Estrogen receptor 1 (ESR1) mutations are an acquired mechanism of resistance to aromatase inhibitors in estrogen receptor-positive advanced breast cancer, established by sequencing studies published in Nature Genetics in 2013 and later tracked in circulating tumor DNA during treatment. In one of the landmark studies, Toy and colleagues found ligand-binding-domain ESR1 mutations in 14 of 80 metastatic hormone-resistant tumors and showed that the altered receptors could activate estrogen-dependent transcription even when estrogen was absent.
Aromatase inhibitors remove estrogen, but ESR1 mutations change the receptor itself
Estrogen receptor-positive breast cancers depend on estrogen receptor signaling for growth and survival. Estrogen receptor 1 (ESR1) encodes estrogen receptor alpha (ERα), the receptor that binds estrogen and then regulates genes involved in cell growth and survival. An aromatase inhibitor (AI), such as anastrozole or letrozole, suppresses estrogen production by blocking the aromatase enzyme. It does not remove the estrogen receptor from the cancer cell.
That distinction explains why ESR1 mutations matter. Many clinically important mutations occur in the receptor’s ligand-binding domain, the region that normally changes shape when estrogen binds. Toy and colleagues identified recurrent Y537S, Y537N, and D538G alterations and found that the mutant proteins favored an active receptor conformation. As the investigators wrote, mutant receptors could “drive ER-dependent transcription and proliferation in the absence of hormone.”
The cancer therefore remains dependent on estrogen receptor signaling, but the receptor becomes less dependent on estrogen itself. Lowering estrogen with an AI becomes less effective because the altered receptor can continue signaling under estrogen-deprived conditions.
Y537 and D538 mutations are selected under treatment pressure rather than defining most untreated tumors
ESR1 mutations are best understood as an evolutionary response to treatment pressure, not as a mutation carried by every estrogen receptor-positive breast cancer from diagnosis. The AI does not need to directly create the mutation. Instead, profound estrogen deprivation can favor cancer-cell clones whose altered estrogen receptor remains active when estrogen is scarce.
A 2015 Science Translational Medicine study by Schiavon and colleagues analyzed circulating tumor DNA (ctDNA) from 171 women with advanced breast cancer. ESR1 mutations were found only in estrogen receptor-positive cancers that had previously been exposed to an AI. Prevalence differed sharply according to treatment setting: 5.8% of patients first exposed to an AI in the adjuvant setting had a detectable ESR1 mutation, compared with 36.4% of those first exposed during treatment of metastatic disease.
Those numbers should not be treated as a universal prevalence estimate. The frequency of ESR1 mutations depends on prior treatment, disease setting, assay sensitivity, and when the sample is collected. The important biological point is that the mutation can emerge and expand during therapy, which makes a historical biopsy from the original tumor an incomplete snapshot of later metastatic disease.
Blood testing can reveal an ESR1 mutation without another tumor biopsy
Circulating tumor DNA consists of fragments of tumor-derived DNA released into the bloodstream. Because metastatic cancer can contain genetically different subclones in different lesions, ctDNA can sometimes capture resistance alterations that are difficult to assess with a biopsy from one metastatic site.
In the Schiavon study, ESR1 mutation status in ctDNA showed high concordance with contemporaneous tumor biopsies. In one patient with serial sampling, an ESR1-mutant clone was selected during metastatic AI therapy and became the dominant cancer clone. The finding showed how repeated blood sampling can capture resistance as it evolves over time.
The same principle now sits at the center of the FDA-approved camizestrant strategy for ESR1-mutated advanced breast cancer. In SERENA-6, patients were tested repeatedly while receiving an AI plus a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, and eligible patients switched therapy when an ESR1 mutation was detected before standard imaging showed progression.
ESR1 testing has moved from a resistance marker to a treatment decision
For years, detecting ESR1 mainly explained why an AI had stopped working. The phase 3 SERENA-6 trial changed the clinical question by asking whether the mutation could be acted on earlier. Patients with newly detected ESR1 mutations and no radiographic progression switched from an AI to camizestrant while continuing the same CDK4/6 inhibitor, or remained on the AI combination. The early-switch strategy prolonged progression-free survival, leading to FDA accelerated approval in September 2026.
This is a specific form of molecularly guided oncology. Other Bites of Bio examples include ziftomenib for NPM1-mutated acute myeloid leukemia and daraxonrasib for RAS-mutated metastatic pancreatic cancer. ESR1 is different in one important respect: the clinically relevant mutation can emerge during treatment, so the biomarker itself may need to be monitored over time.
What the evidence cannot yet answer
ESR1 mutations do not explain every case of endocrine resistance. Breast cancers can escape therapy through multiple pathways, and a tumor without a detectable ESR1 mutation can still progress on an AI. Conversely, an ESR1 mutation does not mean that every form of estrogen receptor-directed therapy will fail. Different antagonists and degraders can retain activity against mutant receptors to different degrees.
The current early-switch strategy also applies to a narrow clinical setting. SERENA-6 enrolled patients with estrogen receptor-positive, HER2-negative advanced breast cancer whose ESR1 mutation emerged during first-line AI plus CDK4/6 inhibitor therapy before radiographic progression. Its results should not be automatically extended to newly diagnosed early-stage disease, mutations detected after imaging progression, or other endocrine-treatment sequences.
SERENA-6 was funded by AstraZeneca, the manufacturer of camizestrant, and FDA used the accelerated approval pathway because the long-term clinical benefit of switching at molecular progression still requires confirmation. Overall survival was not mature at the primary analysis. The mutation is therefore clinically actionable, but the evidence does not establish that early molecular switching improves survival.
ESR1 mutations show why resistance can change during treatment
The central lesson from ESR1 biology is that a cancer’s treatment-relevant genome is not fixed at diagnosis. A therapy can alter which clones survive, making a mutation that was absent or undetectable earlier clinically important months or years later. Repeated ctDNA testing can make that evolution visible. In its September 2026 announcement, FDA described camizestrant as the first cancer therapy approval guided by a resistance mutation detected in ctDNA before radiographic progression.
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References
- Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nature Genetics. 2013;45:1439-1445. DOI: 10.1038/ng.2822.
- Schiavon G, Hrebien S, Garcia-Murillas I, et al. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Science Translational Medicine. 2015;7(313):313ra182. DOI: 10.1126/scitranslmed.aac7551.