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

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
Source: PubMed

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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Human epidermal growth factor receptor 2 (HER2) amplification/overexpression is an effective therapeutic target in breast and gastric cancer. Although HER2 positivity has been reported in other malignancies, previous studies generally focused on one cancer type, making it challenging to compare HER2 positivity across studies/malignancies. Herein, we examined 37,992 patient samples for HER2 expression (+/- amplification) in a single laboratory. All 37,992 patients were tested by immunohistochemistry (IHC); 21,642 of them were also examined for HER2 amplification with either fluorescent in situ hybridization (FISH) (11,670 patients) or chromogenic in situ hybridization (CISH) (9,972 patients); 18,262 patients had tumors other than breast or gastric cancer. All tissues were analyzed in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Caris Life Sciences) at the request of referring physicians. HER2 protein overexpression was found in 2.7 % of samples. Over-expressed HER2 was detected predominantly in malignancies of epithelial origin; for cancers derived from mesenchyme, neuroendocrine tissue, central nervous system, and kidney, HER2 expression and amplification were remarkably rare or non-existent. Bladder carcinomas, gallbladder, extrahepatic cholangiocarcinomas, cervical, uterine, and testicular cancers showed HER2 positivity rates of 12.4, 9.8, 6.3, 3.9, 3.0, and 2.4 %, respectively. HER2 overexpression and/or amplification is frequently found across tumor types. These observations may have significant therapeutic implications in cancers not traditionally thought to benefit from anti-HER2 therapies.
    Cancer and metastasis reviews 02/2015; DOI:10.1007/s10555-015-9552-6 · 6.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Trastuzumab has been approved for use in combination with fluoropyrimidine plus cisplatin for the treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC). Although capecitabine plus oxaliplatin (XELOX) is a standard first-line regimen for AGC, combination trastuzumab plus XELOX has not been studied. Patients with metastatic or unresectable HER2-positive AGC were diagnosed by either HER2 immunohistochemistry (IHC) 3+ or IHC 2+/fluorescence in-situ hybridisation (FISH)+ received intravenous trastuzumab (8mg/m(2) for first cycle and 6mg/m(2) for subsequent cycles on day 1) plus oral capecitabine (1000mg/m(2) twice daily on days 1-14) and intravenous oxaliplatin (130mg/m(2) on day 1), every 3weeks. The primary end-point was the objective response rate, and secondary end-points included progression-free survival (PFS), overall survival (OS) and toxicity profiles. Fifty-five HER2-positive AGC patients were enrolled between August 2011 and February 2013. The median age was 57years (range=29-74). The confirmed objective response rate was 67% (95% confidence interval (CI)=54-80%). After a median follow-up period of 13.8months (range=6.1-23.9), the median PFS and OS were 9.8months (95% CI=7.0-12.6) and 21.0months (95% CI=6.4-35.7), respectively. Frequently encountered grade 3-4 toxicities included neutropenia (18%), anaemia (11%), and peripheral neuropathy (11%). There was a treatment-related death caused by severe diarrhoea and complicated sepsis. Combination of trastuzumab and XELOX is well tolerated and highly effective in patients with HER2-positive AGC. Copyright © 2015 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 02/2015; 51(4). DOI:10.1016/j.ejca.2014.12.015 · 4.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aim: Previous studies demonstrated discordant expression of human epidermal growth‑factor receptor 2 (HER2) between primary cancer and their recurrence/metastasis. This study further evaluated HER2 status between primary gastric and breast invasive carcinomas and paired metastatic disease to lymph nodes. Methods: This study collected formalin‑fixed paraffin‑embedded representative tissue blocks from 62 gastric and 65 breast primary carcinomas as well as synchronous metastatic lymph nodes (male:female = 39:88; age ranged between 44 and 95 years with mean age of 69.32 years) for immunohistochemical staining of HER2 expression (DAKO HercepTest™ kit). If immunohistochemical HER2 score reached to 2+, HER2 amplification was then assessed using fluorescence in situ hybridization (PharmDx™ kit DAKO). Results: The discordant HER2 pooled rate, regardless either negative or positive conversion, was 9.67% in primary gastric carcinoma and corresponding nodal metastasis, while the changes in HER2 expression were revealed in 4.61% of mammary and lymph node neoplastic samples. A high‑level concordance in HER2 expression between primary carcinoma and synchronous metastatic lymph nodes was confirmed in both types of cancer; the observed event of discordant HER2 status should be ascribed to intra‑tumor heterogeneity, mostly appreciable in gastric cancer. Conclusion: In any case, the shift from positive to negative HER2 expression suggests that trastuzumab could be the targeted treatment choice whereas the opposite shift should be evaluated by a simultaneous HER2 determination in both primary and metastatic lymph nodes.

Full-text (2 Sources)

Available from
May 16, 2014