Study Suggests Next-Generation Breast Cancer Drug Can Overcome Resistance

New details about a key mechanism underlying treatment resistance in breast cancer are reported this week in Science Translational Medicine, along with data suggesting that a new type of targeted therapy can overcome the mutations driving this resistance. Most breast cancer tumors express estrogen receptor-alpha (ER-alpha), a transcription factor that can drive cancer cell growth and the target of many cancer treatments. However, mutations in the gene encoding ER-alpha — called ESR1 — are a major source of resistance to such drugs, prompting the development of next-generation treatments targeting the estrogen receptor such as Genentech’s giredestrant. In this week’s study, a team led by scientists from the biotech firm generated mouse mammary glands expressing ESR1 mutations to examine their impact on drug resistance, finding that the genetic alterations caused estrogen receptors to be unusually sensitive to the hormone progesterone, boosting cell proliferation. Experiments in patient-derived xenografts, meantime, showed that giredestrant was still effective against tumors with ESR1 mutations. The researchers also looked at Phase I clinical data on giredestrant, finding that the drug decreased the activity of ER-alpha and led to tumor shrinkage in a patient with metastatic, estrogen receptor-positive breast cancer. “Giredestrant is currently being extensively evaluated in patients with metastatic [estrogen receptor positive] breast cancer, including those whose tumors harbor ESR1 mutations, and will hopefully provide a new and efficacious treatment for patients,” the study’s authors write.