Prevalence of HER2 low in breast cancer subtypes using the VENTANA anti-HER2/neu (4B5) assay.

person Marietta Scott AstraZeneca R&D, Cambridge, United Kingdom info_outline Marietta Scott, Michel Erminio Vandenberghe, Paul Scorer, Anne-Marie Boothman, Craig Barker

Authors person Marietta Scott AstraZeneca R&D, Cambridge, United Kingdom info_outline Marietta Scott, Michel Erminio Vandenberghe, Paul Scorer, Anne-Marie Boothman, Craig Barker Organizations AstraZeneca R&D, Cambridge, United Kingdom Abstract Disclosures Research Funding Pharmaceutical/Biotech Company AstraZeneca Background: Breast cancer patients with HER2 low expression by immunohistochemistry (IHC), defined as IHC1+ or IHC2+ without gene amplification (ISH-) do not respond to conventional anti-HER2 therapies such as trastuzumab or pertuzumab. The HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) showed efficacy in late line HER2-overexpressing patients, with some responses in patients with low HER2 expression. Two of the market leading IHC IVDs are Dako Herceptest and Ventana 4B5. T-DXd is being investigated in HER2 low patients as determined by the VENTANA anti-HER2/neu (4B5) assay in the phase III DESTINY-Breast04 study. There is a paucity of information on prevalence of IHC1+/2+ in different breast cancer subtypes, which this study aims to address. Methods: HER2 status was calculated from 3750 consecutive primary or metastatic breast cancer patient samples successfully stained using the 4B5 assay and scored locally according to ASCO/CAP 2018 guidelines. Samples were obtained from 3 anatomic pathology labs that support networks of US community hospitals. 500 additional breast cancer samples, pre-selected to include a range of IHC staining (concordance cohort), were stained with both 4B5 and HercepTest (Dako/Agilent) and scored (IHC0, IHC1+, IHC2+, IHC3+) at a central laboratory. Results: Prevalence of HER2 categories in 3750 consecutive breast cancer samples is presented in the table below. >50% of estrogen-receptor positive (ER+ve) and progesterone receptor positive (PR+ve) subtypes are HER2 low. In the 500 sample concordance cohort, 28.0% were IHC1+/2+ using the 4B5 assay compared with 11.6% using HercepTest. HercepTest identified IHC1+/2+ staining in 21.6% [95%CI:15.1,29.4] of the patients classified as IHC1+/2+ by 4B5. 98.3% [95%CI: 96.2, 99.5] of samples IHC0 by 4B5 were also IHC0 by Herceptest. Conclusions: HER2 IHC1+/2+ (ISH-) by Ventana 4B5 represent a significant proportion of breast cancer patients and more than 50% of ER+ve and PR+ve subtypes. The 4B5 assay classed several patients as IHC1+/2+ that are IHC0 by Herceptest, but almost all patients IHC0 by 4B5 were also IHC0 by Herceptest. Subtype (n) Prevalence IHC0 % [95% CI] Prevalence IHC1+/2+ (ISH-) [HER2 low] % [95% CI] Prevalence IHC2+ (ISH+)/IHC3+ % [95% CI] Total breast cancer (3727) 35.9 [34.4, 37.5] 51.1 [49.5, 52.8] 13.0 [11.9, 14.1] ER+ve (3028) 34.1 [32.5, 35.9] 55.4 [53.6, 57.2] 10.4 [9.4, 11.6] ER-ve (588) 43.9 [39.0, 48.0] 29.8 [26.1, 33.6] 26.4 [22.8, 30.1] PR+ve (2671) 34.6 [32.8, 36.4] 55.9 [54.0, 57.8] 9.5 [8.4, 10.7] PR-ve (945) 39.0 [35.9, 42.2] 38.0 [34.9, 41.2] 23.0 [20.3, 25.8] ER or PR+ve (3086) 34.1 [32.4, 35.8] 55.2 [53.4, 57.0] 10.7 [9.6, 11.8] ER/PR-ve (530) 45.3 [41.0, 49.6] 28.1 [24.3, 32.1] 26.6 [22.9, 30.6] Triple negative (389) 61.7 [56.7, 66.6] 38.3 [33.4, 43.3] Not applicable