Liquid Biopsy Impact: ESR1 impact
Exploring advancements in breast cancer management
This year’s European Breast Cancer Conference in Milan (EBCC) and ESMO (European Society for Medical Oncology) Breast Cancer in Berlin discussed several crucial topics for breast cancer patient management, but the approval of the new generation of SERDS (Selective Estrogen Receptor Degraders) captured the community’s attention.
Treating advanced/metastatic patients has always presented a challenge, but with last year’s approval of elacestrant from Streamline Therapeutics in the USA and Europe, a new hope sprang forth for ER+/HER2- patients.
Before this approval, guidelines recommended a step-by-step approach to endocrine therapy until the exhaustion of all other endocrine options and/or there was a visceral crisis. Another option for later-line therapy was tamoxifen, with or without everolimus. However, the effectiveness of endocrine monotherapy can quickly diminish in patients who have already undergone CDK4/6 or mTOR inhibitors, which typically results in a median progression-free survival (PFS) of only 2 months.
The phase III EMERALD trial[2] randomized 477 patients who had previously received endocrine therapies. The groups were either treated with elacestrant or with the standard of care (SOC). Patients who received the new treatment experienced prolonged progression-free survival and a reduced risk of progression or death by 30%, with only 3.4% of patients discontinuing treatment due to adverse events, compared to 0.9% in the SOC arm.
Elacestrant is particularly effective in a special cohort: patients carrying ESR1 mutations. For them, the risk of progression or death was reduced by 45% compared to the SOC. The drug’s approval is currently limited to these patients.
Understanding ESR1 Mutations: Implications for Breast Cancer Treatment
ESR1 mutations are a long-known mechanism of resistance to aromatase inhibitors[8], impacting treatment response and appearing in up to 55% of patients during treatment[11]. As it is a novel event and rare in primary tumours, it is crucial to track the dynamics of the tumour’s mutational status.
The EMERALD trial highlighted the importance of monitoring patients with liquid biopsy and showed that this diagnostic approach is the best tool to capture tumour heterogeneity. These results prompted the American Society of Clinical Oncology (ASCO) to update its guidelines to recommend routine testing of ESR1 mutational status[4]. The European Society for Medical Oncology (ESMO) had already indicated this application in 2022[12] and updated it to a direct recommendation in the latest update [10]. It is notable that these mutations are relevant even for other treatments, and many new studies have assessed their impact as prognostic and predictive biomarkers [3,5,6,7,8,13].
Choosing the right biomarker monitoring solution: balancing costs and benefits
Now that elacestrant is gradually entering the clinics in Europe, the need for robust and accessible testing solutions that detect key ESR1 mutations (D538G, L536H/P, E380Q, Y537N/C) encouraged diagnostic companies to propose various liquid biopsy solutions, that all have their own respective, individual benefits.
More economical liquid biopsy solutions may seem initially more attractive than costlier ones during the decision process, as reimbursement is still unclear or limited in many countries. Quantitative-PCR (qPCR)-based solutions use less expensive reagents, while fully automated solutions reduce the burden on laboratory staff. However, it is important to take into account their lack of sensitivity (above 1% MAF) and would miss almost 50% of the patients[9].
Digital PCR (dPCR) kits are a bit more complex, but they are still a relatively fast solution that provides much better sensitivity (down to 0.01%). However, both qPCR, as well as dPCR, might lack the probes required to detect all mutations mentioned in the phase I study of elacestrant[1] and could, therefore, miss patients[7] who are carrying mutations that appear slightly less frequently (such as E542D/Q of 7% or V534L with 5%)[1]. NGS (Next-Generation Sequencing) expands the number of possible targets and was the method of choice for the EMERALD trials. Nevertheless, it comes with its own challenges. It is far more complex to navigate solution, due to the vast variety of library preparation kits offered in various panel sizes, sensitivities, and even sequencing platforms that might, depending on the solution, significantly increase, not just the cost of testing, but also the time to results.
When considering the patient's benefit and navigating reimbursement, it is critical to balance possible targets, sequencing costs, and sensitivity of the chosen solution. A broad panel that can cover the entire gene may seem the most beneficial at first glance, but when sequencing at the necessary sensitivity, the associated costs may not be feasible outside the research scope. A focused NGS panel covering all the most frequent ESR1 mutations combining high sensitivity with fast and cost-efficient workflow may be the wisest choice for those who wish to incorporate patient monitoring into routine practice
The Future
The revolution of the care of HR+/HER2- patients has been expanding treatment therapies. Alpesalib, a Selective Estrogen Receptor Modulator (SERM) which has been indicated for patients harbouring PIK3CA mutations, has been available for some time now.
Other clinical trials with new drugs that focus on specific biomarkers and pathways are ongoing, which has sparked more curiosity on how to routinely include the use of relevant panels in order to ensure that no patient is left behind.
Plasma-SeqSensei and the ESR1 mutation status detection
Are you curious about Sysmex’s work with SensID and how the Plasma-SeqSensei Breast Cancer IVD kit can detect ESR1 mutations, even in the lowest MAFs?
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For additional resources and in-depth information on liquid biopsy
References
[1] Bardia A, Kaklamani V, Wilks S, Weise A, Richards D, Harb W, Osborne C, Wesolowski R, Karuturi M, Conkling P, Bagley RG, Wang Y, Conlan MG, Kabos P. (2021): Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer. J Clin Oncol. 2021 Apr 20;39(12):1360-1370. doi: 10.1200/JCO.20.02272. Epub 2021 Jan 29. PMID: 33513026; PMCID: PMC8078341
[2] Bidard, Francois-Clement, et al. (2022): Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: results from the randomized phase III EMERALD trial. Journal of Clinical Oncology 40.28: 3246-3256.
[3] Brett, Jamie O., et al. (2021): ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Research 23: 1-15.
[4] Burstein, Harold J., et al. (2023): Testing for ESR1 mutations to guide therapy for hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer: ASCO guideline rapid recommendation update. ." Journal of Clinical Oncology 41.18: 3423-3425.
[5] Clatot, Florian, et al. (2020): Risk of early progression according to circulating ESR1 mutation, CA-15.3 and cfDNA increases under first-line anti-aromatase treatment in metastatic breast cancer. Breast Cancer Research 22: 1-12.
[6] De Santo, Irene, et al. (2019): The emerging role of ESR1 mutations in luminal breast cancer as a prognostic and predictive biomarker of response to endocrine therapy. Cancers 11.12: 1894.
[7] Fuentes-Antrás, J.; Martínez-Rodríguez, A.; Guevara-Hoyer, K.; López-Cade, I.; Lorca, V.; Pascual, A.; de Luna, A.; Ramírez-Ruda, C.; Swindell, J.; Flores, P.; et al. (2023): Real-World Use of Highly Sensitive Liquid Biopsy Monitoring in Metastatic Breast Cancer Patients Treated with Endocrine Agents after Exposure to Aromatase Inhibitors. Int. J. Mol. Sci., 24, 11419.
[8] Lloyd, Maxwell R., et al. (2024): Improved Detection of Disease Progression in Metastatic Breast Cancer by Absolute Molecular Counting of Circulating Tumor DNA: A 100 Copies Question. NEJM Evidence 3.5: EVIDoa2300231.
[9] Martens, Geert, et al. (2023): Improved Detection of Disease Progression in Metastatic Breast Cancer by Absolute Molecular Counting of Circulating Tumor DNA: A 100 Copies Question. Available at SSRN 4458026.
[10] Mosele, M. F., et al. (2024): Recommendations for the use of next-generation sequencing (NGS) for patients with advanced cancer in 2024: a report from the ESMO Precision Medicine Working Group. Annals of Oncology 35.7: 588-606.
[11] Najim O, Huizing M, Papadimitriou K, Trinh XB, Pauwels P, Goethals S, Zwaenepoel K, Peterson K, Weyler J, Altintas S, van Dam P, Tjalma W. (2019): The prevalence of estrogen receptor-1 mutation in advanced breast cancer: The estrogen receptor one study (EROS1). Cancer Treat Res Commun.;19:100123. doi: 10.1016/j.ctarc.2019.100123. Epub 2019 Feb 21. PMID: 30826563.
[12] Pascual J, Attard G, Bidard FC, Curigliano G, De Mattos-Arruda L, Diehn M, Italiano A, Lindberg J, Merker JD, Montagut C, Normanno N, Pantel K, Pentheroudakis G, Popat S, Reis-Filho JS, Tie J, Seoane J, Tarazona N, Yoshino T, Turner NC. (2022): ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2022 Aug;33(8):750-768. doi: 10.1016/j.annonc.2022.05.520. Epub 2022 Jul 6. PMID: 35809752.
[13] Vitale, Silvia R., et al. (2022): The prognostic and predictive value of ESR1 fusion gene transcripts in primary breast cancer. BMC cancer 22.1: 165.