KONGRESSBERICHT

ESP 2024
Updates on Cancer of Unknown Primary – Highlights from the Congress of the European Society of Pathology (ESP) 2024 and beyond
Cancer of unknown primary (CUP) represents a heterogeneous group of metastatic epithelial or undifferentiated neoplasms where the primary tumour remains undetectable despite a standardized diagnostic evaluation. It is a rare condition accounting for less than 5% of all cancers and poses unique diagnostic and therapeutic challenges (1).
CUP can only be diagnosed after a standardized diagnostic multidisciplinary work-up, including clinical, histopathological and radiological evaluation, has failed to identify a primary tumor. The first step of the histopathological evaluation is lineage-classification and the exclusion of a nonepithelial malignancy such as a lymphoma, melanoma, sarcoma or mesothelioma. After lineage classification, a stepwise approach, including CK7 and CK20 staining patterns for adenocarcinomas, and the use of additional immunohistochemical markers, should be employed to identify a primary tumor. Subsequently, a multidisciplinary team should correlate pathological, clinical and imaging findings to determine whether any of the radiologically visible lesions might represent the primary tumor (1). The importance of this standardized diagnostic approach has been highlighted by two studies which showed that 1525% of patients with a metastasized malignancy, where CUP was suspected initially, did not qualify for a definitive CUP diagnosis after expert review (2,3). Prognostically, CUP is classified into favourable and unfavourable subgroups. Favourable CUP includes single site and oligometastatic CUP that can be treated with locally ablative therapy. In addition, a group of favourable CUPs are characterized by specific clinico-pathological constellations, closely resembling a specific primary tumor, so that site-specific therapy can be employed. For example, breast-like CUP is defined as an isolated axillary lymph node metastasis of a carcinoma histologically compatible with breast cancer in the absence of a primary breast tumor. Conversely, unfavourable CUP comprises most patient cases (80%) and is characterized by a poor prognosis (1). Traditionally, standard of care treatment for patients with unfavourable CUP has been platinum-based chemotherapy (1). However, genomic profiling of 464 unfavourable adenocarcinoma or undifferentiated CUP samples has revealed that up to one third of patients carry potentially targetable genomic alterations (4). Recently published data from the CUPISCO trial has assessed the potential of molecularly guided therapy. CUPISCO is a randomized, multi-

center trial that analyzed the efficacy of molecularly guided therapy (MGT) vs. standard (platinum-based) chemotherapy in patients with newly diagnosed, treatment-naïve unfavourable non-squamous CUP (5). After three initial cycles of standard first-line chemotherapy, patients who reached disease control were randomly assigned to MGT or continuation of chemotherapy. Within the MGT group patients with a targetable genomic alteration received molecularly targeted therapy, while patients without a targetable alteration received chemotherapy and atezolizumab. MGT resulted in improved median progression-free survival (PFS) compared to standard chemotherapy (median PFS 6.1 vs 4.4 months respectively, HR 0.72), particularly for patients with a targetable genomic alteration (median PFS 8.1 months). For patients with refractory unfavourable CUP, two recent non-randomized trials with limited sample sizes have indicated that a subgroup of patients may benefit from immune checkpoint inhibitor therapy with high tumor mutational burden and microsatellite instability as potential predictive biomarkers (6,7). In conclusion, CUP is a rare and heterogeneous group of metastasized neoplasms, which can only be diagnosed through a standardized and multidisciplinary diagnostic approach. The findings of the CUPISCO trial suggest that unfavourable CUP patients should receive genomic profiling to identify a potential therapeutic target.
Author: Dr. Viola Vetter, Universitätsspital Zürich (USZ) Mentor: Laurence de Leval, Centre Hospitalier Universitaire Vaudois CHUV
References: 1. Kramer A et al.: Cancer of unknown primary: ESMO Clinical Practice Guideline
for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(3):228–46. 2. Pauli C et al.: A challenging task: Identifying patients with cancer of unknown
primary (CUP) according to ESMO guidelines: The CUPISCO trial experience. Oncologist. 2021;26(5):e769–e79. 3. Pisacane A et al.: Real-world histopathological approach to malignancy of undefined primary origin (MUO) to diagnose cancers of unknown primary (CUPs). Virchows Arch. 2023;482(3):463–75. 4. Westphalen CB et al.: Baseline mutational profiles of patients with carcinoma of unknown primary origin enrolled in the CUPISCO study. ESMO Open. 2023;8(6):102035. 5. Kramer A et al.: Molecularly guided therapy versus chemotherapy after disease control in unfavourable cancer of unknown primary (CUPISCO): An open-label, randomised, phase 2 study. Lancet. 2024;404(10452):527–39. 6. Pouyiourou M et al.: Nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: A phase II trial. Nat Commun. 2023;14(1):6761. 7. Tanizaki J et al.: Open-label phase II study of the efficacy of nivolumab for cancer of unknown primary. Ann Oncol. 2022;33(2):216–26.

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