Shedding Light on Mechanisms Behind Fulvestrant Resistance in Advanced ER-Positive Breast Cancer

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Researchers may have uncovered the factors contributing to hormone therapy resistance in some patients with advanced estrogen receptor (ER)-positive breast cancer, according to a recent study published by Kingston et al in Cancer Discovery. The findings may indicate drugs currently in development that could maintain longer disease stability in these patients.


The hormone therapy fulvestrant is administered to patients with ER-positive breast cancer as either first-line therapy or once other treatments prove to be unsuccessful. However, many patients develop resistance to fulvestrant over time.

“These findings help us understand how secondary breast cancer can become resistant to hormone therapies like fulvestrant and what other treatments we could use in the future if this resistance happens. With an estimated 61,000 [patients] living with secondary breast cancer in the [United Kingdom], research like this is vital,” emphasized Kotryna Temicinaite, PhD, Head of Research Communication and Engagement at Breast Cancer Now.

Study Methods and Results

In the recent study, the researchers collected blood samples from patients with advanced ER-positive breast cancer who participated in the plasmaMATCH clinical trial. They then analyzed the blood samples for genetic mutations in the circulating tumor DNA (ctDNA) and observed how they responded to fulvestrant—with the goal of determining how ESR1 mutations may contribute to treatment resistance.

The researchers found that among 4% of the patients, ESR1 F404 mutations caused overt resistance to fulvestrant hormone therapy. These mutations occurred only in patients who had specific preexisting mutations in the ESR1 gene prior to treatment with fulvestrant.

Further, the tumor cells with ESR1 F404 mutations remained sensitive to four new hormone therapies that are currently being tested in clinical trials involving cancer cells with these mutations. The researchers hope that if these drugs are approved, patients likely to develop treatment resistance through ESR1 F404 mutations may be identified with a blood test and offered novel, alternative therapies.


“Our study makes use of innovative blood tests [that] detect genetic changes present in a patient’s cancer, without the need for any invasive procedures. The discovery of these specific genetic changes in [ER]-positive breast cancer helps to explain one mechanism by which some patients develop resistance to fulvestrant, and which upcoming treatments will be likely to work instead. This could revolutionize the way we treat breast cancer by making use of these simple blood tests to match patients to alternative treatments, bringing them the best possible outcome,” underscored senior study author Nicholas Turner, PhD, Professor of Molecular Oncology at The Institute of Cancer Research and a consultant medical oncologist at The Royal Marsden National Health Service Foundation Trust.

“Research discoveries like this help scientists find better ways to treat cancer. Understanding why a drug like fulvestrant stops being effective will help researchers and [physicians] identify the best medicines available for [patients] living with certain types of breast cancers and develop new therapies. This would provide [patients] … with more effective treatment options, ultimately helping them to live longer, better lives,” concluded Nisharnthi Duggan, PhD, Science Engagement Manager at Cancer Research UK.

Disclosure: The research in this study was funded by Breast Cancer Now, Cancer Research UK, and the National Institutes of Health and Care Research. For full disclosures of the study authors, visit

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®.