Inactivating WDR5 by knockdown or inhibitors phenocopies the effects of PML1 loss, reducing BCSC-related gene expression and tumorsphere formation and enhancing fulvestrant's anticancer activity. Our findings challenge the conventional understanding of PML as a tumor suppressor, redefine its role as a promoter of tumor growth in breast cancer, and offer new insights into the unique roles of PML isoforms in breast cancer.

Pharmacological blockade or siRNA silencing of ERα limited cell survival and metastasis while restoring tight junction protein expression. In conclusion, these findings highlight the potential of ERα as a prognostic marker for CRC and its role in metastasis.

P1, N=28, Completed, Eli Lilly and Company | Recruiting --> Completed | N=42 --> 28

Approximately 177 mBC patients were enrolled, of whom 66 were treated with CD4/6 inhibitors plus letrozole and 111 were treated with CDK4/6 inhibitors and fulvestrant. Furthermore, neutropenia status was associated with a more than doubled risk of progression/death compared to patients without neutropenia (HR = 2.311; p = 0.025). Having identified certain factors that could be associated with the development of neutropenia and considering that neutropenia itself is associated with an increased risk of progression, we believe that the baseline characteristics should be taken into account to reduce cases of neutropenia and disease progression.

P2, N=80, Recruiting, Stemline Therapeutics, Inc. | Trial primary completion date: Feb 2024 --> Feb 2025

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.

P1, N=500, Active, not recruiting, Eli Lilly and Company | Phase classification: P1a/1b --> P1

P2, N=40, Active, not recruiting, Beth Israel Deaconess Medical Center | Trial completion date: Jun 2023 --> Mar 2025 | Trial primary completion date: Jun 2023 --> Mar 2025

We've pioneered a nanoparticle system loaded with radioactive isotope 131I, endocrine therapeutic agents, and a photosensitizer precursor. This system offers a combined modality of radiotherapy, endocrine treatment, and PDT for breast cancer.

UCHL1 plays a pivotal role in TNBC by deubiquitinating and stabilizing KLF5, contributing to endocrine therapy resistance. TET1 and TET3 promote UCHL1 transcription through promoter demethylation and maintain KLF5 protein level in a UCHL1-dependent manner, implying their potential as therapeutic targets in TNBC.

P1, N=22, Completed, AstraZeneca | Recruiting --> Completed

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.

P1, N=396, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

P2, N=30, Completed, AstraZeneca | Active, not recruiting --> Completed

P1, N=61, Recruiting, Kind Pharmaceuticals LLC | Trial completion date: May 2025 --> May 2026 | Trial primary completion date: May 2025 --> May 2026

The ET-FES trial demonstrated that ER+/HER2- MBC patients are a heterogeneous population, with different levels of endocrine responsiveness based on 18F-FES CT/PET SUV.

ctDNA detection at baseline and PIK3CA mutation had an adverse prognostic impact on PFS and OS in multivariate analysis. This prospective cohort study documents the efficacy of fulvestrant and everolimus in CDK4/6i-pretreated ER + /HER2- mBC and highlights the clinical validity of early ctDNA changes as pharmacodynamic biomarker.

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.

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=303, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Mar 2024 --> Jun 2024

P2, N=367, Active, not recruiting, Sanofi | Trial completion date: Dec 2023 --> Mar 2024

P3, N=462, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2023 --> Dec 2024

P2, N=201, Active, not recruiting, Priscilla McAuliffe | Recruiting --> Active, not recruiting | Trial completion date: Mar 2023 --> Mar 2025 | Trial primary completion date: Mar 2023 --> Mar 2024

P2, N=48, Recruiting, SOLTI Breast Cancer Research Group | Not yet recruiting --> Recruiting

P3, N=1370, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

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.

Paclitaxel and fulvestrant were administered sequentially, the bleeding from the right breast mass stopped and the mass flattened...Therefore, hemostatic treatment with Mohs paste was performed in parallel with tamoxifen...Although systemic drug therapy has been discontinued at the patient's request, she is still alive. While systemic drug therapy was discontinued, we were able to confirm the pure local control effect of combination of radiation therapy and Mohs paste.

She initiated endocrine therapy by letrozole. By changing the endocrine therapy to toremifene followed by fulvestrant, the therapy achieved a partial response...She was administered lapatinib as anti-HER2 therapy in addition to the endocrine therapy. Two years and 6 months after surgery, there has been no worsening of bone metastasis or appearance of visceral metastasis.

P2, N=220, Recruiting, ETOP IBCSG Partners Foundation | Not yet recruiting --> Recruiting

P1/2, N=350, Not yet recruiting, Shandong Suncadia Medicine Co., Ltd.

P3; Not yet recruiting --> Recruiting

Exemestane: OS 22.1 (95%CI 9.7-34.6); TTF 6.0 (95%CI 4.1-7.8). Estimated effectiveness (OS) of letrozole and fulvestrant was, respectively, 3.2-3.5 months lower than reported. The clinical meaning seems uncertain and may be explained a higher proportion of worse prognostic characteristics in patients treated in the real-world.

The significant advantage of this method is that the mathematical model does not have to contain a small parameter (as is standard in perturbation theory). However, it is possible to artificially introduce a small parameter into the system of equations, making it possible to study the model using asymptotic methods.

P3; Differential NET response by PAM50 subtype in exploratory analyses warrants further investigation. ClinicalTrials.gov Identifier: NCT01953588.

P2, N=220, Not yet recruiting, ETOP IBCSG Partners Foundation | Initiation date: Dec 2023 --> Mar 2024

P2, N=30, Recruiting, Hoffmann-La Roche | N=45 --> 30 | Trial completion date: Oct 2024 --> Dec 2025 | Trial primary completion date: Oct 2024 --> Dec 2025

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.

This real-world analysis confirms the effectiveness of CDK4/6 inhibitor-based regimens in French patients and highlights the frequent use of chemotherapy as second line therapy.

P2; Trial completion date: Mar 2028 --> Dec 2028 | Initiation date: Sep 2023 --> Dec 2023 | Trial primary completion date: Dec 2024 --> Dec 2028

P2, N=176, Not yet recruiting, German Breast Group

P1, N=90, Recruiting, Olema Pharmaceuticals, Inc. | Phase classification: P1b --> P1 | N=60 --> 90