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Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification
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 profi...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111004/ https://www.ncbi.nlm.nih.gov/pubmed/27900363 http://dx.doi.org/10.1101/mcs.a001180 |
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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 |
author_facet | 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 |
author_sort | Gröschel, Stefan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5111004 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-51110042016-11-29 Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification 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 Cold Spring Harb Mol Case Stud Research Report 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. Cold Spring Harbor Laboratory Press 2016-11 /pmc/articles/PMC5111004/ /pubmed/27900363 http://dx.doi.org/10.1101/mcs.a001180 Text en © 2016 Gröschel et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited. |
spellingShingle | Research Report 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 Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification |
title | Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification |
title_full | Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification |
title_fullStr | Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification |
title_full_unstemmed | Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification |
title_short | Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification |
title_sort | integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with pdl1 amplification |
topic | Research Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111004/ https://www.ncbi.nlm.nih.gov/pubmed/27900363 http://dx.doi.org/10.1101/mcs.a001180 |
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