# Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to Sacituzumab Govitecan in Triple-Negative Breast Cancer

Source: https://onco.cc/key-papers/paper-coates-sacituzumab-resistance-tacstd2-cancer-discov-2021/  
OnCo record `paper-coates-sacituzumab-resistance-tacstd2-cancer-discov-2021` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

When triple-negative breast cancer became resistant to sacituzumab govitecan in one patient, one branch of the tumour had changed the drug's payload target and a different branch had changed TROP2 itself.

## Summary

RNA and whole-exome sequencing of tumour specimens before treatment and after progression on sacituzumab govitecan in triple-negative breast cancer. A patient with de novo progression lacked TROP2 expression, while a patient with a deep, prolonged response had robust TROP2 expression and focal amplification of TACSTD2, the TROP2 gene. At acquired resistance in that patient, one phylogenetic branch carried the canonical TOP1 E418K resistance mutation and a later frameshift TOP1 mutation, while a distinct branch carried a new TACSTD2 T256R missense mutation. Reconstitution experiments showed that T256R causes resistance through defective plasma membrane localisation and reduced cell-surface binding by hRS7, the antibody in the drug.

## Fields

- Kind: Key paper
- Last checked: 2026-11-04
- Journal: Cancer Discovery
- Year: 2021
- DOI: 10.1158/2159-8290.CD-21-0702
- Authors: Coates JT, Sun S, Leshchiner I, et al.
- Findings: De novo progression in a patient whose tumour lacked TROP2 expression.; Acquired resistance in one patient arose on two branches: TOP1 E418K (payload target) on one, TACSTD2 T256R (antibody target) on another.; TROP2 T256R reduces membrane localisation and hRS7 binding.
- What it means: Resistance can come from different subclones in the same person, each with its own mechanism, and one of them changed the TROP2 protein itself. It is the clearest published link between a residual clone and a TROP2 phenotype, made from tissue at progression rather than from blood.
- Caveats: Case-level evidence from a small number of patients.; Tissue at progression in metastatic disease, not plasma at residual-disease levels.

## Sources

- Coates et al., Cancer Discov 2021: https://doi.org/10.1158/2159-8290.CD-21-0702
- PubMed: https://pubmed.ncbi.nlm.nih.gov/34404686/

## Connected records

- cancers: [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- fronts: [Antibody-Drug Conjugates](https://onco.cc/fronts/adcs/)
- targets: [TROP2](https://onco.cc/targets/trop2/)
- drugs: [Sacituzumab govitecan](https://onco.cc/drugs/sacituzumab-govitecan/)
- bottlenecks: [Naming which clone or phenotype is left after treatment](https://onco.cc/bottlenecks/b-subclone-attribution-residual-disease/)
- journals: [Cancer Discovery](https://onco.cc/journals/cancer-discovery/)
- ideas: [Read methylation and mutation on the same cell-free DNA fragment to tell what kind of cancer is left](https://onco.cc/ideas/idea-same-fragment-methylation-and-mutation/)

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