作者：Roxanne Nelson 齣處：WebMD醫學新聞 　　October 22, 2008 —KRAS基因的突變狀態 與化療失敗後接受cetuximab(Erbitux 大腸直腸癌的KRAS突變可以用來預測對Cetuximab的反應 - 趣味新聞網

發表日期 2008-11-01T06:53:12+08:00

     作者：Roxanne Nelson
齣處：WebMD醫學新聞

October 22, 2008 —KRAS基因的突變狀態，與化療失敗後接受cetuximab(Erbitux，Bristol-Myers Squibb, ImClone Systems)治療的末期大腸直腸癌患者的整體存活有關；研究者在10月23日的新英格蘭醫學期刊報告指齣，cetuximab的活性好處侷限於野生型KRAS 腫瘤的病患；有KRAS突變之病患並未發現cetuximab有明顯的存活利益。

主要作者、醫學中心腫瘤科醫師、癌癥照護協調人員Christos S. Karapetis醫師錶示，結果顯示，有KRAS基因突變的腫瘤病患使用cetuximab並無好處；基本上，當和完全沒有活性腫瘤治療相比時，cetuximab對這些病患沒有差異。

Cetuximab是一種單株抗體，直接對抗上皮生長因子受體(EGFR)，顯示齣隻對KRAS基因未突變的腫瘤病患有好處，一如Medscape Oncology之前所報導的；KRAS突變也顯示可以預測類似藥物panitumumab (Vectibix，Amgen)的反應。

Karapetis醫師嚮Medscape Oncology錶示，我們相信這個突變造成cetuximab不活性，因為它讓KRAS蛋白質維持在活性型態；當KRAS突變存在時，它維持在「啓動狀態」，與任何目標在EGFR以提升KRAS的治療無關，因此，KRAS 突變會使cetuximab失效。

他指齣，KRAS突變在大腸直腸癌初期即會發生，我們知道將近40%的腸道癌癥有此突變。

【好處僅限於野生型KRAS 腫瘤】
在這個研究中，Karapetis醫師等人分析KRAS基因的突變狀態是否與末期難治型大腸直腸癌病患的存活有關；在這572名病患中，287人隨機接受cetuximab加上支持照護，其他285人隻有接受支持照護；總共有394個腫瘤樣本(198個來自cetuximab組，196個來自支持照護組)進行KRAS 突變狀態分析。

研究者發現，KRAS突變病患接受cetuximab組的平均整體存活是4.5個月，僅接受支持照護組的平均整體存活是4.6 個月；cetuximab組的1年整體存活率為13.2%，支持照護組為19.6%。

野生型KRAS腫瘤的病患有存活差異；接受cetuximab組的平均整體存活是 9.5個月，僅接受支持照護組的平均整體存活是4.8個月；cetuximab組的1年整體存活率為28.3%，支持照護組為20.1%。

無惡化存活也有類似的結果；在兩個研究組中，KRAS腫瘤突變病患的平均無惡化存活為1.8個月，而野生型KRAS腫瘤的病患，cetuximab組的平均無惡化存活為 3.7個月，僅接受支持照護組則為1.9個月。

野生型KRAS腫瘤病患的反應率，cetuximab組為12.8%，KRAS腫瘤突變的病患隻有1個有反應(1.2%)。

Karapetis醫師錶示，我們知道的證據強烈地支持，在使用cetuximab之前，需確認KRAS突變狀態，cetuximab隻可以給沒有突變的病患。

在一篇編輯評論中，科羅拉多大學癌癥中心的Wells A. Messersmith醫師與丹佛榮民醫學中心的Dennis J. Ahnen醫師指齣，這篇與其他報告傾嚮支持考慮接受抗EGFR治療的大腸直腸癌病患需接受KRAS檢測。

他們寫道，這些試驗的結果已經有重要的成果；歐盟藥物管理局已經核準panitumumab隻可用於治療野生型KRAS腫瘤病患。就我們所知，這是首次根據基因試驗核準某一藥物治療用於實質腫瘤。

國傢癌癥研究中心贊助的10個cetuximab研究將修改以納入KRAS 檢測，雖然目前還沒有食品藥物管理局(FDA)核準的KRAS 突變狀態檢測，但他們指齣，可能很快就會有所改變瞭。

這些大型臨床試驗的資料指齣樣本銀行的價值，即便標記未知，將可後續確認哪些病患可從治療獲益；這些努力可以幫助將昂貴的抗EGFR抗體治療侷限在野生型KRAS大腸直腸癌病患， 將可以節省那些沒有獲益機會患者的數百萬開銷。

不過，他們警告錶示，唯恐EGFR生物學領域變成執迷於將KRAS作為分子標記，應指齣是否接受KRAS檢測者之間的存活差異並不大。

編輯結論錶示，或許後續的分子分析可以獲得其他標記，可以分辨哪些病患可從EGFR標靶抗體獲益，以及可以指齣其他標靶、併用策略等來剋服藥物阻抗性。

此研究接受加拿大國傢癌癥研究中心、 ImClone System與 Bristol-Myers Squibb的贊助；Karapetis醫師報告接受Merck Serono之諮商費用；多位共同作者保告擁有藥廠股票與擔任藥廠員工和/或接受藥廠的資金與顧問費用。詳見文內揭告。

Response to Cetuximab Predicted by KRAS Mutation in Colorectal Cancer

By Roxanne Nelson
Medscape Medical News

October 22, 2008 — The mutation status of the KRAS gene is associated with overall survival in patients with advanced colorectal cancer who receive treatment with cetuximab (Erbitux, Bristol-Myers Squibb, ImClone Systems) after previous chemotherapy has failed. The beneficial activity of cetuximab is confined to patients with wild-type KRAS tumors, researchers report in the October 23 issue of the New England Journal of Medicine; no significant survival benefit was observed with cetuximab in patients with tumors that had KRAS mutations.

"The results demonstrate absence of benefit in using cetuximab for patients with tumors that exhibit mutations in the KRAS gene," said lead author Christos S. Karapetis, MD, a medical oncologist and cancer care coordinator at Flinders Medical Centre, in Bedford Park, Australia. "Basically, cetuximab made no difference in these patients, when compared with no active cancer treatment at all."

Cetuximab, a monoclonal antibody directed against the epidermal growth-factor receptor (EGFR), appears to only benefit patients with tumors that bear unmutated copies of the KRAS gene, as previously reported by Medscape Oncology. KRAS mutations have also been shown to predict the response to a similar drug, panitumumab (Vectibix, Amgen).

"We believe that the mutation renders cetuximab inactive because it leads to the KRAS protein staying in an active form," Dr. Karapetis told Medscape Oncology. "When the KRAS mutation is present, it stays 'switched on,' independent of any treatment that targets the EGFR upstream of KRAS. Thus, the KRAS mutation may render cetuximab useless."

The KRAS mutation appears very early in the development of colorectal cancer, he added. "We know that approximately 40% of bowel cancers have the mutation."

Benefit Limited to Wild-Type KRAS Tumors

In this study, Dr. Karapetis and colleagues assessed whether the mutation status of the KRAS gene was associated with survival in patients with advanced refractory colorectal cancer. Of 572 patients who were included in the cohort, 287 were randomized to receive cetuximab plus supportive care, and the remaining 285 received supportive care alone. A total of 394 tumor specimens (198 from the cetuximab group and 196 from the supportive-care group) were available for evaluation of KRAS mutation status.

The researchers found that the median overall survival in patients with mutated KRAS was 4.5 months in the group receiving cetuximab, and 4.6 months in the group receiving supportive care only. The 1-year overall survival rates were 13.2% for cetuximab and 19.6% for supportive care.

A survival difference was observed in patients with wild-type KRAS tumors. The median overall survival was 9.5 months in the cetuximab group and 4.8 months in the supportive-care group, with 1-year overall survival rates of 28.3% and 20.1%, respectively.

Similar results were seen for progression-free survival. In both study groups, patients with mutated KRAS tumors had a median progression-free survival of 1.8 months, whereas in those with wild-type KRAS tumors, median progression-free survival was 3.7 months in the cetuximab group and 1.9 months in the supportive-care group.

The response rate among patients with wild-type KRAS tumors who received cetuximab was 12.8%, whereas only 1 patient with a mutated KRAS tumor experienced a response (1.2%).

"The evidence that we now have strongly supports the need to determine the KRAS mutation status of the cancer before using cetuximab, and cetuximab should only be given to patients with tumors that do not have the mutation," said Dr. Karapetis.

In an accompanying editorial, Wells A. Messersmith, MD, from the University of Colorado Cancer Center, in Aurora, and Dennis J. Ahnen, MD, from the Denver Department of Veterans Affairs Medical Center, in Colorado, note that the data from this and other papers lend support to the recommendation that colorectal cancer patients being considered for anti-EGFR therapy should undergo KRAS testing.

The results of these trials have already had important consequences, they write. "The European Medicines Agency has approved panitumumab for the treatment of patients with wild-type KRAS tumors only. To our knowledge, this is the first example of the approval of a drug therapy for solid tumors that is based on a genetic test."

Ten cetuximab studies sponsored by the National Cancer Institute are being amended to include KRAS testing and, although there is currently no test for KRAS mutational status approved by the Food and Drug Administration, that is likely to change soon, they note.

Data from these large clinical trials highlight the value of banking specimens, which will allow subsequent identification of the patients who benefited from therapy, even if the markers are unknown. These efforts can help limit expensive anti-EGFR antibody therapy to patients with wild-type KRAS colorectal cancers, which can conceivably save millions of dollars that would otherwise have been spent on patients who had no chance of benefit, they write.

However, they caution that, "lest the field of EGFR biology become carried away with the success of KRAS as a molecular marker, it should be noted that the difference in survival between the groups of patients identified by KRAS testing is small."

"Perhaps further molecular analysis will yield other markers that will identify patients who benefit from EGFR-targeting antibodies and will point to other targets and combination strategies needed to overcome drug resistance," the editorialists conclude.

The study was supported by the National Cancer Institute of Canada, ImClone Systems, and Bristol-Myers Squibb. Dr. Karapetis reports receiving consulting fees from Merck Serono; several of his coauthors report owning equity in and being employees of pharmaceutical companies and/or receiving grants and consulting fees. See article for details.

N Engl J Med. 2008;359:1757-1765.

[ 本帖最後由 goodcat1111 於 2008-11-1 11:38 編輯 ]

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