作者：Zosia Chustecka
出處：WebMD醫學新聞
December 18, 2008 (德州聖安東尼奧) — 明尼蘇達羅契斯特市梅約診所的研究者建議，所有雌激素受體陽性乳癌之停經婦女且考慮使用tamoxifen作為輔助治療者，需接受基因檢測，以辨識出哪些患者對該藥物沒有反應；不過，一名專家認為此檢測仍有爭議。
該檢測辨識CYP2D6基因有遺傳缺陷的婦女，該基因與將tamoxifen分解成活性代謝物的酵素有關，缺乏此基因的婦女對於tamoxifen的代謝不佳，因而無法對此藥物有良好反應；聖安東尼奧乳癌研討會第31屆年會中發表的新資料顯示，這一類婦女有較大的復發風險。
這個新資料來自Austrian Breast and Colorectal Study Group-8 (ABCSG-8)試驗的次組病患分析，該試驗發表於2005年，包括了將近3,900名雌激素受體陽性乳癌之停經婦女，隨機分組於術後接受五年的 tamoxifen、或者接受兩年 tamoxifen之後改用芳香胺酶抑制劑 anastrozole (Arimidex，阿斯特捷利康藥廠製造)三年。
五年之後，相較於有廣泛代謝者，在隨機分組接受tamoxifen者中，代謝不佳的婦女復發乳癌風險增加3.8倍。
該分析也顯示，代謝不佳的婦女中，轉換成anastrozole者在第三至五年的復發風險沒有增加；主要研究者、梅約診所腫瘤與藥理助理教授Matthew Goetz醫師表示，最初兩年的tamoxifen療程中有幸未發生乳癌復發的代謝不佳者 ，可以用anastrozole獲得更大助益。
Goetz醫師在聲明中表示，這些新結果確認了我們稍早的發現，他們強烈認為，未來，停經婦女考慮進行tamoxifen治療者，應在開始治療前檢測CYP2D6 。
【對該檢測有些爭議】
該檢測方式已經上市，但是它目前未被大多數醫學中心常規運用。
未參與此研究的Vermont癌症中心醫師Hyman Muss表示，對於該檢測有些爭論；有些研究顯示 tamoxifen代謝不佳之婦女，或者代謝程度中等者，效果和tamoxifen代謝正常或者廣泛代謝者不一樣 —Goetz 醫師是此領域中的領導者。
他指出，其他研究未確認這點。
如果不論這些不確定性，Muss醫師向Medscape Oncology表示，在與病患討論之後，且得到病患同意時，他樂意使用此檢測。
Muss醫師表示，約有5%至10%的白人婦女屬於代謝不佳者，大約有30%婦女屬中度代謝者；他指出，如果資料正確，這些婦女對於tamoxifen會反應不佳。
Muss醫師解釋，使用該檢測可確認這類婦女，並讓醫師提供其他適當療法；舉例來說，對一名停經婦女，你可以使用芳香胺酶抑制劑或者其他類似tamoxifen的藥物，如 toremifene。對於未停經的婦女，你可以考慮卵巢抑制或者其他[選擇性雌激素受體調節劑]，不過，這些的檢測都沒像tamoxifen那麼廣泛。
Muss醫師表示，即使最後證明這些都錯了，你也不會有傷害；但是如果證明它是重要的，你就是做了正確選擇，因為其他5%至10%的婦女就未獲得適當的治療，那些婦女服用tamoxifen但未能因此獲益。此外，這些代謝不佳的婦女比較不會發生治療副作用，她們可能會告訴醫師她們對tamoxifen耐受良好，所以她們會繼續服用，但卻無法獲得治療利益。
Muss醫師表示，因此我對於使用此檢測有所議論— 如果它最後證明不重要，我不會因為將病患改用其他適當替代療法而有任何損失，但是如果證明它是對的，而我未用該檢測，那麼就是我治療的10%的病患都沒有效。
ABCSG-8 試驗接受阿斯特捷利康藥廠贊助，梅約診所在CYP2D6技術上有財務利益，可能可以從該研究的成功結果獲利；Goetz醫師宣稱沒有相關資金上的往來。Muss醫師表示擔任輝瑞、Genentech、Amgen、羅氏、Bristol-Myers Squibb與Tragara等藥廠的顧問；接受 阿斯特捷利康藥廠、輝瑞、葛蘭素史克、Genentech與諾華藥廠的研究資金。
聖安東尼奧乳癌研討會第31屆年會：摘要57。發表於2008年12月13日。
SABCS 2008: Gene Test Identifies Poor Responders to Tamoxifen
By Zosia Chustecka
Medscape Medical News
December 18, 2008 (San Antonio, Texas) — Researchers from the Mayo Clinic, in Rochester, Minnesota, are recommending that allpostmenopausal women with estrogen-receptor-positive breast cancer for whom tamoxifen is being considered as an adjuvant therapy undergo a gene test that can pinpoint those who will not respond to the drug. However, this test is controversial, one expert commented.
The test identifies women who have an inherited deficiency in the CYP2D6 gene, which codes for an enzyme that breaks tamoxifen down into its active metabolites. Women deficient in this gene are poor metabolizers of tamoxifen and do not respond well to the drug. New data reported here at the 31st Annual San Antonio Breast Cancer Symposium show that such women are at greater risk of developing relapses.
The new data come from an analysis of a subgroup of patients who took part in the Austrian Breast and Colorectal Study Group-8 (ABCSG-8) trial. This trial, reported in 2005, involved nearly 3900 postmenopausal women with estrogen-receptor-positive breast cancer who were randomized to either tamoxifen for 5 years after surgery or to tamoxifen for 2 years and then the aromatase inhibitor anastrozole (Arimidex, AstraZeneca) for 3 years.
Among the patients randomized to tamoxifen, women who were poor metabolizers had a 3.8-fold increased risk of developing breast cancer recurrence, compared with women who were extensive metabolizers, across the 5-year period.
The analysis also showed that in women who were poor metabolizers and who switched from tamoxifen to anastrozole, there was no increase in risk for recurrence during years 3 to 5. "Poor metabolizers who were fortunate to not develop breast cancer recurrence in the first 2 years of tamoxifen appear to be rescued by anastrozole," commented lead researcher, Matthew Goetz, MD, assistant professor of oncology and pharmacology at the Mayo Clinic.
"These new results validate our earlier findings," Dr. Goetz said in a statement, "and they strongly suggest that, going forward, postmenopausal women being considered for tamoxifen therapy be tested for CYP2D6 before beginning therapy."
Some Controversy Over the Test
The test is commercially available, but it is not currently being used on a routine basis at most medical centers.
"There is some controversy over this test," commented Hyman Muss, MD, from the Vermont Cancer Center, in Burlington, who was not involved in the research. "Some studies — and Dr. Goetz is a leader in this field — have shown that women who are poor metabolizers, or maybe even intermediate metabolizers, of tamoxifen do not do as well as women who are normal or extensive metabolizers of tamoxifen," Dr. Muss commented.
"However, other studies have not confirmed this," he pointed out.
Despite this uncertainty, Dr. Muss told Medscape Oncology that he is in favor of using the test, after discussing it with the patient, and if the patient agrees.
About 5% to 10% of white women are poor metabolizers and probably about 30% of women are intermediate metabolizers, Dr. Muss said. "These are the women — if the data are correct — who would not respond well to tamoxifen," he added.
Dr. Muss explained that using the test would identify such women and allow the physician to offer an alternative but appropriate treatment. "For example, in a postmenopausal woman, you could use an aromatase inhibitor or another drug like tamoxifen, such as toremifene," he commented. "In a premenopausal woman, you could consider ovarian suppression or possibly another [selective estrogen-receptor modulator], although nothing has been tested as extensively as tamoxifen," he added.
Even if it turns out that this is all wrong, you have done no harm.
"Even it turns out that this is all wrong, you have done no harm," Dr. Muss said. "But if it turns out that this is important, then you have done some good, because otherwise 5% to 10% of women would not have been treated appropriately." Those women would have been taking tamoxifen without benefiting from it. "But also, these women who are poor metabolizers are less likely to suffer from side effects of the treatment, so they will be telling their doctor how well they are doing on tamoxifen," he said. They tolerate the drug well, and so they continue on it, but they are not getting any benefit from it, he pointed out.
"That is why I would argue in favor of using this test — if it turns out not to be important, I haven't loss anything by changing my patients to alternative effective options, but if it turns out to be true, and I don't use the test, then I will have been treating 10% of my patients with a drug that doesn't work," Dr. Muss said.
The ABCSG-8 trial was sponsored by AstraZeneca. The Mayo Clinic has a potential financial interest in the CYP2D6 technology, and may stand to gain financially from the successful outcome of this research. Dr. Goetz has disclosed no relevant financial relationships. Dr. Muss reported acting as a consultant for Pfizer, Genentech, Amgen, Roche, Bristol-Myers Squibb, and Tragara; and receiving research funding from AstraZeneca, Pfizer, GlaxoSmithKline, Genentech, and Novartis.
31st Annual San Antonio Breast Cancer Symposium (SABCS): Abstract 57. Presented December 13, 2008.
[ 本帖最後由 goodcat1111 於 2008-12-30 15:24 編輯 ] |
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