Central pathology laboratory review of HER2 and ER in early breast cancer: an ALTTO trial [BIG 2-06/NCCTG N063D (Alliance)] ring study

Abstract

Background/Purpose Choice of therapy for breast cancer relies on human epidermal growth factor receptor-2 (HER2) and estrogen receptor (ER) status. Before randomization in the phase III adjuvant ALTTO trial for HER2-positive disease, HER2 and ER were centrally reviewed by Mayo Clinic (Rochester, MN and Scottsdale, AZ) for North America and by the European Institute of Oncology (IEO; Milan, Italy) for rest of world (except China). Discordance rates (local vs. central review) differed between Mayo and IEO. Among locally HER2-positive cases, 5.8% (Mayo) and 14.5% (IEO) were centrally HER2-negative. Among locally ER-positive cases, 16.2% (Mayo) and 4.2% (IEO) were centrally ER-negative. Among locally ER-negative cases, 3.4% (Mayo) and 21.4% (IEO) were centrally ER-positive. We, therefore, performed a ring study to identify features contributing to these differing discordance rates. Methods Mayo and IEO exchanged slides for 25 HER2 and 35 ER locally/centrally discordant cases. Both laboratories performed IHC and FISH for HER2 using the HercepTest® and PathVysion HER2 DNA probe kit/HER2/centromere 17 probe mixture. IHC for ER was tested centrally using the monoclonal ER 1D5 antibody (Mayo) or the DAKO cocktail of ER 1D5 and 2.123 antibodies (IEO). Results Mayo and IEO confirmed the central HER2-negative result in 100% of 25 cases. Mayo and IEO confirmed the central ER result in 29 (85%) of 34 evaluable cases. The five Mayo negative/IEO positive cases were ER-positive when retested at Mayo using the DAKO ER cocktail. Conclusions In this ring study, ALTTO ineligibility did not change when HER2 testing was performed by either IEO or Mayo central laboratories. However, a dual antibody ER assay had fewer false negative test results than an assay with a single antibody, there was more discordance between the two ER reagents than has been previously reported, and using even slightly different assay methods yielded different results, even between experienced central laboratories.

An international study comparing conventional versus mRNA level testing (TargetPrint) for ER, PR, and HER2 status of breast cancer

“…The data for the two tests are in agreement with the overlapping mRNA expression levels between conventionally assessed positive and negative HER2 cases as reported by Pinhel et al [39]. Also comparative protein studies for IHC/ISH assessments of HER2 indicate that even when adhering to highest quality standards, discordance similar discordance results are seen, indicating the difficulty of reaching satisfactory quality for HER2 assessment [40,41]. The gold standard for HER2 testing today remains IHC and ISH from high-quality laboratories (i.e., those that are CAP accredited or meet accreditation and proficiency testing requirements).…”

OPTIMA prelim: a randomised feasibility study of personalised care in the treatment of women with early breast cancer

“…For example, among cases regarded locally as ER-positive, 4% and 16%, respectively, were centrally redefined as ER-negative in two reviewing centres in Italy and the USA in the BIG 2-06/NCCTG N063D trial. 192 Similarly, in a centrally reviewed consecutive series of node-negative breast cancer from the Netherlands, 4% and 5% disagreement was seen for ER and HER2, respectively, between local and central tests (n = 694). 193 The low level of disagreement in receptor status between local and central laboratories that we report in this study reflects improvements in standardisation of receptor testing and the high levels of quality assurance in the UK including, for example, mandatory participation in National External Quality Assessment Service for Immunohistochemistry.…”

Central pathology review with two-stage quality assurance for pathological response after neoadjuvant chemotherapy in the ARTemis Trial

“…10 An important distinction must be drawn here between re-testing, potentially using different reagents and conditions, and the review of original diagnostic material. In…”