Rethinking ESR1 Testing in HR+/HER2− Advanced Breast Cancer

Announcer:
You’re listening to ReachMD. This medical industry feature, titled "A Potential Paradigm Shift in Testing Strategies in First-Line HR-Positive, HER2-Negative Advanced Breast Cancer: Can We Identify Emerging Endocrine Resistance Earlier?" is sponsored by AstraZeneca.

Narrator:
Two recent Phase 3 trials in HR-positive breast cancer have been designed to explore whether changing from the current ESR1 testing strategy to an investigational strategy may delay endocrine resistance in the first-line advanced or metastatic setting.

To provide context for this investigational approach, it is important to understand the role of ESR1 mutations in breast cancer progression. The ESR1 gene encodes the estrogen receptor protein, which normally becomes activated when it binds to estrogen. But extended exposure to aromatase inhibitors may lead to the development of the ESR1 mutations.

ESR1 activating mutations cause the estrogen receptor-mediated pathway to always be active, even in the absence of estrogen. As the exposure to aromatase inhibitors increases, so does the rate of developing an ESR1 mutation. Current data suggests that the rate of ESR1 mutations at diagnosis of advanced breast cancer is about 5%, which may increase up to 40% after progression on an AI regimen in the first-line metastatic setting.

Because endocrine resistance inevitably develops, there is a need to identify alternative approaches to help prolong a patient’s time on endocrine therapy. The current ESR1 testing strategy in HR-positive, HER2-negative metastatic breast cancer is to test at progression on first-line treatment to determine eligibility for second-line therapies, including targetable mutations. However, an investigational testing strategy is to monitor circulating tumor DNA for the emergence of ESR1 mutations during first-line treatment. This may allow for earlier identification of patients at risk of disease progression on their current treatment regimen.

Here's how it might work. Patients on a first-line regimen typically have routine blood tests every 1 to 3 months. The tumors of those taking an AI regimen are particularly susceptible to developing ESR1 mutations. Two studies were conducted to determine if integrating early monitoring for ESR1 mutations into routine blood tests might allow for detecting emerging resistance mutations before disease progression.

If ESR1 mutations are detected earlier, this investigational testing strategy may help identify patients who may require alternative treatment approaches, with the possibility of addressing emerging endocrine resistance mechanisms earlier in the patient journey, and ahead of disease progression.

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References:

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