作者：Roxanne Nelson
出處：WebMD醫學新聞
October 31, 2008 —第四期非小細胞肺癌(NSCLC)病患，其組織和血清DNA中的上皮細胞生長因子接受體(EGFR)突變會影響erlotinib (Tarceva, Genentech公司)的治療結果。
這項研究結果發表於美國臨床腫瘤學會、國家癌症研究中心、歐洲癌症治療與研究組織等機構共同贊助的第二屆癌症分子標記年會中，發現兩組NSCLC病患之間對於erlotinib的治療反應相似：只有腫瘤有EGFR 突變者，腫瘤組織和血清都有EGFR 突變者。不過，只有腫瘤有EGFR突變之病患，有比較長的無惡化存活(17個月)，腫瘤組織和血清都有EGFR突變者為12個月。
共同作者、Catalan腫瘤研究中心分子生物實驗室主任Miquel Taron博士於記者會中發表資料時表示，這是迄今分析週邊血液中EGFR突變狀態的最大型研究資料；分析血清和血漿中的EGFR突變，是在缺乏腫瘤組織時的一個有效的方法。
Erlotinib是一種EGFR抑制劑，已經核准用於治療那些化療至少失敗過一次的末期和轉移NSCLC。在此研究中，Taron博士等人評估腫瘤和開始時血清中的EGFR突變，在一個對第四期NSCLC病患進行第一線和第二線 erlotinib 治療的多中心試驗中，探究它們作為預測因子的角色。
【研究詳情】
特定目標是確認血清與血漿DNA中出現EGFR突變，以及與腫瘤突變的關係，以確認臨床特徵和突變類型之間的關聯，繼而找出第四期NSCLC病患以第一線和第二線erlotinib治療時，血清/血漿突變和臨床結果之間的關聯。
總共有2,281名NSCLC病患進行腫瘤之EGFR突變篩檢，其中有327人有突變；第四期NSCLC病患且有突變者中，211名病患接受erlotinib治療，分析其有無出現EGFR 突變。以螢光標記聚合酶鏈鎖反應(PCR)產物長度分析檢測外顯子(exon)19 之刪除，以PCR Taqman分析外顯子21 L858R突變。
有120名(57%)病患的血清EGFR-突變狀態和腫瘤組織相符，表現狀態(PS)為0的病患有45.6%相符，PS 1的病患有57.3%，而大部份病患(75%)屬PS 2 (P= .01)；根據血清或者腫瘤類型的突變，研究者在疾病轉移型態未觀察有任何差異。
Erlotinib治療的反應率在只有腫瘤突變和腫瘤與血清都有突變者之間相似(67%)，血清突變者的疾病惡化率比較高 (120名病患中有15人)，而只有腫瘤突變者較低(91人中有3人)；在這18名疾病惡化者中，血清突變者佔83.3%。
【外顯子19刪除會改善結果】
所有病患的整體惡化時間為13個月，但是只有腫瘤突變者較長；血清EGFR 外顯子19 刪除者發生惡化的時間(13個月)也比血清L858R突變者長。
研究者也指出，這些病患的平均存活期為25個月，但是只有腫瘤有突變者的存活較佳(27個月)，腫瘤和血清都有突變者為20個月；血清EGFR 外顯子19 刪除者的平均存活時間(32個月)也遠高於血清L858R突變者(14個月) 。
突變類型、病患性別、腦部和骨骼轉移等，是發生惡化時間的獨立變項；突變類型、PS、腦部轉移是存活的獨立變項。
Taron博士表示，幾乎有90%的PS 2病患有血清EGFR突變，表示血清EGFR突變可以成為基因圖譜的輔助非侵犯式方法。
發表時的主持人、達那-法柏癌症研究治療中心的Bruce E. Johnson醫師表示，正向與負向預測生物標記的使用，會改變癌症治療。觀念之一是，大部份藥廠的投入，讓我們認為可以加速研發內容，在某種程度上，我們的合作可以100%讓病患獲得20%的改善；這種改善相對上較小。
使用預測標記，則是嘗試讓20%的病患獲得100%的改善。
2008 ASCO–NCI–EORTC癌症分子標記年會。發表於2008年10月31日。
Serum EGFR Mutations Predict Worse Outcomes with Erlotinib in NSCLC Patients
By Roxanne Nelson
Medscape Medical News
October 31, 2008 — Epidermal growth-factor receptor (EGFR) mutations found in the tissue and serum DNA of patients with stage?4 non-small-cell lung cancer (NSCLC) can influence treatment outcomes with erlotinib (Tarceva, Genentech).
The study results, which were presented at the second Annual Molecular Markers in Cancer Meeting, in Hollywood, Florida, which is cosponsored by the American Society of Clinical Oncology, the National Cancer Institute, and the European Organisation for Research and Treatment of Cancer, found that response to therapy with erlotinib was similar between 2 groups of NSCLC patients: those with EGFR mutations in the tumor only, and those with EGFR mutations both in tumor tissue and serum. However, patients with tumor-only EGFR mutations had longer progression-free survival than patients with mutations in both tumor tissue and serum (17 months vs 12 months).
"This is the largest study to date assessing the role of EGFR-mutation status in peripheral blood," said coauthor Miquel Taron, PhD, head of the molecular biology laboratory at the Catalan Institute of Oncology, in Barcelona, Spain, who presented the data at a press briefing. "Analysis of EGFR mutations in serum and plasma is a valid method in the absence of available tumor tissue."
Erlotinib, an EGFR inhibitor, has been approved for the treatment of locally advanced or metastatic NSCLC that has failed at least 1 previous chemotherapy regimen. In this study, Dr. Taron and colleagues evaluated EGFR mutations in tumor and matched serum at baseline and studied their role as a predictive marker in a multicenter trial of first- and second-line erlotinib therapy in stage?4 NSCLC patients.
Study Details
The specific goals were to determine the presence of EGFR mutations in serum and plasma DNA and the correlation with mutations in tumor, to determine the relation between clinical characteristics and type of mutation, and to correlate serum/plasma mutations with clinical outcome in stage?4 NSCLC patients treated with first- or second-line erlotinib.
A total of 2281 patients with NSCLC were screened for EGFR mutations in their tumors and, of this group, 327 had mutations. Of this subgroup of patients with stage?4 disease with mutations, 211 patients received treatment with erlotinib, and the presence of EGFR mutations was assessed. Testing for exon?19 deletions was performed by length analysis of fluorescently labeled polymerase chain reaction (PCR) products, and exon?21 L858R mutations were tested with a PCR Taqman assay.
EGFR-mutation status in serum matched that in tumor tissue in 120 patients (57%), and matched in 45.6% of patients with performance status (PS)?0, in 57.3% of those with PS?1, and in the majority of patients (75%) with PS?2 (P?= .01). The researchers did not observe any differences in disease metastatic patterns, according to the presence of mutations in serum or the type of mutation.
The response rate to erlotinib therapy was similar in patients with tumor-only mutations and in those with tumor and serum mutations (67%). The rate of progressive disease was higher in patients with serum mutations (15 of 120 patients) than in those with tumor-only mutations (3 of 91 patients). Of the 18 patients with progressive disease, patients with serum mutations accounted for 83.3% of that number.
Exon 19 Deletion Improves Outcome
Overall time to progression for all patients was 13 months, but it was longer in patients with tumor-only mutations than in those with tumor and serum mutations. Time to progression was also longer for patients with an EGFR exon?19 deletion in serum (13 months) than in those with an L858R serum mutation.
The researchers also noted that the median survival for the cohort was 25 months, but survival was better for those with EGFR mutations in the tumor only than for those with mutations in the tumor and serum (27 months vs 20 months). Median survival time for patients with an EGFR exon?19 deletion in serum was also substantially higher than in those with L858R mutations (32 months vs 14 months).
The type of mutation, the sex of the patient, and the presence of brain and bone metastases were observed to be independent variables for time to progression; mutation type, PS, and brain metastases were independent variables for survival.
"EGFR mutations in serum were found in almost 90% of patients with PS?2," said Dr. Taron, adding that EGFR mutations in serum can be an ancillary noninvasive method of genotyping.
The use of predictive markers is trying to make 20% of the patients 100% better.
The use of positive and negative predictive biomarkers is changing cancer treatment, said Bruce E. Johnson, MD, from the Dana-Farber Cancer Institute, in Boston, Massachusetts, who served as the briefing moderator. "One of the concepts that we think can be speeded up is that most of the pharmaceutical industry and, to some extent, our cooperative groups are focused on making 100% of the patients 20% better. That makes for relatively small increments," he added. "The use of predictive markers is trying to make 20% of the patients 100% better."
2008 ASCO–NCI–EORTC Annual Meeting on Molecular Markers in Cancer. Presented October 31, 2008
[ 本帖最後由 goodcat1111 於 2008-11-11 14:06 編輯 ] |
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