Examining ESR1 Alterations in HR-Positive Metastatic Breast Cancer

Jamie Brett, resident in internal medicine at Massachusetts General Hospital, discusses the similarities and differences between ESR1 mutations and fusions and why they are grouped together.

According to Brett, ESR1 mutations and fusions are grouped together as they are the same gene and have similar overall effects. However, all ESR1 alterations are heterogeneous.

ESR1 mutations occur in roughly 20%-40% of patients with metastatic breast cancer treated with an aromatase inhibitor, and are not typically found in other settings. Then, ESR1 fusions occur in approximately 1%-10% of new or treated breast cancers, mostly as a luminal B type.

Transcription:

0:08 | We group them together because it's the same gene and they have similar overall effects, but the whole space of ESR1 alterations is heterogeneous. ESR1 mutations are point mutations in the ligand binding domain of the estrogen receptor. They are known to occur in about 20% to 40% of patients with metastatic breast cancer who have been treated with an aromatase inhibitor in the metastatic setting and do not really occur in other settings. These mutations make the estrogen receptor independent of estrogen and they create complete aromatase inhibition resistance and some relative resistance to other estrogen receptor targeted therapies.

0:57 | Then there's ESR1 fusions that are less studied overall. They are thought to occur roughly in the range of 1% to 10% of new breast cancer or treated breast cancer, mostly a luminal B type. They are heterogeneous, so they cause different effects. The 2 main categories are that you can swap the ligand binding domain of the estrogen receptor for that of a different protein, and then you create sort of a hyperactive ligand independent estrogen receptor, or you can have the other protein, which is typically CCDC170, become altered by the fusion to the estrogen receptor.