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)

Edith A. Perez, Michael F. Press, Amylou Dueck, Robert Brian Jenkins, Chungyeul Kim, Beiyun Chen, Ivonne Villalobos, Soonmyung Paik, Marc Buyse, Anne E. Wiktor, Reid Meyer, Melanie Finnigan, Joanne Zujewski, Mona Shing, Howard M. Stern, Wilma L. Lingle, Monica M. Reinholz, Dennis J. Slamon

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)99-108
Number of pages10
JournalBreast Cancer Research and Treatment
Volume138
Issue number1
DOIs
StatePublished - 2013

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Fluorescence In Situ Hybridization
Immunohistochemistry
Clinical Trials
Breast Neoplasms
Therapeutics
Disease-Free Survival
Neoplasms
Guidelines
Pathology
Drug Therapy

Keywords

  • Breast cancer
  • Concordance
  • FISH
  • HER2 testing
  • IHC

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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). / Perez, Edith A.; Press, Michael F.; Dueck, Amylou; Jenkins, Robert Brian; Kim, Chungyeul; Chen, Beiyun; Villalobos, Ivonne; Paik, Soonmyung; Buyse, Marc; Wiktor, Anne E.; Meyer, Reid; Finnigan, Melanie; Zujewski, Joanne; Shing, Mona; Stern, Howard M.; Lingle, Wilma L.; Reinholz, Monica M.; Slamon, Dennis J.

In: Breast Cancer Research and Treatment, Vol. 138, No. 1, 2013, p. 99-108.

Research output: Contribution to journalArticle

Perez, EA, Press, MF, Dueck, A, Jenkins, RB, Kim, C, Chen, B, Villalobos, I, Paik, S, Buyse, M, Wiktor, AE, Meyer, R, Finnigan, M, Zujewski, J, Shing, M, Stern, HM, Lingle, WL, Reinholz, MM & Slamon, DJ 2013, '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)', Breast Cancer Research and Treatment, vol. 138, no. 1, pp. 99-108. https://doi.org/10.1007/s10549-013-2444-y
Perez, Edith A. ; Press, Michael F. ; Dueck, Amylou ; Jenkins, Robert Brian ; Kim, Chungyeul ; Chen, Beiyun ; Villalobos, Ivonne ; Paik, Soonmyung ; Buyse, Marc ; Wiktor, Anne E. ; Meyer, Reid ; Finnigan, Melanie ; Zujewski, Joanne ; Shing, Mona ; Stern, Howard M. ; Lingle, Wilma L. ; Reinholz, Monica M. ; Slamon, Dennis J. / 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). In: Breast Cancer Research and Treatment. 2013 ; Vol. 138, No. 1. pp. 99-108.
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AU - Perez, Edith A.

AU - Press, Michael F.

AU - Dueck, Amylou

AU - Jenkins, Robert Brian

AU - Kim, Chungyeul

AU - Chen, Beiyun

AU - Villalobos, Ivonne

AU - Paik, Soonmyung

AU - Buyse, Marc

AU - Wiktor, Anne E.

AU - Meyer, Reid

AU - Finnigan, Melanie

AU - Zujewski, Joanne

AU - Shing, Mona

AU - Stern, Howard M.

AU - Lingle, Wilma L.

AU - Reinholz, Monica M.

AU - Slamon, Dennis J.

PY - 2013

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N2 - 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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