For the first time, the resistance mechanisms of triple-negative breast cancer to a treatment, sacituzumab govitecan, marketed under the name Trodelvy, have been identified.
- In women with metastatic triple-negative breast cancer, one of the few treatments to improve life expectancy is Trodelvy.
- But some patients develop resistance after initially responding well to treatment.
- For the first time, the researchers found genetic changes in metastatic tumor cells, not present in the primary tumor.
- It is these mutations that lead to resistance to Trodelvy.
The most common cancer in women, breast cancer remains curable in the majority of cases. Detected early, it is a cancer with a good prognosis: more than 87% of patients are still alive five years after diagnosis. But, in 15% of women affected by this disease, breast cancer is said to be “triple negative”. This means that it does not express hormone receptors (estrogen and progesterone), and does not overexpress HER2 on the surface of cancer cells. This feature promotes tumor growth, while the absence of a marker greatly reduces the effectiveness of targeted therapies. In patients who have developed metastases, the prognosis is often very unfavorable, which offers them a short survival.
There are, however, promising targeted therapies, including one using the compound sacituzumab govitecan (SG). Marketed under the name Trodelvy, this drug has doubled the life expectancy of patients compared to those treated with chemotherapy alone.
Countering resistance to treatment with Trodelvy
The SG compound is made up of an antibody targeting a receptor called Trop2 found on the surface of most breast cancer cells, and an anti-cancer compound called SN-38 (topoisomerase I inhibitor). This treatment is designed to specifically seek out breast cancer cells and deliver SN-38 as a toxic “payload”.
Although it has shown encouraging results in patients with metastatic triple-negative breast cancer, some develop resistance to this drug, after showing an initial response. In a study published in the journal CancerDiscoveryresearchers at Massachusetts General Hospital (MGH) have identified the resistance mechanisms of triple-negative breast cancer to SG therapy for the first time.
Genetic changes in tumor cells driving resistance
Researchers have identified two distinct alterations in the genome of triple-negative breast cancer cells that allow them to develop resistance to this antibody drug in patients with triple-negative breast cancer.
“We have undertaken a study to examine the mechanisms of acquired resistance”says Leif Ellisen, director of medical breast oncology at the Massachusetts General Cancer Center.
The researchers studied the genomic profiles of tissues taken before treatment and after disease progression from a woman with triple-negative breast cancer who initially responded well to SG. However, the treatment then stopped working on her, resulting in her death. This analysis revealed that there were different molecular mechanisms of resistance in the metastatic lesions.
“All of the resistance mechanisms were due to genetic changes in the metastatic tumor cells that were not present in the primary tumor. Remarkably, in one series of metastatic lesions, there was a mutation in the Trop2 target of the antibodies, and in another set of lesions there was actually a mutation in the cytotoxic payload target [tueuse de cellules]”develops Professor Ellisen.
“This is the first report describing the mechanisms of acquired resistance to sacituzumab govitecan, adds Aditya Bardia, co-author of the work. IThe results have potential clinical significance to guide the sequencing of antibody-drug conjugates for breast cancer patients.”
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