Tumor evolution following treatment with sacituzumab govitecan for metastatic breast cancer: A proteomic analysis.

Abstract

e13006 Background: Sacituzumab Govitecan (SG) is a Trop2-targeting antibody drug conjugate (ADC) approved for the treatment of HER2-non amplified metastatic breast cancer (MBC). While changes to receptor target density can be associated with response and resistance in HER2-targeted ADCs, the relationship between dynamic changes in Trop2 (or other ADC targets) and SG resistance is unknown. Methods: Institutional databases were used to identify patients treated with SG for MBC who had paired pre and post treatment biopsies. Paired tissue samples were sectioned and submitted to both mass spectrometry (MS, mPROBE) and multiplex immunofluorescence (mIF, Zeiss). Proteomic quantification of key proteins was compared using the Wilcoxon signed rank test. mIF was described qualitatively. Results: Fourteen patients had tissue pairs from both pre and post-SG that passed quality control and underwent quantitative analysis. Seven patients (50%) had ER+ disease. Median progression free-survival (PFS) on SG was 4.7 months and median overall survival was 15.8 months. Baseline Trop2 expression ranged from 296-6,453amol/ug (median 1,560 amol/ug). At the individual patient level, temporal changes in Trop2 expression varied between -96% to 400% (median -18%) after SG treatment. Similar findings were apparent with TOPO1, where 6/14 (43%) of patients had > 25% loss in TOPO1 expression, and the remaining had stable or increased expression. In aggregate, after adjusting for multiple hypothesis testing, no unidirectional quantitative changes in mean protein expression were observed for Trop2 (-393 amol/ug, p = 0.6), TOPO1 (-200 amol/ug, p = 0.12), TOPO2A (-40 amol/ug, p = 0.2), SLFN11 (66 amol/ug, p > 0.9), HER2 (-53 amol/ug, p > 0.9), HER3 (-16 amol/ug, p = 0.8), or Nectin4 (-127 amol/ug, p = 0.042, q = 0.6). mIF results helped visualize protein changes in Trop2, HER2, HER3, and Nectin4 and corroborated observed changes seen from mass spectrometry. Conclusions: Dynamic patient-level changes in Trop2 and several other putative ADC biomarkers were observed, suggesting heterogeneity in ADC resistance. Further mechanistic investigation will be important to understanding heterogeneity in resistance, and quantitative proteomic methods such as MS and mIF may have utility in characterizing ADC resistance and response.