In recent clinical trials of metastatic ER+ BC, next-generation SERDs demonstrated clinical activity, and elacestrant received an approval for advanced ESR1-mutant disease. NR tumors instead up-regulate multiple ERα-independent proliferative pathways, such as EGFR/MAPK and Hippo/TEAD, which may represent targetable dependencies in NR disease. Modeling resistance and lineage plasticity in vitro, we find that giredestrant-resistant ER+ BC cell lines exhibit profound shifts in chromatin accessibility, with the transcription factors, FOXA1 and FOXM1, implicated in gene expression of NR-upregulated proliferative pathways.

P3, N=1100, Not yet recruiting, Karolinska Institutet

P2, N=140, Not yet recruiting, Dana-Farber Cancer Institute

Hot flashes were frequent, affecting 33% of patients, but showed no clear pharmacogenetic associations. This study demonstrates that pharmacogenetic variation is associated with interindividual differences in treatment-related side effects, underscoring the need to expand research in African populations to better inform precision endocrine therapy.

The pro-migratory effects of PFIs on MCF-7 cells were abolished by an ERα antagonist of 4-hydroxytamoxifen, indicating the substantial role of ERα signaling in cancer cell progression...Although PFI-induced RARα antagonism alone had no effects on the migration of MDA-RARα cells, it did recover that compromised by atRA. This study provides new evidence on the promotion effects of PFIs on breast cancer cells, and reveals the multi-nuclear receptor-regulated mechanisms for understanding intricate toxicological effects of emerging pollutants.

To investigate the mechanisms leading to valve loss, we combined the lymphatic-specific and tamoxifen-inducible Flt4CreERT2 with Kras-loxP-stop-loxP-G12D (Kras+/G12D) mice and Prox1GFP reporter mice to induce the restricted expression of KRAS-G12D and enable valve quantification in postnatal pups...We conclude that hyperactive KRAS signaling upregulates MMPs that become excessively activated by the upregulation of the PA pathway. MMPs then degrade the lymphatic valve ECM core, preventing valve formation.

Adjuvant treatment included combination chemotherapy, radiotherapy, and dual hormonal therapy with tamoxifen and an AR inhibitor. This case highlights the diagnostic and therapeutic challenges of hormone receptor-positive AC and underscores the importance of comprehensive immunohistochemical profiling for individualized management.

Comparative docking and pharmacokinetic analyses with standard drugs Lapatinib and Tamoxifen indicated better drug-like properties and pharmacokinetic advantages for DdpMPyPEPhU. Additional validation using Density Functional Theory (DFT) optimisation, 5 ns WaterMap analysis, and 250 ns molecular dynamics simulations under neutralised conditions confirmed structural stability and strong intermolecular interactions, supported by binding free energy calculations. Overall, our computational findings suggest that DdpMPyPEPhU is a promising therapeutic candidate for breast cancer, providing a rational basis for further experimental evaluation.

Functional organoid assays validate that these epithelial states exhibit differential sensitivity to tamoxifen and demonstrate that inflammatory signals can induce immune-modulatory epithelial programs. Together, our findings identify hormone signaling and immune programs as key determinants of endocrine responsiveness in breast tissue and provide a biological basis for interpreting radiologic markers relevant to cancer prevention.

SIGNIFICANCE STATEMENT: Metabolite M14 of camizestrant (AZD9833), a major circulating metabolite in humans, was successfully identified as an N-glucuronide of an acid metabolite of camizestrant, and its unusual chromatographic and stability properties were characterized. The development of a novel hybrid chemical and biological synthesis for M14 has introduced a new approach to synthesizing glucuronides of compounds with acidic functional groups that otherwise interfere with their own in vitro glucuronidation.

P2, N=176, Recruiting, Memorial Sloan Kettering Cancer Center