A Global Ring Study: Concordance Between Ventana PATHWAY anti-HER2/neu (4B5) Companion Diagnostic Assay and Comparators in Detecting HER2-low Breast Cancer.

Trastuzumab deruxtecan showed improved efficacy compared with treatment of physician's choice in human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization-negative) metastatic breast cancer (BC) patients in the DESTINY-Breast04 and -06 phase 3 clinical trials. Both trials used the Ventana PATHWAY HER2/neu (4B5) IHC assay (PATHWAY 4B5) to select patients. The variety of HER2 IHC assays in clinical use complicate real-world differentiation between HER2-low and HER2 IHC 0. This study assessed concordance between PATHWAY 4B5 and comparator assays in identifying HER2-low samples. Fifty clinical BC samples from a cohort of 300 were stained using PATHWAY 4B5 and centrally scored, according to ASCO-CAP 2018 guidelines, as HER2 IHC 0, 1+, 2+, and 3+. Unstained samples were sent to participating laboratories in the Americas, Europe, and the Asia-Pacific regions who were actively scoring HER2 IHC for BC, had 2 independent pathologists, and did not routinely use PATHWAY 4B5 following the CDx protocol. Pathologists stained and scored the samples using their laboratory's routine protocols. Following virtual alignment on interpretation of HER2 IHC scoring guidelines (postalignment), pathologists were directed to rescore the samples. Pathologist scores were compared with centrally assessed scores; the primary endpoint was positive percentage agreement (PPA) and negative percentage agreement (NPA) for HER2-low versus HER2 IHC 0 based on postalignment scores. Overall, 129 pathologists from 68 laboratories submitted 6270 postalignment scores for analysis. PPA (agreement in identifying HER2-low) and NPA (agreement in identifying HER2 IHC 0) were 84.8% (95% CI, 83.6%-86.0%) and 69.2% (95% CI, 67.0%-71.2%), respectively. Across assay types, postalignment PPA ranged from 61.6%-95.5% and postalignment NPA ranged from 36.9%-81.7%. The variation in concordance rates observed between assays suggests assay choice may be important for correct identification of patients with low-levels of HER2-expression who may benefit from HER2-targeted therapies.