by aggressive biology, frequent metastatic presentation, and poor prognosis, with standard chemotherapy offering limited efficacy. Comprehensive molecular profiling offers the potential to identify actionable biomarkers and guide treatment in this challenging setting.\n                    <jats:bold>Patients and Methods:<\/jats:bold>\n                    We conducted a retrospective analysis of 8,809 formalin-fixed, paraffin-embedded tumor samples from patients with CUP (2009\u20132023) who underwent DNA (592-gene panel and whole-exome) and RNA (whole-transcriptome) sequencing, as well as immunohistochemistry (IHC). Potentially actionable biomarkers were identified and correlated with treatment and survival outcomes.\n                    <jats:bold>Results:<\/jats:bold>\n                    Of the tumor samples, 62% of CUP tumors harbored \u22651 potentially actionable biomarker. Biomarkers for agents approved across all tumor types were present in 24.2% of cases, including tumor mutational burden\u2013high (21.1%) and deficient mismatch repair\/microsatellite instability\u2013high (3.3%). Biomarkers associated with therapies approved for specific tumor types, such as PD-L1 IHC positivity (24.4%), homologous recombination deficiency (20.3%), and genomic loss of heterozygosity, were detected in 55.4% of cases. Patients who received biomarker-associated therapies demonstrated significantly longer median overall survival (mOS) than those who did not (17.7 vs 7.0 months; hazard ratio, 0.560;\n                    <jats:italic>P<\/jats:italic>\n                    &lt;.0001). Survival benefits were observed across all biomarker subgroups, including immune checkpoint inhibitors and tumor-specific targeted therapies. Notably, ICIs improved mOS even in patients who were biomarker-negative (15.2 vs 8.6 months;\n                    <jats:italic>P<\/jats:italic>\n                    &lt;.0001).\n                    <jats:bold>Conclusions:<\/jats:bold>\n                    Molecular profiling revealed a high prevalence of actionable biomarkers in CUP and was associated with improved survival with guided therapy. These findings support the integration of molecular profiling into routine clinical practice for CUP management to enable precision oncology and improve patient outcomes. Further prospective validation is warranted.\n                  <\/jats:p>","DOI":"10.6004\/jnccn.2025.7127","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T17:55:53Z","timestamp":1774374953000},"source":"Crossref","is-referenced-by-count":1,"title":["Real-World Biomarker-Associated Therapy in Metastatic Carcinoma of Unknown Primary: Prevalence, Impact, and Outcomes"],"prefix":"10.6004","volume":"24","author":[{"given":"Dipesh","family":"Uprety","sequence":"first","affiliation":[{"name":"Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kieran","family":"Sweeney","sequence":"additional","affiliation":[{"name":"CARIS Life Sciences, Irving, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lubina","family":"Arjyal","sequence":"additional","affiliation":[{"name":"Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarik","family":"Hadid","sequence":"additional","affiliation":[{"name":"Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Shields","sequence":"additional","affiliation":[{"name":"Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Lieu","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Huey","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanwal","family":"Raghav","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Elliott","sequence":"additional","affiliation":[{"name":"CARIS Life Sciences, Irving, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D.","family":"Fountain","sequence":"additional","affiliation":[{"name":"CARIS Life Sciences, Irving, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Oberley","sequence":"additional","affiliation":[{"name":"CARIS Life Sciences, Irving, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek","family":"Subbiah","sequence":"additional","affiliation":[{"name":"Sarah Cannon Research Institute, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Seeber","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria"},{"name":"Department of Oncology, Hematology and Palliative Care, Hospital of Oberwart, Oberwart, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4047","reference":[{"key":"B1","series-title":"Clin Transl Oncol","first-page":"1361","article-title":"2018 consensus statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology on the diagnosis and treatment of cancer of unknown primary","volume":"20","author":"Losa F","year":"2018","unstructured":"Losa F, Iglesias L, Pan\u00e9 M,  2018 consensus statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology on the diagnosis and treatment of cancer of unknown primary. Clin Transl Oncol 2018;20:1361\u20131372."},{"key":"B2","series-title":"Semin Oncol","first-page":"238","article-title":"The biology of unknown primary tumors","volume":"20","author":"Abbruzzese JL","year":"1993","unstructured":"Abbruzzese JL, Lenzi R, Raber MN,  The biology of unknown primary tumors. Semin Oncol 1993;20:238\u2013243."},{"key":"B3","series-title":"Lancet","first-page":"1428","article-title":"Cancer of unknown primary site","volume":"379","author":"Pavlidis N","year":"2012","unstructured":"Pavlidis N, Pentheroudakis G. Cancer of unknown primary site. Lancet 2012;379:1428\u20131435."},{"key":"B4","series-title":"Cancer Epidemiol","first-page":"139","article-title":"The currently declining incidence of cancer of unknown primary","volume":"61","author":"Rassy E","year":"2019","unstructured":"Rassy E, Pavlidis N. The currently declining incidence of cancer of unknown primary. Cancer Epidemiol 2019;61:139\u2013141."},{"key":"B5","article-title":"NCCN Clinical Practice Guidelines in Oncology: Occult Primary. Version 1.2026","author":"Stevenson MM","unstructured":"Stevenson MM, Bowles DW, Abad J,  NCCN Clinical Practice Guidelines in Oncology: Occult Primary. Version 1.2026. Accessed January 20, 2026. To view the most recent version, visit https:\/\/www.nccn.org"},{"key":"B6","series-title":"Crit Rev Oncol Hematol","first-page":"102882","article-title":"New rising entities in cancer of unknown primary: is there a real therapeutic benefit?","volume":"147","author":"Rassy E","year":"2020","unstructured":"Rassy E, Parent P, Lefort F,  New rising entities in cancer of unknown primary: is there a real therapeutic benefit? Crit Rev Oncol Hematol 2020;147:102882."},{"key":"B7","article-title":"NCCN Clinical Practice Guidelines in Oncology: Occult Primary","author":"Ettinger DS","unstructured":"Ettinger DS, Agulnik M, Cates JMM,  NCCN Clinical Practice Guidelines in Oncology: Occult Primary. Accessed January 20, 2026. To view the most recent version, visit https:\/\/www.nccn.org"},{"key":"B8","series-title":"Ann Oncol","first-page":"1854","article-title":"Survival in cancer of unknown primary site: population-based analysis by site and histology","volume":"23","author":"Hemminki K","year":"2012","unstructured":"Hemminki K, Bevier M, Hemminki A, Sundquist J. Survival in cancer of unknown primary site: population-based analysis by site and histology. Ann Oncol 2012;23:1854\u20131863."},{"key":"B9","series-title":"Crit Rev Oncol Hematol","first-page":"103208","article-title":"Melanoma of unknown primary: new perspectives for an old story","volume":"158","author":"Boussios S","year":"2021","unstructured":"Boussios S, Rassy E, Samartzis E,  Melanoma of unknown primary: new perspectives for an old story. Crit Rev Oncol Hematol 2021;158:103208."},{"key":"B10","series-title":"Cancers (Basel)","first-page":"451","article-title":"Cancer of unknown primary: challenges and progress in clinical management","volume":"13","author":"Laprovitera N","year":"2021","unstructured":"Laprovitera N, Riefolo M, Ambrosini E,  Cancer of unknown primary: challenges and progress in clinical management. 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Eur J Clin Invest 2021;51:e13583."},{"key":"B15","series-title":"Ann Oncol","first-page":"936","article-title":"The ESMO Tumour-Agnostic Classifier and Screener (ETAC-S): a tool for assessing tumour-agnostic potential of molecularly guided therapies and for steering drug development","volume":"35","author":"Westphalen CB","year":"2024","unstructured":"Westphalen CB, Martins-Branco D, Beal JR,  The ESMO Tumour-Agnostic Classifier and Screener (ETAC-S): a tool for assessing tumour-agnostic potential of molecularly guided therapies and for steering drug development. Ann Oncol 2024;35:936\u2013953."},{"key":"B16","series-title":"Lancet Oncol","first-page":"1353","article-title":"Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study","volume":"21","author":"Marabelle A","year":"2020","unstructured":"Marabelle A, Fakih M, Lopez J,  Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. 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Nat Rev Clin Oncol 2017;14:682\u2013694."},{"key":"B21","series-title":"Oncologist","first-page":"e769","article-title":"A challenging task: identifying patients with cancer of unknown primary (CUP) according to ESMO guidelines: the CUPISCO trial experience","volume":"26","author":"Pauli C","year":"2021","unstructured":"Pauli C, Bochtler T, Mileshkin L,  A challenging task: identifying patients with cancer of unknown primary (CUP) according to ESMO guidelines: the CUPISCO trial experience. Oncologist 2021;26:e769\u2013779."},{"key":"B22","series-title":"Cancer Treat Rev","first-page":"102407","article-title":"Systematic review of the CUP trials characteristics and perspectives for next-generation studies","volume":"107","author":"Rassy E","year":"2022","unstructured":"Rassy E, Labaki C, Chebel R,  Systematic review of the CUP trials characteristics and perspectives for next-generation studies. 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