Prevalence of “HER2 ultra-low” among patients with advanced breast cancer with historical IHC0 status.

person Sandhya Mehta Daiichi Sankyo Inc., Basking Ridge, NJ info_outline Sandhya Mehta, Anushree Iyengar, Hannah Barman, Nivedita Rangarajan, Michele Sue-Ann Woo, Simone T. Sredni, Rosemarie Di Donato, Safak Simsek, Erinn P. Downs, Aziza Nassar, Darren M. Wilson, Katherine Krieser, Elise Bieri Patzke, Natalie Kyek, Jason Hipp, Tyler Wagner

Authors person Sandhya Mehta Daiichi Sankyo Inc., Basking Ridge, NJ info_outline Sandhya Mehta, Anushree Iyengar, Hannah Barman, Nivedita Rangarajan, Michele Sue-Ann Woo, Simone T. Sredni, Rosemarie Di Donato, Safak Simsek, Erinn P. Downs, Aziza Nassar, Darren M. Wilson, Katherine Krieser, Elise Bieri Patzke, Natalie Kyek, Jason Hipp, Tyler Wagner Organizations Daiichi Sankyo Inc., Basking Ridge, NJ, nference Inc., Cambridge, MA, AstraZeneca LLC, Gaithersburg, MD, Mayo Clinic, Scottsdale, AZ, Mayo Clinic Florida, Jacksonville, FL, Mayo Clinic, Rochester, MN Abstract Disclosures Research Funding Daiichi Sankyo, Inc. Background: Breast Cancer (BC) patients are classified as HER2-positive (IHC3+ or IHC2+/ISH+) or HER2-negative (IHC0, IHC1+ and 2+/ISH-). Within the HER2-negative category, patients who meet HER2-low (IHC1+ or IHC2+/ISH-) criteria can benefit from HER2 targeted therapy like trastuzumab deruxtecan. Patients who meet IHC0 criteria with incomplete and faint membrane staining in >0 but ≤10% of tumor cells — defined as “HER2 Ultra-low”, may also benefit from HER2 targeted therapy. This study aimed to assess the prevalence of “HER2 Ultra-Low” expression based on re-scored HER2 IHC biopsy slides. Methods: This study utilized EHR data from all three US Mayo Clinic campuses. A total of 300 patients with advanced BC (stages III-IV), and clinically documented HER2 IHC0 status between Jan 2017 and Jan 2023, were identified. One biopsy slide per patient (IHC assay: VENTANA Pathway anti-HER2/neu (4B5) rabbit monoclonal primary antibody) was digitized and scanned at 40x magnification. Two Mayo Clinic pathologists independently scored and reported HER2 status according to 2023 ASCO-CAP guidelines and included tumor stain percentage for each slide. Patients were considered “HER2 Ultra-Low” if their slide was scored as IHC0 with >0% but ≤10% staining. Cohen’s κ was used to quantify agreement between pathologists. Results: The re-scored patients (n=300) had a mean age of 57.8 years (SD=13.5), with ~97% having IHC0 documentation within 30 days of the reviewed biopsy slide. A total of 285 (95%) patients remained classified as IHC0 by at least one pathologist. Of these, 60% (n=171) were determined as “HER2 Ultra-low” by at least one pathologist. The rate of “HER2 Ultra-Low” per pathologist ranged from 43% (n=121) to 45% (n=104). The overall inter-pathologist concordance was 57%; patients with no observable HER2 IHC staining accounted for majority of the concordant patients (Table). Conclusions: About 3 in 5 advanced BC patients originally classified as HER2 IHC0 met the “HER2 Ultra-Low” criteria by at least one pathologist, implying that significant number of additional patients may benefit from HER2 targeted therapy. The relatively low concordance between HER2 expert pathologists in identifying lower levels of HER2 expression suggests the need for increased precision enabled by digital tools, leveraging AI, training for community practice pathologists, and continuing to follow best practice recommendations in determining HER2 IHC status. Concordance among two pathologists’ (P1/P2) review of IHC biopsy slides. P2 No Observable IHC Staining P2 “HER2 Ultra-Low” P2 IHC 1+ P2 IHC2+/ Indeterminate P1 Total P1 No observable IHC staining 104 κ=0.47 23 2 0 129 (43%) P1 “HER2 Ultra-Low” 48 54 κ=0.17 2 0 104 (35%) P1 IHC 1+ 7 44 11 κ=0.21 0 62 (21%) P1 IHC 2+/ Indeterminate 1 0 2 2 κ=0.57 5 (2%) P2 Total 160 (53%) 121 (40%) 17 (6%) 2 (1%) 300 Concordance 171 (57%) Discordance 129 (43%) κ: ≤0.2 poor, 0.21-0.4 fair, 0.41-0.6 good, 0.81-1 very good.