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Hofmann M, Stoss O, Shi D, Buttner R, van de Vijver M, Kim W, Ochiai A, Ruschoff J, Henkel TAssessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 52(7): 797-805

Institute of Pathology, Klinikum Kassel, Kassel, Germany.
Histopathology (Impact Factor: 3.3). 07/2008; 52(7):797-805. DOI: 10.1111/j.1365-2559.2008.03028.x
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ABSTRACT Human epidermal growth factor receptor 2 (HER2) overexpression/amplification is implicated in the development of various solid tumour types. Validated methods and scoring systems for evaluating HER2 status exist in breast cancer, but not in gastric cancer. The aim was to establish a HER2 scoring system for gastric cancer to identify suitable patients for enrollment in a trial of trastuzumab (Herceptin) in advanced metastatic gastric cancer.
Formalin-fixed paraffin-embedded gastric cancer samples were tested for HER2 status using the fluorescence in situ hybridization (FISH) pharmDxt kit (Dako Denmark A/S). Immunohistochemistry (IHC) was performed using the HercepTest (Dako). Concordance between FISH and IHC was 93.5% in 168 evaluable samples. Eleven samples were scored as FISH+ but IHC- or equivocal.
IHC/FISH discrepancies were attributed to basolateral membranous immunoreactivity of glandular cells resulting in incomplete membranous reactivity and/or a higher rate of tumour heterogeneity in gastric cancer compared with breast cancer. With modifications to the IHC scoring system, the HercepTest is considered valid for the identification of HER2+ gastric tumours for this clinical trial. Correlation of HER2 scores with clinical outcomes will be needed to determine which patients might benefit from trastuzumab therapy.

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Available from: Josef Rüschoff, Dec 16, 2013
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    • "SISH was scored with the use of a brightfield microscope (Olympus BX41) with 40× objective. HER2 amplification was considered to be positive when the HER2/cen17 ratio was ≥2 within 20 tumor cell nuclei [5] [17] "
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    ABSTRACT: In contrast to breast HER2 testing, the optimal ISH method and antibody for gastric HER2 testing are unclear. The aim of this study was to find out gastric HER2 positivity rates in our institutional data, and to compare the two novel ISH methods with A0485 antibody and HercepTest™. IHC and ISH were carried out on gastrectomy specimens of 88 patients up to the standardly advised procedure protocols, and interpretations were also carried out up to widely accepted international protocols., HER2 expression was (-) in 65, (+) in 5, (++) in 6, and (+++) in 12 cases by A0485 IHC. IHC (+) 4 cases and (++) 3 cases were (-) by HercepTest™. One IHC (-) amplified case was (++) by HercepTest™. All A0485 and HercepTest™ (+++) 12 cases were amplified by ISH. HER2 amplification was detected in 18 (20.4%) and in 15 (17.2%) cases by SISH and FISH, respectively. Of the 18 cases, 4 showed focal heterogeneous low level amplification by SISH. Focal amplification was noted in only 2 cases by FISH. The HER2 status of our gastric cancer file is 17.2% by FISH, 20.4% by SISH. The concordance between HercepTest™/A0485 IHC and ISH is perfect in (+++) cases. Equivocal results (++) with any IHC method should be clarified by one of the molecular methods (SISH and FISH). Probably up to the higher level of heterogeneity of gastric carcinomas, there is a 4.5% dilemma of cases that are negative or weakly positive by conventional IHC methods. Therefore, regarding HER2 status in gastric carcinoma, the reliability of IHC methods should be checked.
    Pathology - Research and Practice 06/2013; DOI:10.1016/j.prp.2013.05.008 · 1.56 Impact Factor
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    • "Inourstudy,matchedbiopsy/surgicalsamplesshowabetter concordancerateforFISHamplification(95%)withrespecttoIHC (80%).ThelowerconcordancerateinIHCismostlydependenton arelevantnumberofpatients(15cases)whowereunderscored onbiopsysamples(IHCscore0/1+)versussurgicalsample(IHC score2+/3+).Fortherapeuticpurposes,thesepatients(withIHC score0/1+)shouldnotbetestedfurtherwithFISHandareexcluded fromanti-HER2therapyassignment.However,whenevaluatingtheir surgicalspecimens,theyturnedIHCscore2+/3+andthereforewould haveundergonefurtherevaluationbyFISH(score2+)orwouldhave beentreateddirectly(score3+).Thepercentageofthesecasesthatwe canidentifybyapplyingFISHanalysisonallbiopsiescorrespondsto 8.5%ofIHCscore0and25%ofIHCscore1+:thislattervalueis notdissimilartoIHCscore2+biopsieswithamplification(33%). SimilarresultswerealsoshownintheToGAscreeningprogram,where 23%ofIHCscore0/1+and26%ofIHCscore2+wereamplified [31].WhereasIHCevaluationhasbeenmodifiedinGC/GEJC [20],theflowcharttoFISHanalysisofIHCscore2+casesremains unvariedwithrespecttobreastcancer,inwhich36%ofIHCscore2 "equivocal"casesareFISHamplified[15] [32].However,ToGAtrial [31]post-hocanalysishasshownthattrastuzumabpluschemotherapy substantiallyimprovedoverallsurvivalinpatientswithhighexpression ofHER2(i.e.,IHCscore2+andamplificationorIHCscore3+) comparedwithpatientswithlowexpressionofHER2protein(i.e., IHCscore0or1+withFISHamplification).Inthispost-hocanalysis, casesweresubdividedonthebasisofIHCscoresfollowingtheflow- chartusedforbreastcancer(IHCscore0or1+consideredas"negative" andIHCscore2+or3+consideredas"positive").Ourfindingson "
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    ABSTRACT: The aim of this study is to validate the accuracy of HER2 assessment on biopsies by comparing matched biopsy/surgical material from the same patients. HER2 status was evaluated by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 103 cases of gastric and gastroesophageal junction cancers in coupled biopsy and surgical material. Complete concordance between IHC and FISH results on biopsy versus surgical samples was noted in 80% and 95% of cases, respectively. At comprehensive comparison, including IHC and FISH data on biopsy and surgical samples, 89% of biopsies were predictive of HER2 status in surgical samples, whereas 11% showed variable inconsistencies. The majority of these (10 of 12 cases) showed IHC score 0/1+ on biopsy but were all IHC positive and amplified at surgery; in particular, three (3 of 35; 8.5%) IHC score 0 and four (4 of 16; 25%) IHC score 1+ cases were FISH amplified on biopsy material also, whereas the remaining three cases were FISH non-amplified on biopsy. The percentage of cases, which were FISH amplified with IHC score 1+ or 2+ on biopsies, were similar (25% and 33%, respectively) and they also shared a similar grade of amplification. These data suggest that both IHC score 1+ and 2+ on biopsy material represent "equivocal cases" that may merit further investigation. The predictive value of HER2 IHC in biopsies is high. FISH analysis should be considered for IHC score 2+ and 1+ biopsy cases. Approximately 8% of cases will not be accurately predicted by biopsy evaluation.
    Translational oncology 02/2013; 6(1):10-6. DOI:10.1593/tlo.12334 · 3.40 Impact Factor
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    • "Only membranous staining was considered. This scoring system has been validated for use in gastric cancer with minimal modifications: 0/negative = staining or membranous reactivity in <10% of cells, 1+/negative = faint membranous reactivity in >10% of cells or cells with reactivity only in part of their membrane, 2+/equivocal = weak/moderate complete or basolateral membranous staining in >10% of tumour cells; and 3+/pos- itive = strong complete or basolateral membranous staining in >10% of tumour cells [25] [26]. "
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    ABSTRACT: Aims. The aim of this study was to determine the prognostic significance of HER2 receptor expression in operable oesophagogastric adenocarcinoma. Methods. Eighty-five consecutive patients diagnosed with oesophagogastric adenocarcinoma [18 oesophageal (OC), 32 junctional (JC) and 35 gastric (GC)] undergoing potentially curative resection were studied retrospectively. Immunohistochemistry was used to determine HER2 status at endoscopic biopsy and resection specimen. The primary outcome measure was survival. Results. Twenty (24%) patients had HER2 positive tumours which was commoner in JC (14/32, 44% versus 2/18, 11% in OC and 4/35, 11% in GC, P = 0.003). The sensitivity, specificity, positive and negative predictive values of HER2 status at endoscopic biopsy were 56%, 93%, 63%, 91% respectively (weighted Kappa = 0.504, P < 0.0001). Five-year survival in OC HER2 positive negative was 100% and 36% (P = 0.167) compared with 14% and 44% (P = 0.0726) in JC and 50% and 46% (P = 0.942) in GC respectively. Conclusions. Endoscopic biopsy had a high specificity and negative predictive value in determining HER2 status. Patients with JC had a significantly higher rate of HER2 overexpression and this was associated with a nonsignificant poorer survival trend. A larger study is needed to confirm these findings because of the implications for neoadjuvant and adjuvant chemotherapy regimens.
    07/2012; 2012:804891. DOI:10.5402/2012/804891
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