Vered Stearns, Anne ONeill, Bryan P Schneider, Todd C Skaar, Minetta C Liu, Caroline Lohrisch, Matthew P Goetz, Carlos S Vallejos, Joseph A Sparano, Diego Villa, Paula Silverman, Puneet S Cheema, Dennis F Moore, George W Sledge
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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).</p><p><strong>Results: </strong>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).</p><p><strong>Conclusion: </strong>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.</p><p><strong>Trial id: </strong>NCT01124695 (registered May 14, 2010).</p>","PeriodicalId":9133,"journal":{"name":"Breast Cancer Research and Treatment","volume":null,"pages":null},"PeriodicalIF":3.0000,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"CYP2D6 activity in patients with metastatic breast cancer treated with single agent tamoxifen: results from ECOG-ACRIN E3108.\",\"authors\":\"Vered Stearns, Anne ONeill, Bryan P Schneider, Todd C Skaar, Minetta C Liu, Caroline Lohrisch, Matthew P Goetz, Carlos S Vallejos, Joseph A Sparano, Diego Villa, Paula Silverman, Puneet S Cheema, Dennis F Moore, George W Sledge\",\"doi\":\"10.1007/s10549-024-07519-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>In tamoxifen-treated individuals, reduced-function genetic variants in the CYP2D6 gene or inhibition of the enzyme result in low circulating endoxifen concentrations. 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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).</p><p><strong>Conclusion: </strong>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.</p><p><strong>Trial id: </strong>NCT01124695 (registered May 14, 2010).</p>\",\"PeriodicalId\":9133,\"journal\":{\"name\":\"Breast Cancer Research and Treatment\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.0000,\"publicationDate\":\"2024-10-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Breast Cancer Research and Treatment\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s10549-024-07519-z\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Breast Cancer Research and Treatment","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10549-024-07519-z","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
目的：在接受他莫昔芬治疗的个体中，CYP2D6基因的功能降低或该酶受到抑制会导致循环中的内奥昔芬浓度较低。我们评估了CYP2D6活性降低和循环中内奥昔芬浓度降低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，每天接受开放标签他莫昔芬 20 毫克（PO）。主要目的是评估CYP2D6不良代谢者（PM）与中间和正常代谢者状态（IM + NM）与无进展生存期（PFS）的关系。CYP2D6表型由全血样本（Roche Amplichip）测定，次要终点评估由注册后3个月的血浆样本（Quest Diagnostics）测定的内奥昔芬浓度：2010年9月至2013年6月，在计划的204名患者中，有113人登记参加试验并开始接受方案治疗。由于CYP2D6代谢不良者的比例低于预期，试验提前结束。中位年龄为 62 岁，86%（97/113）为白人，33%（30/113）为西班牙裔，83%（92/113）为绝经后患者。75%（85/113）的患者样本可进行 CYP2D6 评估（2/85 PM、27/85 IM 和 56/85 NM）。PM 和 IM + NM 的中位 PFS 分别为 12.9 个月和 6.9 个月。低浓度（≤15.5）和高浓度（>15.5）内昔芬患者的中位生存期分别为11.1个月和13.8个月：结论：我们没有观察到CYP2D6代谢物状态或内奥昔芬与PFS之间存在明显的关联。该试验的样本量较小，且无法获得足够的样本，因此无法确定这些标记物与 PFS 之间的关系：NCT01124695（2010年5月14日注册）。
CYP2D6 activity in patients with metastatic breast cancer treated with single agent tamoxifen: results from ECOG-ACRIN E3108.
Purpose: 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 and methods: 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).
Results: 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).
Conclusion: 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.
期刊介绍：
Breast Cancer Research and Treatment provides the surgeon, radiotherapist, medical oncologist, endocrinologist, epidemiologist, immunologist or cell biologist investigating problems in breast cancer a single forum for communication. The journal creates a "market place" for breast cancer topics which cuts across all the usual lines of disciplines, providing a site for presenting pertinent investigations, and for discussing critical questions relevant to the entire field. It seeks to develop a new focus and new perspectives for all those concerned with breast cancer.
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