SEOM-GECOD clinical guideline for cancer of unknown primary - update 2025

Sep 22, 2026

Cancer of unknown primary (CUP) denotes a diverse set of tumors presenting as metastases when a standard diagnostic work-up cannot determine the tissue of origin. High-level evidence supports routine assessment of actionable genomic alterations in CUP patients to enable molecularly guided therapy. This 2025-updated guideline summarizes diagnostic pathways and treatment options and highlights molecular medicine advances aimed at improving the historically poor outcomes of this disease entity.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Introduction

Methodology

Summary of recommendations (Table 1)

Clinical and Translational Oncology (2026) 28:1610–1623 [https://doi.org/10.1007/s12094-026-04241-8](https://doi.org/10.1007/s12094-026-04241-8) SEOM‑GECOD clinical guideline for cancer of unknown primary (update 2025) Ferrán Losa1 · Olatz Etxaniz2 · Alejandra Giménez3 · Paula Gomila4 · Lara Iglesias5 · Federico Longo6 · Esteban Nogales7 · Antonio Sánchez8 · Gemma Soler9 · Isaura Fernández10 Received: 12 January 2026 / Accepted: 14 January 2026 / Published online: 10 March 2026 © The Author(s) 2026 Abstract Cancer of unknown primary (CUP) is defined as a heterogeneous group of tumors that appear as metastases for which a standard diagnostic work-up fails to identify the tissue of origin. There is now high-level evidence showing that actionable genomic alterations should be routinely determined in patients with CUP to enable molecularly guided therapy as appropriate. In this guideline (updated in 2025), we summarize diagnostic processes and therapeutic options for CUP, as well as new developments in molecular medicine that will help to improve the poor outcomes associated with this unique disease entity. Keywords Cancer · Diagnosis · Treatment · Unknown primary site Introduction Cancer of unknown primary (CUP) represents a heterogeneous group of histologically confirmed metastatic carcinomas or undifferentiated neoplasms for which a thorough diagnostic work-up (including clinical history, physical examination, blood tests and biochemistry, and computed tomography [CT]) cannot identify the origin of the primary tumor [1, 2] . CUP currently accounts for approximately 2–5% of cancer diagnoses globally [2] . Probably because of improvements in diagnostic techniques for the identification of primary tumor sites, the incidence of CUP has been declining, * Ferrán Losa[flosa@csi.cat](flosa@csi.cat) Olatz Etxaniz [oetxaniz@iconcologia.net](oetxaniz@iconcologia.net) Alejandra Giménez [sandragimenezortiz@yahoo.es](sandragimenezortiz@yahoo.es)[ ](sandragimenezortiz@yahoo.es)Paula Gomila [pgomila@salud.aragon.es](pgomila@salud.aragon.es) Lara Iglesias [Laracarmen.iglesias@salud.madrid.org](Laracarmen.iglesias@salud.madrid.org)[ ](Laracarmen.iglesias@salud.madrid.org)Federico Longo[fedelongomunoz@hotmail.com](fedelongomunoz@hotmail.com) Esteban Nogales [esteban.nogales@gmail.com](esteban.nogales@gmail.com) Antonio Sánchez [acsr71@hotmail.com](acsr71@hotmail.com) Gemma Soler [gsoler@iconcologia.net](gsoler@iconcologia.net) Isaura Fernández [isaura.fernandez.perez@sergas.es](isaura.fernandez.perez@sergas.es) 1 Hospital de Sant Joan Despí Moisés Broggi-ICO Hospitalet, Barcelona, Spain 2 Hospital Germans Trias I Pujol-ICO Badalona, Barcelona, Spain 3 Hospital Lluís Alcanys de Xàtiva, Valencia, Spain 4 Hospital Miguel Servet (Zaragoza)/H, de Barbastro, Spain 5 Hospital Universitario 12 de Octubre, Madrid, Spain 6 Hospital Universitario Ramón y Cajal, IRYCIS, CIBERONC, Madrid, Spain 7 Hospital Universitario Virgen Macarena, Seville, Spain 8 Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain 9 Hospital Germans Trias i Pujol/Hospital Mataró, ICO-Badalona, Barcelona, Spain 10 Hospital Álvaro Cunqueiro-IIGS, Vigo, Spain but it remains a leading cause of cancer-related death worldwide [1, 2] . Given the poor prognosis of CUP, it is necessary to incorporate molecular testing into the diagnostic work-up to help predict the putative primary (tissue of origin) and identify actionable therapeutic targets, thereby facilitating site-specific and molecularly guided therapy (MGT) options [2, 3] . Given recent advances in molecular profiling and MGT, the optimal management of CUP is changing rapidly [4, 5] . This updated guideline incorporates data from recently published milestone trials demonstrating the potential of MGT in the evolving management of CUP [6, 7] . Methodology This updated guideline has been developed with the consensus of ten oncologists highly exp

FAQs

What is cancer of unknown primary (CUP)?

CUP refers to a heterogeneous group of histologically confirmed metastatic carcinomas or undifferentiated neoplasms in which a thorough diagnostic work-up cannot identify the origin of the primary tumor.

Why does the guideline emphasize molecular profiling in CUP?

Actionable genomic alterations should be routinely determined to support molecularly guided therapy and to help predict the putative primary site and actionable therapeutic targets.

What treatment approaches does Table 1 recommend for tumor-agnostic targeted therapy or immunotherapy?

The guideline recommends tumor-agnostic targeted treatments and immune checkpoint inhibitors according to biomarker status, including NTRK inhibitors, PD-1/PD-L1 inhibitors for MSI-H or TMB-H, RET inhibitors for RET fusions, BRAF plus MEK inhibitors for BRAF mutations, pan-FGFR TKIs for FGFR alterations, and CUP-specific indications such as ALK TKIs for ALK fusions.

Sep 22, 2026

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