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.
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.
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DOI：
10.1158/1078-0432.ccr-22-2305
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发表时间：
2022-12-01
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内分泌治疗(ET)的敏感性对于帕波西利联合ET治疗激素受体阳性/HER2阴性(HR+/HER2−)晚期乳腺癌的临床益处至关重要。巴多昔芬是一种第三代选择性ER调节剂和选择性ER降解剂，在内分泌耐药乳腺癌的临床前模型中具有活性，包括携带ESR1突变的模型。对健康女性的临床试验表明，巴多昔芬耐受性良好。我们在HR+/HER2−晚期乳腺癌患者中进行了巴多昔芬联合帕波西利的Ib/II期研究(N=36)(NCT02448771)。这项研究达到了它的主要终点，临床受益率为33.3%，安全性与之前看到的帕波西利单一疗法一致。中位无进展生存期(PFS)为3.6个月(CI95%2.0~7.2)。在基线水平激活PIK3CA突变与较短的PFS相关(HR=4.4CI95%1.5-13，P=0.0026)，但激活ESR1突变不影响PFS。纵向血浆循环肿瘤DNA全外显子组测序(WES)(N=68个血浆样本)提供了肿瘤异质性、亚克隆性遗传进化和在治疗期间获得的可操作突变的概述。帕波西利和巴多昔芬联合治疗HR+/HER2−晚期乳腺癌患者，具有临床疗效和可接受的安全性。这些结果值得继续研究巴多昔芬在乳腺癌中的作用。
Sensitivity to endocrine therapy (ET) is critical for the clinical benefit from the combination of palbociclib plus ET in hormone receptor-positive/HER2-negative (HR+/HER2−) advanced breast cancer. Bazedoxifene is a third-generation selective ER modulator and selective ER degrader with activity in preclinical models of endocrine-resistant breast cancer, including models harboring ESR1 mutations. Clinical trials in healthy women showed that bazedoxifene is well tolerated. We conducted a phase Ib/II study of bazedoxifene plus palbociclib in patients with HR+/HER2− advanced breast cancer who progressed on prior ET (N=36) (NCT02448771). The study met its primary endpoint, with a clinical benefit rate of 33.3%, and the safety profile was consistent with what has previously been seen with palbociclib monotherapy. The median progression free survival (PFS) was 3.6 months (CI95% 2.0-7.2). An activating PIK3CA mutation at baseline was associated with a shorter PFS (HR = 4.4, CI95% 1.5-13, P = 0.0026) but activating ESR1 mutations did not impact the PFS. Longitudinal plasma circulating tumor DNA whole exome sequencing (WES) (N=68 plasma samples) provided an overview of the tumor heterogeneity, the sub-clonal genetic evolution and identified actionable mutations acquired during treatment. The combination of palbocilib and bazedoxifene has clinical efficacy and an acceptable safety profile in a heavily pre-treated patient population with advanced HR+/HER2− breast cancer. These results merit continued investigation of bazedoxifene in breast cancer.