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Cancer of unknown primary (CUP)

aka CUP, Occult primary

Cancer found already spread, where doctors cannot find where it started. Most cases are treated with general-purpose chemotherapy and do poorly; molecular tests to guess the origin or find a drug target are slowly changing that.

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.

State of the art today

  • Genomic profiling finds an actionable alteration in about a third of CUP and improved PFS in a randomised trial (CUPISCO).
  • 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.
Show survival figures (1)

Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.

  • Tissue-of-origin prediction is accurate but has not improved survival when used to pick chemotherapy.
Who it affects
Show survival figures (1)

Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.

  • 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.
Group
other

Where the cases are

Cases by country · GLOBOCAN 2022
All countries →

No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.

Standard of care

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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.

ESMO CUP guideline 2023
CarboplatinPaclitaxel / nab-paclitaxelIMRT / IGRT (modern external beam)
Unfavourable, first line

Empiric carboplatin-paclitaxel or cisplatin-gemcitabine ×4-6; comprehensive genomic profiling at diagnosis to find targetable alterations or immunotherapy biomarkers.

NCCN · Category 2A
CarboplatinPaclitaxel / nab-paclitaxelGemcitabine + cisplatinComprehensive genomic profiling
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.

CUPISCO (Lancet 2024)
PembrolizumabNivolumabComprehensive genomic profilingLiquid biopsy (ctDNA)

Subtypes & biomarkers

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Subtypes
Biomarkers clinicians test

Target prevalence in this cancer

History

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  1. 1979Cisplatin-based therapy cures some 'poorly differentiated carcinoma of unknown primary' (Greco, Hainsworth)

    Recognition of the extragonadal germ cell subset.

  2. 2003Favourable subsets codified (Pavlidis, Fizazi)
  3. 2013Tissue-of-origin gene expression tests (CancerTYPE ID) enter practice
  4. 2019GEFCAPI 04: site-specific therapy by molecular classifier no better than empiric chemotherapy
  5. 2021Nivolumab approved for CUP in Japan (NivoCUP)
    Nivolumab
  6. 2023ESMO guideline recommends comprehensive genomic profiling
  7. 2024CUPISCO: molecularly guided therapy improves PFS (Lancet)
    Comprehensive genomic profiling

Pipeline

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ApprovedMonoclonal antibody (anti-PD-1)
Pembrolizumab · Keytruda / Keytruda Qlex (SC)
Comprehensive genomic profilingLiquid biopsy (ctDNA)DNA methylation profiling

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.

Trials

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Recruiting now (live from ClinicalTrials.gov)

Recruiting trials near you · live from ClinicalTrials.gov
Cancer of unknown primary (CUP)
condition: Cancer of unknown primary
Open on ClinicalTrials.gov →

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Expert centres

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Where the expertise is

Centres linked to this cancer in OnCo

Seeking a second opinion: ask your oncologist for a referral to a high-volume centre; most accept records and pathology by mail or telehealth. In the US, use the NCI's Find a Cancer Center tool or the nonprofit Cancer Commons, which navigates options for advanced cancers at no cost.

Questions to ask

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Bring to your appointment

Questions to ask your oncologist about Cancer of unknown primary

Generated from this cancer's standard of care, biomarkers, and pipeline · 15 questions

Newly diagnosed

  1. What is my exact diagnosis, stage, and grade, and which tests established them?
    Why: Everything else follows from an accurate stage and subtype.
  2. Which biomarkers have been tested on my tumour (for example Immunohistochemistry panel, Comprehensive genomic profiling, MSI, TMB, PD-L1, Tissue-of-origin classifiers, AFP, hCG, PSA, CA-125), and what were the results?
    Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
  3. Which subtype is my cancer, and does that change the recommended treatment?
    Why: Recognised subtypes for this cancer include Favourable subsets, Unfavourable: adenocarcinoma with liver/multiple metastases, Poorly differentiated carcinoma.
  4. Is germline (inherited) genetic testing recommended for me or my family?
    Why: Inherited variants can change treatment and matter for relatives.

Favourable subsets

  1. For my situation (favourable subsets), which of the standard options do you recommend and why?
    Why: Guideline options include: 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.
  2. Am I a candidate for Carboplatin, Paclitaxel / nab-paclitaxel, and what side effects should I expect?
    Why: Knowing the expected toxicities helps you plan work, family, and supportive care.

Unfavourable, first line

  1. For my situation (unfavourable, first line), which of the standard options do you recommend and why?
    Why: Guideline options include: Empiric carboplatin-paclitaxel or cisplatin-gemcitabine ×4-6; comprehensive genomic profiling at diagnosis to find targetable alterations or immunotherapy biomarkers.
  2. Am I a candidate for Carboplatin, Paclitaxel / nab-paclitaxel, Gemcitabine + cisplatin, and what side effects should I expect?
    Why: Knowing the expected toxicities helps you plan work, family, and supportive care.

Molecularly directed

  1. For my situation (molecularly directed), which of the standard options do you recommend and why?
    Why: Guideline options include: 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.
  2. Am I a candidate for Pembrolizumab, Nivolumab, and what side effects should I expect?
    Why: Knowing the expected toxicities helps you plan work, family, and supportive care.

Any stage

  1. Are there clinical trials I could join, for example of Comprehensive genomic profiling, Liquid biopsy (ctDNA), DNA methylation profiling, Pembrolizumab?
    Why: Trials are how the next standard of care is set; asking early keeps options open.
  2. Would a second opinion at a high-volume centre change anything, and can you help arrange it?
    Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
  3. What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?
    Why: Supportive care improves quality of life and helps patients complete treatment.
  4. I read that “Whether finding the primary matters, or only finding the target”. How does that affect my plan?
    Why: Open problems are where trials and second opinions matter most.
  5. I read that “Median survival under a year for unfavourable CUP despite decades of trials”. How does that affect my plan?
    Why: Open problems are where trials and second opinions matter most.

Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.

Everything relevant

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Direct links plus the targets, companies, and technologies of this cancer's products.

technologies

9
Comprehensive genomic profilingCytotoxic chemotherapyDNA methylation profilingHistopathology & immunohistochemistryImmune checkpoint inhibitorsIMRT / IGRT (modern external beam)Liquid biopsy (ctDNA)PET/CTPlatinum agents

targets

4
BRAFHER2NTRKPD-1

drugs

5
ApprovedCytotoxic chemotherapy (platinum)
Carboplatin
Not mapped hereCytotoxic regimen
Gemcitabine + cisplatin
ApprovedMonoclonal antibody (anti-PD-1)
Nivolumab · Opdivo / Opdivo Qvantig (SC)
ApprovedCytotoxic chemotherapy (taxane)
Paclitaxel / nab-paclitaxel · Taxol / Abraxane
ApprovedMonoclonal antibody (anti-PD-1)
Pembrolizumab · Keytruda / Keytruda Qlex (SC)

companies

4
Bristol Myers SquibbFoundation Medicine (Roche)Merck & Co. (MSD)Roche / Genentech

terms

4
Immunohistochemistry (IHC)Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)Tumour mutational burden (TMB)Tumour-agnostic (tissue-agnostic) approval

people

1
Jim Valvano

Latest papers

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Latest papers · live from Europe PMC
Open in Europe PMC

Query for this cancer: (TITLE:"Cancer of unknown primary" OR ABSTRACT:"Cancer of unknown primary" OR TITLE:"CUP" OR ABSTRACT:"CUP" OR TITLE:"Occult primary" OR ABSTRACT:"Occult primary") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Cancer of unknown primary (CUP), not a curated reading list.

Connected

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technologies

8
Comprehensive genomic profilingDNA methylation profilingHistopathology & immunohistochemistryImmune checkpoint inhibitorsIMRT / IGRT (modern external beam)Liquid biopsy (ctDNA)PET/CTPlatinum agents

targets

4
BRAFHER2NTRKPD-1

drugs

5
ApprovedCytotoxic chemotherapy (platinum)
Carboplatin
Not mapped hereCytotoxic regimen
Gemcitabine + cisplatin
ApprovedMonoclonal antibody (anti-PD-1)
Nivolumab · Opdivo / Opdivo Qvantig (SC)
ApprovedCytotoxic chemotherapy (taxane)
Paclitaxel / nab-paclitaxel · Taxol / Abraxane
ApprovedMonoclonal antibody (anti-PD-1)
Pembrolizumab · Keytruda / Keytruda Qlex (SC)

companies

3
Bristol Myers SquibbFoundation Medicine (Roche)Roche / Genentech

terms

4
Immunohistochemistry (IHC)Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)Tumour mutational burden (TMB)Tumour-agnostic (tissue-agnostic) approval

people

1
Jim Valvano