ESR1 mutation

Oral SERDs offer enhanced bioavailability and convenience compared to fulvestrant, representing a critical advancement in endocrine therapy...However, other than ESR1 mutations, clinical refinement for patient selection is limited. Further trials are needed to optimize patient selection for oral SERD use and define the most effective combination strategies with oral SERDs.

ESR1 mutations appear primarily during progression, as no mutations were found in primary tumor samples. The main conclusion of the study is that combined assessment of CTCs and ESR1 status in liquid biopsy may improve the prognostic value of liquid biopsy.

Direct comparison between Crystal Digital PCR™ and the ESR1 NAPA assay revealed a high concordance (97.1%, k = 0.871, p < 0.001) for the detection of D538G mutation. The Stilla 12plex ESR1-AKT 6-color Crystal Digital PCR® assay is multiplex, highly sensitive and robust and can be used in liquid biopsy.

Serial samples from 14 patients demonstrate that CSF LBx can be used for monitoring therapy efficacy. LBx using CSF is clinically reliable and provides informative results in a substantial proportion of patients with metastatic CNS tumors and to a lesser degree in patients with primary CNS tumors.

Mutations, particularly in DNA damage response (DDR) and proliferative signaling pathways (phosphatidyl inositol-4,5-bisphosphate 3-kinase; PIK3CA) suggest an increased risk of therapy resistance, pointing to opportunities for risk stratification and tailored treatment strategies in EBC. ctDNA-based liquid biopsy may provide minimally invasive comprehensive genomic analysis of EBC for identifying actionable targets and risk prediction for better disease management.

We report herein real-world and preclinical evidence that ESR1 mutations, particularly Y537S and D538G, can drive resistance to CDK4/6 inhibitors.

Oral lasofoxifene (5 mg/day), but not fulvestrant, appears to improve GSM vaginal symptoms in women with mBC. These preliminary findings suggest further study is needed; such will be explored in the phase 3, registrational, ELAINE 3 trial in patients with ESR1-mutated, ER+/HER2- mBC.

Importantly, we find that DKK1 is significantly enriched in ER + breast cancer plasma compared to healthy controls. This study shows how new SERMs and SERDs can identify new therapeutic pathways in endocrine-resistant ER + breast cancers.

ESR1-mutant tumors generally retained luminal features and higher ERα activity and exhibited an anti-proliferative response to the ERα antagonist giredestrant. ESR1-mutant tumors acquired mixed-lineage features following treatment. Lineage heterogeneity in advanced ER+ breast cancer may underpin the differential benefit of investigational ERα therapeutics observed in ESR1-mutant versus NMD contexts.

P=N/A, N=80, Recruiting, European Institute of Oncology

P2, N=4, Terminated, M.D. Anderson Cancer Center | Completed --> Terminated; Despite modifications, accrual was poor and the closed

Dissecting multiple ESR1-mutant cell models revealed the different clinical relevance of cell model engineering and identified high-confidence mutant-ER targets, such as NPY1R. These examples demonstrate how EstroGene2.0 helps investigate breast cancer's response to endocrine therapies and explore resistance mechanisms.

P3, N=510, Active, not recruiting, Olema Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting

Abemaciclib+fulvestrant significantly improved PFS after disease progression on prior CDK4/6i+ET in patients with HR+, HER2- ABC, offering an additional targeted therapy option for these patients.

Our study provides an example of implementation of molecular profiling in an academic pre-screening program. Further analysis will investigate treatment matching rates, drug access schemes, and their impact on treatment efficacy and survival.

We achieved a remarkable response in the metastatic lesions with minor toxicity issues. This case highlights the importance of utilizing up-to-date therapeutic agents and reactive decision-making during personalized cancer treatment.

The APIS ESR1 Mutations Kit demonstrated high sensitivity and specificity as a qualitative qPCR assay for detecting ESR1 mutations in varying WT backgrounds. Its performance with the SensID ESR1 Reference Set 1% AF cfDNA validated the kit's LoD at ≤1% MAF with external samples. The APIS kit is a valuable tool for assessing ESR1 mutations in both clinical and research settings, offering a more accessible alternative to traditional next-generation sequencing (NGS) and dPCR assays.

P3, N=400, Not yet recruiting, Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

Taken together, these data indicate that ESR1 mutations confer chemoresistance through activation of the JNK/MDR1 axis. These finding suggest a novel treatment option for BC tumors expressing ESR1 mutations.

Estrogen receptor one (ESR1) gene mutations, driving resistance to aromatase inhibitors (AIs), may guide the use of fulvestrant or emerging oral selective estrogen receptor degraders (SERDs) like elacestrant. Targeting mutations like breast cancer gene 1 and 2 (BRCA 1/2) with Poly (ADP-ribose) polymerase (PARP) inhibitors or the PI3K/AKT/mTOR pathway provides therapeutic options. The advent of antibody-drug conjugates (ADCs) like trastuzumab deruxtecan (T-DXd) and novel agents targeting Trophoblast cell surface antigen-2 (Trop-2) introduces further complexity, underscoring the need for early intervention targeting specific genomic alterations in metastatic BC.

P3, N=320, Active, not recruiting, Genentech, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Oct 2024 --> Mar 2026

In the liquid biopsies, we detected ESR1 mutations in 42 cases (25.9%) and ERBB2 mutations in six cases (3.7%), arguing for a change in therapy to fulvestrant, elacestrant, or neratinib. Furthermore, 17 cases had detectable TP53 mutations, associated with resistance against endocrine therapy. We conclude that liquid biopsy testing is a noninvasive, sensitive, and helpful method to optimize therapeutic decisions in metastatic BC.

These findings suggest a potential reduction in lasofoxifene efficacy due to the dual mutation. Further experimental validation is required to confirm these results and fully understand the impact of dual mutations on lasofoxifene's effectiveness in ERα + metastatic BC.

The developed novel multi-marker liquid bead array assay for the simultaneous detection of PIK3CA and ESR1 hotspot mutations in single CTCs is highly specific, highly sensitive, high-throughput, and sample-, cost-, and time-saving. This multi-marker liquid bead array assay can be extended to detect up to 100 mutations in many genes at once and can be applied for bulk CTC and ctDNA analysis.

This review highlights recent efforts in drug development of next generation ER-targeted agents, including oral selective ER degraders (SERDs), proteolysis targeting chimera (PROTAC) ER degraders, other innovative molecules such as complete estrogen receptor antagonists (CERANs) and selective estrogen receptor covalent antagonists (SERCAs). The drug design, efficacy and clinical trials for each compound were detailed.

ER+/HER2- mBCs carrying ESR1MUT exhibit a divergent genomic background, characterized by a lower prevalence of TP53 and MAPK pathway alterations. Less common ESR1 alterations falling outside the H11-H12 region seem to occur in tumors with higher TMB, deserving further investigation to understand their potential actionability.

P3, N=312, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

P=N/A, N=70, Recruiting, AstraZeneca | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

This analysis identified acquired gene alterations in patients with HR+/HER2- advanced breast cancer treated with ribociclib plus ET or placebo plus ET. These data may support further studies on acquired resistance mechanisms and inform future systemic interventions in the post-CDK4/6 inhibitor setting.

Oral SERDs constitute an exciting new drug class. Ongoing and future research will further refine the role of these drugs next to standard endocrine treatments and targeted therapies.

The mutant model of the pathogenic SNP H516N was generated, and hydroxytamoxifen was docked with the wild-type and the mutant model. The mutant model lost the formation of stable hydrogen bonds with the active site residues and hydroxytamoxifen, which may result in reduced binding affinity and therefore, will predict the patient's response to estrogenic inhibitors.

No such effect was observed for ESR1 mutations, with a rate ratio of 1.15 (confidence interval 0.67-1.95). We conclude that ER loss and ESR1 mutation together account for 30% of the resistance to endocrine therapy.

More recently, oral SERDs have been tested in patients with early hormone receptor positive breast cancer, although their impact on survival and in this curative setting compared to standard endocrine therapy still needs to be elucidated. The best timing and duration of SERD administration and specific biomarkers in (neo)adjuvant setting remain largely unknown.

Adding the CDK4/6 inhibitor palbociclib enhanced the antitumor activity of EP0062 or fulvestrant in ESR1-mutant models but not in HER2-enriched or PTEN-mutant PDX models...EP0062 triggers an E2F1 downmodulation which mediates a potent antiproliferative activity. For EP0062-resistant tumors that remain ER-driven, the addition of palbociclib displays a potent antitumor effect.

Imlunestrant, as monotherapy or in combination with targeted therapy, had a manageable safety profile with evidence of preliminary antitumor activity in ER+/HER2- ABC.

Molecular profiling allowed the identification of ESR1Y537S, in an aggressive prolactinoma. ESR1Y537S was not detected early in the course of the disease and is likely conferring tumor aggressiveness. This finding emphasizes the significance of estrogen receptor signaling in prolactinomas. It also allowed the use of targeted therapy with successful control of disease progression.

For patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) metastatic breast cancer (mBC) progressed on first-line endocrine therapy plus a cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i), fulvestrant, a selective estrogen receptor degrader (SERD) administered intramuscularly, represented the only monotherapy option until the approval of elacestrant. However, in Europe, the access to this recommended drug depends on the decision of the National Health Authorities of each state. In this communication, we describe the main results and implications of the EMERALD trial, in the context of the biomarker-driven algorithm for patients with HR+/HER2- mBC progressed on CDK4/6i, and conclude that a subgroup of patients with ESR1-mutant tumors and specific clinical features can really derive a clinically meaningful benefit from elacestrant, sparing access to more toxic combination approaches and preserving the quality of life.

P1/2, N=49, Active, not recruiting, Carrick Therapeutics Limited | Recruiting --> Active, not recruiting

The primary endpoint is distant metastasis free survival and secondary endpoints are invasive disease-free survival, relapse-free survival, overall survival, safety and quality of life. Recruitment started in December 2023 in Belgium and is planned to open in 11 more countries in 2024: Cyprus, France, Germany, Greece, Italy, Ireland, the Netherlands, Portugal, Spain, Sweden, and Switzerland.

We present the largest study of BC variant frequencies in a cohort of Irish breast cancer patients to date and confirm NGS is feasible and identifies clinically relevant and actionable variants. We confirm that the frequency of PIK3CA alterations, in addition to codon specificity, are comparable to those observed in European and US cohorts and demonstrate that the detection of clinically relevant biomarkers is not confined to ER positive HER2 negative BC. The tissue failure rate (19%) underscores the need for cfDNA testing to identify the expanding range of actionable targets in BC to improve access to emerging targeted therapies and biomarker-driven clinical trials.

The APIS ESR1 Mutations Kit showcased highly specific and sensitive detection of both the mutations present in the SensID ESR1 Reference Set 1% AF cfDNA and wildtype ESR1 from highly fragmented FFPE-derived DNA. Here, the kit’s LoD was affirmed at ≤1% MAF for cfDNA-based sample types and compatibility for detecting ESR1 mutations was demonstrated with both cfDNA and FFPEderived DNA samples.

P=N/A, N=70, Not yet recruiting, AstraZeneca