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Dr Cristofanilli on the Potential Role of Serial ESR1 Mutation Monitoring in HR+/HER2-Negative Advanced Breast Cancer

Supplements and Featured Publications, Unpacking Pivotal Data Updates in Metastatic Breast Cancer Management, Volume 1, Issue 1

Massimo Cristofanilli, MD, details the implications of serial ESR1 mutation monitoring using ctDNA in HR-positive/HER2-negative advanced breast cancer.

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    "The most important message from [SERENA-6] is that you need to institute a [protocol] for monitoring patient with cell-free DNA very early on in the course of their disease."

    Massimo Cristofanilli, MD, director of Breast Medical Oncology and associate director of Precision Oncology at Weill Cornell Medicine/NewYork-Presbyterian, discussed the clinical implications of serial ESR1 mutation monitoring using circulating tumor DNA (ctDNA) in hormone receptor–positive, HER2-negative advanced breast cancer, based on findings from the phase 3 SERENA-6 trial(NCT04964934).

    Data from SERENA-6 presented at the 2025 ASCO Annual Meeting demonstrated that adding camizestrant to a CDK4/6 inhibitor after the detection of emerging ESR1 mutations through serial ctDNA significantly delayed radiographic disease progression in patients receiving frontline CDK4/6 inhibitor–based therapy.

    Specifically, patients who transitioned to camizestrant, a next-generation oral selective estrogen receptor degrader (SERD), and continued CDK4/6 inhibition upon detection of an ESR1 mutation (n = 157) achieved a median progression-free survival (PFS) of 16.0 months (95% CI, 12.7-18.2) compared with 9.2 months (95% CI, 7.2-9.5) in patients who continued an aromatase inhibitor (AI) plus CDK4/6 inhibition (n = 158; HR, 0.44; 95% CI, 0.31-0.60; P < .00001).

    Cristofanilli highlighted the dynamic nature of metastatic breast cancer biology and stressed that traditional static biomarker assessments may not always capture evolving resistance mechanisms. He underscored that serial ctDNA monitoring represents a significant shift in clinical practice that could enable early intervention based on molecular progression—before radiographic evidence of disease advancement.

    This trial reinforces the necessity of ESR1 mutational testing as a predictive biomarker to drive treatment decisions and demonstrates the actionable value of real-time ctDNA surveillance to tailor endocrine-based treatment strategies, he continued. Cristofanilli noted that an early switch to camizestrant led to a meaningfully alteration of disease trajectory in SERENA-6.

    Findings from SERENA-6 could pave the way for clinicians to adopt routine serial ctDNA testing in HR-positive/HER2-negative advanced breast cancer, particularly for patients receiving endocrine-based therapies, Cristofanilli concluded.


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