PMID- 11352964
OWN - NLM
STAT- MEDLINE
DCOM- 20010607
LR  - 20170210
IS  - 0732-183X (Print)
IS  - 0732-183X (Linking)
VI  - 19
IP  - 10
DP  - 2001 May 15
TI  - Discrepancies in clinical laboratory testing of eligibility for trastuzumab 
      therapy: apparent immunohistochemical false-positives do not get the message.
PG  - 2714-21
AB  - BACKGROUND: Several studies have reported what seem to be false-positive results 
      using the Food and Drug Administration (FDA)-approved HercepTest (Dako Corp, 
      Carpinteria, CA) to profile Her-2/neu amplification and overproduction in breast 
      carcinoma. False-positive status has been based on comparisons with gene copy 
      enumeration by fluorescence in situ hybridization (FISH) and with comparisons to 
      immunohistochemistry (IMH) results using a monoclonal antibody. However, simple 
      overexpression by tumor cells that have normal gene copy has not been evaluated 
      by profiling mRNA expression, ie, such cases could simply represent 
      true-positive, transcriptionally upregulated overexpression. MATERIALS AND 
      METHODS: Four hundred infiltrating ductal carcinomas of breast were evaluated by 
      IMH using monoclonal (CB11; Ventana Medical Systems, Inc, Tucson, AZ) and 
      polyclonal (HercepTest; Dako) antibodies after antigen retrieval (AR). A 
      polyclonal antibody sans AR (PCA/SAR) was also used. All IMH stains were 
      evaluated and scored according to the guidelines for the FDA-approved HercepTest. 
      A total of 145 of 400 carcinomas were subsequently evaluated by direct and 
      digoxigenin-labeled (Dig) FISH, and 144 of 400 were evaluated by detection of 
      mRNA overexpression via autoradiographic RNA:RNA in situ hybridization. RESULTS: 
      Overall HercepTest/CB11 IMH discordance was 12%. Expression of mRNA was highly 
      concordant with FISH and DigFISH amplification and with CB11 and PCA/SAR 
      immunohistology. IMH false-positive cases (no Her-2/neu gene amplification) 
      occurred with both HercepTest (23%) and CB11 (17%), and the majority of 
      false-positive results (34 of 44) were scored as 2+. All 2+ false-positive cases 
      were mRNA-negative. Combined results of HercepTest and CB11 showed that 79% (38 
      of 48) of 3+ cases were Her-2/neu gene amplified, but only 17% (seven of 41) of 
      2+ cases had increased gene copy. CONCLUSION: Discordant HercepTest/FISH results, 
      and to a lesser extent discordance with CB11 IMH, are most commonly 
      false-positive results with a score of 2+. The 2+ score as defined in the 
      guidelines for the FDA-approved HercepTest should not be used as a criterion for 
      trastuzumab therapy unless confirmed by FISH. Determination of Her-2 gene copy 
      number by FISH may be a more accurate and reliable method for selecting patients 
      eligible for trastuzumab therapy.
FAU - Tubbs, R R
AU  - Tubbs RR
AD  - Department of Clinical Pathology, Cleveland Clinic Foundation, Cleveland, OH 
      44195, USA. TubbsR@ccf.org
FAU - Pettay, J D
AU  - Pettay JD
FAU - Roche, P C
AU  - Roche PC
FAU - Stoler, M H
AU  - Stoler MH
FAU - Jenkins, R B
AU  - Jenkins RB
FAU - Grogan, T M
AU  - Grogan TM
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antineoplastic Agents)
RN  - P188ANX8CK (Trastuzumab)
SB  - IM
MH  - Antibodies, Monoclonal/*therapeutic use
MH  - Antibodies, Monoclonal, Humanized
MH  - Antineoplastic Agents/*therapeutic use
MH  - Breast Neoplasms/drug therapy/*genetics
MH  - Carcinoma, Ductal, Breast/drug therapy/*genetics
MH  - False Positive Reactions
MH  - Female
MH  - Gene Amplification
MH  - Genes, erbB-2/*genetics
MH  - Humans
MH  - Immunohistochemistry
MH  - In Situ Hybridization, Fluorescence
MH  - Reference Standards
MH  - Trastuzumab
EDAT- 2001/05/16 10:00
MHDA- 2001/06/08 10:01
CRDT- 2001/05/16 10:00
PHST- 2001/05/16 10:00 [pubmed]
PHST- 2001/06/08 10:01 [medline]
PHST- 2001/05/16 10:00 [entrez]
AID - 10.1200/JCO.2001.19.10.2714 [doi]
PST - ppublish
SO  - J Clin Oncol. 2001 May 15;19(10):2714-21. doi: 10.1200/JCO.2001.19.10.2714.