Abstract HER2-13: HER2-13 Proficiency assessment of HER2-low breast cancer scoring with the Ventana PATHWAY 4B5 and Dako HercepTest HER2 assays and the impact of pathologist training

Background: Based on the results of the DESTINY-Breast04 study, the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd) and the Ventana PATHWAY 4B5 companion diagnostic were recently approved by the US Food and Drug Administrated for the treatment and identification of patients with HER2-low (IHC2+/ISH- or IHC1+) (Modi et al. N Engl J Med 2022). The efficacy of T-DXd in HER2-low mBC highlights the need to distinguish lower ranges of HER2 IHC expression, which has been reported to be more challenging than scoring high HER2 expression (Fernandez et al. JAMA Oncol 2022). Here we report on current real-world HER2-low interpretation proficiency and the impact of training for participating pathologists in HER2-low scoring. Methods: Pathologists from laboratories across the US, EU, Japan, Australia, and Brazil were invited to use a digital pathology platform (Pathotrainer) to interpret HER2 digital images using ASCO/CAP 2018 scoring criteria. Two whole-slide imaging sample sets of representative study cases were compiled for Ventana PATHWAY 4B5 or Dako HercepTest (HcT) stained tumors. Another sample set (n = 25) was developed for a 4 hour virtual training session based on the ASCO/CAP 2018 guideline with some practical considerations. A steering committee (SC) of 8 pathology experts was formed to guide the study. Pathologists’ score was compared with a reference score as determined by independent review of 3 experts in HER2 pathology. Paired study cases (n = 14) considered challenging due to difficult-to-interpret staining patterns were reevaluated by the SC members. Concordance and efficacy of training were measured by Cohen’s weighted kappa (κ) coefficient, overall rater agreement (ORA), and receiver operating characteristic curve statistics. The primary endpoint was real-world concordance and ORA. The secondary endpoints were post-training concordance and ORA and correct identification of HER2 IHC 0 and HER2-low. Results: Pre-training baseline or real-world scores were taken by 77 pathologists in 14 countries (n = 49 for 4B5, n = 28 for HcT) and 74 pathologists completed post-training scores (n = 48 for 4B5, n = 26 for HcT). HER2 scoring proficiency of pathologists was high for both assays when assessed on ASCO/CAP binary HER2-negative and -positive status, irrespective of training (4B5: κ = 0.96, ORA =98.9.%; HcT: κ = 0.84, ORA = 94.3%) Concordance per ORA for the new 3-tier classification (HER2 IHC 0 vs HER2-low [IHC 2+/ISH- or IHC 1+] vs HER2-positive [IHC 3+ or IHC 2+/ISH+]) was greater than 80% for both assays at baseline and after training (see Table). In a subgroup analysis assessing training effect for 4B5 assay, concordance rates for HER2 IHC 0 were 74.6% at baseline and 89.2% after training (P < 0.001), and for HER2-low, NPA was 80.6% before and 91.1% after training (P < 0.001); there were no statistically significant changes after training for HcT (data not shown). Conclusions: Results from this real-world global study demonstrate that overall score concordance with a new category of HER2-low was above the 80% ORA benchmark for both 4B5 and HcT and is higher than previously reported (Fernandez et al. JAMA Oncol 2022). These data demonstrate pathologists’ ability to achieve an acceptable level of accuracy for identifying HER2 IHC 0 and HER2-low patients even after short-term training; however, additional training techniques and experience are needed to further improve accuracy. Acknowledgment Judy Yu, a former AstraZeneca employee, provided expertise and technical insights to support the study. Editorial Acknowledgment Under guidance of the authors, assistance in medical writing and editorial support was provided by Toinette Labuschagné, MSc, of ApotheCom, and was funded by Daiichi Sankyo. Funding This study was funded by Daiichi Sankyo and AstraZeneca. Table. Summary of Pathologist Concordance and Interobserver Variability Citation Format: Josef Rüschoff, Alexander Penner, Ian O. Ellis, M. Elizabeth H. Hammond, Annette Lebeau, Robert Y. Osamura, Frédérique Penault-Llorca, Federico Rojo, Neil Atkey, Andreas H. Scheel, Corrado D´Arrigo, Hans-Ulrich Schildhaus, Akira Moh, Chirag Desai, Giuseppe Viale. HER2-13 Proficiency assessment of HER2-low breast cancer scoring with the Ventana PATHWAY 4B5 and Dako HercepTest HER2 assays and the impact of pathologist training [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr HER2-13.