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HER2 status in colorectal cancer: its clinical significance and the relationship between HER2 gene amplification and expression.

ABSTRACT: This study aimed at determining the incidence and clinical implications of HER2 status in primary colorectal cancer (CRC). HER2 status was investigated in two retrospective cohorts of 365 consecutive CRC patients (cohort 1) and 174 advanced CRC patients with synchronous or metachronous distant metastasis (cohort 2). HER2 status was determined by performing dual-color silver in-situ hybridization (SISH), mRNA in-situ hybridization (ISH), and immunohistochemistry (IHC). The incidence of HER2 protein overexpression (IHC 2+/3+) was approximately 6% (22 of 365 in cohort 1; 10 of 174 in cohort 2). HER2 gene amplification was observed in 5.8% of the patients from cohort 1 and 6.3% of the patients from cohort 2. HER2 gene amplification was more frequently observed in CRCs located in the rectum than in the right and left colon (P = 0.013 in cohort 1; P = 0.009 in cohort 2). HER2 status, determined by IHC, ISH, and dual-color SISH, was not significantly associated with aggressive CRC behaviour or patients' prognosis in both the cohorts. Of the combined cohort with a total of 539 cases, the concordance rate was 95.5% between dual-color SISH and IHC detection methods. On excluding equivocally immunostained cases (IHC 2+), the concordance rate was 97.7%. HER2 mRNA overtranscription, detected by ISH, significantly correlated with protein overexpression and gene amplification (P<0.001). HER2 gene amplification was identified in a minority of CRC patients with high concordance rates between dual-color SISH and IHC detection methods. Although HER2 status did not predict patients' prognosis, our findings may serve as a basis for future studies on patient selection for HER2 targeted therapy.

SUBMITTER: Seo AN

PROVIDER: S-EPMC4039475 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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HER2 status in colorectal cancer: its clinical significance and the relationship between HER2 gene amplification and expression.

Seo An Na AN Kwak Yoonjin Y Kim Duck-Woo DW Kang Sung-Bum SB Choe Gheeyoung G Kim Woo Ho WH Lee Hye Seung HS

PloS one 20140530 5

This study aimed at determining the incidence and clinical implications of HER2 status in primary colorectal cancer (CRC). HER2 status was investigated in two retrospective cohorts of 365 consecutive CRC patients (cohort 1) and 174 advanced CRC patients with synchronous or metachronous distant metastasis (cohort 2). HER2 status was determined by performing dual-color silver in-situ hybridization (SISH), mRNA in-situ hybridization (ISH), and immunohistochemistry (IHC). The incidence of HER2 prote ...[more]

PMID: 24879338

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Project description:Background:The aims of this study were to determine whether the quantitative HER2 gene amplification level is related to the key clinicopathological features that represent the aggressiveness of breast cancer (BC) and to determine whether the quantitative HER2 gene amplification level could predict the treatment response in the subset of HER2-positive patients who received neoadjuvant targeted therapy. Materials and methods:Patients treated with weekly cisplatin- and paclitaxel-based neoadjuvant chemotherapy, who had undergone both immunohistochemistry and the fluorescence in situ hybridization test for HER2, were included in the study (n=103). For HER2-positive patients, defined as immunohistochemistry score 3+ or fluorescence in situ hybridization ratio ?2.0, trastuzumab was recommended with neoadjuvant chemotherapy (n=45). Pathological complete response was defined as complete pathological remission of tumor cells both in breast and axillary lymph nodes postoperation. Results:In all patients enrolled in the study, a higher HER2 amplification level was significantly correlated with larger tumor size and the absence of ER and PR expression. In HER2-positive patients treated with neoadjuvant trastuzumab concurrent with chemotherapy, both univariate and multivariate logistic regression showed that a higher HER2/CEP17 ratio and HER2 gene copy number were associated with a higher pathological complete response rate. When calculated by receiver operating characteristics analysis, an optimal cutoff of 4.5 for the HER2/CEP17 ratio was expected to distinguish the most sensitive candidate for treatment with a combination of trastuzumab and neoadjuvant chemotherapy. Conclusion:A higher HER2 amplification level was correlated with larger tumor size and reduced ER and PR expression, which may indicate more aggressive tumor behavior. For HER2-positive patients, the HER2/CEP17 ratio and HER2 gene copy number may be good predictive factors for concurrent neoadjuvant trastuzumab and chemotherapy.

Project description:Purpose: This study aimed to identify a novel biomarker or a target of treatment for colorectal cancer (CRC). Experimental Design: The expression profiles of cancer cells in 104 patients with CRC were examined using laser microdissection and oligonucleotide microarray analysis. Overexpression in CRC cells especially in patients with distant metastasis was a prerequisite to select candidate genes. The mRNA expression of candidate gene was investigated by quantitative reversetranscription polymerase chain reaction (RT-PCR) in 77 patients as a validation study. We analyzed the protein expression and localization of the candidate gene by immunohistochemical study, and investigated the relationship between the expression and the clinicopathological feature in 274 CRC patients. Results: We identified 6 genes as candidates related to distant metastasis in CRC patients by microarray analysis. Among these genes, Osteoprotegerin (OPG) is known to have an association with aggressiveness in several cancers through inhibiting apoptosis by neutralizing the function of tumor necrosis factor related apoptosis inducing ligand (TRAIL). The mRNA expression of OPG in cancer tissues was significantly higher in patients with distant metastasis than those without metastasis. The overexpression of OPG protein was significantly associated with worse overall survival and relapse free survival (RFS). Moreover, the overexpression of OPG protein was an independent risk factor for recurrence of CRC. Conclusion: The overexpression of OPG would be a predictive biomarker of recurrence and a target of the treatment for CRC. Total of 148 microarray datasets obtained from LCM and homogenized tissues of colorectal cancer patients were normalized using robust multi-array average (RMA) method under R 2.6.2 statistical software with affy package from BioConductor. Normalization was separately performed for LCM dataset and homogenized tissue dataset. The normalized gene expression levels were presented as log2-transformed values by RMA.

Dataset Information

HER2 status in colorectal cancer: its clinical significance and the relationship between HER2 gene amplification and expression.

Publications

HER2 status in colorectal cancer: its clinical significance and the relationship between HER2 gene amplification and expression.

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