Crucitta Stefania, Ruglioni Martina, Lorenzini Giulia, Bargagna Irene, Luculli Giovanna Irene, Albanese Irene, Bilancio Diana, Patanè Francesca, Fontana Andrea, Danesi Romano, Del Re Marzia
Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.
Unit of Medical Oncology, Department of Translational Research and New Technologies in Medicine, University of Pisa, 56126 Pisa, Italy.
Cancers (Basel). 2023 Feb 18;15(4):1306. doi: 10.3390/cancers15041306.
ESR1 mutations contribute to endocrine resistance and occur in a high percentage of hormone-receptor-positive (HR+) metastatic breast cancer (mBC) cases. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) changed the treatment landscape of HR+ mBC, as they are able to overcome estrogen resistance. The present retrospective study investigates the clinical benefit of CDK4/6i in ESR1 mutant HR+ mBC patients treated with a CDK4/6i as first- or second-line therapy. Plasma was collected at baseline prior to CDK4/6i plus hormone therapy as a first- or second-line treatment. Circulating free DNA (cfDNA) was extracted from plasma, and ESR1 mutation analysis was performed on a ddPCR. Statistical analyses were performed to investigate the predictive power of ESR1 mutations and any association with clinical factors. A total of 42 patients with mBC treated with CDK4/6i plus endocrine therapy as first- ( = 35) or second-line ( = 7) were enrolled. Twenty-eight patients received hormonal therapy (AI or tamoxifen) in the adjuvant setting. ESR1 mutation status in blood was associated with shorter median disease-free survival (DFS) (30 vs. 110 months; = 0.006). Multivariate analysis confirmed ESR1 mutations as independent factors of resistance in adjuvant hormone therapy. On the contrary, no difference in progression-free survival (PFS) was observed in the presence or absence of an ESR1 mutation in patients treated with CDK4/6i as first-line treatment ( = 0.29). No statistically significant correlation between the best response to CDK4/6i and ESR1 mutation was found ( = 0.46). This study indicates that the ESR1 mutation detected in cfDNA is an independent predictive factor of clinical recurrence in the adjuvant setting and that CDK4/6i can overcome ESR1-dependent resistance.
ESR1突变会导致内分泌抵抗，且在高比例的激素受体阳性（HR+）转移性乳腺癌（mBC）病例中出现。细胞周期蛋白依赖性激酶4/6抑制剂（CDK4/6i）改变了HR+mBC的治疗格局，因为它们能够克服雌激素抵抗。本回顾性研究调查了CDK4/6i在接受CDK4/6i作为一线或二线治疗的ESR1突变HR+mBC患者中的临床获益情况。在CDK4/6i加激素治疗作为一线或二线治疗之前，于基线时采集血浆。从血浆中提取循环游离DNA（cfDNA），并通过数字液滴聚合酶链反应（ddPCR）进行ESR1突变分析。进行统计分析以研究ESR1突变的预测能力以及与临床因素的任何关联。共有42例接受CDK4/6i加内分泌治疗作为一线（n = 35）或二线（n = 7）治疗的mBC患者入组。28例患者在辅助治疗阶段接受了激素治疗（芳香化酶抑制剂或他莫昔芬）。血液中的ESR1突变状态与较短的无病生存期（DFS）中位数相关（30个月对110个月；P = 0.006）。多变量分析证实ESR1突变是辅助激素治疗中耐药的独立因素。相反，在接受CDK4/6i作为一线治疗的患者中，无论有无ESR1突变，无进展生存期（PFS）均未观察到差异（P = 0.29）。未发现对CDK4/6i的最佳反应与ESR1突变之间存在统计学显著相关性（P = 0.46）。本研究表明，在cfDNA中检测到的ESR1突变是辅助治疗中临床复发的独立预测因素，且CDK4/6i可克服ESR1依赖性耐药。
