Implementation of American Society of Clinical Oncology/College of American Pathologists HER2 Guideline Recommendations in a tertiary care facility increases HER2 immunohistochemistry and fluorescence in situ hybridization concordance and decreases the number of inconclusive cases. Arch Pathol Lab Med
The American Society of Clinical Oncology/ College of American Pathologists (ASCO/CAP) guideline recommendations from January 2007 identified many sources of immunohistochemistry (IHC) testing variation.
In this current study, we implemented the guidelines and addressed our institution's preanalytic, analytic, and postanalytic variables relating to HER2 testing to improve clinical outcomes.
We evaluated core biopsies performed on breast lesions from 2006 through 2007. Prognostic/predictive markers obtained by IHC were correlated with HER2 fluorescence in situ hybridization (FISH). Preanalytic sources of biopsy testing variation were studied by collecting data on the number of biopsies that needed repeat testing because of inconclusive FISH results.
In the year preceding implementation of the guidelines, the HER2 IHC and FISH concordance was 98%. In an additional 10.8% of cases, the FISH results were inconclusive. When additional material became available to retest the inconclusive cases, the results were informative. Further evaluation of the inconclusive cases revealed that the core needle biopsies received, on average, 4 hours of formalin fixation. After implementation of a minimum 6 hours of fixation and the ASCO/CAP guideline recommendations, the HER2 IHC and FISH concordance was 98.5%. The number of FISH inconclusive cases decreased from 10.8% to 3.4% (a 64% reduction). Repeat estrogen-receptor IHC requests decreased by 40% from 38 in 2006 to 23 in 2007.
We have shown that standardized fixation and adherence to the ASCO/CAP guidelines for HER2 testing has resulted in a greater HER2 IHC and HER2 FISH correlation, decreased numbers of inconclusive FISH cases, decreased repeat estrogen-receptor requests, and financial savings to the Department of Pathology.
"We scored 30 nuclei per sample, and recorded the number of HER2 (red) and CEP17 (green) signals according to the 2007 ASCO/CAP criteria. Gene amplification was indicated when the HER2/CEP17 ratio > 2.2; amplification was equivocal when 1.8 ≤ HER2/CEP17 ratio ≤ 2.2, and negative when HER2/CEP17 ratio < 1.8    "
"The modified definition for cut-offs for HER2/CEP17 ratios and for score 3+ IHC presumably also played a role in the improved congruency between IHC and FISH technology in our cohort . Similarly to our own results, two larger studies also reported a drop in HER2 positivity and simultaneously a better congruence after implementing the modified guidelines from 2008 [16,18]. Interestingly, the positivity-rate by FISH when using this assay as the primary test in our institution (n = 4843), resulted in a rather constant positivity-rate prior to and after applying the modified ASCO criteria. "
[Show abstract][Hide abstract] ABSTRACT: The gold standard of HER2 status assessment in breast cancer is still debated. Immunohistochemistry (IHC) and in-situ technology as fluorescent-labeled methodology (FISH) can be influenced by pre-analytical factors, assay-conditions and interpretation of test results. We retrospectively conducted this quality control study and analyzed HER2 test results in breast cancer within the routine diagnostic service in a single institution over a period of 12 years. We addressed the question how stable and concordant IHC and FISH methods are and whether HER2 positivity rate has changed over this period.
Data of 7714 consecutive HER2-FISH-assays in a period of 12 years (2001-2012) on breast cancer biopsies and excision specimens were retrospectively analyzed. From 2001 to 2004, FISH tests were performed from all cases with IHC score 3+ and 2+ (and in some tumors with IHC score 1+ and 0). From 2005-2010, HER2 status was only determined by FISH. From 2011-2012, all breast carcinomas were analyzed by both IHC and FISH. Scoring and cut-off-definition were done according to time-current ASCO-CAP and FDA-guidelines.
Between 2001-2004, IHC score 3+ was diagnosed in 22% of cases, 69% of these 3+ cases were amplified by FISH. 6% of IHC score 0/1+ cases were amplified by FISH. There was a mean amplification rate of 15.8% (range 13 -19%) using FISH only HER2-assays (2005-2010). Starting 2008, a slight drop in the amplification rate from 17% to 14% was noticed due to the modified ASCO-criteria in 2007. From 2011-2012, 12% of cases were 3+ by IHC, 84% of them were amplified by FISH. Less than 1% of IHC score 0/1+ cases were amplified by FISH. Concordance between FISH and IHC increased from 83% to 97%.
Our quality control study demonstrates that HER2 positivity rate remained stable by FISH-technology but showed a significant variation by IHC over the analyzed 12 years. Improvement in concordance rate was due to standardization of pre-analytical factors, scoring and interpretation.
BMC Cancer 12/2013; 13(1):615. DOI:10.1186/1471-2407-13-615 · 3.36 Impact Factor
"In addition, unlike the FDA-approved cut-off ratio of 2.0 for HER2/Chromosome 17 centromere (CEP17) testing via FISH (or four HER2 copies in assays without internal CEP17 probes), ASCO/CAP considered the range of ratios between 1.8 and 2.2 (or four to six HER2 copies) as equivocal and stated that only cases with HER2/CEP17 ratios >2.2 (or more than six copies of HER2) could be deemed to be positive based on FISH analysis. The aim of the new ASCO/CAP guidelines was to reduce the number of inconclusive cases and although some groups were positive to these new definitions (27, 28), others saw no added benefit (29). While high concordance between IHC- and FISH-based HER2 testing was demonstrated by several studies, thus justifying the use of routine IHC as an initial test (30), critics are keen to highlight the technical superiority of FISH over IHC and consequently advocate FISH as the gold standard for HER2 testing (31). "
[Show abstract][Hide abstract] ABSTRACT: The emergence of targeted therapies for cancer has created a need for the development of companion diagnostic tests. Assays developed in recent years are aimed at determining both the effectiveness and safety of specific drugs for a defined group of patients, thus, enabling the more efficient design of clinical trials and also supporting physicians when making treatment-related decisions. Immunohistochemistry (IHC) is a widely accepted method for protein expression analyses in human tissues. Immunohistochemical assays, used to localize and quantitate relative protein expression levels within a morphological context, are frequently used as companion diagnostics during clinical trials and also following drug approval. Herein, we describe established immunochemistry-based methods and their application in routine diagnostics. We also explore the possibility of using IHC to detect specific protein mutations in addition to DNA-based tests. Finally, we review alternative protein binders and proximity ligation assays and discuss their potential to facilitate the development of novel, targeted therapies against cancer.
Frontiers in Oncology 10/2013; 3:271. DOI:10.3389/fonc.2013.00271
Sally R. Coassin, Byung-Chul Kim, Hans E. Johansson
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