图片来源：medicalxpress.com
抗激素疗法他莫昔芬可以降低将近一半激素敏感性乳腺癌患者的癌症复发率，但这种疗法却仅对部分女性有效，研究人员并不清楚原因为何。近日，来自密歇根州立大学的研究人员Daniel L. Hertz表示，我们知道某些肿瘤由于产生了遗传突变，所以会对他莫昔芬产生固有的耐药性。
这些肿瘤会寻找到特殊途径来克服抗雌激素的疗法，但研究人员认为某些患者并不会因他莫昔芬或内分泌疗法而获益较多，这或许取决于肿瘤的遗传突变。目前有一种理论认为，在某些患者中，他莫昔芬并不能激活患者机体潜在的雌激素抑制物Endoxifen，而机体中Endoxifen水平较低的患者往往也会因为他莫昔芬的治疗而预后表现较差。
一项来自国际他莫昔芬的遗传药理学研究团队进行了一项对遗传变异的综合分析，研究人员发现，携带CYP2D6基因特定突变的病人或许生存率较差，而随后的临床试验分析并没有发现相同的关联。如今研究人员通过分析此前的研究评估了是否基因分型的错误，即遗传突变的发生可以帮助说明问题所在，原始综合分析中的统计学差异归咎于基因分型的错误，但研究者的二次分析结果表明，统计学的差异和来自多个研究团体招募的病人直接相关，而不是和基因分型错误直接相关。
随后研究者Hertz及其同事利用高级的统计学模型进行研究证实了，基因分型错误或许可以将可忽略的偏差引入到预期试验的分析中；而预期试验中来自肿瘤的基因分型或许并不是分析结果阴性的原因，而某些研究认为CYP2D6或许可以作为假阳性的标志物。研究者进行的另一项研究中，他们发现，CYP2D6和CYP2C9基因的突变或许会促进endoxifen的暴露，而这或许并不是预测是否他莫昔芬发挥作用的单一标志物。
基于这一点，研究人员认为基因分型和其效率之间存在一定的假设性关联，而截止到目前为止，研究人员利用CYP2D6来进行他莫昔芬疗法的选择并未获得临床效益，而后期研究中他们将需要对此进行证实。
推荐的新闻阅读：
Why does tamoxifen work better in some women?
The anti-hormone therapy tamoxifen can reduce breast cancer recurrence by about half in women with hormone-sensitive breast cancer. But it works better in some women than others. Researchers are not sure why.
"We do know that some tumors are inherently resistant to tamoxifen because of tumor genetic changes," says Daniel L. Hertz, Pharm.D., Ph.D., an assistant professor in the University of Michigan College of Pharmacy and member of the U-M Comprehensive Cancer Center.
"These tumor have found pathways to overcome anti-estrogen treatment. But we also believe some patients may be less likely to benefit from tamoxifen or endocrine therapy because of their genetics," Hertz says.
One theory is that in some patients, tamoxifen is not activated to the more potent estrogen inhibitor endoxifen. Patients with low levels of endoxifen may have worse outcomes on tamoxifen.
A meta-analysis by the International Tamoxifen Pharmacogenetics Consortium points to genetic variants. Researchers found patients with certain variants on the gene CYP2D6 had worse survival. Later analyses of prospective clinical trials, however, did not find the same link.
New research presented by Hertz at the San Antonio Breast Cancer Symposium examined these prior studies to assess whether errors in genotyping - how they identify the genetic variants - could have accounted for the differing findings. Statistical deviations seen in the original meta-analysis had been attributed to genotyping error. But their secondary analysis revealed that statistical deviations were linked to enrolling patients from multiple institutions, not genotyping error.
Furthermore, advanced statistical modeling from Hertz and colleagues confirms that genotyping error would introduce negligible bias to the analyses of the prospective trials.
"Genotyping from the tumor in these prospective clinical trials is not the reason these analyses are negative," Hertz says. "Either there is some other reason that the later studies were negative or the initial study suggesting CYP2D6 as a marker was falsely positive."
This leaves more questions than answers about tamoxifen efficacy.
In another study presented in San Antonio, Hertz and colleagues found that variants in CYP2D6 and another gene, CYP2C9, contribute to endoxifen exposure. Hertz suggests that it may not be one single marker that predicts whether tamoxifen works.
"At this point we still have a hypothetical association between genotype and efficacy that has not been validated," he says. "For now, there is no clinical benefit to using CYP2D6 to inform tamoxifen treatment decisions. We need to validate these hypotheses."