Molecularly directed therapy in cancers of unknown primary: A systematic review and meta-analysis

Chris Labaki; Marc Eid; Ziad Bakouny; Charbel Hobeika; Razane El Hajj Chehade; Roy Chebel; Stergios Boussios; F Anthony Greco; Nicholas Pavlidis; Elie Rassy

doi:10.1016/j.ejca.2025.115447

Molecularly directed therapy in cancers of unknown primary: A systematic review and meta-analysis

Eur J Cancer. 2025 Jun 3:222:115447. doi: 10.1016/j.ejca.2025.115447. Epub 2025 Apr 30.

Authors

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
³ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁴ Department of Medicine, Cleveland Clinic Fairview Hospital, Cleveland, OH, USA.
⁵ Department of Surgery, University of Wisconsin, Madison, WI, USA.
⁶ Department of Medical Oncology, Medway NHS Foundation Trust, Gillingham, UK; Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, King's College London, London, UK; Kent and Medway Medical School, University of Kent, Canterbury, UK; Faculty of Medicine, Health and Social Care, Canterbury Christ Church University, Canterbury, UK.
⁷ Sarah Cannon Research Institute and Cancer Center, Tennessee Oncology, Nashville, TN, USA.
⁸ University of Ioannina, Ioannina, Greece.
⁹ Department of Medical Oncology, Gustave Roussy Institut, Villejuif, France. Electronic address: elie.el-rassy@gustaveroussy.fr.

PMID: 40318263
DOI: 10.1016/j.ejca.2025.115447

Abstract

Background: Cancers of unknown primary (CUP) are associated with a high mortality rate, with limited therapeutic options available and platinum-based chemotherapy recommended as standard of care. Over the past decade, molecularly guided approaches aiming to adapt treatment strategies in patients with CUP based on predicted site of origin (site-specific approach) or genomic characteristics (tissue-agnostic approach) have been explored in clinical studies, with heterogenous findings identified.

Methods: PubMed/MEDLINE, Scopus, Web of Science, Embase, the Cochrane Library, and conference abstracts of American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) meetings were searched from inception until October 2024, for clinical studies that assessed molecularly directed therapies (MDT) in the management of patients with CUP, as compared to empiric treatment. A meta-analysis using a random-effects model and the inverse variance method was conducted, with a subgroup analysis by study design (randomized versus non-randomized). The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS).

Results: Six studies encompassing 1644 patients were included, of which 4 randomized controlled trials. A significant improvement of OS in patients with CUP treated with MDT versus empiric therapy was identified (HR: 0.75, 95 %CI: 0.62-0.91), with consistent results seen across randomized (HR: 0.86, 95 %CI: 0.73-1.01) and non-randomized (HR: 0.50, 95 %CI: 0.26-0.96). Similarly, PFS was significantly improved with MDT, as compared to empiric treatment (HR: 0.79, 95 %CI: 0.67-0.94).

Conclusion: The use of MDT is associated with improved survival outcomes among patients with CUP. These findings provide evidence that support the role of MDT as a potential novel standard of care in CUP treatment.

Keywords: Cancer of unknown primary; Genomics; Molecularly-directed therapies; Precision medicine.

Publication types

Systematic Review
Meta-Analysis

MeSH terms

Humans
Molecular Targeted Therapy* / methods
Neoplasms, Unknown Primary* / drug therapy
Neoplasms, Unknown Primary* / genetics
Neoplasms, Unknown Primary* / mortality
Neoplasms, Unknown Primary* / pathology
Progression-Free Survival