Stearns Vered, ONeill Anne, Schneider Bryan P, Skaar Todd C, Liu Minetta C, Lohrisch Caroline, Goetz Matthew P, Vallejos Carlos S, Sparano Joseph A, Villa Diego, Silverman Paula, Cheema Puneet S, Moore Dennis F, Sledge George W
Weill Cornell Medicine, Meyer Cancer Center, 420 East 70th Street, 2nd Floor, New York, NY, 10021, USA.
Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
Breast Cancer Res Treat. 2025 Feb;209(3):595-602. doi: 10.1007/s10549-024-07519-z. Epub 2024 Oct 21.
In tamoxifen-treated individuals, reduced-function genetic variants in the CYP2D6 gene or inhibition of the enzyme result in low circulating endoxifen concentrations. We assessed the impact of reduced CYP2D6 activity and circulating endoxifen concentrations on breast cancer outcomes.
Patients with locally advanced or stage IV hormone receptor-positive breast cancer were enrolled in this single arm phase II trial and received open label tamoxifen 20 mg PO daily. The primary objective was to assess CYP2D6 poor metabolizer (PM) vs intermediate and normal metabolizer status (IM + NM) with progression-free survival (PFS). CYP2D6 phenotype was determined from whole blood samples (Roche Amplichip), and secondary endpoint evaluated endoxifen concentrations determined from 3 month post registration plasma samples (Quest Diagnostics).
From September 2010 to June 2013, 113 of planned 204 patients were registered to the trial and began protocol treatment. Accrual to the trial closed early due to lower-than-expected rate of CYP2D6 poor metabolizers. Median age was 62, 86% (97/113) were white, 33% (30/113) Hispanic, 83% (92/113) postmenopausal. Samples were evaluable for CYP2D6 in 75% (85/113) of patients (2/85 PM, 27/85 IM, and 56/85 NM). Median PFS for PM and IM + NM was 12.9 months and 6.9 months, respectively. Median PFS was 11.1 and 13.8 months respectively for patients with low (≤ 15.5) and high (> 15.5) endoxifen concentrations (ng/ml).
We did not observe significant associations between CYP2D6 metabolizer status or endoxifen with PFS. Small sample sizes and barriers to adequate samples in this trial prohibited determination of relationship between these markers and PFS.
NCT01124695 (registered May 14, 2010).
在接受他莫昔芬治疗的个体中，细胞色素P450 2D6（CYP2D6）基因功能降低的遗传变异或该酶的抑制作用会导致循环中的内昔芬浓度降低。我们评估了CYP2D6活性降低和循环内昔芬浓度对乳腺癌预后的影响。
局部晚期或IV期激素受体阳性乳腺癌患者参加了这项单臂II期试验，接受每日口服20毫克他莫昔芬的开放标签治疗。主要目的是评估CYP2D6慢代谢者（PM）与中间代谢者和正常代谢者状态（IM + NM）的无进展生存期（PFS）。CYP2D6表型通过全血样本（罗氏基因芯片）确定，次要终点评估登记后3个月血浆样本（奎斯特诊断公司）中测定的内昔芬浓度。
从2010年9月至2013年6月，计划入组的204例患者中有113例登记参加试验并开始方案治疗。由于CYP2D6慢代谢者的比例低于预期，试验提前结束入组。中位年龄为62岁，86%（97/113）为白人，33%（30/113）为西班牙裔，83%（92/113）为绝经后女性。75%（85/113）的患者样本可用于CYP2D6评估（2/85为PM，27/85为IM，56/85为NM）。PM和IM + NM的中位PFS分别为12.9个月和6.9个月。内昔芬浓度低（≤15.5）和高（>15.5）（纳克/毫升）的患者中位PFS分别为11.1个月和13.8个月。
我们未观察到CYP2D6代谢者状态或内昔芬与PFS之间存在显著关联。本试验中样本量小以及获取足够样本存在障碍，妨碍了确定这些标志物与PFS之间的关系。
NCT01124695（2010年5月14日注册）
