Association of the EGFR gene polymorphisms with clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with gefitinib
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14516 Background: Mutations in the EGFR gene appear to confer sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Genetic polymorphisms are more prevalent than mutations in human genome. We evaluated the association of polymorphisms in the EGFR gene with the clinical outcomes in the patients with advanced NSCLC treated with gefitinib, an EGFR-TKI. Methods: Candidate polymorphic loci approach was used to determine the functional polymorphisms within the EGFR gene range. Four most representative tagging single nucleotide polymorphisms (SNPs), one well-known CA simple sequence repeat (CA-SSR) in intron 1, and several common SNPs in the region encoding tyrosine kinase domain of EGFR were included in our study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and directly DNA sequencing approach were used to determine the genotypes of 84 advanced NSCLC patients treated with gefitinib. Results: Rs2293347 in exon 25 and CA-SSR in intron 1 were addressed by the candidate loci approach. For rs2293347, the clinical benefit rates were 71.2% and 37.5% (P = 0.0043) in wild-type (G/G genotype) and variation allele carriers (A/G or A/A genotypes). The progression-free survival were 11 months and 3 months (P = 0.0018), respectively, while the results for overall survival were similar. For CA-SSR, the clinical benefit rate was 88.5% in patients carrying at least one shorter CA repeat allele [≤16 (CA)n], and 48.3% in patients carrying two longer CA repeat alleles [>16 (CA)n] (P = 0.0005). However, CA- SSR polymorphism was not found to be associated with the progression-free survival and overall survival. Conclusions: Rs2293347 and CA-SSR polymorphisms may be predictive for clinical outcomes in patients with advanced NSCLC treated with gefitinib. No significant financial relationships to disclose.Keywords:
Candidate gene
背景几临床的试用证明 erlotinib 在在先进非小的房间肺癌症(NSCLC ) 的 gefitinib 的失败以后是有效的。这研究的目的是从我们的医院基于数据在 gefitinib 的失败以后评估 erlotinib 治疗的可行性。从 2007 年 8 月进入上海胸医院到 2008 年 12 月的有先进 NSCLC 的 20 个病人的临床的数据回顾地被分析的方法。所有在 gefitinib 的失败以后病人被给 erlotinib 治疗。幸存分析被 Kaplan-Meier 方法做。艇长回归模型被执行分析在有影响的因素和 erlotinib 之间的关系没有前进的幸存(PFS ) 。结果五个病人有部分回答(PR ) ，九个病人有稳定的疾病(SD ) ，六个病人与 gefitinib 治疗有进步疾病(PD ) 。中部的 PFS 是 277 天(95% C/0-566 ) 。没有病人与 erlotinib 治疗有 PR，七有的 SD 和十四 PD。中部的 PFS 是 31 天(95% Cl 9.1-52.9 ) 。反应率(RR ) 是 0，并且疾病控制率(DCR ) 是 35%(7/20 ) 。考克斯回归分析表明了那性(P=0.96 ) ，年龄(P=0.89 ) ，吸烟历史(P=0.78 ) ，表演地位(PS )(P=0.98 ) ， gefitinib 功效(P=0.90 ) 并且化疗是否用二药(P=0.45 ) 被使用在之间，没与 erlotinib PFS 有重要关联。十五个病人有因素受体(EGFR ) 变化地位决定了的表皮的生长。有五个盒子有在十个变化的 erlotinib 治疗的得到的 SD 否定(野类型) 病人。没有 SD 在五个变化被记录积极病人。在 gefitinib 失败以后的 erlotinib 治疗的功效被限制的结论。然而，是 EGFR 变化的病人否定罐头可能在 gefitinib 以后得益于 erlotinib 治疗失败。
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To evaluate the tolerability and efficacy of erlotinib treatment in advanced non-small cell lung cancer (NSCLC) patients who had previously experienced severe hepatotoxicity after gefitinib treatment.Twenty-five NSCLC patients with epidermal growth factor receptor (EGFR) mutation were initially treated with gefitinib (250 mg/day). However, 7 of these experienced severe hepatotoxicity. After recovery from hepatotoxicity, treatment was switched to erlotinib (150 mg/day) in all 7 patients. Toxicity and efficacy of erlotinib were analyzed.None of the 7 patients reported severe hepatotoxicity with erlotinib despite gefitinib-induced severe hepatotoxicity. All patients achieved response with gefitinib or following erlotinib treatment. The response achieved with gefitinib was maintained after switching to erlotinib. Therefore, an excellent median progression-free survival of 372 days was achieved although gefitinib induced severe hepatotoxicity.Erlotinib treatment was efficient and well-tolerated in NSCLC patients with EGFR mutation, despite their severe hepatotoxicity with prior gefitinib treatment.
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To compare the efficacy of the erlotinib versus gefitinib in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC.Fifty patients with untreated advanced EGFR mutation- positive NSCLC were randomly divided into gefitinib group (n=27) and erlotinib group (n=23). The progression-free survival, objective response rate and disease control rate were evaluated to compare the efficacy of gefitinib and erlotinib.There were no significant differences in the objective response rate (P=0.711) and disease control rate (P=0.861) between the two groups. The progression-free survival of gefitinib group and erlotinib group was 8.0 months and 10.0 months, respectively. The efficacy of the two drugs was similar (P=0.293).There is no significant differences between gefitinib and erlotinib in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC.
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Objective To compare the efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitor gefitinib and erlotinib alone as a second line treatment for patients with advanced non-small cell lung cancer(NSCLC) who were failed in the first-line chemotherapy.Methods Among the 83 patients who were failed in the first-line treatment for NSCLC,41 received gefitinib(gefitinib group) and 42 received erlotinib(erlotinib) therapy.The efficacy,progression-free survival time(PFS),median survival time(MST),and toxicity of the two groups were compared.Results The median PFS and median OS were not significantly different between the two groups(P 0.05).The rate of adverse events in erlotinib group was higher than that in gefitinib group.The histological types of tumor were significantly different between the two groups(P 0.05),and the survival time in patients with squamous carcinoma in erlotinib group was longer than that in gefitinib group.Conclusion In the advanced NSCLC patients with standard first-line chemotherapy treatment failure,gefitinib and erlotinib had the similar overall efficacy.
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Tyrosine kinase inhibitors of the epidermal growth factor receptor, gefitinib and erlotinib, have changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). Many phase II or III studies have proven the efficacy of gefitinib or erlotinib as the first-line, second-line, or third-line treatment. However, it is not clear whether gefitinib or erlotinib has different activities in advanced NSCLC patients with different clinicopathological features or at different stages. We review the published clinical trials that used gefitinib or erlotinib in NSCLC and compare their efficacy. The selection criteria and efficacy measurement in these trials that might affect the final results of the studies are listed and discussed. The adequate-powered, direct comparisons of gefitinib against erlotinib under the same clinical scenarios are lacking. There is no evidence at present that the efficacy of these two agents in NSCLC is different.
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Erlotinib and gefitinib are tyrosine kinase inhibitors (TKI) associated with the EGFR, which is involved in cell proliferation, growth, migration, invasion and survival, and has been found to be overexpressed in non-small-cell lung cancer. Erlotinib was the first target agent approved for the treatment of NSCLC in second- and third line, in patients unselected for EGFR mutations; gefitinib was the first EGFR tyrosine kinase inhibitor approved for the treatment of NSCLC in all lines of setting in patients harbouring EGFR mutations. In elderly patients, with a poor prognosis, and different co-morbidities, erlotinib and gefitinib could be considered as valid therapeutic options. This paper reviews the role of both drugs, in the management of elderly patients affected by advanced NSCLC based on an update analysis of randomised and non-randomised clinical trials.
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The epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib are effective in the treatment of advanced nonsmall-cell lung cancer (NSCLC), but the median survival of patients is short.Here, we describe 2 patients with NSCLC receiving conventional chemotherapy and alternative treatment with gefitinib or erlotinib as second-line therapy.The first patient was alive at 8 years with alternative conventional chemotherapy and gefitinib, and the second patient was alive at long-term follow-up with conventional chemotherapy and gefitinib or erlotinib.Gefitinib, erlotinib, and conventional chemotherapy can be combined for satisfactory therapy for NSCLC.
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목적: 우리나라에서 비소세포폐암의 발생 빈도는 증가하는 추세에 있다. 여성 폐암은 대부분이 비흡연자이고 선암이 주로 발병하는 것으로 알려지고 있으며 표피성장인자수용체의 티록신 키나아제 억제제가 동양인 여성에서 더 효과가 있다는 것이 알려져 있다. 본 연구는 gefitinib과 eroltinib은 작용기전은 비슷하나 용량의 차이가 있어 각각의 치료 성적이 보고자 마다 조금씩 달라 두 약제의 치료 성적을 비교하여 보고자 하였다. 방법: 2004년 2월 2007년 4월까지 고신대학교 복음병원에서 진단 및 치료받은 여성 폐암 환자들을 의무기록을 통해 후향적으로 조사했다. 한달 이상 gefitinib, erlotinib을 복용하고 치료 평가가 가능한 환자를 대상으로 생존기간, 약물투여 기간, 독성의 발생빈도를 비교 분석하였다. 결과: 전체 환자는 42명이었고, gefitinib 치료군은 26명, erlotinib 치료군은 16명이었다. 나이의 중간값은 58세였고, 85%가 비흡연가, 83%가 선암이었으며, 병기는 IIIb가 13명(24.0%), IV가 16명(76%)이고, 생존일 중앙값은 793일이었다. gefitinib으로 치료한 군이 26명(62%)이었고, 이 중 18명(69.2%)이 3차 화학요법으로 이 약제를 사용하였고, erlotinib을 사용한 16명 중 12명(87.5%)이 2차약으로 사용하였다. 전체적인 치료 반응율은 14명에서 부분 관해를 보여 33.3%의 반응율을 보였고, 안정성 병변을 포함한 질병 조절율은 76.2%이었다. gefitinib군의 치료 반응율은 39%, erlotinib군 31%이었으며 양군 간의 통계적 차이는 없었고, 평균 생존 기간이 각각 651일, 510일이었으나 통계적 차이는 없었다. 약제 투여 기간의 중앙값은 gefitinib군에서 186일, erlotinib군이 262일로 erlotinib군에서 길었으나 역시 통계적 유의성은 없었다. 피부 독성은 gefitinib군이 27%, erlotinib군 75%로 erlotinib군에서 많이 나타났다. 결론: Gefitinib군과 erlotinib군의 치료 반응율과 생존기간 및 약제 투여기간의 차이는 없었다. Erlotinib군에서 피부 발진 빈도가 더 높게 나타났다.
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Gefitinib and erlotinib are first-generation small molecular inhibitors of EGFR tyrosine kinase activity. To the best of our knowledge, to date, two reports have stated that patients with NSCLC who develop severe hepatotoxicity secondary to gefitinib treatment can be safely switched to erlotinib. However, the reverse situation has not been reported. Here, we present the first case with non-small cell lung cancer harboring EGFR mutation who developed grade 3/4 hepatotoxicity after initiation of erlotinib, which resolved when therapy was changed to gefitinib. As far as we know, this is the first report showing the efficacy of gefitinib for a non-small cell lung cancer patient who developed severe hepatotoxicity while under erlotinib therapy.
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