{"entity":{"id":"cancer-of-unknown-primary","kind":"cancer","name":"Cancer of unknown primary (CUP)","aka":["CUP","Occult primary"],"tldr":"Cancer found already spread, where doctors cannot find where it started. Genomic profiling finds a drug target in about a third of cases and tumour-agnostic approvals apply directly; the rest still rely on general-purpose chemotherapy, which is what those tests are changing.","summary":"CUP is metastatic cancer with no identifiable primary after standardised work-up (history, examination, CT chest/abdomen/pelvis, immunohistochemistry panel, tumour markers, PET-CT and endoscopy where indicated). About 15-20% fall into favourable subsets treated like the presumed primary: extragonadal germ cell tumours, women with isolated axillary adenocarcinoma (treat as breast), women with peritoneal serous carcinoma (treat as ovarian), squamous carcinoma in cervical nodes (treat as head and neck, often HPV+), isolated inguinal squamous nodes, neuroendocrine carcinomas, and single resectable metastases. The unfavourable majority (adenocarcinoma or poorly differentiated carcinoma with visceral spread) receive empiric platinum-taxane or platinum-gemcitabine chemotherapy with median survival ~9-12 months.\n\nTwo molecular strategies compete: tissue-of-origin classifiers (gene expression or methylation) directing site-specific therapy, which did not improve survival in randomised trials (GEFCAPI 04), and genomic profiling directing targeted or immune therapy, which improved progression-free survival in CUPISCO (2024, Lancet). Nivolumab is approved for CUP in Japan (NivoCUP). ESMO 2023 guidelines recommend comprehensive genomic profiling for all unfavourable CUP.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Cancer_of_unknown_primary_origin","links":[{"label":"ESMO CUP guideline 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"},{"label":"NCCN Guidelines: Occult Primary","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1451"},{"label":"CUP Foundation (Jo's Friends)","url":"https://www.cupfoundjo.org/"}],"tags":["gap-fill","site-agnostic"],"related":[],"cancers":[],"sections":[],"technologies":["cgp","histopathology-ihc","pet-ct","liquid-biopsy","methylation-profiling","platinum","checkpoint-inhibitor"],"targets":["ntrk","braf","her2","pd1"],"drugs":["carboplatin","paclitaxel","gemcitabine-cisplatin","pembrolizumab","nivolumab"],"companies":["roche-genentech","foundation-medicine","bms"],"institutions":[],"pathways":[],"terms":["tumour-agnostic","tmb","msi","ihc"],"trials":[],"people":["jim-valvano"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"other","burden":"About 2-3% of all cancer diagnoses (down from ~5% as imaging and pathology improved); median survival for the unfavourable majority remains under a year.","subtypes":["Favourable subsets (extragonadal germ cell, axillary node adenocarcinoma in women, peritoneal serous carcinoma, cervical node SCC, neuroendocrine, single metastasis)","Unfavourable: adenocarcinoma with liver/multiple metastases","Poorly differentiated carcinoma","Squamous carcinoma of unfavourable sites","Provisional CUP resolved by molecular tissue-of-origin"],"biomarkers":["Immunohistochemistry panel (CK7/CK20, TTF-1, CDX2, GATA3, PAX8, NKX3.1, SOX10, p16)","Comprehensive genomic profiling (targetable alterations in ~30%)","MSI, TMB, PD-L1 (tumour-agnostic immunotherapy)","Tissue-of-origin classifiers (gene expression, methylation)","AFP, hCG (germ cell), PSA (men), CA-125","ctDNA"],"standardOfCare":[{"setting":"Favourable subsets","approach":"Treat as the presumed primary: e.g. axillary node-only adenocarcinoma in women as breast cancer (mastectomy or axillary dissection + radiotherapy, systemic therapy); cervical node SCC with chemoradiation; peritoneal serous carcinoma as ovarian.","refs":["carboplatin","paclitaxel","imrt-igrt"],"guideline":{"version":"ESMO CUP guideline 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"}},{"setting":"Unfavourable, first line","approach":"Empiric carboplatin-paclitaxel or cisplatin-gemcitabine ×4-6; comprehensive genomic profiling at diagnosis to find targetable alterations or immunotherapy biomarkers.","refs":["carboplatin","paclitaxel","gemcitabine-cisplatin","cgp"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Occult Primary","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1451"}},{"setting":"Molecularly directed","approach":"Targeted therapy for actionable alterations (e.g. NTRK, BRAF V600E, HER2, ALK) and pembrolizumab for MSI-H/TMB-H; CUPISCO supports molecular-guided therapy after induction chemotherapy.","refs":["pembrolizumab","nivolumab","cgp","liquid-biopsy"],"guideline":{"version":"CUPISCO (Lancet 2024)","url":"https://doi.org/10.1016/S0140-6736(24)00814-6"}}],"stateOfArt":["Genomic profiling finds an actionable alteration in about a third of CUP and improved PFS in a randomised trial (CUPISCO).","Tissue-of-origin prediction is accurate but has not improved survival when used to pick chemotherapy.","Tumour-agnostic approvals (NTRK, MSI-H, TMB-H, BRAF, RET, HER2) apply directly to CUP.","Better imaging and pathology have shrunk the category by half; the residue is biologically aggressive."],"history":[{"year":1979,"title":"Cisplatin-based therapy cures some 'poorly differentiated carcinoma of unknown primary' (Greco, Hainsworth)","note":"Recognition of the extragonadal germ cell subset.","refs":[]},{"year":2003,"title":"Favourable subsets codified (Pavlidis, Fizazi)","refs":[]},{"year":2013,"title":"Tissue-of-origin gene expression tests (CancerTYPE ID) enter practice","refs":[]},{"year":2019,"title":"GEFCAPI 04: site-specific therapy by molecular classifier no better than empiric chemotherapy","refs":[]},{"year":2021,"title":"Nivolumab approved for CUP in Japan (NivoCUP)","refs":["nivolumab"]},{"year":2023,"title":"ESMO guideline recommends comprehensive genomic profiling","refs":[]},{"year":2024,"title":"CUPISCO: molecularly guided therapy improves PFS (Lancet)","refs":["cgp"]}],"pipeline":["cgp","liquid-biopsy","methylation-profiling","pembrolizumab"],"openProblems":["Whether finding the primary matters, or only finding the target.","Median survival under a year for unfavourable CUP despite decades of trials.","Access to genomic profiling for a diagnosis that is over-represented in older and deprived patients.","Trial design when the population is defined by absence."]},"route":"/cancers/cancer-of-unknown-primary/","neighbours":{"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"methylation-profiling","kind":"technology","name":"DNA methylation profiling","route":"/technologies/methylation-profiling/"},{"id":"histopathology-ihc","kind":"technology","name":"Histopathology & immunohistochemistry","route":"/technologies/histopathology-ihc/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"imrt-igrt","kind":"technology","name":"IMRT / IGRT (modern external beam)","route":"/technologies/imrt-igrt/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"pet-ct","kind":"technology","name":"PET/CT","route":"/technologies/pet-ct/"},{"id":"platinum","kind":"technology","name":"Platinum agents","route":"/technologies/platinum/"}],"target":[{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"ntrk","kind":"target","name":"NTRK","route":"/targets/ntrk/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"}],"drug":[{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/"},{"id":"envafolimab","kind":"drug","name":"Envafolimab","route":"/drugs/envafolimab/"},{"id":"gemcitabine-cisplatin","kind":"drug","name":"Gemcitabine + cisplatin","route":"/drugs/gemcitabine-cisplatin/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"paclitaxel","kind":"drug","name":"Paclitaxel / nab-paclitaxel","route":"/drugs/paclitaxel/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"}],"company":[{"id":"bms","kind":"company","name":"Bristol Myers Squibb","route":"/companies/bms/"},{"id":"foundation-medicine","kind":"company","name":"Foundation Medicine (Roche)","route":"/companies/foundation-medicine/"},{"id":"roche-genentech","kind":"company","name":"Roche / Genentech","route":"/companies/roche-genentech/"}],"term":[{"id":"emergency-presentation","kind":"term","name":"Emergency presentation (route to diagnosis)","route":"/terms/emergency-presentation/"},{"id":"ihc","kind":"term","name":"Immunohistochemistry (IHC)","route":"/terms/ihc/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"organ-of-origin-signal","kind":"term","name":"Tissue-of-origin signal in tumour data","route":"/terms/organ-of-origin-signal/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"},{"id":"tumour-agnostic","kind":"term","name":"Tumour-agnostic (tissue-agnostic) approval","route":"/terms/tumour-agnostic/"}],"person":[{"id":"jim-valvano","kind":"person","name":"Jim Valvano","route":"/people/jim-valvano/"},{"id":"linda-mileshkin","kind":"person","name":"Linda Mileshkin","route":"/people/linda-mileshkin/"}],"cancer":[{"id":"cup-favourable-subsets","kind":"cancer","name":"Cancer of unknown primary, favourable subsets","route":"/cancers/cup-favourable-subsets/"},{"id":"cup-unfavourable","kind":"cancer","name":"Cancer of unknown primary, unfavourable (adenocarcinoma and poorly differentiated carcinoma)","route":"/cancers/cup-unfavourable/"},{"id":"colorectal-medullary-carcinoma","kind":"cancer","name":"Medullary carcinoma of the colon","route":"/cancers/colorectal-medullary-carcinoma/"},{"id":"metastatic-cancer","kind":"cancer","name":"Metastatic cancer (cancer that has spread)","route":"/cancers/metastatic-cancer/"}],"institution":[{"id":"mcw-cancer-center","kind":"institution","name":"Medical College of Wisconsin Cancer Center","route":"/institutions/mcw-cancer-center/"}],"trial":[{"id":"nct07761429","kind":"trial","name":"A Phase II/III Study of F520 Combined With Paclitaxel Plus Carboplatin in the Treatment of Cancer of Unknown Primary (CUP)","route":"/trials/nct07761429/"},{"id":"cupisco","kind":"trial","name":"CUPISCO","route":"/trials/cupisco/"}]}}