Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification
- Stefan Gröschel1,2,3,19,
- Martin Bommer4,19,
- Barbara Hutter3,5,
- Jan Budczies6,7,
- David Bonekamp8,
- Christoph Heining1,2,3,
- Peter Horak1,2,3,
- Martina Fröhlich3,5,
- Sebastian Uhrig3,5,
- Daniel Hübschmann9,10,11,
- Christina Geörg1,3,12,
- Daniela Richter1,3,
- Nicole Pfarr13,
- Katrin Pfütze1,3,12,
- Stephan Wolf3,14,
- Peter Schirmacher3,15,
- Dirk Jäger16,
- Christof von Kalle1,2,3,12,
- Benedikt Brors3,5,
- Hanno Glimm1,2,3,
- Wilko Weichert13,17,
- Albrecht Stenzinger15,18,19 and
- Stefan Fröhling1,2,3,19
- 1Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;
- 2Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany;
- 3German Cancer Consortium (DKTK), Heidelberg 69120, Germany;
- 4Klinikum am Eichert, Department of Hematology, Oncology and Infectious Diseases, Göppingen 73035, Germany;
- 5Division Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg 69120, Germany;
- 6Institute of Pathology, Charité University Hospital, Berlin 10117, Germany;
- 7DKTK, Berlin 10117, Germany;
- 8Department of Radiology, DKFZ, Heidelberg 69120, Germany;
- 9Division of Theoretical Bioinformatics, DKFZ, Heidelberg 69120, Germany;
- 10Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology and BioQuant, Heidelberg University, Heidelberg 69120, Germany;
- 11Department of Pediatric Immunology, Hematology and Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany;
- 12DKFZ, Heidelberg Center for Personalized Oncology (HIPO), Heidelberg 69120, Germany;
- 13Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Munich 81675, Germany;
- 14Genomics and Proteomics Core Facility, High Throughput Sequencing Unit, DKFZ, Heidelberg 69120, Germany;
- 15Institute of Pathology, Heidelberg University Hospital and NCT Heidelberg, Heidelberg 69120, Germany;
- 16Department of Medical Oncology, NCT Heidelberg, Heidelberg University Hospital, Heidelberg 69120, Germany;
- 17DKTK, Munich 80539, Germany;
- 18Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA
- Corresponding authors: stefan.groeschel{at}nct-heidelberg.de; stefan.froehling{at}nct-heidelberg.de
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↵19 These authors contributed equally to this work.
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 amplified KRAS G12S mutation, compound-heterozygous TP53 mutation/deletion, high mutational load, and focal high-level amplification of Chromosomes 9p (including PDL1 [CD274] and JAK2) and 10p (including GATA3). 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, revealing PDL1 copy number gains coinciding with excessive PDL1 mRNA 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 of PDL1 amplification for immune checkpoint inhibitors (ICIs), and suggest a targeted therapeutic strategy in Chromosome 9p24.1/PDL1-amplified cancers.
Footnotes
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[Supplemental material is available for this article.]
- Received April 27, 2016.
- Accepted August 16, 2016.
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