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Study Identifies Potential Mechanisms of Resistance to Sacituzumab Govitecan-hziy in Patients With Triple-Negative Breast Cancer


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Researchers have determined how a highly aggressive type of breast cancer may evade treatment with the compound sacituzumab govitecan-hziy, according to findings published by Coates et al in Cancer Discovery. Their results could help improve therapy and ultimately prolong survival for patients with metastatic triple-negative breast cancer.

Treating Triple-Negative Breast Cancer

Triple-negative breast cancer is notoriously difficult to treat because it lacks receptors for the hormones estrogen and progesterone and the growth factor HER2, all three of which can be targeted with effective cancer therapies. Standard chemotherapy regimens provide limited benefit against triple-negative breast cancer, and patients with metastatic disease have a poor prognosis and short survival.

Aditya Bardia, MD, MPH

Aditya Bardia, MD, MPH

However, as Aditya Bardia, MD, MPH, of the Massachusetts General Cancer Center and colleagues previously reported, patients with metastatic triple-negative breast cancer treated in a large clinical trial with the compound sacituzumab govitecan lived nearly twice as long as patients treated with chemotherapy alone. Sacituzumab govitecan is an antibody-drug conjugate, consisting of an antibody targeted to the Trop2 receptor found on the surface of most breast cancer cells, plus a cancer-killing compound known as SN-38 (a topoisomerase I inhibitor). The agent is designed to specifically seek out breast cancer cells and deliver SN-38 as its toxic “payload.”

Yet some patients with metastatic triple-negative breast cancer either do not benefit from treatment with sacituzumab govitecan, or have an initial response to treatment but then develop drug-resistant disease.

Current Study

Now, Dr. Bardia, with Leif Ellisen, MD, PhD, Director of Breast Medical Oncology at Massachusetts General Cancer Center, and colleagues report that they have identified—for the first time—two separate alterations in the genome of triple-negative breast cancer cells that allow patients with the disease to develop resistance to sacituzumab govitecan.

Leif Ellisen, MD, PhD

Leif Ellisen, MD, PhD

“We undertook a study to look at the mechanisms of acquired resistance,” said Dr. Ellisen. “In terms of de novo resistance, the data supported prior studies that suggested the complete absence of Trop2 could be an important predictor of primary resistance. But the really remarkable part of the study had to do with acquired resistance.”

When they studied the genomic profiles of tissues sampled both before treatment and after disease progression, they found that in multiple metastatic lesions from one woman who had an initial robust response to sacituzumab govitecan—but later experienced disease progression and died from the disease—that there were different molecular mechanisms of resistance in different metastatic lesions. 

“All of the resistance mechanisms were driven by genetic changes in the metastatic tumor cells that were not present in the primary tumor. Remarkably, in one set of metastatic lesions, there was a mutation in the Trop2 target of the antibody, and in another set of lesions, there was actually a mutation in the target of the cytotoxic payload,” said Dr. Ellisen.

The authors noted that this was in contrast to robust TROP2 expression and focal genomic amplification of TACSTD2/TROP2 observed in another patient with a deep, prolonged response to sacituzumab govitecan.

In their report, the authors also wrote, “Analysis of acquired genomic resistance [in the mentioned case] revealed one phylogenetic branch harboring a canonical TOP1 E418K resistance mutation and subsequent frameshift TOP1 mutation, while a distinct branch exhibited a novel TACSTD2/TROP2 T256R missense mutation. Reconstitution experiments demonstrated that TROP2 T256R confers sacituzumab govitecan resistance via defective plasma membrane localization and reduced cell surface binding by hRS7.”

“This is the first report describing mechanisms of acquired resistance to sacituzumab govitecan,” added Dr. Bardia. “The findings have potential clinical significance for guiding antibody-drug conjugate sequencing for patients with breast cancer.”

Disclosure: The study was supported by grants from the National Institutes of Health, the DoD Breast Cancer Research Program, the Terri Brodeur Breast Cancer Foundation Fellowship, MGH ECOR Fund for Medical Discovery Fellowship, Susan Eid Tumor Heterogeneity Initiative, Tracey Davis Breast Cancer Research Fund and by the Broad/IBM Cancer Resistance Research Project. For full disclosures of the study authors, visit cancerdiscovery.aacrjournals.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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