Oncotarget

Research Papers:

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 and David M. Goldenberg

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Oncotarget. 2020; 11:3849-3862. https://doi.org/10.18632/oncotarget.27766

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Abstract

Thomas M. Cardillo1, Diane L. Rossi1, Maria B. Zalath1, Donglin Liu1,2, Roberto Arrojo1, Robert M. Sharkey1,*, Chien-Hsing Chang1,* and David M. Goldenberg1,3,#

1 Immunomedics, Inc., Morris Plains, NJ 07950, USA

2 Currently employed with FrontAim Biomedicines Inc., Princeton, NJ 08540, USA

3 Current address: Center for Molecular Medicine and Immunology, Mendham, NJ 07945, USA

* At the time the work was conducted, these authors were employees of Immunomedics, Inc., Morris Plains, NJ 07950, USA

# At the time the work was conducted, this author was Chairman and Chief Scientific Officer of Immunomedics, Inc., Morris Plains, NJ 07950, USA

Correspondence to:

Thomas M. Cardillo,email: [email protected]

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

Received: May 01, 2020     Accepted: September 23, 2020     Published: October 27, 2020

Copyright: © 2020 Cardillo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.


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