Teaching pack: Cancer of unknown primary (CUP)

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.

• 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.

1. 1979Cisplatin-based therapy cures some 'poorly differentiated carcinoma of unknown primary' (Greco, Hainsworth)
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)
6. 2023ESMO guideline recommends comprehensive genomic profiling
7. 2024CUPISCO: molecularly guided therapy improves PFS (Lancet)

• Comprehensive genomic profiling (technology)
• Liquid biopsy (ctDNA) (technology)
• DNA methylation profiling (technology)
• Pembrolizumab (product)

• 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.

1. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
2. What fraction of advanced melanoma patients on nivolumab plus ipilimumab are alive at ten years?
   Answer

   About 43% overall survival (CheckMate 067), with melanoma-specific survival around 52%.
3. What is a liquid biopsy used for in cancer care today?
   Answer

   A blood test reading tumour DNA fragments: to genotype a tumour when tissue is scarce, to track resistance mutations (EGFR T790M, ESR1), to detect minimal residual disease after surgery, and, experimentally, to screen for cancer.
4. Which cooperative group ran the trial that put nivolumab into first-line Hodgkin lymphoma?
   Answer

   SWOG (S1826, nivolumab-AVD vs BV-AVD), leading to FDA approval in March 2026 for ages 12 and over.

• 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/
• Wikipedia: https://en.wikipedia.org/wiki/Cancer_of_unknown_primary_origin
• Guideline: https://doi.org/10.1016/j.annonc.2022.11.013
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1451
• Guideline: https://doi.org/10.1016/S0140-6736(24)00814-6