Diagnostic pathology of early systemic cancer

TY - JOUR

T1 - Diagnostic pathology of early systemic cancer

T2 - ERBB2 gene amplification in single disseminated cancer cells determines patient survival in operable esophageal cancer

AU - Hoffmann, Martin

AU - Pasch, Sophie

AU - Schamberger, Thomas

AU - Maneck, Matthias

AU - Möhlendick, Birte

AU - Schumacher, Sarah

AU - Brockhoff, Gero

AU - Knoefel, Wolfram Trudo

AU - Izbicki, Jakob

AU - Polzer, Bernhard

AU - Stoecklein, Nikolas H

AU - Klein, Christoph A

N1 - © 2017 UICC.

PY - 2018/2/15

Y1 - 2018/2/15

N2 - Early metastatic dissemination and evolution of disseminated cancer cells (DCCs) outside the primary tumor is one reason for the failure of adjuvant therapies because it generates molecular genotypes and phenotypes different from primary tumors, which still underlie therapy decisions. Since ERBB2 amplification in esophageal DCCs but not in primary tumor cells predict outcome, we aimed to establish an assay with diagnostic reliability for single DCCs or circulating tumor cells. For this, we evaluated copy number alterations of more than 600 single DCCs from multiple cancer types to define reference regions suitable for quantification of target regions, such as ERBB2. We then compared ERBB2 quantitative PCR (qPCR) measurements with fluorescent in situ hybridization (FISH) data of various breast cancer cell lines and identified the aberration-calling threshold. The method was applied to two independent cohorts of esophageal cancer patients from Hamburg (n = 59) and Düsseldorf (n = 53). We found a high correlation between the single cell qPCR assay and the standard FISH assay (R = 0.98) and significant associations between amplification and survival for both patient cohorts (Hamburg (HH), p = 0.033; Düsseldorf (D), p = 0.052; pooled HH + D, p = 0.002) when applied to DCCs of esophageal cancer patients. Detection of a single ERBB2-amplified DCC was the most important risk factor for death from esophageal cancer (relative risk = 4.22; 95% CI = 1.91-9.32; p < 0.001). In our study, we detected ERBB2-amplified cells in 7% of patients. These patients could benefit from anti-ERBB2 targeting therapies.

AB - Early metastatic dissemination and evolution of disseminated cancer cells (DCCs) outside the primary tumor is one reason for the failure of adjuvant therapies because it generates molecular genotypes and phenotypes different from primary tumors, which still underlie therapy decisions. Since ERBB2 amplification in esophageal DCCs but not in primary tumor cells predict outcome, we aimed to establish an assay with diagnostic reliability for single DCCs or circulating tumor cells. For this, we evaluated copy number alterations of more than 600 single DCCs from multiple cancer types to define reference regions suitable for quantification of target regions, such as ERBB2. We then compared ERBB2 quantitative PCR (qPCR) measurements with fluorescent in situ hybridization (FISH) data of various breast cancer cell lines and identified the aberration-calling threshold. The method was applied to two independent cohorts of esophageal cancer patients from Hamburg (n = 59) and Düsseldorf (n = 53). We found a high correlation between the single cell qPCR assay and the standard FISH assay (R = 0.98) and significant associations between amplification and survival for both patient cohorts (Hamburg (HH), p = 0.033; Düsseldorf (D), p = 0.052; pooled HH + D, p = 0.002) when applied to DCCs of esophageal cancer patients. Detection of a single ERBB2-amplified DCC was the most important risk factor for death from esophageal cancer (relative risk = 4.22; 95% CI = 1.91-9.32; p < 0.001). In our study, we detected ERBB2-amplified cells in 7% of patients. These patients could benefit from anti-ERBB2 targeting therapies.

KW - Esophageal Neoplasms/genetics

KW - Female

KW - Gene Amplification

KW - Genes, erbB-2

KW - Humans

KW - Male

KW - Middle Aged

KW - Neoplastic Cells, Circulating/pathology

KW - Receptor, ErbB-2/genetics

U2 - 10.1002/ijc.31108

DO - 10.1002/ijc.31108

M3 - SCORING: Journal article

C2 - 29044505

VL - 142

SP - 833

EP - 843

JO - INT J CANCER

JF - INT J CANCER

SN - 0020-7136

IS - 4

ER -