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分子检验的新时代,EGFR-TKI 治疗的新时代

Published at: 2013年第33卷第4期

王欢欢 1 , 孟茂斌 1
1 天津医科大学附属肿瘤医院放射治疗科,天津300060
DOI: 10.3978/j.issn.2095-6959.10.3978/j.issn.2095-6959.2013.04.002
基金:

摘要

大约30年前,表皮生长因子受体(epithelial growth factor receptor,EGFR)被认为是癌症治疗较为合适的靶点[1-2]。随后,肿瘤学家尝试去观察部分恶性肿瘤细胞的增殖是否依赖于EGFR的激活以及相应细胞内酪氨酸激酶下游信号的传递。

关键词:

Abstract

大约30年前,表皮生长因子受体(epithelial growth factor receptor,EGFR)被认为是癌症治疗较为合适的靶点[1-2]。随后,肿瘤学家尝试去观察部分恶性肿瘤细胞的增殖是否依赖于EGFR的激活以及相应细胞内酪氨酸激酶下游信号的传递。针对该增殖信号通路的药物如酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)在不同恶性肿瘤中作用的研究结果发现:偶尔在非小细胞癌患者中可以观察到患者对该类药物具有良好应答[3]。各种临床因素(如亚裔、非吸烟者、女性)[4-7]以及分子生物学因素(如EGFR蛋白表达量,EGFR拷贝数)曾被认为是这一选择性优势的原因[8-10]。后来人们认识到EGFR酪氨酸激酶域突变(mutations in the kinase domain of the EGFR,EGFR-MT)可能是引起这些良好应答的主要原因[11-14]

在鉴定出EGFR-MT的同时,厄洛替尼治疗经化学治疗(化疗)后仍进展的转移性非小细胞肺癌的BR21临床研究结果显示:与未经厄洛替尼治疗的非小细胞肺癌患者相比,经治疗的患者在无进展生存期(progression free survival,PFS)及总生存期(overall survival,OS)方面均略有优势[15]。虽然在PFS方面仅延长数周就认为该治疗具有临床意义颇具争议,而且另外一项类似的针对该人群的吉非替尼临床试验结果为阴性[15],但患者的OS却得到了改善。因此厄洛替尼被美国食品药品管理局批准治疗非小细胞肺癌。随后,由于缺少对EGFR-MT的检测,加之高昂的检测费用及对治疗延迟方面的考虑[16-17],许多医生会对那些之前接受过治疗但未经突变检测的非小细胞肺癌患者进行厄洛替尼治疗;而对于那些表型相符的患者,则进行EGFR-MT检测[18]。《柳叶刀·肿瘤学》刊登的关于厄洛替尼与标准一线化疗方案治疗EGFR突变阳性的晚期非小细胞肺癌欧洲患者(European patients with advanced EGFR mutation-positive non-small-cell lung cancer,EURTAC)的临床试验[19],与来自东亚的大量证据使我们重新思考这一治疗策略[20-23]

在EURTAC试验中,伴有EGFR-MT且未经治疗的转移性非小细胞肺癌患者随机接受厄洛替尼化疗(150 mg)或者基于顺铂的双药化疗(多西他赛或吉西他滨)。对于不能耐受顺铂化疗的患者则采用卡铂化疗,且所有患者最多接受4个周期化疗。法国、意大利及西班牙的几家医院共筛选出1227例患者参与该临床试验,224例(17.6%)患者伴有EGFR-MT。其中174例符合纳入标准的患者接受1:1随机分组。令人印象深刻的是,研究者在7 d内即获得来自40多个参与该试验的研究中心EGFR突变的检测结果。

在预先的中期分析中,由于厄洛替尼组获益明显,故该研究提前中止。该研究的主要终点指标PFS令人满意,厄洛替尼治疗组患者的PFS改善了9.7个月;而化疗组患者仅改善了5.2个月(HR= 0.37,P<0.0001)。但两组患者的OS相似:厄洛替尼组为19.3个月,标准化疗方案组19.5个月。

然而在进行组间交叉研究最终分析时,纳入研究的患者有近半数死亡。厄洛替尼组的应答率为64%,高于标准化疗方案组的18%。这些研究结果同之前报告的将EGFR-TKI作为一线方案治疗伴有EGFR-MT的亚裔非小细胞肺癌患者(OPTIMAL,NEJ002,WJOTG3405和IPASS)的结果相一致,肯定了EGFR-TKI作为一线方案治疗伴有EGFR-MT的非小细胞肺癌患者的优越性,但并未考虑患者的种族差别或EGFR-TKI的选择(表1)。在这些试验中,EGFR-TKI治疗与化疗使患者在应答率及PFS方面的差异,除机会因素之外,化疗方案的敏感度不同及特异性EGFR-MT的频率不同也可能是其原因(Rosell,2010#1153;Sun,2011#1154)。

值得注意的是,所有这些研究均未显示EGFR-TKI作为一线治疗方案与以铂类为基础的化疗方案在患者生存期方面,哪一个更具优势,且考虑到EGFR-MT的测试,这些研究结果尚不令人满意。这些研究阐释了二线治疗时采用EGFR-TKI对EGFR-MT的非小细胞肺癌患者来说可能并不是最佳治疗方案。正如表2中所详述,除了WJTOG 3405研究外,几乎每个研究中标准化疗组3至4级不良事件的发生率均较高,治疗终止率也较高。此外,OPTIMAL及IPASS研究还报告在患者生存质量改善方面,采用EGFR-TKI治疗优于化疗。更为重要的是,接受一线化疗的患者中,有5%~39%的患者从未接受EGFR-TKI二线治疗,这使得这些患者不能获得更有效又安全的治疗方案。与此相反,对于EGFR野生型接受标准一线化疗的患者其PFS要优于接受EGFR-TKI 治疗的患者[20,24]

当然,从转移性非小细胞肺癌患者获取合适的组织,并在可接受的时间范围内进行EGFR-MT检测均存在着困难。虽然在EURTAC研究中,7 d之内完成了EGFR-MT检测,但在社区似乎不太可行,故迫使医生选择化疗而并非等待检测结果。鉴于快速获取检测结果会使治疗策略发生重大改变,改善以上状况的可能途径是对转移性非小细胞肺癌患者标本进行包括EGFR-MT及ALK在内的可能存在的分子异常情况进行灵活检测。假如未能进行局部灵活检测,则需要改善标本及追踪步骤[16-17,25]。此外,对切除术及根治术的IIIA/B期非小细胞肺癌也可进行灵活检测,其结果可用于了解复发情况。如今的病理报告详尽地报告转移性肿瘤活检的免疫组织化学染色结果,除非有明确要求,否则不会检测EGFR-MT以及ALK的状态,这是一个历史性的局限。只有尽力缩短EGFR-MT的检测时间,医生方能从EURTAC临床试验中获得信息。通过对患者的表型推断哪些患者接受EGFR-TKI治疗能够获益的时代已经过去,我们已步入对非小细胞肺癌患者进行早期广泛的分子检验时代,以及如何尽可能使EGFR-MT的非小细胞肺癌患者接受EGFR-TKI一线治疗的时代。

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引用本文: 欢欢 王, 茂斌 孟. 分子检验的新时代,EGFR-TKI 治疗的新时代[J]. 临床与病理杂志, 2013, 33(4): 286-289.
Cite this article as: WANG Huanhuan, MENG Maobin . [J]. Journal of Clinical and Pathological Research, 2013, 33(4): 286-289.