Cancers of unknown primary site (CUPs) represent a heterogeneous group of metastatic tumors, which accounts for 3-5% of malignancies. Due to the poor prognosis and limited local and systemic treatment options, there is an urgent need for improvement of molecularly driven treatment strategies. We investigated the molecular profile and clinical course of 70 patients enrolled in a prospective precision oncology registry trial conducted by the National Center for Tumor Diseases (NCT) Heidelberg/Dresden and the German Cancer Consortium (DKTK) that addresses younger adults with advanced-stage cancer across histologies as well as patients with rare tumors (NCT/DKTK MASTER). Molecular analyses included whole genome sequencing (WGS, n=29), whole exome sequencing (WES, n=41) and transcriptome analysis (n=55). All patients were diagnosed with CUP-syndrome, 61/70 (87.1%) of diagnoses fulfilled the ESMO Clinical Practice Guidelines. Progression free survival (PFS) of the first treatment based on MASTER (PFS2) was compared to the PFS of the last prior systemic treatment (PFS1) in each individual patient. Within the coding sequence, we identified 0 to 1386 nonsynonymous point mutations (SNVs, median=41) and 0 to 38 insertions/deletions (indels, median=3) per sample. Hypermutation (≥100 SNVs and indels) was observed in 14 samples. Mutations of TP53 and KRAS were significantly enriched. Analysis of copy-number changes (CNVs) was performed in 51 samples (27 WGS and 24 WES) and revealed complex CNV profiles in most cases. Gains and losses involved single arms or whole chromosomes. Gains in chromosome 8q, 1q and 7 and losses in chromosome 6q and 17p occurred in more than 40% of the patients. Fusions of EML4-ALK and FGFR2 were found in three and six cases, respectively. In one case, pathological reevaluation for NUT midline carcinoma was recommended based on a NUTM1-MXI1 fusion. In total, pathological reevaluation based on characteristic genetic events was recommended in five cases. Germline analysis of 70 cases revealed five pathogenic variants (ACMG Class 5) in CHEK2, BRCA1, CDKN2A, NBN and ERCC3. In addition, one likely pathogenic variant (ACMG Class 4) was found in FH. The molecular tumor board recommended targeted therapy in 56/70 (80.0%) patients which could be applied in 20/56 (35.7%) cases. The molecularly driven treatment approaches translated into a median PFS2/1 ratio of 2.25 (n=17). Median PFS1 was 89 days (range 31-304, n=17) compared to a median PFS2 of 180 days (range 50-805, n=17). For three patients in which PFS1 could not be determined median PFS2 was 305 days (range 182-336). We demonstrate that a comprehensive molecular analysis of CUPs provides clinically relevant information and additional, molecularly stratified treatment approaches in many cases. These targeted therapies can be highly beneficial even in heavily pretreated patients.
Citation Format: Maximilian Werner, Lino Möhrmann, Małgorzata Oleś, Andreas Mock, Arne Jahn, Simon Kreutzfeldt, Sebastian Uhrig, Martina Fröhlich, Barbara Hutter, Daniela Richter, Gina Rüter, Ivan Jelas, Rainer Hamacher, Johanna Falkenhorst, Sebastian Wagner, Christian Brandts, Melanie Börries, Anna Illert, Klaus Metzeler, Benedikt Westphalen, Alexander Desuki, Thomas Kindler, Albrecht Stenzinger, Evelin Schröck, Benedikt Brors, Peter Horak, Christoph Heining, Stefan Fröhling, Hanno Glimm. Genomics based personalized oncology of cancer of unknown primary [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 820.
