HER-2/neu gene amplification by FISH predicts poor survival in Barrett's esophagus-associated adenocarcinoma

doi:10.1016/S0046-8177(00)80195-1

Human Pathology

Volume 31, Issue 1, January 2000, Pages 35-39

https://doi.org/10.1016/S0046-8177(00)80195-1 Get rights and content

The HER-2/neu oncogene is localized to chromosome 17q and shares significant homology with the epidermal growth factor receptor. HER-2/neu protein overexpression has been associated with poor prognosis in a variety of tumors, but its significance in Barrett's esophagus-associated adenocarcinoma (BEAd) is unknown. Therefore, the aim of this study was to evaluate the prevalence and prognostic value of HER-2/neu gene amplification by fluorescence in situ hybridization (FISH) in 63 cases of BEAd. Routinely processed tissue sections from resection specimens of 63 patients with BEAd (M/F ratio, 10:1; mean age, 63 years) were assayed for HER-2/neu gene amplification by FISH using the Ventana unique sequence probe (Ventana Medical Systems, Inc, Tuscon, AZ). FISH results were correlated with the pathological features of the tumors and with patient survival. Clinical follow-up data were available for 54 patients (mean follow-up, 31 months [range, 1 to 152 months]). The HER-2/neu gene was amplified in 12 of 63 (19%) cases. The presence of HER-2/neu gene amplification showed a trend toward a correlation with depth of tumor invasion (P = .07), lymph node metastasis (P = .13), and pathological stage (P = .14), but did not correlate with any of the other pathological features, such as degree of differentiation or tumor size. On both univariate and multivariate analysis, HER-2/neu gene amplification was associated with shortened survival (P = .03). HER-2/neu oncogene amplification, as determined by FISH, correlates with shortened patient survival and independently predicts poor outcome in patients with BEAd.

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Clinical Relevance of Tissue and Serum Human Epidermal Growth Factor Receptor 2 Expression in Patients With Esophageal Squamous Cell Carcinoma
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Serum and tissue human epidermal growth factor receptor 2 (HER2) levels were evaluated in resected esophageal squamous cell carcinoma (SCC) specimens to assess the relationship between HER2 expression and long-term prognosis.
We included 95 patients who underwent esophagectomy for esophageal SCC. The serum HER2-extracellular domain (sHER2-ECD) levels were measured using an ELISA kit. A time-dependent receiver operating characteristics curve for censored survival outcomes was constructed to estimate the optimal cut-off value of sHER2-ECD (set at 4211 pg/mL). Immunohistochemical (IHC) staining was performed for HER2, and specimens were classified based on low (0 or 1+) or high HER2-IHC expression (2+ or 3+).
Patients with low sHER2-ECD levels showed poorly differentiated tumors, nodal involvement, and larger tumor size more frequently compared to patients with high sHER2-ECD levels. There were no differences in clinicopathological features based on HER2-IHC expression. Between patients with high and low HER2-IHC expression, the former group showed significantly higher sHER2-ECD levels. Patients with high sHER2-ECD levels had significantly favorable relapse-free survival (RFS) and overall survival (OS) compared to those with low sHER2-ECD levels. Conversely, patients with high HER2-IHC expression had significantly poorer RFS than did patients with low HER2-IHC expression, although no difference was observed in OS. Additionally, patients with high sHER2-ECD levels and low HER2-IHC expression had the highest OS and RFS among the patients studied.
The correlation among sHER2-ECD levels, HER2-IHC expression, and prognosis was demonstrated. Prospective studies are required to validate the impact of serum and tissue HER2 expression in esophageal SCC prognosis.
Management of Locally Advanced Esophageal Cancer
2020, Surgical Oncology Clinics of North America
Cancer of the Esophagus
2019, Abeloff’s Clinical Oncology
Esophageal cancer is an uncommon cancer in the U.S., although the incidence of adenocarcinomas of the lower esophagus and gastroesophageal junction has steadily increased since the 1970s. Globally, esophageal cancer (mostly squamous cell carcinomas) is endemic in parts of the world, such as East Asia. In this chapter, we discuss validated pre-, peri- and post-operative strategies for locally advanced disease, which include chemotherapy and/or chemoradiation. We discuss surgical techniques for operable tumors and systemic therapy options for metastatic disease, including chemotherapy, targeted therapies and immunotherapy. Finally, we also focus on treatments to palliate dysphagia from obstructing tumors.
HER2 expression in oesophageal carcinoma and Barrett's oesophagus associated adenocarcinoma: An Australian study
2016, European Journal of Surgical Oncology
Several studies have evaluated the prognostic value of HER2 in oesophageal cancer, but the prognostic influence of HER2 overexpression in oesophageal cancer remains uncertain. The aim of this study was to assess the incidence of HER2 positivity and relationship with clinicopathological features in patients with oesophageal cancer.
The study cohort consisted of 269 patients diagnosed with oesophageal carcinoma in a single institution. HER2 expression was analysed by immunohistochemistry (IHC) and silver in situ hybridization (SISH) in 152 archival oesophageal cancer specimens. Survival analysis was assessed using Hazard models.
HER2 expression was IHC3+ in 14 (9.2%), IHC2+ in 14 (9.2%), IHC1+ in 57 (37.5%), and IHC0 in 67 (44.1%) cases. SISH results confirmed that 15 specimens (9.9%) were HER2 gene amplified. Among 27 squamous cell carcinomas (SCCs) only 3.7% were HER2 positive whereas 11.2% of 125 adenocarcinomas were HER2 positive. The HER2 positive tumours were more likely to occur in men (OR: 5.00, 95% CI: 1.69–14.29), smokers (OR: 10.00, 95% CI: 4.17–25) and in patients with Barrett's oesophagus (OR: 8.33, 95% CI: 3.71–20.00). There was no significant difference in survival between the (HER2 +ve, 14.3 months vs HER2 −ve, 24.6 months, p = 0.42)
A HER2 prevalence rate of 9.9% was found among patients with oesophageal cancer and no correlation with survival was detected overall.
A systematic review and meta-analysis of somatic and germline DNA sequence biomarkers of esophageal cancer survival, therapy response and stage
2015, Annals of Oncology
Recent advances in next generation sequencing reinforce the potential for DNA sequence markers to guide esophageal cancer management. We report the first systematic review and meta-analysis, identifying 94 markers of outcome and 41 of stage. Overall, evidence was poor. Meta-analyses demonstrated outcome associations for 6 tumor and 9 germline variants: priorities for prospective evaluation.
There is an urgent need for biomarkers to help predict prognosis and guide management of esophageal cancer. This review identifies, evaluates and meta-analyses the evidence for reported somatic and germline DNA sequence biomarkers of outcome and stage.
A systematic review was carried out of the PubMed, EMBASE and Cochrane databases (20 August 2014), in conjunction with the ASCO Level of Evidence scale for biomarker research. Meta-analyses were carried out for all reported markers associated with outcome measures by more than one study.
Four thousand and four articles were identified, 762 retrieved and 182 studies included. There were 65 reported markers of survival or recurrence 12 (18.5%) were excluded due to multiple comparisons. Following meta-analysis, significant associations were seen for six tumor variants (mutantTP53 andPIK3CA, copy number gain of ERBB2/HER2,CCND1 and FGF3, and chromosomal instability/ploidy) and seven germline polymorphisms:ERCC1 rs3212986,ERCC2 rs1799793,TP53 rs1042522,MDM2 rs2279744,TYMS rs34743033,ABCB1 rs1045642 andMTHFR rs1801133. Twelve germline markers of treatment complications were reported; 10 were excluded. Two tumor and 15 germline markers (11 excluded) of chemo (radio)therapy response were reported. Following meta-analysis, associations were demonstrated for mutant TP53, ERCC1 rs11615 and XRCC1 rs25487. There were 41 tumor/germline reported markers of stage; 27 (65.9%) were excluded.
Numerous DNA markers of outcome and stage have been reported, yet few are backed by high-quality evidence. Despite this, a small number of variants appear reliable. These merit evaluation in prospective trials, within the context of high-throughput sequencing and gene expression.
Brain Metastases from Esophageal Cancer in the Presence of HER-2 Overexpression
2015, Brain Metastases from Primary Tumors: Epidemiology, Biology, and Therapy
Locally advanced esophageal carcinoma is treated with multimodality therapy, utilizing the benefits of chemotherapy, radiation therapy, and esophagectomy with curative intent. At the time of posttherapy relapse, sites of disease include both local recurrence as well as distant disease. Notably, brain metastasis is an uncommon form of relapse for this malignancy. Human epidermal growth factor receptor 2 (HER-2) is a member of a family of receptors that are associated with cell proliferation, differentiation, migration, and adhesion. This receptor is overexpressed on the cell surface of a number of carcinomas and has been noted to be amplified in a proportion of gastroesophageal tumors. Additionally, an association between the presence of HER-2 overexpression and the development of brain metastases in breast cancers has been well described. A recent study has shown potential association between brain metastases from esophageal carcinoma and HER-2 overexpression. This association could have significant clinical impact in staging procedures, upfront therapy selection, and treatment choices for metastases to the central nervous system.

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^*: Supported in part by funds from a Pathology Applications Grant from Ventana Medical Systems. Dr. Ross serves as Medical Director of Ventana Medical Systems.

^**: Presented in part at the 88th Annual Meeting of the United States and Canadian Academy of Pathology, San Francisco, CA, March 1999.

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Human Pathology

References (23)

Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction

Gastroenterology

Immunohistochemical detection of p53 and c-erbB-2 in oesophageal carcinoma; no correlation with prognosis

Eur J Surg Oncol

The increasing frequency of adenocarcinoma of the esophagus

Cancer

Continuing climb in rates of esophageal adenocarcinoma: An update

JAMA

Changing patterns in the incidence of esophageal and gastric carcinoma in the United States

Cancer

Correlation of c-erbB-2 gene amplification and protein expression in human breast carcinoma with nodal status and nuclear grading

Cancer Res

Immunohistochemical assay of neu/c-erbB-2 oncogene product in paraffin-embedded tissues in early breast cancer: Retrospective follow-up study of 245 stage I and II cases

Mod Pathol

Her-2/neu expression in node-negative breast cancer: Direct tissue quantification by computerized image analysis and association of overexpression with increased risk of recurrent disease

Cancer Res

Clinical significance of HER-2/neu oncogene amplification in primary breast cancer: The South Australian Breast Cancer Study Group

J Clin Oncol

Oncogenes and oncosuppressor gene in adeonocarcinoma of the oesophagus

Gut

Amplification and over-expression of the EGFR and erbB-2 genes in human esophageal adenocarcinomas

Int J Cancer

Cited by (133)

Clinical Relevance of Tissue and Serum Human Epidermal Growth Factor Receptor 2 Expression in Patients With Esophageal Squamous Cell Carcinoma

Management of Locally Advanced Esophageal Cancer

Cancer of the Esophagus

HER2 expression in oesophageal carcinoma and Barrett's oesophagus associated adenocarcinoma: An Australian study

A systematic review and meta-analysis of somatic and germline DNA sequence biomarkers of esophageal cancer survival, therapy response and stage

Brain Metastases from Esophageal Cancer in the Presence of HER-2 Overexpression

Original ContributionHER-2/neu gene amplification by FISH predicts poor survival in Barrett's esophagus-associated adenocarcinoma*,**

Gastroenterology

Eur J Surg Oncol

The increasing frequency of adenocarcinoma of the esophagus

Cancer

Continuing climb in rates of esophageal adenocarcinoma: An update

JAMA

Changing patterns in the incidence of esophageal and gastric carcinoma in the United States

Cancer

Correlation of c-erbB-2 gene amplification and protein expression in human breast carcinoma with nodal status and nuclear grading

Cancer Res

Immunohistochemical assay of neu/c-erbB-2 oncogene product in paraffin-embedded tissues in early breast cancer: Retrospective follow-up study of 245 stage I and II cases

Mod Pathol

Her-2/neu expression in node-negative breast cancer: Direct tissue quantification by computerized image analysis and association of overexpression with increased risk of recurrent disease

Cancer Res

Clinical significance of HER-2/neu oncogene amplification in primary breast cancer: The South Australian Breast Cancer Study Group

J Clin Oncol

Oncogenes and oncosuppressor gene in adeonocarcinoma of the oesophagus

Gut

Amplification and over-expression of the EGFR and erbB-2 genes in human esophageal adenocarcinomas

Int J Cancer

Original Contribution
HER-2/neu gene amplification by FISH predicts poor survival in Barrett's esophagus-associated adenocarcinoma*,**