|
肝臟細(xì)胞色素P450酶2D6是由CYP2D6基因編碼的代謝酶，參與大約四分之一臨床藥物的代謝，可將最常用的乳腺癌雌激素受體調(diào)節(jié)劑他莫昔芬（舊稱三苯氧胺）代謝為安多昔芬而發(fā)揮作用。對(duì)于服用他莫昔芬的乳腺癌患者，不同的CYP2D6基因型可能引起安多昔芬濃度不同。不過(guò)，對(duì)于CYP2D6基因型能否指導(dǎo)雌激素受體陽(yáng)性乳腺癌患者他莫昔芬治療劑量，既往研究結(jié)果大多來(lái)自回顧分析，目前仍然存在爭(zhēng)議，尤其對(duì)于東方女性。 2019年12月10日，美國(guó)臨床腫瘤學(xué)會(huì)《臨床腫瘤學(xué)雜志》在線發(fā)表日本國(guó)家癌癥中心醫(yī)院、慶應(yīng)義塾大學(xué)、虎之門醫(yī)院、福島醫(yī)科大學(xué)、橫濱市立大學(xué)、北海道癌癥中心、近畿大學(xué)、昭和大學(xué)、熊本神道綜合醫(yī)院、東京西德州會(huì)醫(yī)院、圣隸佐倉(cāng)市民醫(yī)院、橫濱理化學(xué)研究所生命醫(yī)學(xué)研究中心、美國(guó)德克薩斯大學(xué)MD安德森癌癥中心的TARGET-1研究報(bào)告，前瞻評(píng)估了CYP2D6基因型指導(dǎo)雌激素受體陽(yáng)性晚期乳腺癌患者他莫昔芬治療劑量能否影響臨床結(jié)局。 該多中心非盲隨機(jī)對(duì)照二期臨床研究于2012年12月～2016年7月從日本54家醫(yī)院入組雌激素受體陽(yáng)性HER2陰性晚期乳腺癌需要他莫昔芬一線治療女性患者186例，進(jìn)行CYP2D6基因分型，其中136例患者攜帶等位基因功能降低或喪失的野生型/變異型雜合子或變異型/變異型純合子、48例患者攜帶等位基因功能正常的野生型/野生型純合子。將野生型/變異型或變異/變異型患者按1∶1隨機(jī)分入兩組：他莫昔芬每天40毫克增加劑量組70例或每天20毫克常規(guī)劑量組66例；野生型/野生型純合子患者每天20毫克。主要研究終點(diǎn)為6個(gè)月時(shí)無(wú)進(jìn)展生存率。次要研究終點(diǎn)包括無(wú)進(jìn)展生存時(shí)間、順式安多昔芬濃度與臨床結(jié)局的關(guān)系。 結(jié)果，6個(gè)月時(shí)，增加劑量組與常規(guī)劑量組的患者相比，無(wú)進(jìn)展生存率相似（67.6%比66.7%）。 增加劑量組與常規(guī)劑量組的患者相比，順式安多昔芬的血清谷濃度顯著較高（中位：89.2nM比51.1nM，P<0.0001），也高于野生型/野生型純合子患者（72.0nM，P=0.045）。 6個(gè)月時(shí)，疾病進(jìn)展與未進(jìn)展的患者相比，順式安多昔芬濃度相似（P=0.43）。 因此，該研究結(jié)果表明，對(duì)于CYP2D6等位基因變異的雌雌激素受體陽(yáng)性晚期乳腺癌患者，增加他莫昔芬治療劑量6個(gè)月時(shí)，無(wú)進(jìn)展生存率并未顯著提高。他莫昔芬療效個(gè)體差異無(wú)法單純根據(jù)CYP2D6基因型解釋。 相關(guān)閱讀 J Clin Oncol. 2019 Dec 10. [Epub ahead of print] CYP2D6 Genotype-Guided Tamoxifen Dosing in Hormone Receptor-Positive Metastatic Breast Cancer (TARGET-1): A Randomized, Open-Label, Phase II Study. Tamura K, Imamura CK, Takano T, Saji S, Yamanaka T, Yonemori K, Takahashi M, Tsurutani J,, Nishimura R, Sato K, Kitani A, Ueno NT, Mushiroda T, Kubo M, Fujiwara Y, Tanigawara Y. National Cancer Center Hospital, Tokyo, Japan; Keio University School of Medicine, Tokyo, Japan; Toranomon Hospital, Tokyo, Japan; Fukushima Medical University, Fukushima, Japan; Yokohama City University School of Medicine, Yokohama, Japan; National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan; Kindai University, Osaka, Japan; Showa University, Tokyo, Japan; Kumamoto Shinto General Hospital, Kumamoto, Japan; Tokyo-West Tokushukai Hospital, Tokyo, Japan; Seirei Sakura Citizen Hospital, Chiba, Japan; The University of Texas MD Anderson Cancer Center, Houston, TX; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. PURPOSE: In patients taking tamoxifen, the CYP2D6 genotype causes different exposure of active metabolite endoxifen. The objective of this randomized, open-label, multicenter, phase II study was to prospectively evaluate whether CYP2D6 genotype-guided tamoxifen dosing in patients with hormone receptor-positive metastatic breast cancer could have an impact on the clinical outcome. METHODS: Patients who needed first-line tamoxifen therapy were enrolled. Based on individual CYP2D6 genotype, patients heterozygous (wild type [wt]/variant [V]) or homozygous (V/V) for variant alleles of decreased or no function were randomly assigned to receive tamoxifen at an increased dose (ID arm; 40 mg daily) or regular dose (RD arm; 20 mg daily), and patients homozygous for wild-type alleles (wt/wt) received tamoxifen at 20 mg daily. The primary endpoint was the progression-free survival (PFS) rate at 6 months. The secondary endpoints included PFS and correlation of Z-endoxifen concentration with clinical outcomes. RESULTS: Between December 2012 and July 2016, 186 patients were enrolled in Japan. Of 184 evaluable patients, 136 carried wt/V or V/V (ID arm, 70; RD arm, 66), and 48 carried wt/wt. PFS rates at 6 months were not significantly different between the ID and RD arms (67.6% v 66.7%). The serum trough concentrations of Z-endoxifen in the ID arm were significantly higher than those in the RD arm (median, 89.2 nM v 51.1 nM; P < .0001) and were also higher compared with wt/wt patients (72.0 nM; P = .045). No significant difference in Z-endoxifen concentrations was observed between patients with disease progression and those who were progression free at 6 months (P = .43). CONCLUSION: In patients with CYP2D6-variant alleles, increasing tamoxifen dosing did not achieve a higher PFS rate at 6 months. The CYP2D6 genotype solely cannot explain individual variability in the efficacy of tamoxifen. PMID: 31821071 DOI: 10.1200/JCO.19.01412
|
|
|
