The following is a summary of “Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor–Positive Breast Cancer” published in the December 2022 issue of Oncology by Tsuji et al.

In advanced hormone receptor positive/hER2- negative (HR+/HER2) breast cancer, sensitivity to endocrine therapy (ET) is essential for the therapeutic benefit from the combination of palbociclib plus ET. Bazedoxifene is an ER (estrogen receptor) selective modulator and degrader that has shown effectiveness in preclinical models of endocrine-resistant breast cancer, particularly those with ESR1 mutations. Bazadoxifene was found to have a favorable safety profile in clinical investigations, including healthy females.

Patients with HR+/HER2 metastatic breast cancer who had progressed on earlier ET were enrolled in a phase Ib/II study of bazedoxifene plus palbociclib (N=36; NCT02448771). Clinical benefit was shown in 33.0% of patients, and the safety profile was consistent with that of prior studies evaluating palbociclib monotherapy. Median progression-free survival (PFS) (95% CI) was 3.6 months. At baseline, having a mutation in PIK3CA that activates the protein was linked to a shorter (HR=4.4; 95% CI, 1.5-13; P=0.0026), while having a mutation in ESR1 that activates the protein had no effect on PFS. 

Whole-exome sequencing (WES; N=68 plasma samples) of circulating tumor DNA throughout time shed light on tumor heterogeneity and subclonal genetic evolution and revealed treatment-relevant mutations that arose as a result of treatment. Patient populations with advanced HR+/HER2 breast cancer that has been through extensive prior treatment nevertheless benefit clinically from the combination of palbociclib and bazedoxifene, and do so with an acceptable safety profile. Based on these findings, further examination of bazedoxifene in breast cancer is warranted.