ESR1 mutation

P3, N=240, Not yet recruiting, MedSIR

We summarized the ctDNA and cancer tissue mutational landscape, including overall neoplastic burden and PIK3CA and ESR1 hotspot mutations in abemaciclib-treated patients with HR+/HER2- MBC. The data provide insights that could help optimize treatment strategies in this population.

In this review we discuss the history of ERα, current research unlocking unknown aspects of ERα signaling including the structural basis for receptor antagonism, and future directions of ESR1 investigation. In addition, we discuss the development of endocrine therapies from their inception to present day and survey new avenues of drug development to improve pharmaceutical profiles, targeting, and efficacy.

Until 2023, fulvestrant was the only approved SERD; fulvestrant is administered intramuscularly, and in some cases may also have limited efficacy in the setting of certain ESR1 mutations. Elacestrant's recent approval sheds light on the use of biomarkers such as ESR1 to gauge a tumor's endocrine sensitivity. Ongoing therapeutic and correlative biomarker studies will offer new insight and expanding treatment options for patients with advanced breast cancer.

P2, N=100, Active, not recruiting, Sermonix Pharmaceuticals Inc. | Trial completion date: Feb 2024 --> Dec 2024 | Trial primary completion date: Feb 2024 --> Dec 2024

P2, N=100, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jul 2024 --> Feb 2025 | Trial primary completion date: Mar 2024 --> Oct 2024

Additionally, protein expression and phosphorylation patterns, while under different regulation, still recapitulated the estrogen-independent phenotype of ER mutant cells. Our study is the first proteome-centric characterization of ESR1 mutant models, out of which we confirm estrogen independence of ER mutants and reveal the enrichment of immune signaling pathways at the proteomic level.

Although the acelERA BC study did not reach statistical significance for its primary INV-PFS end point, there was a consistent treatment effect with giredestrant across most key subgroups and a trend toward favorable benefit among patients with ESR1-mutated tumors. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks. Overall, these data support the continued investigation of giredestrant in other studies.

Multi-omics data from the phase IIa patients (n = 24 tumor/17 blood biopsy exomes; n = 27 tumor transcriptomes) showed potential mechanisms of resistance (convergent evolution of HER2 activation, BRAFV600E), identified joint genomic/transcriptomic resistance features (ESR1 mutations, high estrogen receptor pathway activity, and a Luminal A/B subtype; ERBB2/BRAF mutations, high RTK/MAPK pathway activity, and a HER2-E subtype), and provided hypothesis-generating results suggesting that mTOR pathway activation correlates with response to the trial's therapy. Our results illustrate how genome and transcriptome sequencing may help better identify patients likely to respond to CDK4/6i therapies.

However, following the breast cancer-specific FDA approvals of alpelisib+fulvestrant for PIK3CA-mutant disease in 2019 and elacestrant for ESR1-mutant disease in 2023, a significant shift in Level 1 actionability was observed between EUR (45%) and AFR (34%) attributed in part to the paucity of PIK3CA (26.3% vs. 36.2% in EUR) and ESR1 (4.1% vs. 7.5% in EUR) oncogenic alterations in AFR.We further observed AFR with CRC to have lower prevalence of MSI-H (5.8% vs.10.7% in EUR), TMB (12.5% vs. 18.8% in EUR) and BRAF V600E (5.1% vs. 9% in EUR). Correspondingly, in 2023, 16.4% of AFR with CRC have Level 1 alterations compared to 25.4% of EUR. Moreover, while AFR have higher rates of KRAS mutations (57.2% vs. 42.6% in EUR), they have a lower prevalence of the standard care biomarker KRAS G12C (3.4% vs. 7% of KRAS-mutant CRC in EUR) further exacerbating the disparities in CRC clinical actionability.Taken together, here we demonstrate that a significant disparity exists in the clinical actionability landscape of AFR with cancer compared to EUR, largely due to differences in relative mutational frequencies of Level 1 genomic alterations.

Patients with ESR1m acquired on AI may retain treatment response if switched to selective estrogen receptor degraders (SERDs) like fulvestrant... xF Monitor is a ctDNA assay that tracks changes in quantitative ctDNA TF and simultaneously monitors for the emergence of ESR1m, providing a diagnostic that identifies resistance to AI therapy and enables early switch to therapies that could improve outcomes in a patient population with poor prognosis. A larger prospective clinical study is needed to validate these findings.

Mutations in ESR1 and in PI3K pathway genes at T0 were associated with worse prognosis in palbociclib-treated patients. We describe the emergence of newly acquired mutations in palbociclib-treated patients, which might potentially affect subsequent treatment.

Our data provide a comprehensive characterization of the behaviors and mechanisms of ESR1 mutant liver metastasis, paving the way for the development of personalized therapy to target liver metastasis for patients with ESR1 mutant breast cancer.

Fulvestrant is the first approved SERD with proven efficacy and good tolerability in clinical practice...Elacestrant is an orally bioavailable SERD that has been recently approved by the FDA for postmenopausal women with ER+, human epidermal growth factor receptor 2-negative (HER2-), estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Other molecules of the same class currently tested in clinical trials are amcenestrant, giredestrant, camizestrant, and imlunestrant. The current review article offers a detailed pharmacological perspective of this emerging drug class, which may help with their possible future clinical applications.

In conclusion, our work uncovers opportunities for further treatment personalization and stresses the need for effective combination treatments to address the altered tumor genomic landscape following AI+CDK4/6i exposure. Further, we demonstrated the potential of RWD for refining patient treatment strategy and guiding clinical trial design.

Cancer panel testing for cfDNA identified prognostic and predictive biomarkers for palbociclib add-on therapy after acquiring fulvestrant resistance in patients with HR+/HER2- ABC/MBC.

The approval of elacestrant in ER+, HER2- advanced or metastatic breast cancer was restricted to patients with ESR1 mutations. Benefit-risk assessment in the ESR1-mut subgroup was favorable on the basis of a statistically significant improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in OS. By contrast, the benefit-risk assessment in patients without ESR1 mutations was not favorable. Elacestrant is the first oral estrogen receptor antagonist to receive FDA approval for patients with ESR1 mutations.

P2, N=60, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial primary completion date: Jan 2024 --> Jul 2024

P2, N=29, Active, not recruiting, Sermonix Pharmaceuticals Inc. | Trial completion date: Jan 2024 --> May 2024 | Trial primary completion date: Jan 2024 --> May 2024

According to the findings of this meta-analysis, the assessment for plasma ESR1 mutations may provide prognostic and clinical guidance regarding subsequent endocrine therapy decisions for ER-positive, metastatic BC patients who had received prior therapy with AIs.

We then show the presence of human T cells reactive to ESR1mut epitopes in an ER+ BC patient. These findings support the development of ESR1mut vaccines, which we are testing in a Phase I clinical trial.

The first-generation selective estrogen receptor degrader (SERD) fulvestrant has shown some activity against ESR1 mutant tumors...Several oral SERDs are now in phase III trials for early and advanced ER+ breast cancer. This review summarizes the background of oral SERD development, the current status, and future perspectives.

Ultimately, we identified five peptides derived from the three most common ESR1 mutations (D538G, Y537S, and E380Q) and their associated wild-type peptides, which were the most immunogenic. Overall, these data confirm the immunogenicity of epitopes derived from ESR1 and highlight the potential of these peptides to be targeted by novel immunotherapy strategies.

The whole-exome and whole-transcriptome sequencing approach identified both common and rare missense mutations and fusions. ESR1 alterations were present in tumors from 5.3 % of endometrial cancers and 2.7% of ovarian cancers. From a clinical perspective, the frequency of ESR1 alterations was similar between local and metastatic samples.

This study suggests that unique actionable biomarkers are detected by both concurrent tissue and ctDNA testing, with higher ctDNA identification among patients with breast cancer. Integration of concurrent NGS testing into the routine management of advanced solid cancers may expand the delivery of molecularly guided therapy and improve patient outcomes.

Monitoring c-MET+ CTC, rather than assessing c-MET expression in the primary BC site, could provide valuable information for predicting disease progression, as c-MET expression can change during treatment. The c-MET+ CTC count and cfDNA concentration could provide complementary information on disease progression in HR+ /HER2- mBC, highlighting the importance of integrated liquid biopsy.

To investigate the basis of this lack of recognition we performed immunopeptidomics analysis of a mutant-overexpressing lymphoblastoid cell line and found that the ESR1 Y537S neopeptide was not endogenously processed, despite binding to HLA-B*40:02 when exogenously pulsed onto the target cell. These results indicate that stimulation of T cells that likely derive from the naïve repertoire with pulsed minimal peptides may lead to the expansion of clones that recognize non-processed peptides, and highlights the importance of using methods that selectively expand T cells with specificity for antigens that are efficiently processed and presented.

Novel endocrine options including oral selective estrogen receptor down-regulators (SERDs) are in late phases of development, with elacestrant being the first oral SERD to be approved for ESR1-mutant mBC...Trastuzumab deruxtecan offers a novel therapeutic option for patients with HR+/HER2-low mBC and sacituzumab govitecan is a novel therapeutic option for patients with HR+/HER2- mBC, including those with unmet treatment need in the later-line endocrine-refractory setting. Data gaps still exist regarding optimal sequencing of these novel agents; additional studies into mechanisms of resistance in the metastatic setting would provide further insights. Herein, we describe the current treatment options for HR+/HER2- mBC, including the latest practice-impacting data, and provide commentary on future directions.

Epigenetic changes, such as DNA methylation and histone modifications, can also contribute to ET resistance by altering the expression of genes that are involved in estrogen signaling. Understanding the mechanisms of resistance to ET is crucial for the development of new therapies that can overcome resistance and improve outcomes for patients with HR + BC.

The oral SERD regimen provides a significant PFS benefit compared to standard-of-care ET in patients with HR+/HER2- aBC after progression on ≥ 1 line of ET. In particular, we recommend oral SERDs as a preferred choice for those patients with ESR1m, and it could be a potential replacement for fulvestrant. The oral SERD regimen is also beneficial after progression on CDK4/6 inhibitors combined with endocrine therapy.

P3, N=400, Recruiting, Sermonix Pharmaceuticals Inc.

P2, N=36, Recruiting, Dartmouth-Hitchcock Medical Center

P1/2, N=206, Completed, Eisai Inc. | Active, not recruiting --> Completed

No abstract available

OP-1250 combines well with cyclin-dependent kinase 4 and 6 inhibitors in xenograft studies of ER+ breast cancer models and effectively shrinks intracranially implanted tumors, resulting in prolonged animal survival. With demonstrated preclinical efficacy exceeding fulvestrant in wild-type models, elacestrant in ESR1-mutant models, and tamoxifen in intracranial xenografts, OP-1250 has the potential to benefit patients with ER+ breast cancer.

P1/2, N=48, Recruiting, Carrick Therapeutics Limited | Phase classification: P1b/2 --> P1/2

P1/2, N=48, Recruiting, Carrick Therapeutics Limited

The original diagnosis was usually high-grade non-intestinal-type adenocarcinoma or high-grade myoepithelial carcinoma. A correct diagnosis of these aggressive tumors could lead to improved targeted therapies with potentially better overall disease-specific survival.

Lasofoxifene plus abemaciclib had an acceptable safety profile, was well tolerated, and exhibited meaningful antitumor activity in women with ESR1-mutated, ER+/HER2- mBC after disease progression on prior CDK4/6i. Observed decreases in ESR1-mutant ctDNA with lasofoxifene concordant with clinical response suggest target engagement. If the ELAINE 2 findings are confirmed in the initiated, phase III, ELAINE 3 trial, these data could be practice-changing and help address a critical unmet need.

Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.

For more than 20 years, fulvestrant (given as an intramuscular injection) was the only SERD approved by the US Food and Drug Administration for the treatment of ER+/HER2- metastatic breast cancer, and a standard second-line therapy following progression on an AI. This review discusses (1) the importance of routine testing for ESR1 mutations after disease recurrence or progression and the role of liquid biopsy in this regard; (2) elacestrant, a novel oral SERD approved in 2023 for the treatment of postmenopausal women and adult men with ER+/HER2-, ESR1-mutated advanced or metastatic breast cancer with disease progression following 1 or more lines of endocrine therapy (unlike other SERDs, elacestrant is not associated with cardiac or ocular toxicity); and (3) new agents in development, including SERDs and innovative molecules targeting the ER-PROTACs, SERCAs, and CERANs-currently being tested in early-phase trials in combination with targeted agents, including CDK4/6 inhibitors.

Of these, IRS1 stood out as a gene of interest, and ERα and PR occupancy at chromatin binding sites along IRS1 were uniquely altered in the context of ERα Y537S. Furthermore, siRNA knockdown of IRS1 or treatment with the IRS1 inhibitor NT-157 had a significant anti-proliferative effect in ERα Y537S cell lines, implicating IRS1 as a potential therapeutic target for restoring treatment sensitivity to patients with breast cancers harboring ERα Y537S mutations.