DeCensi Andrea, Johansson Harriet, Helland Thomas, Puntoni Matteo, Macis Debora, Aristarco Valentina, Caviglia Silvia, Webber Tania Buttiron, Briata Irene Maria, D'Amico Mauro, Serrano Davide, Guerrieri-Gonzaga Aliana, Bifulco Ersilia, Hustad Steinar, Søiland Håvard, Boni Luca, Bonanni Bernardo, Mellgren Gunnar
Division of Medical Oncology, E.O. Galliera Hospital, Genoa, Italy.
Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy.
NPJ Breast Cancer. 2021 Mar 25;7(1):34. doi: 10.1038/s41523-021-00236-6.
Low-dose tamoxifen halves recurrence in non-invasive breast cancer without significant adverse events. Some adjuvant trials with tamoxifen 20 mg/day had shown an association between low endoxifen levels (9-16 nM) and recurrence, but no association with CYP2D6 was shown in the NSABP P1 and P2 prevention trials. We studied the association of CYP2D6 genotype and tamoxifen metabolites with tumor biomarkers and recurrence in a randomized phase III trial of low-dose tamoxifen. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3-11.4) in patients who recurred vs 7.5 (5.1-10.2) in those who did not recur (p = 0.60). Tamoxifen and metabolites significantly decreased C-reactive protein (CRP, p < 0.05), and a CRP increase after 3 years was associated with higher risk of recurrence (HR = 4.37, 95% CI, 1.14-16.73, P = 0.03). In conclusion, endoxifen is below 9 nM in most subjects treated with 5 mg/day despite strong efficacy and there is no association with recurrence, suggesting that the reason for tamoxifen failure is not poor drug metabolism. Trial registration: ClinicalTrials.gov, Identifier: NCT01357772 .
低剂量他莫昔芬可使非浸润性乳腺癌的复发率减半，且无明显不良事件。一些关于每日20毫克他莫昔芬的辅助试验表明，内氧苯水平低（9 - 16纳摩尔）与复发之间存在关联，但在NSABP P1和P2预防试验中未显示与CYP2D6有关联。我们在一项低剂量他莫昔芬的随机III期试验中研究了CYP2D6基因型和他莫昔芬代谢物与肿瘤生物标志物及复发之间的关联。复发患者第1年的内氧苯水平中位数（IQR）为8.4（5.3 - 11.4），未复发患者为7.5（5.1 - 10.2）（p = 0.60）。他莫昔芬及其代谢物显著降低C反应蛋白（CRP，p < 0.05），3年后CRP升高与更高的复发风险相关（HR = 4.37，95% CI，1.14 - 16.73，P = 0.03）。总之，尽管疗效显著，但大多数接受每日5毫克治疗的患者内氧苯水平低于9纳摩尔，且与复发无关，这表明他莫昔芬治疗失败的原因并非药物代谢不良。试验注册：ClinicalTrials.gov，标识符：NCT01357772 。
