Standard ERBB2 IHC Testing Has Limitations for Identifying ERBB2-Low Breast Cancer

The inaccuracy of standard immunohistochemistry testing to identify ERBB2-low breast cancer could lead to real-world mismanagement of patients who may be eligible for fam-trastuzumab deruxtecan-nxki.

Using standard ERBB2 immunohistochemistry (IHC) testing in patients with breast cancer may lead to deficiencies in treatment selection, especially for those with low ERBB2 expression, and could lead to missed opportunities to use fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) in those who may otherwise benefit from its use, according to research published in JAMA Oncology.

Surveys conducted by the College of American Pathologists (CAP) indicated that 19% of cases evaluated in the analysis generated findings with a concordance amongst laboratories of 70% or less for IHC ERBB2 scores of 0 compared with 1+.

In another analytical data set, a total of 18 pathologists served as raters and assessed slides containing breast biopsy samples with the 4-point IHC scale. Out of a total of 170 cases, 92 were determined to be IHC 0 by at least one pathologist; of those, concordance of 90% was achieved in only 26% of cases. By comparison, IHC 3+ was identified by at least one clinician in 45 cases, of which 90% concordance was achieved in 58% of cases.

Investigators noted, “While the interrater agreement of only 58% is concerning for a 2+ vs 3+ read, this is not a clinical problem because the 2+ cases are resolved by [fluorescence in situ hybridization] prior to decisions for therapy. No such adjudicator exists for 0 vs 1+ cases. Note also that the consensus of the pathologists on the critical 0 and 1+ score cases is insufficient to define a criterion standard, and thus the preanalytic questions will need to be addressed in a future study.”

Investigators assessed 2 years’ worth of CAP ERBB2 surveys from 2019 to 2020. Laboratories that participated were given 2 tissue microarrays of 10 ERBB2 cores twice annually. The assays were conducted using standard methods. The dataset included scores from 1391 to 1452 laboratories, with 40 ERBB2 cores from each. Additionally, investigators used a second independent dataset that was pulled from Yale University’s archive of breast biopsies that were collected in 2018.

Investigators reported that 65% of samples that were assessed in the CAP survey had a concordance rate of 90% of more; notably, this high agreement appeared limited to score of 0 or 3+. The lowest agreement was identified in samples with an ERBB2 score of 0 and 1+. Out of all 80 cores, 56 were considered negative of which 25% resulted in a 70% agreement or less.

Based on these findings, investigators stated that there are likely to be inaccuracies when distinguishing between ERBB2 scores of 0 or 1+.

“Given the efficacy of T-DXd, we believe that patients may be misassigned for treatment or no treatment if the decision depends on performance of the current standard ERBB2 assays in use around the world. This problem could be remedied by new assays that stratify cases with lower ERBB2 expression combined with standardization of the assays with calibration slides,” investigators concluded.


Fernandez AI, Liu M, Bellizzi A, et al. Examination of low ERBB2 protein expression in breast cancer tissue. JAMA Oncol. Published online February 3, 2022. doi:10.1001/jamaoncol.2021.7239