The prognostic value of HER2 gene dosage and heterogeneity at a single-cell resolution in gastroesophageal adenocarcinoma.

• DOI: 10.1200/jco.2025.43.4_suppl.473
• Publication Date: 2025-01-27T14:37:03Z
• Authors: Yashika Parashar; Leigh Culnane; Joshua Remland; Chetan Nambiar; Chen Yuan; Shagun Nasta; Adam Bard; Haeseong Park; Samuel J. Klempner; Marios Giannakis; Andrew Aguirre; Kimmie Ng; Jeffrey A. Meyerh...; Brian M. Wolpin; Rona Yaeger; James M. Cleary; Charlotte Wang; Peter C. Enzinger; Nilay S. Sethi; Harshabad Singh
• Keywords: Esophageal adenocarcinoma; Value (mathematics)

473 Background: HER2 gene dosage (i.e. level of amplification) and heterogeneity are key prognostic variables for HER2+ gastroesophageal adenocarcinoma (GEA), yet no standardized approach to test these in routine clinical use exists. Here we modify the analytical pipeline FISH quantitatively estimate correlate them with outcomes. Methods: Patients metastatic GEA who received trastuzumab-based therapy between 2011-2024 at Dana-Farber Cancer Institute had available pre-treatment tissue analysis were included. was conducted a CLIA approved pathology laboratory. Standard HER2/CEP17 ratio (an average 50 cells) individual cell calculated. Kaplan-Meier method used progression free (PFS) on overall survival (OS). Survival outcomes adjusted age, gender, tumor site, grade, prior resection, number sites, IHC using cox proportional hazard regression models. Results: A total 77 patients Median age 60 years, 88% male, 92% 3+ tumors. Individual cells ≥ 2.0 defined as amplified (same cutoff current bulk standard) those 4.95 (population median) labeled highly providing objective metrics assess dosage. Using three subgroups: 1. Heterogenous (Het, n = 15): <75% HER2+; 2. Homogenous, low (HL, 30): >75% HER2+, <50% high amplification; 3. (HH, 32): >50% amplification. Cutoffs both determined data distribution patterns. The subgroups prognostically relevant PFS OS significantly lower heterogenous tumors numerically homogenous after multivariable adjustment (Table). Conclusions: impact GEA. More importantly by deconvoluting single level, demonstrate an metric value that could be adopted patient stratification. Further insights into differing biology molecular subtypes needed. Outcomes Hazards (HR) p values model. Patients, No. Median, mo HR (95%CI) P Value HH 32 16.2 1 16.4 HL 30 12.1 1.70 (0.79-3.66) 0.173 15.7 1.71 (0.93-3.14) 0.085 Het 15 6.7 3.12 (1.35-7.2) 0.008 12.4 2.72 (1.28-5.75) 0.009