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Clinical Lung Cancer:HER2基因改变在EGFR突变型非小细胞肺癌(NSCLC)中的作用

2021-11-23 何丽 何丽

研究表明, EGFR突变的NSCLC患者中只有很少发生HER2改变。常见的双突变为EGFR的21外显子突变和HER2的8外显子突变。今后有必要进一步研究其临床预后价值。

研究表明, EGFR突变的NSCLC患者中只有很少发生HER2改变。常见的双突变为EGFR的21外显子突变和HER2的8外显子突变。今后有必要进一步研究其临床预后价值。


肺癌仍然是癌症相关死亡的主要原因。随着各种驱动基因突变的识别,晚期非小细胞肺癌(NSCLC)的治疗模式已从化疗为基础的治疗转向以分子靶向治疗为基础的治疗。对于EGFR敏感突变(19外显子缺失,21外显子L858R点突变)的转移性NSCLC患者,多种口服酪氨酸激酶抑制剂(TKI)药物已获批准,包括厄洛替尼、吉非替尼、阿法替尼、达可替尼和奥希替尼。


HER2基因扩增和过表达存在于多种肿瘤类型中,包括NSCLC。在NSCLC中HER2基因扩增的发生率为2 - 22.8%,而蛋白过表达的发生率为11 - 32%。NSCLC中过表达的潜在机制是转录和转录后机制的上调。也有报道发现在大约2% - 3%的NSCLC腺癌中有 HER2突变,特别是在亚洲患者、女性和非吸烟者中。HER2靶向治疗通常用于HER2阳性乳腺癌胃癌的治疗。相比之下,HER2单克隆抗体和酪氨酸激酶抑制剂,如曲妥珠单抗和拉帕替尼,在HER2扩增和/或过表达的NSCLC中令人失望。在一项2期研究中,曲妥珠单抗耦合物(T-DM1)的客观缓解率(ORR)为44.4%,并被列入国家综合癌症网络(NCCN)指南。然而,目前FDA还没有批准针对NSCLC中HER2突变或扩增的治疗方法。近期,国外学者开展了相关研究,评估HER2基因变异对于NSCLC患者的疗效影响。相关结果发表在Clinical Lung Cancer杂志上。



本研究共纳入12,946例NSCLC患者用可分析EGFR和HER2 NGS数据。在这个队列中,有12492名患者有HER2拷贝数改变(CNA)数据可用。其中50.1%为男性,中位年龄为68岁,89%为腺癌组织学亚型。


321例患者(2.5%)HER2基因发生改变(突变和/或扩增)。197例患者存在HER2突变(1.5%),134例患者存在扩增(1.1%)。HER2突变患者的中位年龄为65岁,其中62%为女性,84%的患者有腺癌组织学亚型。10例患者同时伴有HER2突变和扩增,8例为外显子20插入突变,1例跨膜结构域突变,1例细胞外结构域(ECD)突变。没有一个患者有HER2多发突变。在197例HER2突变患者中,最常见的亚型是外显子20插入突变135例(69%)患者中。6% (8/135) 患者HER2外显子20插入突变患者同时出现HER2扩增。


1551例患者(12%)存在EGFR突变,其中68%为女性,中位平均年龄68岁。186例患者发生复合EGFR突变。最常见的EGFR突变类型为第19外显子(47%),其次为第21外显子L858R (33%)。


在EGFR突变的样本中,24例(1.5%)同时存在HER2改变(8例HER2突变,16例HER2 CNA), 8例同时发生EGFR和HER2突变的患者中,有3例发生19外显子EGFR突变(E746-A750del)和8外显子HER2突变(S310F)。其余5例患者EGFR突变位于21外显子(L858R), HER2突变包括3例患者的8外显子(S310F), 1例患者的8外显子(S310Y), 1例患者的17外显子(G660D)。在8例EGFR和HER2同时突变的患者中,有7例(87.5%)HER2突变位于S310位点的细胞外结构域(ECD)。1 / 3 (7/21) HER2 ECD突变患者同时发生EGFR突变。在与EGFR共突变的7个HER2 ECD突变中,均为S310。



HER2改变分布


EGFR突变和HER2扩增患者的中位治疗时间为846天(N=12),而EGFR突变和HER2未扩增患者的中位治疗时间为286天(N=826), HR=2.284 (95% CI: 1.289-4.049, p=0.004)。



预后


同样, EGFR突变和HER2 ECD突变患者的中位治疗时间为462天(N=8),而EGFR突变和HER2野生型患者的中位治疗时间为287天(N=891), HR=1.152 (95% CI: 0.574-2.311, p=0.687)。
综上,研究表明, EGFR突变的NSCLC患者中只有很少发生HER2改变。常见的双突变为EGFR的21外显子突变和HER2的8外显子突变。今后有必要进一步研究其临床预后价值。

原始出处:
Misako Nagasaka , Vijendra Singh , Yasmine Baca, et al. The Effects of HER2 alterations in EGFR mutant non-small cell lung cancer. Clinical Lung Cancer. DOI: https://doi.org/10.1016/j.cllc.2021.08.012

 

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