Immunohistochemistry and fluorescence in situ hybridization assessment of HER2 in clinical trials of adjuvant therapy for breast cancer (NCCTG N9831, BCIRG 006, and BCIRG 005)

Mayo Clinic, 4500 San Pablo Road S., Jacksonville, FL, 32224, USA, .
Breast Cancer Research and Treatment (Impact Factor: 3.94). 02/2013; 138(1):99-108. DOI: 10.1007/s10549-013-2444-y
Source: PubMed


A comprehensive, blinded, pathology evaluation of HER2 testing in HER2-positive/negative breast cancers was performed among three central laboratories. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analyses were performed on 389 tumor blocks from three large adjuvant trials: N9831, BCIRG-006, and BCIRG-005. In 123 cases, multiple blocks were examined. HER2 status was defined according to FDA-approved guidelines and was independently re-assessed at each site. Discordant cases were adjudicated at an on-site, face-to-face meeting. Results across three independent pathologists were concordant by IHC in 351/381 (92 %) and FISH in 343/373 (92 %) blocks. Upon adjudication, consensus was reached on 16/30 and 18/30 of discordant IHC and FISH cases, respectively, resulting in overall concordance rates of 96 and 97 %. Among 155 HER2-negative blocks, HER2 status was confirmed in 153 (99 %). In the subset of 102 HER2-positive patients from N9831/BCIRG-006, primary blocks from discordant cases were selected, especially those with discordant test between local and central laboratories. HER2 status was confirmed in 73 (72 %) of these cases. Among 118 and 113 cases with IHC and FISH results and >1 block evaluable, block-to-block variability/heterogeneity in HER2 results was seen in 10 and 5 %, respectively. IHC−/FISH− was confirmed for 57/59 (97 %) primary blocks from N9831 (locally positive, but centrally negative); however, 5/22 (23 %) secondary blocks showed HER2 positivity. Among 53 N9831 patients with HER2-normal disease adjudicated as IHC−/FISH—(although locally positive), there was a non-statistically significant improvement in disease-free survival with concurrent trastuzumab compared to chemotherapy alone (adjusted hazard ratio 0.34; 95 % CI, 0.11–1.05; p = 0.06). There were similar agreements for IHC and FISH among pathologists (92 % each). Agreement was improved at adjudication (96 %). HER2 tumor heterogeneity appears to partially explain discordant results in cases initially tested as positive and subsequently called negative.

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Available from: Marc Buyse, Jan 12, 2014
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    • "FISH analysis of 2+ confirmed 12% of amplification and 90% for 3+ [9]. In other words, they found 10% of false-positive HER2 IHC that can be partially explained by the HER2 tumor heterogeneity [11]. "
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    ABSTRACT: Aims. The differences between the 2007 and the 2013 ASCO/CAP HER2 guidelines have been compared. We also discussed the potential consequences in our pathological practice. Material and Methodology. 189 HER2 fluorescence in situ hybridisation (FISH) tests were performed from 1016 preliminary HER2 immunohistochemical tests (IHC). All cases were reviewed and reclassed following the 2007 and 2013 ASCO/CAP recommendations. Results. The 2013 version decreased false-negative IHC (3/118 versus 1/54, P = ns) and created more 2+ IHC (40/186 versus 89/186, P = 0.001) or more 3+ IHC (9/186 versus 39/186, P = 0.001). One false-positive IHC was described for the 2013 version (0/9 versus 1/39, P = ns). Equivocal FISH was reduced (8/186 versus 2/186, P = ns). An estimation based on our data for 1000 patients showed a rise of our FISH tests for the control of 2+ IHC (180 tests for the 2007 version versus 274 tests for the 2013 version or FISH work overflow is +52%) and for the control of 2+/3+ IHC (300 for the 2007 version versus 475 for the 2013 version or FISH work overflow is +58%). Conclusions. The new 2013 ASCO/CAP guidelines have detected more HER2 positive cases but have increased the number of FISH tests.
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    • "Perez et al. [22] "
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    ABSTRACT: Accurate determination of human epidermal growth factor receptor 2 (HER2) status is critical for optimizing breast cancer outcomes. In 2007, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) developed guidelines for HER2 testing to reduce inaccuracy. However, current ASCO/CAP criteria may restrict access to HER2-targeted therapy for some patient groups who would derive a clear clinical benefit. ASCO/CAP are currently reviewing their guidelines to further optimize HER2 testing and include emerging techniques. Guidelines are critical for optimizing care, as is ongoing research into techniques that accurately and reproducibly assess HER2 status.
    Cancer Treatment Reviews 09/2013; 40(2). DOI:10.1016/j.ctrv.2013.09.001 · 7.59 Impact Factor
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    • "The best response is seen in cases showing strong HER2 over-expression and/or HER2 gene amplification. Lack of accuracy in HER2 testing represents a major obstacle to correct selection of patients and (analogously to ER/PR testing inaccuracy) may impact on clinical outcomes [17] "

    EJC Supplements 09/2013; 11(2):23–26. DOI:10.1016/j.ejcsup.2013.07.027 · 9.39 Impact Factor
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