title: Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary withPDL1amplification.
abstract: Identification of the tissue of origin in cancer of unknown primary (CUP) poses a diagnostic challenge and is critical for directing site-specific therapy. Currently, clinical decision-making in patients with CUP primarily relies on histopathology and clinical features. Comprehensive molecular profiling has the potential to contribute to diagnostic categorization and, most importantly, guide CUP therapy through identification of actionable lesions. We here report the case of an advanced-stage malignancy initially mimicking poorly differentiated soft-tissue sarcoma that did not respond to multiagent chemotherapy. Molecular profiling within a clinical whole-exome and transcriptome sequencing program revealed a heterozygous, highly amplifiedKRASG12S mutation, compound-heterozygousTP53mutation/deletion, high mutational load, and focal high-level amplification of Chromosomes 9p (includingPDL1[CD274] andJAK2) and 10p (includingGATA3). Integrated analysis of molecular data and histopathology provided a rationale for immune checkpoint inhibitor (ICI) therapy with pembrolizumab, which resulted in rapid clinical improvement and a lasting partial remission. Histopathological analyses ruled out sarcoma and established the diagnosis of a poorly differentiated adenocarcinoma. Although neither histopathology nor molecular data were able to pinpoint the tissue of origin, our analyses established several differential diagnoses including triple-negative breast cancer (TNBC). We analyzed 157 TNBC samples from The Cancer Genome Atlas, revealingPDL1copy number gains coinciding with excessivePDL1mRNA expression in 24% of cases. Collectively, these results illustrate the impact of multidimensional tumor profiling in cases with nondescript histology and immunophenotype, show the predictive potential ofPDL1amplification for immune checkpoint inhibitors (ICIs),and suggest a targeted therapeutic strategy in Chromosome 9p24.1/PDL1-amplified cancers.
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;; Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany;; German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gröschel
authors.affiliation: Klinikum am Eichert, Department of Hematology, Oncology and Infectious Diseases, Göppingen 73035, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Bommer
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg 69120, Germany;; Division Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg 69120, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hutter
authors.affiliation: Institute of Pathology, Charité University Hospital, Berlin 10117, Germany;; DKTK, Berlin 10117, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Budczies
authors.affiliation: Department of Radiology, DKFZ, Heidelberg 69120, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Bonekamp
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;; Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany;; German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Heining
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;; Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany;; German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Horak
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg 69120, Germany;; Division Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg 69120, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Fröhlich
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg 69120, Germany;; Division Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg 69120, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Uhrig
authors.affiliation: Division of Theoretical Bioinformatics, DKFZ, Heidelberg 69120, Germany;; Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology and BioQuant, Heidelberg University, Heidelberg 69120, Germany;; Department of Pediatric Immunology, Hematology and Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hübschmann
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;; German Cancer Consortium (DKTK), Heidelberg 69120, Germany;; DKFZ, Heidelberg Center for Personalized Oncology (HIPO), Heidelberg 69120, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Geörg
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;; German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Richter
authors.affiliation: Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Munich 81675, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pfarr
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;; German Cancer Consortium (DKTK), Heidelberg 69120, Germany;; DKFZ, Heidelberg Center for Personalized Oncology (HIPO), Heidelberg 69120, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Pfütze
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg 69120, Germany;; Genomics and Proteomics Core Facility, High Throughput Sequencing Unit, DKFZ, Heidelberg 69120, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wolf
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg 69120, Germany;; Institute of Pathology, Heidelberg University Hospital and NCT Heidelberg, Heidelberg 69120, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Department of Medical Oncology, NCT Heidelberg, Heidelberg University Hospital, Heidelberg 69120, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;; Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany;; German Cancer Consortium (DKTK), Heidelberg 69120, Germany;; DKFZ, Heidelberg Center for Personalized Oncology (HIPO), Heidelberg 69120, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg 69120, Germany;; Division Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg 69120, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;; Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany;; German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Glimm
authors.affiliation: Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Munich 81675, Germany;; DKTK, Munich 80539, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Institute of Pathology, Heidelberg University Hospital and NCT Heidelberg, Heidelberg 69120, Germany;; Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;; Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany;; German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
mesh_terms: D000328:Adult; D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis; D000066491:Clinical Decision-Making / Q000379:methods; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D009154:Mutation; D009367:Neoplasm Staging / Q000379:methods; D009382:Neoplasms, Unknown Primary / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C117307:KRAS protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D016283:Proto-Oncogene Proteins p21(ras)
keywords: multifocal breast carcinoma; neoplasm of the gastrointestinal tract