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Clinical and molecular characterization of HER2 amplified-pancreatic cancer.

ABSTRACT: BACKGROUND: Pancreatic cancer is one of the most lethal and molecularly diverse malignancies. Repurposing of therapeutics that target specific molecular mechanisms in different disease types offers potential for rapid improvements in outcome. Although HER2 amplification occurs in pancreatic cancer, it is inadequately characterized to exploit the potential of anti-HER2 therapies. METHODS: HER2 amplification was detected and further analyzed using multiple genomic sequencing approaches. Standardized reference laboratory assays defined HER2 amplification in a large cohort of patients (n = 469) with pancreatic ductal adenocarcinoma (PDAC). RESULTS: An amplified inversion event (1 MB) was identified at the HER2 locus in a patient with PDAC. Using standardized laboratory assays, we established diagnostic criteria for HER2 amplification in PDAC, and observed a prevalence of 2%. Clinically, HER2- amplified PDAC was characterized by a lack of liver metastases, and a preponderance of lung and brain metastases. Excluding breast and gastric cancer, the incidence of HER2-amplified cancers in the USA is >22,000 per annum. CONCLUSIONS: HER2 amplification occurs in 2% of PDAC, and has distinct features with implications for clinical practice. The molecular heterogeneity of PDAC implies that even an incidence of 2% represents an attractive target for anti-HER2 therapies, as options for PDAC are limited. Recruiting patients based on HER2 amplification, rather than organ of origin, could make trials of anti-HER2 therapies feasible in less common cancer types.

SUBMITTER: Chou A

PROVIDER: S-EPMC3978667 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Clinical and molecular characterization of HER2 amplified-pancreatic cancer.

Chou Angela A Waddell Nicola N Cowley Mark J MJ Gill Anthony J AJ Chang David K DK Patch Ann-Marie AM Nones Katia K Wu Jianmin J Pinese Mark M Johns Amber L AL Miller David K DK Kassahn Karin S KS Nagrial Adnan M AM Wasan Harpreet H Goldstein David D Toon Christopher W CW Chin Venessa V Chantrill Lorraine L Humphris Jeremy J Mead R Scott RS Rooman Ilse I Samra Jaswinder S JS Pajic Marina M Musgrove Elizabeth A EA Pearson John V JV Morey Adrienne L AL Grimmond Sean M SM Biankin Andrew V AV

Genome medicine 20130831 8

<h4>Background</h4>Pancreatic cancer is one of the most lethal and molecularly diverse malignancies. Repurposing of therapeutics that target specific molecular mechanisms in different disease types offers potential for rapid improvements in outcome. Although HER2 amplification occurs in pancreatic cancer, it is inadequately characterized to exploit the potential of anti-HER2 therapies.<h4>Methods</h4>HER2 amplification was detected and further analyzed using multiple genomic sequencing approache ...[more]

PMID: 24004612

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Project description:Pancreatic ductal adenocarcinoma is a highly lethal malignancy, which has now become the seventh most common cause of cancer death in the world, with the highest mortality rates in Europe and North America. In the past 30 years, there has been some progress in 5-year survival (rates increasing from 2.5 to 10%), but this is still extremely poor compared to all other common cancer types. Targeted therapies for advanced pancreatic cancer based on actionable mutations have been disappointing, with only 3-5% showing even a short clinical benefit. There is, however, a molecular diversity beyond mutations in genes responsible for producing classical canonical signaling pathways. Pancreatic cancer is almost unique in promoting an excess production of other components of the stroma, resulting in a complex tumor microenvironment that contributes to tumor development, progression, and response to treatment. Various transcriptional subtypes have also been described. Most notably, there is a strong alignment between the Classical/Pancreatic progenitor and Quasi-mesenchymal/Basal-like/Squamous subtype signatures of Moffit, Collinson, Bailey, Puleo, and Chan-Seng-Yue, which have potential clinical impact. Sequencing of epithelial cell populations enriched by laser capture microscopy combined with single-cell RNA sequencing has revealed the potential genomic evolution of pancreatic cancer as being a consequence of a gene expression continuum from mixed Basal-like and Classical cell populations within the same tumor, linked to allelic imbalances in mutant KRAS, with metastatic tumors being more copy number-unstable compared to primary tumors. The Basal-like subtype appears more chemoresistant with reduced survival compared to the Classical subtype. Chemotherapy and/or chemoradiation will also enrich the Basal-like subtype. Squamous/Basal-like programs facilitate immune infiltration compared with the Classical-like programs. The immune infiltrates associated with Basal and Classical type cells are distinct, potentially opening the door to differential strategies. Single-cell and spatial transcriptomics will now allow single cell profiling of tumor and resident immune cell populations that may further advance subtyping. Multiple clinical trials have been launched based on transcriptomic response signatures and molecular subtyping including COMPASS, Precision Promise, ESPAC6/7, PREDICT-PACA, and PASS1. We review several approaches to explore the clinical relevance of molecular profiling to provide optimal bench-to-beside translation with clinical impact.

Dataset Information

Clinical and molecular characterization of HER2 amplified-pancreatic cancer.

Publications

Clinical and molecular characterization of HER2 amplified-pancreatic cancer.

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