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.

Molecular profiling of 6,892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites

“…The rate of HER2/ neu amplification was lower in our study compared to published literature but differential amplification was observed in primary colon tumors and lung metastases (1.8% vs 4%). Previous studies have quoted a 5-9% incidence of HER2/neu amplification in CRC 26,27 and HER2/neu amplification was shown to be concordant in only 5% of the primary and metastatic lesions. 27 In a study by Ramanathan et al, HER2/neu-positive patients with advanced colorectal cancer were treated with trastuzumab (Herceptin Ò and irinotecan).…”

Assessment of a HER2 scoring system for colorectal cancer: results from a validation study

“…[6][7][8][9][12][13][14][15][16][17][18][19][20] The present study is unique because the only study with an equally large sample size, albeit without clinical validation, reported much lower rates of both ERBB2 expression (2.7%) and positive amplification (1.6%). 8 This difference very likely resides in the fact that while our findings have been obtained on a primarily metastatic population, Heppner et al 8 tested only primary tumors using a different staining antibody (SP3) and a different in situ hybridization method (CISH), and employed gastric cancer criteria to test and score the samples.…”

“…1,2 Overexpression of ERBB2 is an established therapeutic target in breast and gastric cancers and is successfully exploited in the clinic using a variety of anti-ERBB2 agents, leading to remarkable outcome improvements. 3,4 Although the comprehensive molecular characterization of human colorectal cancer has identified ERBB2 amplification as a potential therapeutic target 5 and ERBB2 overexpression has been controversially linked to prognosis, [6][7][8][9] the clinical significance of ERBB2 alterations remains elusive. Recently, we and others have found that activation of ERBB2 signaling causes resistance to anti-EGFR therapy in a fraction of metastatic colorectal patients, wild type for RAS codons 12-13.…”

“…These are routinely used to establish ERBB2 status in breast and gastric cancer but have not been customized for colorectal cancer for which the reported rate for ERBB2 positivity ranges enormously from o1% to 450%. [6][7][8][9][12][13][14][15][16][17][18][19][20] The aim of the present study was to develop a validated ERBB2 scoring system for colorectal cancer with the goal of identifying ERBB2-positive patients suitable for enrollment in the HERACLES trial.…”

Eastern Canadian Colorectal Cancer Consensus Conference 2017

“…Activation of her2 plays a key role in cell proliferation, cell differentiation, inhibition of apoptosis, and tumour progression 100 . Several trials tried to assess the overexpression of her2 in the gastrointestinal tract, with results ranging from 0%-83%, the wide range being thought to be a result of differences in methods and reagents used for the tests 101 .…”