Diagnostic pathology of early systemic cancer: ERBB2 gene amplification in single disseminated cancer cells determines patient survival in operable esophageal cancer

Abstract

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.

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“…Equally important, ErbB2 can further improve the ability of tumour cells to migrate and adhere, promote tumour invasion and encourage local and/or distant metastasis 37 . Hoffmann 38 proposed a diagnostic method to detect ErbB2 amplification in single disseminated cancer cells, demonstrating that ErbB2 amplification in esophageal cancer patients is significantly correlated with short-term survival. Previous studies have shown that ESCA can be treated by taking ErbB2 inhibitors such as trastuzumab and ramiximab 39 .…”

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“…Tumor cells have been known to disseminate into the vascular and lymphatic system, migrating to distant organs and initiating tumor regrowth and recurrence [3]. Clinical evidence has detected CTCs in the blood and DTCs in the bone marrow and lymph nodes; their population is an important indicator for diagnosis, prognosis, and therapeutic response in hepatocellular, breast, brain, and esophageal cancers [11–15]. CTC numbers increase following surgery for gastric [4], lung [5], breast [6], hepatocellular [7] and colorectal [8] cancers, and are associated with poor survival.…”

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“…Some of the upstream regulators can be used as potential diagnostic markers. For example, HNF4A expression can be used as a potential diagnostic tool to discriminate primary gastric cancer from breast cancer metastasis in a Brazilian cohort [46], the ERBB2 gene can be used as a diagnostic marker of early systemic cancer [47], and VCAN is a potential prognostic biomarker for gastric cancer [48]. Some can be used as potential therapeutic targets; for example, NFE2L2 can be used as a therapeutic target for glioblastoma [49], and upregulation of miR-383-5p can suppress proliferation and enhance chemosensitivity in ovarian cancer cells [50].…”