- Sacituzumab govitecan is an antibody–drug conjugate (ADC) that makes use of an anti-TROP2 monoclonal antibody to guide SN-38, the active metabolite of the topoisomerase I (TOP1) inhibitor irinotecan, to tumor cells that express TROP2
- In this study, genomic analyses of pre-treatment and post-progression lesions were used to investigate the mechanism of acquired resistance to sacituzumab govitecan in a patient with metastatic triple-negative breast cancer
- One phylogenetic branch of resistance exhibited a TOP1 E418K mutation and frameshift TOP1 mutation; the hallmark of the other major branch was T256R, a missense mutation of TACSTD2/TROP2, the gene that encodes TROP2
- Resistance to sacituzumab govitecan due to alterations in TOP1 probably confer cross-resistance to ADCs that have similar payloads, but treatment with the same antibody and a different payload may still be efficacious
- Conversely, resistance due to TACSTD2/TROP2 alteration would probably confer cross-resistance to other TROP2-directed ADCs, but not to non–TROP2-directed ADCs, regardless of payload
Sacituzumab govitecan (SG), which is now fully approved for the treatment of pre-treated metastatic triple-negative breast cancer (mTNBC), is an antibody–drug conjugate (ADC):
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- The antibody—Most breast cancer cells express trophoblast cell surface antigen-2 (TROP2), and SG makes use of hRS7, an anti-TROP2 monoclonal antibody, to guide a cytotoxic payload to tumor cells
- The payload is SN-38, the active metabolite of irinotecan, which is a topoisomerase I (TOP1) inhibitor
Aditya Bardia, MD, MPH, director of Breast Cancer Research at the Center for Breast Cancer, and Leif W. Ellisen, MD, PhD, program director of Breast Medical Oncology, both at the Massachusetts General Hospital Cancer Center, and colleagues have detected parallel alterations in the genome of mTNBC cells that let them develop resistance to SG. In Cancer Discovery, they explain the relevance of these findings to other ADCs.
The researchers analyzed tumor lesions from a patient with mTNBC who had a profound and prolonged response to SG (45% tumor regression for >8 months). They compared pre-SG lesions with nine lesions obtained after disease progression, then reconstructed the phylogenetic relationships of resistant metastatic lesions.
Two Branches of Resistance
The "phylogenetic tree of resistance" had two major branches, which appeared in mutually exclusive lesions:
TOP1 mutations—One branch, present at high frequency in the liver and periaortic lymph nodes, contained the TOP1 missense mutation E418K, known to confer resistance to TOP1 inhibitors. A TOP1 frameshift mutation appeared to arise from the clone harboring the E418K mutation, which perhaps enhanced resistance to SG.
TACSTD2/TROP2 mutation—The hallmark of the second branch of resistance was T256R, a missense mutation of TACSTD2/TROP2, the gene that encodes TROP2. It was present at high frequency in multiple thoracic lesions. Laboratory studies by the team showed how this mutation may induce resistance, and no somatic mutations of this gene have been reported previously.
Implications for Therapeutic Sequencing
These findings have implications for sequencing ADCs in oncology. Resistance to SG due to alterations in TOP1 probably confer cross-resistance to ADCs that have similar payloads, but treatment with the same antibody and a different payload might be beneficial.
Conversely, resistance due to TACSTD2/TROP2 alteration would probably confer cross-resistance to other TROP2-directed ADCs, but not to non–TROP2-directed ADCs, regardless of payload.
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