Classification of HER2 status across multiple cancers using epigenomic profiles from a novel liquid biopsy assay.

person Anthony D'Ippolito Precede Biosciences, Boston, MA info_outline Anthony D'Ippolito, Jonathan Beagan, Melissa E. Hughes, Matthew Strickland, Martin Samuel Taylor, Corrie Painter, Kalie Smith, Aditya Pandey, Ilexa A Schechter, Mosammat F Afreen, Jayne Stommel, Aparna Gorthi, Nancy U. Lin, Matthew Freedman, Heather Anne Parsons, Samuel J. Klempner, Gordon B. Mills, Sara M. Tolaney, Matthew Eaton, J. Carl Barrett

Authors person Anthony D'Ippolito Precede Biosciences, Boston, MA info_outline Anthony D'Ippolito, Jonathan Beagan, Melissa E. Hughes, Matthew Strickland, Martin Samuel Taylor, Corrie Painter, Kalie Smith, Aditya Pandey, Ilexa A Schechter, Mosammat F Afreen, Jayne Stommel, Aparna Gorthi, Nancy U. Lin, Matthew Freedman, Heather Anne Parsons, Samuel J. Klempner, Gordon B. Mills, Sara M. Tolaney, Matthew Eaton, J. Carl Barrett Organizations Precede Biosciences, Boston, MA, Dana-Farber Cancer Institute, Boston, MA, DFCI/PCC Fellowship Program - Attendings, Boston, MA, Massachusetts General Hospital, Boston, MA, Oregon Health & Science University, Portland, OR, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, Department of Medicine, Division of Hematology-Oncology, Massachusetts General Hospital, Boston, MA, OHSU Knight Cancer Institute, Portland, OR Abstract Disclosures Research Funding No funding sources reported Background: The efficacy of trastuzumab deruxtecan in multiple cancers led to a recent FDA granting of priority review for the treatment of adults with HER2-positive solid tumors. This underscores the critical need for reliable assessment of HER2 expression across cancers. The current standard using IHC/ISH for HER2 scoring is fraught with challenges including scoring discordance and tumor heterogeneity. Here we describe the ability to classify HER2 status from 1 ml of plasma, using epigenomic signatures from a novel multi-analyte liquid biopsy (LBx) platform, offering a minimally invasive approach for patient (pt) selection across cancers. Methods: We selected 179 samples from 172 pts with advanced breast (BC), gastro-esophageal (GEA) and ovarian (OV) cancers who had associated HER2 status scored from tissue-based IHC/ISH according to ASCO/CAP guidelines (table). Samples were taken at baseline or at progression and those with detectable cell free DNA, as assessed by iChorCNA, were profiled for genome-wide epigenomic signals across histone modifications associated with active enhancers, promoters and DNA methylation. A regularized regression model developed to classify HER2 status in BC cell lines and was refined and validated for HER2 status prediction for each pt cohort (HER2+ = 3+, 2+/ISH+; HER2- = 2+/ISH-, 1+, 0). The BC cell-line derived HER2 classifier was refined to incorporate GEA and OV cancer specific features before being applied to those samples. Performance was assessed via AUC in a leave-one-out cross-validation schema. We also evaluated HER2 status at progression in a subset of pts with benchmarked HER2 IHC to assess dynamic changes in receptor status by LBx. Results: The epigenomic HER2 classifier was applied to all samples with ctDNA detectable by ichorCNA (90 of 179; 50%). HER2 classification of BC pts by epigenomic liquid biopsy was concordant with standard tissue-based IHC for 64/72 (89%) BC samples (AUC 0.9, table). HER2 classifier predictions for all longitudinally collected samples were concordant with IHC-based HER2 status, including the one patient whose status switched from HER2+ to HER2- at progression. Accurate classification of 11/14 (79%, GEA) and 4/4 (100%, OV) pts was achieved using the indication-refined HER2 classifier. Conclusions: We demonstrate proof of concept for a HER2 classification approach using comprehensive epigenomic signals from 1 ml of plasma that could be applied across multiple cancers. With further development, our genome-wide profiling approach could alleviate clinical constraints associated with multiple tissue-based HER2 scoring assays (IHC/ISH) and enable longitudinal monitoring of HER2 status on therapy. Patient cohort summary and classifier performance. BC OV GEA Samples Pts AUC Samples Pts AUC Samples Pts AUC Samples processed 119 111 - 14 13 - 46 46 - Samples with detectable ctDNA 72 68 0.9 4 4 1 14 14 0.93