Real-World Biomarker-Associated Therapy in Metastatic Carcinoma of Unknown Primary: Prevalence, Impact, and Outcomes

Carcinoma of unknown primary (CUP) represents a heterogeneous group of cancers with unidentified primary tumor sites, accounting for 3% to 5% of all cancers. CUP is characterized by aggressive biology, frequent metastatic presentation, and poor prognosis, with standard chemotherapy offering limited efficacy. Comprehensive molecular profiling offers the potential to identify actionable biomarkers and guide treatment in this challenging setting.

We conducted a retrospective analysis of 8,809 formalin-fixed, paraffin-embedded tumor samples from patients with CUP (2009-2023) who underwent DNA (592-gene panel and whole-exome) and RNA (whole-transcriptome) sequencing, as well as immunohistochemistry (IHC). Potentially actionable biomarkers were identified and correlated with treatment and survival outcomes.

Of the tumor samples, 62% of CUP tumors harbored ≥1 potentially actionable biomarker. Biomarkers for agents approved across all tumor types were present in 24.2% of cases, including tumor mutational burden-high (21.1%) and deficient mismatch repair/microsatellite instability-high (3.3%). Biomarkers associated with therapies approved for specific tumor types, such as PD-L1 IHC positivity (24.4%), homologous recombination deficiency (20.3%), and genomic loss of heterozygosity, were detected in 55.4% of cases. Patients who received biomarker-associated therapies demonstrated significantly longer median overall survival (mOS) than those who did not (17.7 vs 7.0 months; hazard ratio, 0.560; P<.0001). Survival benefits were observed across all biomarker subgroups, including immune checkpoint inhibitors and tumor-specific targeted therapies. Notably, ICIs improved mOS even in patients who were biomarker-negative (15.2 vs 8.6 months; P<.0001).

Molecular profiling revealed a high prevalence of actionable biomarkers in CUP and was associated with improved survival with guided therapy. These findings support the integration of molecular profiling into routine clinical practice for CUP management to enable precision oncology and improve patient outcomes. Further prospective validation is warranted.