title: 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).
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.
authors: Mayo Clinic, 4500 San Pablo Road S., Jacksonville, FL 32224, USA. perez.edith@mayo.edu
authors: Edith A
authors: EA
authors: Perez
authors: Michael F
authors: MF
authors: Press
authors: Amylou C
authors: AC
authors: Dueck
authors: Robert B
authors: RB
authors: Jenkins
authors: Chungyeul
authors: C
authors: Kim
authors: Beiyun
authors: B
authors: Chen
authors: Ivonne
authors: I
authors: Villalobos
authors: Soonmyung
authors: S
authors: Paik
authors: Marc
authors: M
authors: Buyse
authors: Anne E
authors: AE
authors: Wiktor
authors: Reid
authors: R
authors: Meyer
authors: Melanie
authors: M
authors: Finnigan
authors: Joanne
authors: J
authors: Zujewski
authors: Mona
authors: M
authors: Shing
authors: Howard M
authors: HM
authors: Stern
authors: Wilma L
authors: WL
authors: Lingle
authors: Monica M
authors: MM
authors: Reinholz
authors: Dennis J
authors: DJ
authors: Slamon
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015203:Reproducibility of Results
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases