ESR1 Mutations in Hormone Receptor Positive Breast Cancer

Estrogen receptor 1 (ESR1) mutations have emerged as a critical player in the progression and treatment resistance of breast cancer, particularly in metastatic hormone receptor-positive cases. These mutations are associated with resistance to endocrine therapy, the backbone of treatment for this type of cancer.¹ ESR1 mutations are relatively rare in primary tumors, occurring in approximately 1% of cases.¹ However, their prevalence increases significantly in metastatic, endocrine therapy-resistant cancers, where they are found in 10 - 50% of cases.¹ This suggests that these mutations may be a key mechanism of acquired resistance to endocrine therapy.¹

Interestingly, ESR1 mutations can preexist in primary tumors and can be enriched during metastasis. They express a unique transcriptional profile that favors tumor progression, suggesting that selected ESR1 mutations may influence metastasis.² This highlights the potential role of ESR1 mutations in disease progression and the development of therapeutic resistance.

In terms of clinical implications, de novo or acquired ESR1 mutations have been associated with a shorter progression-free survival. For instance, patients with ESR1 mutations in their loco-regional recurrence tumor had significantly shorter disease-free survival and distant recurrence-free survival.³ This underscores the potential prognostic value of ESR1 mutations in breast cancer.

Moreover, ESR1 mutations have been linked to decreased sensitivity to established and novel therapies.^1,2 For example, patients with ESR1 mutations had a significantly shorter progression-free survival on aromatase inhibitor treatment.³ This suggests that ESR1 mutations may affect tumor sensitivity to various therapies, making the development of effective treatments a challenging task.

However, it’s important to note that the effects of ESR1 mutations on treatment outcomes are still an active area of research.¹ While in vitro studies have shown relative resistance to estrogen receptor-targeting therapies such as tamoxifen and fulvestrant, this resistance continues to be investigated in patients.¹ This indicates that novel agents in this category could still be promising for patients with ESR1 mutations.¹

Major Clinical Trials Related to ESR1 Mutations in Breast Cancer

The ESR1 gene, encoding the estrogen receptor α (ER), plays a pivotal role in the progression and treatment of hormone receptor-positive breast cancer. Mutations in this gene are associated with resistance to endocrine therapy, making it a significant area of focus in clinical trials.¹

One of the most notable clinical trials is the Phase III EMERALD study.⁴ This trial was instrumental in the approval of elacestrant (Orserdu™), a selective estrogen receptor degrader (SERD) for the treatment of advanced or metastatic breast cancer.⁵ The drug was found to be effective in patients whose tumors were ER-positive, HER2-negative, continued to grow after hormone therapy, and had a mutation in the ESR1 gene.⁵ This marked a significant breakthrough in the treatment of breast cancer patients with ESR1 mutations.

The PADA-1 trial is the first to demonstrate benefit from a treatment-switching strategy guided by active monitoring of ESR1 mutations in plasma circulating tumor DNA (ctDNA) from patients with breast cancer. The trial showed that patients with hormone receptor-positive breast cancer treated with an aromatase inhibitor plus palbociclib, who displayed an ESR1 mutation detected in their blood before disease progression, doubled their median progression-free survival following a switch to fulvestrant plus palbociclib.⁶

The PADA-1 trial was a randomized, open-label, multicentric, phase III trial. It focused on patients with estrogen receptor-positive, HER2-negative advanced breast cancer undergoing first-line therapy with an aromatase inhibitor plus palbociclib.⁶ The primary outcome was to evaluate the efficacy of switching hormone therapy (from an aromatase inhibitor to fulvestrant) combined with palbociclib upon the detection of ESR1 mutations in circulating tumor DNA. The secondary outcomes included assessing the safety of the hormone therapy and palbociclib combination in the overall population.⁶

The PADA-1 trial demonstrated that early identification and targeting of ESR1 mutations before tumor progression could double the median progression-free survival. This suggests a statistically and clinically significant benefit when fulvestrant is used during this new window of opportunity.⁷

Finally, the ongoing Serena-6 Phase III trial is assessing camizestrant, a selective estrogen receptor degrader (SERD), in combination with CDK4/6 inhibitors for the first-line treatment of patients with HR-positive metastatic breast cancer who have developed detectable ESR1 mutations during treatment with aromatase inhibitors.⁸ The results of this trial are yet to be published.

In conclusion, clinical trials related to ESR1 mutations in breast cancer are paving the way for personalized treatment strategies. They are not only enhancing our understanding of the mechanisms of endocrine resistance but also helping in the development of novel therapies that can effectively target ESR1 mutations. As research progresses, it is hoped that these trials will lead to improved outcomes for patients with ESR1-mutated breast cancer.

Identifying ESR1 Mutations in Breast Cancer: A Comparative Analysis of NGS, ddPCR, and qPCR Methods

Breast cancer, a heterogeneous disease, often exhibits mutations in the estrogen receptor 1 (ESR1) gene, leading to resistance to endocrine therapy. Various methodologies, including next-generation sequencing (NGS), droplet digital PCR (ddPCR), and quantitative PCR (qPCR), have been developed to detect these mutations. Below is a comparison across these methods, highlighting their advantages and disadvantages.

Next-Generation Sequencing (NGS)

NGS is a high-throughput method that allows for the simultaneous sequencing of millions of DNA fragments.³ It is commonly used for detecting ESR1 mutations in metastatic breast cancer. Advantages include comprehensive genetic coverage, allowing for the detection of multiple mutations in a single test. It can also identify novel mutations, making it a powerful tool for research and discovery. However, NGS is relatively expensive and requires a high level of expertise to interpret the results. Additionally, it may not be as sensitive as other methods for detecting low-frequency mutations as identified in the PADA-1 trial.

Droplet Digital PCR (ddPCR)

ddPCR is a highly sensitive method that allows for the absolute quantification of target DNA molecules. It is often used for detecting ESR1 mutations in plasma samples. ddPCR offers high sensitivity and reproducibility, making it ideal for detecting low-frequency mutations. It is also less invasive and easily accessible, compared to tissue testing, as it can use plasma samples as a liquid biopsy approach. ddPCR is limited to the detection of known mutations and cannot identify novel ones. It also requires a high level of technical expertise to perform and interpret.

Quantitative PCR (qPCR)

qPCR is a widely used method for quantifying the detection and expression of target genes. It also allows for the quantification of gene expression, providing additional information beyond the presence or absence of mutations. Like ddPCR, qPCR can detect low-frequency mutations on various sample types, including tissue and plasma (liquid biopsy) making it suitable for ESR1 mutation monitoring in the right patient populations. Like ddPCR, qPCR is limited to the detection of known mutations. It also requires high-quality nucleic acids, which can be challenging to obtain from certain sample types.

While NGS, ddPCR, and qPCR each have their strengths and weaknesses, they all play crucial roles in the detection of ESR1 mutations in breast cancer. The choice of method depends on the specific requirements of the study or clinical scenario, including the type of sample available, the need for sensitivity or breadth of coverage, and the resources available.

Limitations of Our Current Knowledge

Estrogen receptor 1 (ESR1) mutations have emerged as a significant factor in the progression and treatment resistance of hormone receptor-positive breast cancer.^1,2 Despite the progress made in understanding these mutations, limitations exist in the current knowledge base.

One limitation is the lack of understanding of the differences among distinct ESR1 mutations. ESR1 mutations are heterogeneous, and different mutations may have different effects on disease progression and treatment response. However, current research has largely treated ESR1 mutations as a single entity, limiting our understanding of the specific roles of different mutations.¹

Another limitation is the pending question, does early detection of ESR1 mutations result in an overall survival advantage? Interim results from clinical trials such as PADA-1 have demonstrated a significant progression-free survival for those patients monitored for ESR1 mutations before clinical progression with therapy switching. However, results related to overall survival remain unreported to date. Prior to overall survival data, the progression-free survival benefit could be discounted as a false leading indicator.

Furthermore, there is a need for more effective therapies for patients with ESR1 mutations. While some therapies such as fulvestrant have shown promise, the development of more potent selective estrogen receptor degraders and other targeted biotherapies are needed to overcome the endocrine-resistant phenotype of ESR1 mutant-bearing tumors.¹

Conclusion

In conclusion, while significant progress has been made in understanding ESR1 mutations in breast cancer, several limitations remain. Ongoing clinical trials and research activities hold promise for addressing these limitations and improving the prognosis and treatment outcomes for patients with ESR1-mutated breast cancer.

1. Brett JO, Spring, LM, Bardia A, et al. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021;23(1):85. doi:10.1186/s13058-021-01462-3
2. Dustin D, Gu G, Fuqua SAW. ESR1 mutations in breast cancer. Cancer. 2019;125(21):3714-3728.
3. Zundelevich A, Dadiani M, Kahana-Edwin S, et al. ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis. Breast Cancer Res. 2020;22(1):28. doi:10.1186/s13058-020-01265-y
4. New drug approved to treat metastatic breast cancer patients with ESR1 mutations. https://www.mbcalliance.org/news/new-drug-approved-to-treat-metastatic-breast-cancer-patients-with-esr1-mutations/
5. MSK discovery of ESR1 gene mutation leads to approval of breast cancer drug elacestrant. https://www.mskcc.org/news/msk-discovery-of-esr1-gene-mutation-leads-to-approval-of-breast-cancer-drug-elacestrant
6. Palbociclib and circulating tumor DNA for ESR1 mutation detection (PADA-1). https://classic.clinicaltrials.gov/ct2/show/NCT03079011
7. PADA-1 trial: With early identification of ESR1 mutation, switch to fulvestrant in metastatic breast cancer. https://ascopost.com/issues/january-25-2022/pada-1-trial-with-early-identification-of-esr1-mutation-switch-to-fulvestrant-in-metastatic-breast-cancer/
8. Camizestrant significantly delayed disease progression in advanced ER-positive breast cancer, adding at least 3.5 months benefit versus Faslodex. https://www.astrazeneca.com/media-centre/press-releases/2022/camizestrant-significantly-delayed-disease-progression-in-advanced-er-positive-breast-cancer.html

Jordan Laser, MD, is a board certified anatomic, clinical, and molecular genetic pathologist. Jordan is the Senior Director of Clinical and Medical Affairs at Bio-Techne as well as the CEO and Founder of Laser Laboratory Consulting. Previously, he served as Chief Laboratory Officer at Everly Health. The laboratory services at Everly Health support a wide range of consumer-initiated at-home tests. Having roots in New York, Jordan spent his first 11 years of practice as a pathology leader at Northwell Health. His expertise includes molecular and genomic medicine, laboratory management, healthcare finance, and standards and regulations.