This case represents a rare report of surgical resection for breast cancer liver metastasis after CDK4/6 inhibitor-based therapy. It suggests that local treatment may be effective even in cases with suspected endocrine-resistant disease and provides practical insight into patient selection and treatment strategies, as the case fulfilled previously reported criteria for local therapy.

P2, N=50, Not yet recruiting, Jonsson Comprehensive Cancer Center

P1, N=6, Completed, Shandong Suncadia Medicine Co., Ltd. | Not yet recruiting --> Completed

In therapy-sensitive wild-type ER cells with low basal PML1 levels and PI3K/MAPK activity, fulvestrant's ER-suppressive effects overcome drug-induced elevated PML1 and PI3K/MAPK activity, thereby maintaining therapeutic efficacy...Notably, reducing PML1 levels through knockdown or arsenic trioxide (ATO), an FDA-approved PML1 degrader, disrupts this resistance circuit and restores endocrine sensitivity. Treatment of ATO resensitizes ER Y537S-bearing resistant tumors to endocrine therapy in xenograft models. These findings establish PML1 as a central hub of resistance, linking ER signaling to the activation of the PI3K/MAPK survival pathway.

Mechanistically, the BRD4 PROTAC enhances fulvestrant sensitivity by down-regulation of GREB1 expression. Targeting BRD4 with PROTAC degraders represents a promising therapeutic strategy in breast cancer by suppressing GREB1 expression and enhancing the efficacy of fulvestrant.

The regulatory approval of elacestrant for ESR1-mutant disease and randomized trial data showing progression-free survival (PFS) benefit from ctDNA-guided endocrine switching (PADA-1, SERENA-6) position ESR1 genotyping as a dynamic biomarker with direct therapeutic implications...The convergence of structural mechanisms, liquid biopsy technology, and biomarker-driven drug development provides a framework for precision oncology in endocrine-resistant breast cancer. While these advances are substantial, important challenges remain, including the lack of mature overall survival (OS) data from interception trials, cost and accessibility barriers to serial ctDNA monitoring in diverse global healthcare settings, the unresolved question of optimal therapeutic sequencing in patients with concurrent ESR1 and PI3K pathway alterations, and the need to distinguish clinically actionable low-variant allele frequency (VAF) ESR1 calls from background noise in liquid biopsies.

P2, N=150, Recruiting, MedSIR | Not yet recruiting --> Recruiting | Initiation date: Dec 2025 --> Mar 2026

PFS for the 1st-line cohort was similar to that in PALOMA-2, while the 2nd-line cohort had better outcomes than those in PALOMA-3, even when modelled for potential bias since some patients on 1st-line endocrine monotherapy would have received chemotherapy rather than 2nd-line PAL. Overall, the findings in this study of real-life treatment of patients with HR+/HER2- MBC support randomized control trial data that challenge the need to use a CDK4/6 inhibitor in the 1st-line setting for all patients.

P2, N=24, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

P1/2, N=50, Recruiting, NYU Langone Health

P1, N=24, Completed, Shandong Suncadia Medicine Co., Ltd. | Not yet recruiting --> Completed