Clinical usefulness of human epidermal growth factor receptor-2 extracellular domain as a biomarker for monitoring cancer status and predicting the therapeutic efficacy in breast cancer

Kontani, Keiichi; Kuroda, Noriyuki; Hashimoto, Shinichiro; Murazawa, Chisa; Norimura, Shoko; Tanaka, Hiroaki; Ohtani, Masahiro; Fujiwara-Honjo, Naomi; Kushida, Yoshio; Date, Manabu; Haba, Reiji; Yamauchi, Akira; Yokomise, Hiroyasu

doi:10.4161/cbt.22626

Cited by 8 publications

(10 citation statements)

References 33 publications

(30 reference statements)

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“…Consequently, early screening for elevated sHER2 ECD levels may improve the detection of metastatic breast cancer. Surprisingly, Kontani et al [42], found elevated sHER2 ECD levels in seven patients (22.6%) with metastatic or recurrent HER2− breast cancers. This might be explained if the tumors were derived from HER2-overexpressing cancer cells in the primary tumor in which HER2− cells were dominant.…”

Section: The Prevalence Of Sher2 Ecd In Breast Cancer and Its Correlamentioning

confidence: 94%

“…In another recent study of 2862 cases of stage I-III primary breast cancer patients, 24% were found to be tHER2+, but only 15% of these tHER2+ patients had elevated sHER2 ECD levels [41]. Another study [42] found 23.5% of patients with tHER2+ early-stage breast cancer had elevated sHER2 ECD levels (>15 ng/ml). A later study [43] also showed that the levels of sHER2 ECD did not correlate with the level of HER2 overexpression, whether borderline (2+) or positive (3+) on the IHC testing scale described above.…”

Section: Do Sher2 Ecd Levels Correlate With Tissue Her2 Levels?mentioning

confidence: 95%

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The extracellular domain of Her2 in serum as a biomarker of breast cancer

Perrier

Gligorov

Lefèvre

et al. 2018

Laboratory Investigation

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Breast cancer is a major health problem worldwide. In ~15% of breast cancers, the epidermal growth factor receptor HER2, a transmembrane protein, is overexpressed. This HER2 overexpression is associated with an aggressive form of the disease and a poor clinical prognosis. The extracellular domain (ECD) of HER2 is released into the blood by a proteolytic mechanism known as "ECD shedding". This proteolytic shedding leaves a constitutively active truncated receptor in the membrane that is 10-100-fold more oncogenic than the full-length receptor and promotes the growth and survival of cancer cells. Shedding of the HER2 ECD is increased during metastasis: whereas 15% of primary breast cancer patients have elevated levels of serum HER2 ECD (sHER2 ECD), the levels reach 45% in patients with metastatic disease. Thus, sHER2 ECD has been proposed as a promising biomarker for cancer recurrence and for monitoring the disease status of patients overexpressing HER2. Nevertheless, in 2016, the American Society of Clinical Oncology advises clinicians not to use soluble HER2 levels to guide their choice of adjuvant therapy for patients with HER2-positive breast cancer, because the evidence was considered not strong enough. Currently, biomarkers such as carcinoembryonic antigen and cancer antigen 15-3 are widely used to monitor metastatic breast cancer disease even if the level of evidence of clinical impact of this monitoring is poor. In this article, we review the evidence that sHER2 ECD might be used in some situations as a biomarker for breast cancer. Although this serum biomarker will not replace the direct measurement of tumor HER2 status for diagnosis of early-stage tumors; it might be especially useful in metastatic disease for prognosis, as an indicator of cancer progression and of therapy response, particularly to anti-HER2 therapies. Owing to these data, sHER2 ECD should be considered as a promising biomarker to detect cancer recurrence and metastasis.

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Section: The Prevalence Of Sher2 Ecd In Breast Cancer and Its Correlamentioning

confidence: 94%

Section: Do Sher2 Ecd Levels Correlate With Tissue Her2 Levels?mentioning

confidence: 95%

The extracellular domain of Her2 in serum as a biomarker of breast cancer

Perrier

Gligorov

Lefèvre

et al. 2018

Laboratory Investigation

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“…The high percentage of elevated serum HER2 levels among the patients with tissue HER2-positive tumors (43%), even though the blood samples often were taken after primary treatment, suggests a potential use of serum HER2 in patient follow-up during and after treatment. Comparable numbers (23.5% of the patients with tissue HER2-positive versus 8.7% of the patients with tissue HER2-negative tumors) were published by Kontani et al 30 in a study with 252 patients using the ADVIVA CLIA assay, and they suggested that HER2 may be a useful biomarker for detecting breast cancer recurrence. The higher percentage of patients with elevated HER2 in our study compared to Kontani et al may be explained by different assay antibodies and/ or different cut-off values.…”

Section: Discussionmentioning

confidence: 90%

Specific antibodies and sensitive immunoassays for the human epidermal growth factor receptors (HER2, HER3, and HER4)

et al. 2017

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The use of trastuzumab in patients with breast cancer that overexpresses human epidermal growth factor receptor 2 has significantly improved treatment outcomes. However, a substantial proportion of this patient group still experiences progression of the disease after receiving the drug. Evaluation of the changes in expression of the human epidermal growth factor receptors could be of interest. Monoclonal antibodies against the extracellular domain of the human growth factor receptors, 2, 3, and 4, have been raised, and specific and sensitive immunoassays have been established. Sera from healthy individuals (Nordic Reference Interval Project and Database) were analyzed in the human epidermal growth factor receptor 2 assay (N = 805) and the human epidermal growth factor receptor 3 and 4 assays (N = 114), and reference limits were calculated. In addition, sera from 208 individual patients with breast cancer were tested in all three assays. Finally, the human epidermal growth factor receptor 2 assay was compared with a chemiluminescent immunoassay for serum human epidermal growth factor receptor 2/neu. Reference values were as follows: human epidermal growth factor receptor 2, <2.5 µg/L; human epidermal growth factor receptor 3, <2.8 µg/L; and human epidermal growth factor receptor 4, <1.8 µg/L. There were significant differences in human epidermal growth factor receptor 2 and human epidermal growth factor receptor 3 serum levels between the patients with tissue human epidermal growth factor receptor 2-positive and tissue human epidermal growth factor receptor 2-negative (p = 0.0026, p = 0.000011) tumors, but not in the serum levels of human epidermal growth factor receptor 4 (p = 0.054). There was good agreement between the in-house human epidermal growth factor receptor 2 assay and the chemiluminescent immunoassay. Our new specific antibodies for all the three human epidermal growth factor receptors may prove valuable in the development of novel anti-human epidermal growth factor receptor targeted therapies with sensitive immunoassays for measuring serum levels of the respective targets and in monitoring established treatment.

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“…Moreover, these methods can only determine the HER2 status at the time of diagnosis, and the HER2 status of tumor samples in patients with recurrent or metastatic breast cancer cannot always be determined. It would be useful to monitor patients during follow-up to determine wheth- er they are responding to trastuzumab therapy [22] . RTqPCR is a powerful technique to confirm HER2 gene expression differences or measure transcript abundance.…”

Section: Discussionmentioning

confidence: 99%

Clinical Usefulness of a One-Tube Nested Reverse Transcription Quantitative Polymerase Chain Reaction Assay for Evaluating Human Epidermal Growth Factor Receptor 2 mRNA Overexpression in Formalin-Fixed and Paraffin-Embedded Breast Cancer Tissue Samples

Wang¹,

Ahn

Park

et al. 2016

Pathobiology

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Background: Currently, the two main methods used to analyze human epidermal growth factor receptor 2 (HER2) amplification or overexpression have a limited accuracy and high costs. These limitations can be overcome by the development of complementary quantitative methods. Methods: In this study, we analyzed HER2 mRNA expression in clinical formalin-fixed and paraffin-embedded (FFPE) samples using a one-tube nested reverse transcription quantitative polymerase chain reaction (RT-qPCR) assay. We measured expression relative to 3 reference genes and compared the results to those obtained by conventional immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays with 226 FFPE breast cancer tissue samples. Results: The one-tube nested RT-qPCR assay proved to be highly sensitive and specific based on comparisons with IHC (96.9 and 97.7%, respectively) and FISH (92.4 and 92.9%, respectively) obtained with the validation set. Comparisons with clinicopathological data revealed significant associations between HER2 overexpression and TNM stage (p < 0.01), histological type (p < 0.01), ER status (p < 0.001), PR status (p < 0.05), HER2 status (p < 0.001), and molecular subtypes (p < 0.001). Conclusion: Based on these findings, our one-tube nested RT-qPCR assay is a potentially useful and complementary screening tool for the detection of HER2 mRNA overexpression.

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Clinical usefulness of human epidermal growth factor receptor-2 extracellular domain as a biomarker for monitoring cancer status and predicting the therapeutic efficacy in breast cancer

Cited by 8 publications

References 33 publications

The extracellular domain of Her2 in serum as a biomarker of breast cancer

The extracellular domain of Her2 in serum as a biomarker of breast cancer

Specific antibodies and sensitive immunoassays for the human epidermal growth factor receptors (HER2, HER3, and HER4)

Clinical Usefulness of a One-Tube Nested Reverse Transcription Quantitative Polymerase Chain Reaction Assay for Evaluating Human Epidermal Growth Factor Receptor 2 mRNA Overexpression in Formalin-Fixed and Paraffin-Embedded Breast Cancer Tissue Samples

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