Abstract PS4-03-12: Quantifyher (trial in progress): quantitative immunofluorescence and/or messenger rna to measure her2 expression in patients with metastatic breast cancer treated with trastuzumab deruxtecan (tbcrc066)

Abstract Antibody drug conjugates (ADCs) can be effective therapeutic options for some patients (pts) with metastatic breast cancer (MBC). However, given serious potential toxicities, identifying pts most likely to benefit from ADCs is critical to optimizing quantity and quality of life. Trastuzumab-deruxtecan (T-DXd), a HER2-targeted ADC, is approved for pts with MBC expressing low/ultra-low levels of HER2 by immunohistochemistry (IHC 1+/2+, FISH-neg, or IHC 0 with faint membrane staining in < 10% tumor cells). However, significant inter-reader variability exists in the assessment of HER2 IHC 1+ vs IHC 0 (especially “ultra-low”), with a recent study demonstrating only 26% concordance in IHC 0 across pathologists. We therefore have an incomplete understanding of how HER2 expression informs who will benefit from T-DXd (and for how long), raising concern that IHC is an inadequate biomarker for T-DXd pt selection. A quantitative immunofluorescence (QIF) assay measuring HER2 and TROP-2 (TROPLEX), developed in the Rimm lab, was designed to address the need for accurate quantification of low-level tumor protein expression, detected at amol/mm2 levels. In the TROPLEX analytic validation cohort of >400 retrospective samples, ∼50% of HER2 IHC 0 cases had HER2 QIF levels above the limit of quantification, with a significant relationship demonstrated between HER2 QIF and time-to-next-treatment in a retrospective cohort of pts treated with T-DXd. Retrospective data using Cepheid’s Xpert Breast Cancer STRAT4 mRNA assay have also demonstrated high ERBB2 concordance with HER2 IHC, with potentially greater range. Both assays hold promise to improve measurement of surface protein expression at lower limits of detection than traditional IHC and may better select pts likely to respond to T-DXd. The primary objective of QuantifyHER is to determine the relationship between HER2 QIF and/or ERBB2 mRNA levels and real-world objective response (rwOR) to T-DXd. Secondary objectives include evaluating the relationships between TROP2 and rwOR, HER2 QIF/mRNA and real-world progression-free survival, determining response thresholds and the relationship with ER status, and evaluating a joint QIF/mRNA approach. QuantifyHER (TBCRC066/NCT06551116) is a multi-site prospective cohort study. Key eligibility criteria include biopsy-proven HER2 IHC