Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification
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Author
Gröschel, Stefan
Bommer, Martin
Hutter, Barbara
Budczies, Jan
Bonekamp, David
Heining, Christoph
Horak, Peter
Fröhlich, Martina
Uhrig, Sebastian
Hübschmann, Daniel
Geörg, Christina
Richter, Daniela
Pfarr, Nicole
Pfütze, Katrin
Wolf, Stephan
Schirmacher, Peter
Jäger, Dirk
von Kalle, Christof
Brors, Benedikt
Glimm, Hanno
Weichert, Wilko
Stenzinger, Albrecht
Fröhling, Stefan
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1101/mcs.a001180Metadata
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Gröschel, S., M. Bommer, B. Hutter, J. Budczies, D. Bonekamp, C. Heining, P. Horak, et al. 2016. “Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification.” Cold Spring Harbor Molecular Case Studies 2 (6): a001180. doi:10.1101/mcs.a001180. http://dx.doi.org/10.1101/mcs.a001180.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111004/pdf/Terms of Use
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