Background: 2-4% of newly diagnosed cases of malignant disease involve cancer of unknown primary (CUP). This mixed entity is one of the 6 most common types of malignant disease in Germany. Highly refined treatment strategies can now be offered to patients with CUP. Methods: This review is based on pertinent publications retrieved by a selective search in PubMed with an emphasis on articles from the past decade. The current guidelines and recommendations of specialty societies were also considered in the evaluation. Results: CUP most commonly manifests itself as metastases to the lymph nodes, lungs, liver, or bones. With the aid of imaging studies, including functional hybrid imaging and further medical examination, a primary tumor can be discovered in up to 40% of patients initially diagnosed with CUP. Immunohistochemistry guided by histomorphology often enables precise characterization of the lesion and can be supplemented, in selected cases, by molecular-genetic diagnostic evaluation. The most commonly detected types of primary tumor are cancers of the lung, pancreas, liver, and biliary system. For patients with local metastases, surgical resection or radiotherapy with curative intent is usually indicated, sometimes in the framework of a multimodal treatment concept. The median 2-year survival of patients with disseminated CUP is only 20%. For such patients, specific types of systemic therapy are recommended on the basis of the diagnostic characterization of the disease. Immune-modulatory antibodies can be effective, particularly in the treatment of CUP that has been characterized with biomarkers, but should still be considered experimental at present. Conclusion: A combination of conventional and innovative diagnostic methods enables the provision of highly refined therapeutic strategies to patients with CUP who are undergoing treatment in interdisciplinary cancer centers.

Current guidelines recommend combination chemotherapy for treatment of patients with unfavorable cancer of unknown primary (CUP). Biomarker-guided targeted therapies may offer additional benefit. Data on the feasibility and effectiveness of comprehensive genomic biomarker profiling of CUP in a standard clinical practice setting are limited. This analysis included 156 patients with confirmed unfavorable CUP diagnosis according to ESMO guidelines, who were treated at the West German Cancer Center, Essen, Germany, from 2015 to 2021. Clinical parameters and outcome data were retrieved from the electronic hospital information system. Genomic biomarker analyses were performed in formalin-fixed paraffin-embedded tumor tissue whenever possible using the QIAseq Multimodal-Pancancer-Panel. Non-squamous histologies, high tumor burden, and age above 60 years associated with poor survival outcome. Tissue availability restricted comprehensive biomarker analyses to 50 patients (32%), reflecting a major limitation in the real-world setting. In those patients a total of 24 potentially actionable alterations were identified in 17 patients (34% of profiled patients, 11% of total population). The most prevalent biomarkers were high tumor mutational burden and BRCA-mutations. In a real-world setting precision medicine for patients with CUP is severely restricted by tissue availability, and a limited spectrum of actionable alterations. Progress for patients may require emphasizing the need for sufficient biopsies, and prospective exploration of blood-based biomarker profiling.

Cancer of unknown primary (CUP) is a heterogeneous entity with a limited prognosis. Novel prognostic markers are needed for patient stratification in prospective clinical trials exploring innovative therapies. Methods: In CUP patients treated at the West German Cancer Center Essen, the prognostic value of ¹⁸F-FDG PET/CT at the initial diagnostic workup was analyzed by comparing overall survival (OS) in patients who underwent ¹⁸F-FDG PET/CT with those who did not. Results: Of 154 patients with a CUP diagnosis, 76 underwent ¹⁸F-FDG PET/CT at the initial diagnostic workup. The median overall survival (OS) of the full analysis set was 20.0 mo. Within the PET/CT subgroup, an SUV_max above 20 was associated with significantly superior OS (median OS, not reached vs. 32.0 mo; hazard ratio, 0.261; 95% CI, 0.095–0.713; P = 0.009). Conclusion: Our retrospective work shows that an SUV_max above 20 on ¹⁸F-FDG PET/CT at the initial diagnostic workup is a favorable prognostic factor in patients with CUP. This finding deserves further prospective studies for validation. Visual Abstract

Purpose: In patients with metastatic non‐small cell lung cancer (NSCLC) with high programmed death‐ligand 1 (PD‐L1) expression, there is still a lack of biomarkers to identify patients with maximum benefit from first‐line treatment with checkpoint inhibitor therapy (CIT) alone. This work examines the impact of different ABO blood groups (BG) on the response to CIT monotherapy.Methods: Retrospective analysis of patients with stage IV NSCLC and high PD‐L1 expression (tumor proportional score/TPS ≥ 50%), receiving first‐line therapy with pembrolizumab alone or in combination with chemotherapy at the West German Cancer Center from 2017 to 2022. Study endpoints were overall survival (OS) and progression‐free survival (PFS).Results: Eighty‐two patients were included in the analysis. Twenty‐two patients (27%) received first‐line therapy with pembrolizumab alone (monoimmunotherapy cohort/MIC), of which seven patients (32%) had BGO. Sixty patients (73%) were treated with pembrolizumab combined with platinum‐based chemotherapy (chemoimmunotherapy cohort/CIC), of which 38 (63%) had BGO. In MIC, younger age and BGO were independent predictors of favorable OS (BGO vs. other ABO‐BG: HR 0.22, 95% CI: 0.1–0.9; p = 0.037; median OS 62 versus 19 months) and PFS (BGO vs. other ABO‐BG: HR 0.21, 95% CI: 0.1–0.8; p = 0.024; median PFS 39 vs. 4 months). There was no significant impact of ABO‐BG in patients treated with CIC. In support, a historical control group treated with chemotherapy alone also showed no prognostic impact of the ABO‐BG.Conclusion: BGO associates with favorable survival in patients with NSCLC receiving pembrolizumab monotherapy, but not in patients with chemo‐immunotherapy or chemotherapy. Further validation of this promising strategy for personalized decision‐making is warranted.

Purpose: Cancer of unknown primary (CUP) is a heterogeneous entity with limited overall survival (OS) in most patients. Prognostic biomarkers are needed, particularly for treatment stratification. We investigated the impact of programmed death-ligand 1 (PD-L1) expression as prognostic marker in immunotherapy-na & iuml;ve CUP patients. Methods: Clinical data from patients with confirmed CUP diagnosis according to ESMO guidelines, treated at the West German Cancer Center, Essen from 2015 to 2021, were analyzed. Patients treated with checkpoint inhibitors were excluded. PD-L1 expression was assessed in tumor tissues following established guidelines. Results: Of a cohort of 132 patients, 62 patients, including 30 patients with prognostically unfavorable CUP, met inclusion criteria and were evaluable for PD-L1 expression. Comparing PD-L1 Tumor Proportional Score (TPS) and Combined Positive Score (CPS) revealed almost complete concordance (96.2 %). Patients with PD-L1positive CUP (TPS >= 1 %; n = 36; 58 %) had superior overall survival (median not reached) as compared to patients with PD-L1-negative CUP (median 14 months, 95 %CI 10.0-18.0; HR 0.3, p < 0.001). The benefit of PDL1 positivity (n = 12; 40 %) was maintained in the unfavorable CUP subgroup (median 20 months, 95 %CI 3.0-37.0 versus 10 months, 95 %CI 3.1-16.9; HR 0.4, p = 0.032). In PD-L1-positive CUP there was a positive correlation between the level of PD-L1 expression and survival (TPS >= 50 %: median survival not reached, HR 0.1; TPS 1 to 49 %: OS: 77 months, HR 0.4). Conclusion: PD-L1 expression associates with favorable survival in checkpoint inhibitor-na & iuml;ve CUP patients. This implies a role of cancer immunity in CUP biology and may nominate PD-L1 for patient stratification in further studies and clinical care.

Pancreatic ductal adenocarcinoma (PDAC) comprises two clinically relevant molecular subtypes that are currently determined using tissue biopsies, which are spatially biased and highly invasive. We used whole transcriptome sequencing of 10 plasma samples with tumor‐informed subtypes, complemented by proteomic analysis for minimally invasive identification of PDAC subtype markers. Data were validated in independent large cohorts and correlated with treatment response and patient outcome. Differential transcript abundance analyses revealed 32 subtype‐specific, protein‐coding cell‐free RNA (cfRNA) transcripts. The subtype specificity of these transcripts was validated in two independent tissue cohorts comprising 195 and 250 cases, respectively. Three disease‐relevant cfRNA‐defined subtype markers (DEGS1, KDELC1, and RPL23AP7) that consistently associated with basal‐like tumors across all cohorts were identified. In both tumor and liquid biopsies, the overexpression of these markers correlated with poor survival. Moreover, elevated levels of the identified markers were linked to a poor response to systemic therapy and early relapse in resected patients. Our data indicate clinical applicability of cfRNA markers in determining tumor subtypes and monitoring disease recurrence.