# Cancer of unknown primary (CUP)

Source: https://onco.cc/cancers/cancer-of-unknown-primary/  
OnCo record `cancer-of-unknown-primary` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

Two 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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-08
- Also known as: CUP; Occult primary
- Tags: gap-fill; site-agnostic
- 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

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/cancer-of-unknown-primary/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/cancer-of-unknown-primary/#overview [2 subtypes, 4 state-of-the-art points]
- What it is (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/cancer-of-unknown-primary/#what-it-is [7 subtypes]
- Finding it (on the hub): How it shows itself, how it is confirmed, what screening exists, and the biomarkers clinicians test for. https://onco.cc/cancers/cancer-of-unknown-primary/#finding-it [6 biomarkers]
- Treating it (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/cancer-of-unknown-primary/#treating-it [3 settings, 3 decisions with options]
- Evidence (on the hub): Trials recruiting now, the landmark trials, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/cancer-of-unknown-primary/#evidence [2 trials, 7 milestones]
- The science (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/cancer-of-unknown-primary/#science [5 targets]
- Where you are (own page): Cases by country, the UK and NHS pathway and other country lenses, and the expert centres with trials on record. https://onco.cc/cancers/cancer-of-unknown-primary/where-you-are/ [1 centre]
- Living with it (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/cancer-of-unknown-primary/#living-with-it [15 questions, 6 red cards]
- What is coming (own page): Everything in development, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/cancer-of-unknown-primary/coming/ [6 medicines, 2 trials, 4 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/cancer-of-unknown-primary/data/ [39 connected records]

## Standard of care

- Favourable subsets: 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. ([Carboplatin](https://onco.cc/drugs/carboplatin/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/))
- Unfavourable, first line: Empiric carboplatin-paclitaxel or cisplatin-gemcitabine ×4-6; comprehensive genomic profiling at diagnosis to find targetable alterations or immunotherapy biomarkers. ([Carboplatin](https://onco.cc/drugs/carboplatin/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Gemcitabine + cisplatin](https://onco.cc/drugs/gemcitabine-cisplatin/), [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/))
- Molecularly directed: 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. ([Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/))

## State of the art

- 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.

## Open problems

- 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.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Cancer_of_unknown_primary_origin
- ESMO CUP guideline 2023: https://doi.org/10.1016/j.annonc.2022.11.013
- NCCN Guidelines: Occult Primary: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1451
- CUP Foundation (Jo's Friends): https://www.cupfoundjo.org/

## Connected records

- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [PET/CT](https://onco.cc/technologies/pet-ct/), [Platinum agents](https://onco.cc/technologies/platinum/)
- targets: [BRAF](https://onco.cc/targets/braf/), [HER2](https://onco.cc/targets/her2/), [NTRK](https://onco.cc/targets/ntrk/), [PD-1](https://onco.cc/targets/pd1/)
- drugs: [Carboplatin](https://onco.cc/drugs/carboplatin/), [Envafolimab](https://onco.cc/drugs/envafolimab/), [Gemcitabine + cisplatin](https://onco.cc/drugs/gemcitabine-cisplatin/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- companies: [Bristol Myers Squibb](https://onco.cc/companies/bms/), [Foundation Medicine (Roche)](https://onco.cc/companies/foundation-medicine/), [Roche / Genentech](https://onco.cc/companies/roche-genentech/)
- terms: [Immunohistochemistry (IHC)](https://onco.cc/terms/ihc/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Tissue-of-origin signal in tumour data](https://onco.cc/terms/organ-of-origin-signal/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/), [Tumour-agnostic (tissue-agnostic) approval](https://onco.cc/terms/tumour-agnostic/)
- people: [Jim Valvano](https://onco.cc/people/jim-valvano/), [Linda Mileshkin](https://onco.cc/people/linda-mileshkin/)
- cancers: [Cancer of unknown primary, favourable subsets](https://onco.cc/cancers/cup-favourable-subsets/), [Cancer of unknown primary, unfavourable (adenocarcinoma and poorly differentiated carcinoma)](https://onco.cc/cancers/cup-unfavourable/), [Medullary carcinoma of the colon](https://onco.cc/cancers/colorectal-medullary-carcinoma/), [Metastatic cancer (cancer that has spread)](https://onco.cc/cancers/metastatic-cancer/)
- institutions: [Medical College of Wisconsin Cancer Center](https://onco.cc/institutions/mcw-cancer-center/)
- trials: [A Phase II/III Study of F520 Combined With Paclitaxel Plus Carboplatin in the Treatment of Cancer of Unknown Primary (CUP)](https://onco.cc/trials/nct07761429/), [CUPISCO](https://onco.cc/trials/cupisco/)

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JSON: https://onco.cc/api/v1/entities/cancer-of-unknown-primary.json