点击显示 收起
药物基因研究显示，某些基因型的乳癌病患对tamoxifen更有反应；现在，一个模式研究显示，对于有此基因型的停经后乳癌病患，tamoxifen对减少复发风险的效果和芳香族酶抑制剂一样好，或者更好。
此发现有其临床影响，但是专家并不建议每个妇女都进行tamoxifen的基因图；上述论述由密西根大学综合癌症中心乳房肿瘤小组的Daniel Hayes医师在4月29日的美国国家癌症研究院期刊(Journal of the National Cancer Institute)线上版中所发表，即将在5月7日正式出刊。
编辑对布莱根妇女医院达那-法柏癌症研究治疗中心的Rinaa Punglia医师所领衔的此项研究提出看法，他们使用数学方式探究基因型治疗的影响，分析从Breast International Group Trial 1-98 (BIG 1-98)搜集得来的临床资料；此试验在去年发表(J Clin Oncol. 2007;25:486-492)，比较芳香族酶抑制剂和 tamoxifen对雌激素受体阳性乳癌停经妇女的辅助治疗效果。
【药物代谢中所含酵素的基因码】
这个引起讨论的基因是CYP2D6，是tamoxifen代谢酵素cytochrome P450的基因码，约有60%的欧洲后裔是此一基因活性对偶基因的同型合子，称为“野型”，就是此一类型显示对tamoxifen有最佳反应。
在他们的模式中，Punglia医师等人指出，此一基因型的妇女使用tamoxifen的结果和使用芳香族酶抑制剂者类似或更佳；研究者指出，此一发现不同于未经筛选的族群结果，在这之中，芳香族酶抑制剂对改善无病存活方面优于tamoxifen；他们认为，妇女关心芳香族酶抑制剂的相对毒性或者花费，也考虑接受基因测试；如果她们发现有CYP2D6野型，即可以继续用 tamoxifen治疗。
编辑指出，许多研究显示，在停经后妇女中，芳香族酶抑制剂一般比tamoxifen更有效，这些药物被专家“热切赞同”；不过，此模式显示，有野型基因型的妇女大部分(90%) 使用tamoxifen的效果都比芳香族酶抑制剂好，对他们来说，tamoxifen 会是较佳选择；此模式建议，有此一基因异型合子的妇女对tamoxifen的反应较不好，她们必须使用芳香族酶抑制剂治疗。
不过，编辑指出，此模式是根据基因型影响tamoxifen效果的单一研究，其他研究报告的结果略有不同；他们写道，因为这个不确定性，我们不建议对所有考虑使用tamoxifen的病患进行CYP2D6基因图筛检。
不过，此一研究已经造成临床影响；编辑指出，至少，服用tamoxifen的妇女应尽可能避免同时使用抑制 CYP2D6 活性的药物；讽刺的是，有些CYP2D6最强的抑制剂是选择性血清素再回收抑制剂，如fluoxetine和 paroxetine，通常用于治疗热潮红；如果妇女服用tamoxifen，最好改用其他药物，如选择性血清素和正肾上腺素抑制剂 venlafaxine，这些不会抑制CYP2DR，而且对治疗热潮红同样有效。
编辑认为，我们相信这些研究将药物基因学带入临床医师照护乳癌病患的领域；但是，他们指出，一如所有的肿瘤标记研究，早期研究通常相当正面，而这些研究需要的是严谨的确认。
Tamoxifen More Effective in Br
By Zosia Chustecka
Medscape Medical News
Pharmacogenetic studies have already shown that women with a certain genotype have a better response to tamoxifen. Now, a modeling study has shown that for postmenopausal breast cancer patients with this genotype, tamoxifen is as good or better at reducing the risk for relapse as aromatase inhibitors.
This finding does have clinical implications, but routine genotyping for all women considering tamoxifen is not recommended as yet, say experts. This opinion comes from Daniel Hayes, MD, from the breast oncology program at the University of Michigan Comprehensive Cancer Center in Ann Arbor, and colleagues in an editorial published online April 29 in the Journal of the National Cancer Institute, and scheduled for print in the May 7 issue.
The editorialists were commenting on the results of an accompanying study, headed by Rinaa Punglia, MD, MPH, from the Dana-Farber Cancer Institute at Brigham and Women's Hospital, in Boston, Massachusetts. They used a mathematical model to explore how genotype information affects therapy recommendations, analyzing clinical data collected in the Breast International Group Trial 1-98 (BIG 1-98). This trial, published last year (J Clin Oncol. 2007;25:486-492), compared an aromatase inhibitor with tamoxifen in the adjuvant setting in postmenopausal women with estrogen-receptor-positive breast cancer.
Gene Codes for Enzyme Involved in Drug Metabolism
The gene in question is CYP2D6, which codes for a cytochrome P450 enzyme involved in tamoxifen's metabolism. About 60% of individuals of European descent are homozygous for the active alleles of this gene, known as "wild type," and it is this group that shows the best response to tamoxifen.
In their model, Dr. Punglia and colleagues showed that women with this genotype had an outcome with tamoxifen that was similar or superior to the outcome seen with aromatase inhibitors. "This finding differs from the results in unselected populations, in which aromatase inhibitors have demonstrated statistically significant improvements in disease-free survival over tamoxifen," the researchers point out. They suggest that women who are concerned about the relative toxicity or cost of an aromatase inhibitor consider undergoing genetic testing; if they are found to be wild type for CYP2D6, they could then pursue treatment with tamoxifen.
Several studies have shown that in postmenopausal women, aromatase inhibitors are generally more effective than tamoxifen, the editorialists comment, and these drugs have been "enthusiastically endorsed" by experts. However, this model suggests that the majority of women (90%) with the wild-type genotype have better outcomes with tamoxifen than with an aromatase inhibitor and, for them, tamoxifen would be the preferred choice, they point out. The model also suggests that women who are heterozygous for this gene respond less well to tamoxifen, and so they should be treated with an aromatase inhibitor.
However, the editorialists note, this model is based on a single study of the genotype influencing response to tamoxifen; other studies have reported slightly different results. "Because of this uncertainty...we do not recommend routine CYP2D6 genotyping for all patients who are considering tamoxifen," they write.
Nevertheless, there are already clinical implications from this research. "At the least," the editorialists comment, "women who are taking tamoxifen should avoid the concomitant use of drugs that inhibit CYP2D6 activity if possible." Ironically, some of the most potent inhibitors of CYP2D6 are the selective serotonin reuptake inhibitors, such as fluoxetine and paroxetine, which are frequently used for the treatment of hot flashes. In women taking tamoxifen, it would be preferable to use another drug, for example the selective serotonin and norepinephrine inhibitor venlafaxine, which does not inhibit CYP2DR but is quite effective in the treatment of hot flashes, they add.
"We believe that these studies have brought the field of pharmacogenetics onto the radar screen of clinicians caring for breast cancer patients," the editorialists comment. But they add that, "as with all tumor-marker research, early studies are often quite positive and rigorous validation of these results is critical."
J Natl Cancer Inst. 2008;100:642-648 and 610-613.