Predictive biomarkers for sacituzumab govitecan efficacy in Trop-2-expressing triple-negative breast cancer

Thomas M Cardillo; Diane L Rossi; Maria B Zalath; Donglin Liu; Roberto Arrojo; Robert M Sharkey; Chien-Hsing Chang; David M Goldenberg

doi:10.18632/oncotarget.27766

Predictive biomarkers for sacituzumab govitecan efficacy in Trop-2-expressing triple-negative breast cancer

Oncotarget. 2020 Oct 27;11(43):3849-3862. doi: 10.18632/oncotarget.27766.

Authors

Thomas M Cardillo¹, Diane L Rossi¹, Maria B Zalath¹, Donglin Liu^{1

2}, Roberto Arrojo¹, Robert M Sharkey^{1

3}, Chien-Hsing Chang^{1

3}, David M Goldenberg^{1

4

5}

Affiliations

¹ Immunomedics, Inc., Morris Plains, NJ 07950, USA.
² Currently employed with FrontAim Biomedicines Inc., Princeton, NJ 08540, USA.
³ At the time the work was conducted, these authors were employees of Immunomedics, Inc., Morris Plains, NJ 07950, USA.
⁴ Current address: Center for Molecular Medicine and Immunology, Mendham, NJ 07945, USA.
⁵ At the time the work was conducted, this author was Chairman and Chief Scientific Officer of Immunomedics, Inc., Morris Plains, NJ 07950, USA.

Abstract

Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of a humanized anti-Trop-2 IgG antibody conjugated via a hydrolysable linker to SN-38, the topoisomerase I-inhibitory active component of irinotecan. We investigated whether Trop-2-expression and homologous recombination repair (HRR) of SN-38-mediated double-strand DNA (dsDNA) breaks play a role in the sensitivity of triple-negative breast cancer (TNBC) to SG. Activation of HRR pathways, as evidenced by Rad51 expression, was assessed in SG-sensitive cell lines with low and moderate Trop-2-expression (SK-MES-1 squamous cell lung carcinoma and HCC1806 TNBC, respectively), compared to a low Trop-2-expressing, less SG-sensitive TNBC cell line (MDA-MB-231). Further, two Trop-2-transfectants of MDA-MB-231, C13 and C39 (4- and 25-fold higher Trop-2, respectively), were treated in mice with SG to determine whether increasing Trop-2 expression improves SG efficacy. SG mediated >2-fold increase in Rad51 in MDA-MB-231 but had no effect in SK-MES-1 or HCC1806, resulting in lower levels of dsDNA breaks in MDA-MB-231. SG and saline produced similar effects in parental MDA-MB-231 tumor-bearing mice (median survival time (MST) = 21d and 19.5d, respectively). However, in mice bearing higher Trop-2-expressing C13 and C39 tumors after Trop-2 transfection, SG provided a significant survival benefit, even compared to irinotecan (MST = 97d vs. 35d for C13, and 81d vs. 28d for C39, respectively; P < 0.0007). These results suggest that SG could provide better clinical benefit than irinotecan in patients with HRR-proficient tumors expressing high levels of Trop-2, as well as to patients with HRR-deficient tumors expressing low/moderate levels of Trop-2.

Keywords: RAD51; Trop-2; biomarker; sacituzumab govitecan; triple-negative breast cancer.