他莫昔芬屬于選擇性雌激素受體調(diào)節(jié)劑，自1967年起被廣泛用于雌激素受體陽性乳腺癌患者的內(nèi)分泌治療，已被世界衛(wèi)生組織列入基本藥物標(biāo)準(zhǔn)清單。他莫昔芬必須通過肝臟細(xì)胞色素酶P450代謝，才能轉(zhuǎn)化為活性代謝產(chǎn)物安多昔芬（N-去甲基-4-羥基他莫昔芬）產(chǎn)生較強(qiáng)抗雌激素作用。細(xì)胞色素酶CYP2D6是P450代謝所需重要氧化代謝酶，更是他莫昔芬起效的關(guān)鍵因素。既往研究表明，他莫昔芬耐藥很大程度與CYP2D6基因突變相關(guān)。根據(jù)推測(cè)，安多昔芬濃度與CYP2D6基因分析相比，更能預(yù)測(cè)他莫昔芬的療效。雖然回顧研究描述了安多昔芬的有效性臨界值為5.9ng/mL，但是缺乏前瞻研究確認(rèn)。
2019年1月24日，美國臨床腫瘤學(xué)會(huì)《臨床腫瘤學(xué)雜志》在線發(fā)表荷蘭萊頓大學(xué)醫(yī)療中心、萊頓醫(yī)院、荷蘭癌癥研究所、阿姆斯特丹列文虎克醫(yī)院、賴尼爾伯爵醫(yī)院、阿爾克馬爾醫(yī)療中心、贊瑟斯醫(yī)療中心、萊德多普醫(yī)院、圣安東尼斯醫(yī)院、比利時(shí)魯汶大學(xué)、魯汶大學(xué)醫(yī)院的前瞻研究報(bào)告，分析了安多昔芬濃度和CYP2D6基因型與他莫昔芬治療早期乳腺癌患者的生存結(jié)局。
該多中心前瞻研究（CYPTAM，荷蘭全國研究登記編號(hào)：NTR1509）于2008年2月～2010年12月從荷蘭和比利時(shí)入組絕經(jīng)前和絕經(jīng)后早期乳腺癌術(shù)后他莫昔芬輔助治療≤12個(gè)月的患者667例，通過基因擴(kuò)增芯片和高效液相色譜串聯(lián)質(zhì)譜分別測(cè)定血液標(biāo)本的CYP2D6基因型和安多昔芬濃度。將安多昔芬濃度作為連續(xù)變量進(jìn)行分析，按四分位對(duì)患者進(jìn)行分組，并將5.9ng/mL作為安多昔芬的臨界值。通過多因素比例風(fēng)險(xiǎn)回歸模型，對(duì)安多昔芬濃度、CYP2D6基因型與無復(fù)發(fā)生存（截至他莫昔芬停藥時(shí)）之間的相關(guān)性進(jìn)行分析。
結(jié)果，研究入組前接受他莫昔芬輔助治療的中位時(shí)間為0.37年（范圍：0.23～0.6年），中位隨訪6.4年（范圍：0.10～9.30年）。
安多昔芬濃度與無復(fù)發(fā)生存時(shí)間之間無顯著相關(guān)性（校正風(fēng)險(xiǎn)比：0.991，95%置信區(qū)間：0.946～1.038，P=0.691）。此外，無論按安多昔芬濃度四分位還是按5.9ng/mL臨界值進(jìn)行分析，結(jié)果均無顯著相關(guān)性。
代謝酶基因型與無復(fù)發(fā)生存時(shí)間之間無顯著相關(guān)性（校正風(fēng)險(xiǎn)比：0.929，95%置信區(qū)間：0.525～1.642，P=0.799）。
因此，該前瞻臨床研究結(jié)果表明，對(duì)于接受他莫昔芬輔助治療的早期乳腺癌患者，安多昔芬濃度或CYP2D6基因型與臨床結(jié)局無關(guān)。
對(duì)此，美國霍普金斯大學(xué)醫(yī)學(xué)院腫瘤學(xué)教授葳蕤德·斯登斯發(fā)表錄音訪談：他莫昔芬治療女性檢測(cè)恩多昔芬代謝產(chǎn)物和CYP2D6基因型的終結(jié)？
The End of ENDoxifen Metabolite and CYP2D6 Testing in Tamoxifen-Treated Women? By Vered Stearns.
相關(guān)閱讀
J Clin Oncol. 2019 Jan 24. [Epub ahead of print]
Tamoxifen Pharmacogenetics and Metabolism: Results From the Prospective CYPTAM Study.
Sanchez-Spitman A, Dezentjé V, Swen J, Moes DJAR, Bohringer S, Batman E, van Druten E, Smorenburg C, van Bochove A, Zeillemaker A, Jongen L, Los M, Neven P, Gelderblom H, Guchelaar HJ.
Leiden University Medical Center, Leiden, the Netherlands; Netherlands Cancer Institute/Antoni van Leeuwenhoek, Amsterdam, the Netherlands; Alrijne Leiden, Leiden, the Netherlands; Reinier de Graaf Gasthuis, Delft, the Netherlands; Medical Center Alkmaar, Alkmaar, the Netherlands; Zaans Medisch Centrum, Zaandam, the Netherlands; Alrijne Leiderdorp, Leiderdorp, the Netherlands; Katholieke Universiteit Leuven, Leuven, Belgium; St Antonius Ziekenhuis, Nieuwegein, the Netherlands; University Hospitals Leuven, Leuven, Belgium.
PURPOSE: Tamoxifen is widely prescribed as adjuvant therapy in patients with early-stage breast cancer. It has been postulated that concentrations of endoxifen, the active metabolite of tamoxifen, are a better predictor of tamoxifen efficacy than CYP2D6 genotypes. Although in a retrospective study, an endoxifen threshold of 5.9 ng/mL for efficacy was described, confirmation based on prospective studies is lacking. The objective of the prospective CYPTAM (The Netherlands National Trial Register: NTR1509) study was to associate endoxifen concentrations and CYP2D6 genotypes with clinical outcome in patients with early-stage breast cancer receiving tamoxifen.
PATIENTS AND METHODS: From February 2008 to December 2010, patients with breast cancer treated with adjuvant tamoxifen were included. Patients could be enrolled up to a maximum of 12 months after tamoxifen initiation. Blood samples were retrieved for CYP2D6 genotyping and endoxifen measurements by Amplichip (Roche Diagnostics, Indianapolis, IN) and high-performance liquid chromatography-tandem mass spectrometry, respectively. Endoxifen concentrations were analyzed as a continuous variable, classifying patients into quartiles and using an endoxifen threshold of 5.9 ng/mL. Endoxifen concentrations and CYP2D6 genotypes were associated with relapse-free survival (censored at the time of tamoxifen discontinuation; RFSt) by Cox regression analysis.
RESULTS: A total of 667 pre- and postmenopausal patients were enrolled and had received tamoxifen for a median time of 0.37 years (range, 0.23 to 0.6 years) before study entry. No association was found between endoxifen concentrations and RFSt (adjusted hazard ratio, 0.991; 95% CI, 0.946 to 1.038; P = .691). Also, neither categorizing endoxifen concentrations into quartiles nor using 5.9 ng/mL as threshold altered these results. In addition, no association was found between CYP2D6 genotype and RFSt (adjusted hazard ratio, 0.929; 95% CI, 0.525 to 1.642; P = .799).
CONCLUSION: This prospective clinical study shows no association between endoxifen concentrations or CYP2D6 genotypes and clinical outcome in patients with early-stage breast cancer receiving adjuvant tamoxifen.
PMID: 30676859
DOI: 10.1200/JCO.18.00307
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