ER Y537S

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.

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

Baseline ESR1 mutations in EV-DNA were associated with shorter progression-free survival (PFS) across the cohort, with the Y537S mutation showing a particularly strong impact on the outcome of fulvestrant-treated patients. In contrast, PIK3CA mutations in EV-DNA did not significantly correlate with PFS, whereas in ctDNA, they were linked to poor outcomes. Altogether, this study positions EV-DNA as a valuable biomarker alongside ctDNA, enriching the understanding of different analytes in liquid biopsy and supporting strategies for HR+/HER2-mBC in precision oncology.

ERD-12310A achieved a DC50 value of 47 pM and is 10 times more potent than ARV-471...Importantly, ERD-12310A achieved strong tumor growth inhibition in MCF-7 xenograft tumors harboring the clinically relevant ESR1Y537S mutation, which confers resistance to traditional antiestrogens. Our data position ERD-12310A as a promising candidate for further development as a potential therapy for ER+ breast cancer.

YS mutant BC cells induced the conversion of fibroblasts into CAFs, via YAP, which represent a potential therapeutic target which interrupt the functional interactions between mutant cells/TME and to be implemented in the novel therapeutic strategy of a subset of metastatic BC patients carrying the frequent Y537S mutations.

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

In 1 pt, eribulin and abraxane did not have the same effect; ESR1 polyclonality was maintained. One pt with 1 ESR1 clone after 2.5 years of fulvestrant+palbociclib developed 15 additional clones after 1.5 years of an experimental SERD+everolimus. Another pt with 1 ESR1 clone after anastrozole+palbociclib developed 9 additional ESR1 clones after 10 months of AKT inhibition+anastrozole... This is the first investigation of dynamic changes in extreme ESR1 polyclonality in association with treatment outcomes in pts with ER+ MBC. Capecitabine was associated with a decrease in detectable ESR1-mutant clones, while increased polyclonality was found at progression on SERD+everolimus, AKT-inhibitor+AI, and an ADC. Although extreme ESR1 polyclonality is rare, understanding mutational dynamics will improve our understanding of polyclonality more broadly and its impact on treatment resistance.

None of the patients received ESR1-targeted therapy with Elacestrant. Our findings indicate that the level changes of ctDNA ESR1 mutations have implications with regards to treatment sensitivity and resistance to various therapies in patients with HR+/HER2- mBC. These results suggest a potentially effective method for monitoring treatment response and guiding future therapy by providing new insights into targeting ESR1 pathways to overcome resistance.

Elacestrant demonstrated a significant improvement in mPFS vs SOC in patients with both high and low ESR1 VAF. The clinical benefit and activity of elacestrant vs SOC was maintained regardless of type of ESR1 mutation variant and the abundance/quantity of ESR1 mutations in patients with ER+/HER2- mBC. In all patients with ER+/HER2, ESR1-mut mBC, elacestrant may replace fulvestrant-based combinations, and delay chemotherapy or ADC-based regimens.

ERD-1233 was developed based on Lasofoxifene as the ER binding moiety and a novel cereblon ligand through extensive optimization of the linker...Oral administration of ERD-1233 effectively reduces ER protein in ER+ tumors and achieves tumor regression in the ER wild-type MCF-7 xenograft tumor model and strong tumor growth inhibition in the ESR1Y537S mutated model in mice. Our data demonstrate that ERD-1233 is a promising ER PROTAC degrader for extensive evaluation as a new therapy for the treatment of ER+ human breast cancer.

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.