JTO:病例分享——见微知著,KRAS突变肺腺癌转化为小细胞肺癌是免疫治疗的耐药机制?

2019-02-12 肿瘤资讯 肿瘤资讯

随着免疫治疗2.0时代的进一步推进,免疫治疗耐药不可避免成为众矢之的。探讨免疫耐药机制、克服免疫耐药是扩大免疫检查点抑制剂的获益人群、实现精准治疗的关键所在。肺腺癌向小细胞肺癌(SCLC)转化是表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)的耐药机制之一,但肺腺癌经免疫治疗后罕有病例会出现转化。但有研究发现,经过纳武利尤单抗治疗后有2例KRAS突变肺腺癌患者发生了小细胞肺癌转化,近日发表在J

随着免疫治疗2.0时代的进一步推进,免疫治疗耐药不可避免成为众矢之的。探讨免疫耐药机制、克服免疫耐药是扩大免疫检查点抑制剂的获益人群、实现精准治疗的关键所在。肺腺癌向小细胞肺癌(SCLC)转化是表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)的耐药机制之一,但肺腺癌经免疫治疗后罕有病例会出现转化。但有研究发现,经过纳武利尤单抗治疗后有2例KRAS突变肺腺癌患者发生了小细胞肺癌转化,近日发表在Journal of Thoracic Oncology杂志上。

病例1

女性患者,67岁,有吸烟史50包/年。确诊为KRAS G12C突变肺腺癌(图1)。一线治疗为卡铂+紫杉醇,有效,无进展生存为19个月。首次进展时患者拒绝接受活检,直接接受纳武利尤单抗(nivolumab)治疗。患者在接受第36个周期的纳武利尤单抗治疗后的2周,疾病再次出现广泛进展,出现心包积液伴心脏压塞,需行心包穿刺术。胸腔或心包积液细胞学检查提示小细胞肺癌可能。积液癌细胞二代测序技术(NGS)检测并发现没有KRAS突变,而出现TP53 S315S移码突变和RB1基因的剪接位点突变。随后该患者接受了卡铂、依托泊苷和紫杉醇联合治疗,该患者在小细胞肺癌转化后的第11个月,即初诊后第4年死亡。



图1.肺腺癌转化为小细胞肺癌时的治疗方案、影像学结果和可用病理影像(病例1)

病例2

女性患者,75岁,有吸烟史30包/年,诊断为KRAS G12C突变肺腺癌(图2)。一线卡铂、紫杉醇和贝伐珠单抗治疗有效,在诊断后的第24个月后出现疾病进展,组织再活检显示肺腺癌。患者开始接受33个周期的纳武利尤单抗治疗,根据RECICST 1.1疗效评价为稳定。经过11个月的治疗,患者出现无症状疾病进展,活检证实为小细胞肺癌转化。同时外周血游离DNA(cfDNA)分析显示,KRAS G12C突变的等位基因频率(AF)为19.47%,TP53 R273C突变的AF为0.55%,未检测到RB1突变。之后患者依次接受卡铂+依托泊苷、纳武利尤单抗+伊匹单抗和伊立替康单药治疗。该患者在小细胞肺癌转化后的第16个月,即初诊后第5.5年死亡。



图2.肺腺癌转化为小细胞肺癌时的治疗方案、影像学结果和可用病理影像(病例2)

讨论

在5%~15%接受EGFR抑制剂治疗的患者中发现肺腺癌转化为小细胞肺癌。从既往报道的病例看,接受纳武利尤单抗治疗后仅发现了1例患者从肺腺癌转化为小细胞肺癌。在病例1中,KRAS G12C突变的丢失增加了第二原发性恶性肿瘤小细胞肺癌的可能性。而相比于病例1,病例2转化为小细胞肺癌时,初始KRAS G12C突变较保守。

这两个病例提示,肺腺癌去分化为小细胞肺癌可能是PD-1耐药机制之一,有研究提出肺腺癌和小细胞肺癌来源于同种细胞——Ⅱ型肺泡细胞。在这两个病例中,初诊时没有获取TP53和RB1突变的信息,但可以推测,这两个突变可能会增加肺腺癌患者接受PD-1抑制剂治疗后转化为小细胞肺癌的风险,这与最近关于EGFR突变肺腺癌的研究结果类似。随着免疫检查点抑制剂在肺腺癌患者中的广泛应用,临床医师必须意识到肺腺癌向小细胞肺癌转化是可能一种潜在的耐药机制。

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    2019-02-14 yinhl1978
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    2019-02-14 bioon7

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