Are Genetic Alterations Linked to Resistance to Antibody-Drug Conjugate in Triple-Negative Breast Cancer?
Posted: Friday, September 17, 2021
Although the antibody-drug conjugate sacituzumab govitecan-hziy has benefited many patients with metastatic triple-negative breast cancer, many do not benefit from some treatment or initially respond and then develop drug-resistant disease. A study published in Cancer Discovery focused on how these breast cancer cells may become resistant to such treatment and what may be done to improve outcomes in these patients.
“All of the resistance mechanisms were driven by genetic changes in the metastatic tumor cells that were not present in the primary tumor,” stated study author Leif Ellisen, MD, PhD, in a press release from Massachusetts General Hospital (MGH). “The findings have potential clinical significance for guiding antibody-drug conjugate sequencing for patients with breast cancer,” added coauthor Aditya Bardia, MD, MPH, also of MGH.
The investigators focused mainly on three patients at MGH with metastatic triple-negative breast cancer treated with sacituzumab govitecan. All had experienced disease progression while receiving at least two prior therapies. The mechanisms by which the patients’ cancer resisted treatment were identified using RNA and whole-exome sequencing of cells before and after treatment.
One patient, lacking TROP2 expression, experienced no benefit from the antibody-drug conjugate, confirming that a lack of TROP2 expression seems to be associated with de novo resistance to the drug.
Analysis of acquired resistance centered on a 42-year-old female patient who exhibited a 45% reduction in cancer, 2 months after treatment with sacituzumab govitecan. After 8 months, the cancer showed resistance to the drug and recurred at multiple sites. Thoracic metastatic lesions contained mutations in the target of the antibody, TACSTD2/TROP2. Furthermore, lesions in the liver and periaortic lymph nodes had a TOP1 missense mutation, the target of the cytotoxic payload.
Disclosure: For full disclosures of the study authors, visit cancerdiscovery.aacrjournals.org.
