Significance of HER2 protein expression and HER2 gene amplification in colorectal adenocarcinomas

Abstract

BACKGROUND Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. While the role of HER2 as a prognostic biomarker in colorectal adenocarcinomas (CRCs) remains uncertain, its relevance as a therapeutic target has been established. We undertook the present study to evaluate the frequency of HER2 expression in CRC and to correlate it with various clinicopathological variables. AIM To correlate HER2 protein expression and HER2 gene amplification with clinicopathological features and survival in surgically resected CRC. METHODS About 1195 consecutive surgically resected CRCs were analyzed by immunohistochemical staining (IHC) to assess HER2 protein expression, and 141 selected tumors were further evaluated by fluorescence in situ hybridization (FISH) to assess HER2 gene amplification. Follow-up information was available for 1058 patients, and using this information we investigated the prevalence of HER2 protein overexpression and gene amplification in a large series of surgically resected CRCs, and evaluated the relationship between overexpression and clinicopathological parameters and prognosis. RESULTS HER2 IHC scores of 3+, 2+, 1+, and 0 were seen in 31 (2.6%), 105 (8.8%), 475 (39.7%), and 584 (48.9%) tumors, respectively. HER2 gene amplification was seen in 24/29 tumors with an IHC score of 3+ (82.8%; unreadable in 2/31), 12/102 tumors with an IHC score of 2+ (11.8%; unreadable in 2/104), and 0 tumors with IHC score of 1+ (0/10). HER2 gene amplification was seen in 36/1191 tumors (3.0%; unreadable in 4/1195). Among the tumors with HER2 IHC scores of 3+ and 2+, the mean percentage of tumor cells with positive IHC staining was 90% (median 100%, range 40%-100%) and 67% (median 75%, range 5%-95%), respectively ( P < 0.05). Among tumors with IHC scores of 2+, those with HER2 gene amplification had a higher number of tumors cells with positive IHC staining ( n = 12, mean 93%, median 95%, range 90%-95%) than those without ( n = 90, mean 70%, median 50%, range 5%-95%) ( P < 0.05). HER2 gene status was significantly associated with distant tumor metastasis and stage ( P = 0.028 and 0.025). HER2 protein overexpression as measured by IHC or HER2 gene amplification as measured by FISH was not associated with overall survival (OS) or disease-specific survival for the overall group of 1058 patients. However, further stratification revealed that among patients with tubular adenocarcinomas who were 65 years old or younger ( n = 601), those exhibiting HER...

HER2 and BRAF mutation in colorectal cancer patients: a retrospective study in Eastern China

“…The number of studies suggests that HER2 may play some role in tumor progression and would be a valuable prognostic factor for CRC patients (Laurentpuig et al, 2016;Stahler et al, 2017). But in other studies, HER2 gene amplification was higher in patients with more advanced stage or distant metastases, and no significant difference in prognosis for CRC patients (Pietrantonio et al, 2017;Wang et al, 2019).…”

“…The different criteria of membrane positivity may also cause for the conflicting results, Liu et al (2019) argued HER2 status evaluated by the HERACLES criteria showed survival predictive for stage II-III CRC, but the results were not represented based on the GEA diagnostic criteria. In present study, the GEA criteria was used, and 33.3% (18/54) samples with IHC staining 2+ were confirmed to harbor HER2 gene amplification, but Wang et al (2019) judged only 20% of tumors with HER2 IHC 2+ staining showing gene amplification based on this criteria. IHC is a semiquantitative method and may be influenced by subjective perception of pathologists frequently, so exactly HER2 positive standardized by IHC in CRC is urgently needed.…”

Application of smart solid lipid nanoparticles to enhance the efficacy of 5-fluorouracil in the treatment of colorectal cancer

“…Most importantly, 5FU-SLN 4 activity in mouse bearing HCT-116 subcutaneous tumor significantly inhibited the HER2 expression. In literature, HER2 overexpression or amplification has been implicated as one of the drivers in CRC progression 34,35 . But further investigation of 5FU-SLN 4 's biodistribution in vivo needs to be carried out to fully determine its pattern of distribution in tissues relative to tumor tissue.…”

“…C max , peak plasma concentration; T max , peak time; AUC (0 − t) , area under the plasma concentration-time curve; MRT, mean residence time; k 10 , elimination rate constant; Cl, clearance; V d , volume of distribution; k a , absorption rate constant (Data analyzed using unpaired t-test, two-tailed). www.nature.com/scientificreports/ eral solid tumors including CRC [34][35][36] . These receptors are frequently reported to harbor aberrant activities that lead to the proliferation, survival, migration and differentiation required for CRC pathogenesis.…”

Somatic mutation profiling and HER2 status in KRAS-positive Chinese colorectal cancer patients

“…However, in the report described by Wang et al . 39 , 11.8% (12/102) of CRCs with HER2 IHC scores of 2+ and in 82.8% (24/29) of CRCs with HER2 IHC scores of 3+ were identified as HER2 amplification. One explanation for these differences may be that antibodies used for IHC or positive criteria for FISH varied among research groups.…”