知识科普 | EGFR突变检测知多少?

　　EGFR检测适用人群

　　根据现有临床数据,对符合条件的转移性NSCLC患者应当进行EGFR检测,其中包含有常见突变及罕见突变。同时,NCCN专家建议对符合条件的的可切除IB至IIIA期NSCLC患者进行 EGFR突变的分子检测，以确定是否可以选择使用奥希替尼进行辅助治疗。

　　EGFR检测与TKI药物

　　EGFR 19号外显子缺失和21号外显子突变 (L858R)是NSCLC患者中最常见的突变,这两种突变分别占所有突变患者的45%和40%。两种突变都会导致酪氨酸激酶结构域的激活, 并与小分子 EGFR TKI 药物的敏感性有关，例如厄洛替尼、吉非替尼、阿法替尼、奥希替尼和达克替尼^[12]。在以前,这些突变常被表述为敏感性突变,但现在更多的特殊突变被人们发现。这些常见的 EGFR 突变存在于大约 10% 的非小细胞肺癌白种人患者和高达 50% 的亚洲患者中^[13]。其他不太常见的突变（约 10%）也对 EGFR TKI 敏感，包括exon 19 插入, p.S768I, p.L861Q和p.G719X^[14,15]。目前的证据表明,对于没有这些特异性EGFR 突变的肿瘤患者,不应在任何治疗方案中使用 EGFR TKI 进行治疗。

　　图片来源: Riely GJ, Clin Cancer Res, 2006 Dec 15.

　　绝大多数具有常见 EGFR 突变的腺癌患者是不吸烟者或轻度吸烟者。有数据表明，腺鳞癌患者也可发生 EGFR 突变，但腺鳞癌在小标本中很难与鳞状细胞癌区分[16]。单纯的鳞状细胞癌患者不太可能出现常见的 EGFR 突变；但那些患有腺鳞癌的人可能会有突变[3,4,16] 。尽管如此,吸烟状况、种族和组织学类型都不应当作为选择检测人群的标准。尽管发生率低于转移性 NSCLC 腺癌患者[2,3,4,8,9], NCCN 的专家组仍然建议对所有转移性 NSCLC 鳞状细胞癌患者进行分子检测，因为这些患者也可能具有临床意义的生物标志物变异，例如 EGFR 突变。

　　EGFR 19 号外显子缺失和 L858R 突变预测TKI药物疗效的作用已被确认。具有这些常见 EGFR 突变的患者对阿法替尼、达克替尼、厄洛替尼、吉非替尼或奥希替尼的反应明显更好^[12]。目前的临床实验数据表明, EGFR TKI 疗法作为晚期 NSCLC 中常见 EGFR 突变患者的一线单药治疗是有效的。与细胞毒性的全身治疗(化疗)相比，使用 EGFR TKI 单药治疗携带EGFR 突变的患者,其无进展生存期 (PFS) 更长,但阿法替尼、厄洛替尼、吉非替尼的总生存期没有统计学差异^{[17,18,23,24]}。对 EGFR TKI 治疗无反应则与 KRAS 和 BRAF 突变以及 ALK 或 ROS1 基因重排有关。另外,EGFR 外显子 20 插入突变的患者通常对厄洛替尼、吉非替尼、阿法替尼或达克替尼耐药，但也有罕见的例外（例如，p.A763_Y764insFQEA）。患者通常会在一线 EGFR TKI 单一疗法治疗后出现疾病的进展(耐药) 。

　　EGFR TKI的耐药

　　当大多数普通EGFR突变患者对阿法替尼、厄洛替尼或吉非替尼产生耐药性时,其PFS为9.7至13个月^{[18,24,27-29]}。EGFR p.Thr790Met (T790M) 是一种与 EGFR TKI 治疗相关的获得性耐药突变，据报道,约 60%在对厄洛替尼、吉非替尼、吉非替尼、或阿法替尼初始敏感的患者,其发生耐药后会出现T790M突变^[10,29-35]。有研究表明，T790M很少发生在以前从未接受过厄洛替尼、吉非替尼或阿法替尼治疗的患者中^[36]。另外,无论是否吸烟, 基因组上携带 p.T790M 者,都有高风险罹患肺癌^[37-39]。 因此,如果在治疗前就发现了T790M突变,则建议患者进行遗传咨询。对 EGFR TKI 的获得性耐药也可能与患者从 NSCLC 到 SCLC 的组织学转化以及上皮到间质转化有关^[40-44]。专家们建议在疾病进展时可以考虑进行活检以排除 SCLC 转化并评估其耐药机制[41]。最后,获得性耐药也可由其它分子事件介导,如ALK重排,MET或ERBB2扩增等^[45]。

　　图片来源: Yu HA, Clin Cancer Res. 2013 Apr 15.

　　综上,基于阿法替尼、达科米替尼、埃洛替尼、吉非替尼和奥西替尼疗效的数据[1,17-22],专家组建议对转移性非鳞状细胞肺癌或非特指型NSCLC患者的EGFR突变状态和其他生物标志物进行检测。同时,如前所述,鳞状细胞癌的患者也可以进行同样的检测。

　　EGFR的检测方法

　　DNA突变分析被用于评估EGFR状态,IHC则不建议用于检测EGFR突变^[46-49]。荧光定量PCR、Sanger测序和NGS是常用的检测EGFR技术^[7,46]。直接测序18至21号外显子(或者仅检测19,21号外显子),是一种比较合理的方案;但也有更灵敏的方法^{[13,48,50,51]}。如利用多重PCR进行的突变筛查可以同时检测50多个点突变^[52] 。然而,NGS仍然是检测EGFR变体的首选方法, 因靶向PCR方法可能会漏掉一些EGFR外显子20插入突变^[11]。

　　EGFR突变阳性患者的治疗

　　对于EGFR突变阳性（外显子19缺失，L858R）的转移性NSCLC患者,其一线治疗方案已确认。奥西替尼是EGFR阳性的转移性NSCLC患者首选的一线EGFR TKI选择。埃洛替尼（±贝伐单抗或拉穆昔单抗）、阿法替尼、达科替尼或吉非替尼等是一线EGFR TKI治疗的“其他推荐”选项。
　　而对于EGFR T790M阳性的转移性非小细胞肺癌或埃洛替尼（±贝伐单抗或拉穆昔单抗）、阿法替尼、达科替尼、吉非替尼治疗的疾病进展患者，则推荐奥西替尼作为二线及后续治疗[28,53]。

　　对第一代、第二代和第三代EGFR TKI（如埃洛替尼、阿法替尼、吉非替尼、奥西替尼；经典EGFR TKIs）同样敏感的较不常见的EGFR突变（约10%）包括外显子19插入，p.L861Q、p.G719X和p.S768I[14,15,23,54]。有鉴于阿法替尼或奥西替尼是携带EGFR S768I、L861Q和G719X患者一线治疗方案,推荐对转移性NSCLC患者进行这些位点的检测[23,54]。在此情形中,其它推荐的TKI药物还有埃洛替尼、吉非替尼或达科米替尼^[55,56]。

　　EGFR外显子20插入突变

　　20号外显子插入突变是第三种常见的EGFR突变, 它们发生在约2%的NSCLC患者和4%至12%的EGFR突变患者中^[6,26,57,58]。尽管有许多不同的EGFR外显子20插入突变，但这三种（insASV、insSVD和insNPH）最为常见[6]。大多数EGFR外显子20插入突变患者对埃洛替尼、阿法替尼或吉非替尼的应答率较低（≤9%）^[5,6]。但p.A763_Y764insFQEA突变是个例外, 埃洛替尼、阿法替尼或吉非替尼对这个EGFR 20外显子插入突变的患者有效^[25]。

　　当以高剂量（160 mg/天）使用时，奥西替尼对EGFR 20外显子插入突变的患者应答率约为25%，这远低于EGFR外显子19缺失或L858R突变携带者^[59]。一线铂类化疗（±免疫疗法）是EGFR 20外显子突变患者的推荐疗法^[60-62]。与接受厄洛替尼、阿法替尼或吉非替尼靶向治疗（约39个月）的EGFR外显子19缺失或L858R突变患者相比,接受一线铂类治疗的EGFR 20外显子插入突变的患者的中位总生存期较短（约16个月）^[5,63,64]。其免疫治疗的应答率(0-25%)则取决于不同的EGFR 20外显子插入种类^[6,65,66]。

　　有鉴于amivantamab-vmjw(JNJ-6732)和莫博塞替尼(TAK788)在后线治疗EGFR 20外显子插入突变患者的数据,NCCN专家们推荐在转移性NSCLC患者中进行EGFR 20外显子插入突变的检测[5,6]。NGS是检测EGFR 20插入突变的首选,PCR策略则会漏掉一些变异。

　　图片来源;Zhou C, JAMA Oncol. 2021 Dec 1

　　华测肺癌个性化用药

　　对肺癌常见的 52 个热点突变基因进行高深度测序，覆盖国内外 FDA/NMPA 批准上市、NCCN 指 南推荐，以及在临床试验阶段的 279 种靶向药物;同时提供 lynch 综合症相关 EPCAM、MLH1、MSH2、 MSH6、PMS2 等 MMR 基因的致病突变解读，以及基于万人级别药物基因组数据的 PharmGKB 数据 库中肿瘤常用 38 种化疗药物疗效及毒副作用评估结果，适用于初诊患者的全面靶点检测和药物筛选，同时对于复发转移、多发耐药的肺癌患者提供跨适应症用药、治疗方案更换的分子依据。

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