Abstract:

Resistance to endocrine therapies can arise from prolonged exposure or inherent mechanisms pre-existing treatment. These mechanisms include heightened estrogen receptor (ER) activity due to estrogen receptor (ESR1) mutations, fusions or activation of ER-independent pathways promoting cell survival. Administering specific tyrosine-kinase inhibitors in kinase fusion positive cancers, like lung and pancreatic cancer, has significantly improved outcomes. Gene fusions involving ESR1 gene, a non-kinase, has previously been detected in breast and gynecologic cancers, including ovarian and uterine cancer.

Despite the longstanding success of ERa inhibitors in breast cancer, conventional ER signaling, reliant on estrogen binding to ER, hasn’t been replicated in these cases. Treatment approaches involve aromatase inhibitors, selective ER modulators and selective ER degraders. However, most ESR1 fusion cases lack the ligand binding domain, rendering these therapies ineffective. To address this, we’ve characterized ESR1 fusions and proposed targeting a downstream surrogate as an effective approach for ESR1 fusion positive breast cancer.