Impact of TROP-2 and its cellular localization on prognosis of breast cancer in the GAIN cohort

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TROP-2, involved in regulating cancer growth and invasion in different tumour types, is a relevant therapeutic target for antibody drug conjugates (ADC). This study evaluates the impact of TROP-2 on breast cancer (BC) prognosis in high-risk, node-positive BC of the German adjuvant intergroup node-positive (GAIN) cohort. Tissue microarrays (TMA) were generated from FFPE-pre-therapeutic tissue. Membranous (m) and cytoplasmic (c) expression of TROP-2 in invasive tumor cells was assessed with human TROP-2 antibody SP295. Cutoff Finder web application was used for identification of the best cutoff according to disease-free survival (DFS) and overall survival (OS). We evaluated association of mTROP-2 and cTROP-2 expression with DFS, OS and baseline parameters. For 1237 TMA spots valid TROP-2 evaluation was available. Cutoff Finder analysis was performed for overall and molecular subgroups identifying 70% as best cutoff for cTROP-2 and 0.5% for mTROP-2. cTROP-2>70% was significantly associated with worse grading (16% vs. 7.9%), negative hormone receptor (17.5% vs. 10.1%) and positive HER2 status (18.6% vs. 9.9%), each p <0.001. In multivariate Cox regression analysis, cTROP-2>70% was associated with worse DFS in overall (hazard ratio (hr) 1.389 [95% CI 1.039-1.856], p =0.026), luminal (hr 1.592 [95% CI 1.070-2.368], p =0.022) and HER2- cohorts (hr 1.614 [95% CI 1.151-2.263], p =0.006). mTROP-2>0.5% was associated with improved DFS in overall (hr 0.729 [95% CI 0.564-0.942], p =0.016) and HER2-negative cohorts (hr 0.708 [95% CI 0.534-0.938], p =0.016) in multivariate analysis. Cellular localization of TROP2 differentially affects survival in BC. The results are relevant for biomarker strategies for future therapeutic concepts. Publication History Article published online: 03 May 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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