晚期肺腺癌靶向耐药后小细胞癌转化2例并文献复习

具有表皮生长因子受体(epidermal growth factor receptor,EGFR)敏感突变的晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者应用EGFR酪氨酸激酶抑制剂(EGFR-tyrosine kinase inhibitors,EGFR-TKIs)治疗可取得良好的疾病控制,但不可避免会产生耐药。其中3%-10%左右的耐药机制为小细胞癌转化。本文报道2例IV期肺腺癌存在EGFR突变、经EGFR-TKIs治疗后疾病得到控制的病例。病例1发生小细胞癌转化前的无进展生存期(progression-free survival,PFS)为16个月,病例2发生小细胞癌转化前的PFS为24个月。疾病进展后再次活检提示小细胞癌转化。经后续治疗再次稳定,病例1发生小细胞癌转化后的PFS为6个月,总生存期(overall survival,OS)暂未出现,病例2发生小细胞癌转化后的PFS为8个月,OS为36个月,显著延长了患者生存。同时对此类耐药突变进行文献复习。对于晚期NSCLC存在敏感突变的患者,经EGFR-TKIs治疗耐药后进行二次组织病理检测,根据不同耐药机制选择后续治疗对疾病全程管理十分必要。

ALK融合肺腺癌小细胞转化1例并文献复习

间变淋巴瘤激酶(anaplastic lymphoma kinase,ALK)融合的肺腺癌患者经ALK-酪氨酸激酶抑制剂(ALK-tyrosine kinase inhibitor,ALK-TKI)治疗后可能会产生耐药,其耐药机制尚未完全明确。遵义医科大学附属医院2021年9月收治1例ALK融合的肺腺癌患者,经ALK-TKI治疗后出现耐药,疾病进展后再次活体组织检查(以下简称“活检”),病理类型转化为小细胞肺癌。该患者为54岁女性,首诊主要症状为咳嗽、咳痰、胸痛4个月。胸部CT检查见右上叶后段-右下叶肿瘤性病变并阻塞性肺炎,右肺下叶转移瘤,纵隔、右肺门淋巴结增多、增大,右肺门软组织增厚;支气管镜检查病理活检明确诊断肺腺癌;二代测序基因检测结果提示棘皮动物微管样蛋白4-间变淋巴瘤激酶(echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase,EML4-ALK)融合伴随肿瘤蛋白53(tumor protein 53,TP53)和视网膜母细胞瘤1(retinoblastoma 1,RB1)基因突变。给予二代ALK-TKI阿来替尼靶向治疗,无进展生存期11个月。随后出现疾病进展,考虑对阿来替尼耐药,改为三代ALK-TKI洛拉替尼靶向治疗1个月无效,疾病快速系统性进展,神经元特异性烯醇化酶(neuron specific enolase,NSE)明显升高,短期内新发胸膜、心包、颅内、肝脏、骨转移。二次活检的结果提示为小细胞肺癌,更改治疗方案为化学治疗联合免疫治疗,症状缓解。ALK-TKI治疗ALK融合的晚期非小细胞肺癌耐药机制复杂,病理类型小细胞转化也是耐药机制之一,发生率极低,伴随TP53和RB1基因突变可能是其向小细胞转化的特征,NSE异常升高是腺癌向小细胞转化有预测作用的血清标志物,耐药后及时进行二次活检,根据不同耐药机制选择后续治疗对疾病全程管理非常重要。

Relationship between epithelial to mesenchymaltransition and chemoresistance of lung cancer

Objective： The aim of this study was to explore the correlation between epithelial to mesenchymal transition （EMT） and chemoresistance of non-small-cell lung cancer （NSCLC）. Methods： In vitro, the drug resistance index of cisplatin resistant lung adenocarcinoma cell line （A549/DDP） was detected by CCK-8 assay; the morphological change between A549/ DDP cells and lung adenocarcinoma cells （A549） was observed by phase contrast microscope; expression of EMT markers （including E-cadherin and vimentin） and resistance protein, excision repair cross-complementing 1 （ERCC1） was detected by immunocytochemistry. The expression of E-cadherin, vimentin and ERCC1 was investigated by immunohistochemistry in 120 cases of NSCLC, half of that were treated with pre-operative neoadjuvant chemotherapy （neoadjuvant chemotherapy group）, and the other underwent surgery alone （simple surgery group）. Results： There was a significant difference between the ICso （half maximal inhibitory concentration） of A549/DDP cells （5.20） and A549 cells （1.88） （P 〈 0.05）, and the drug resistance index of A549/DDP cells was 2.77. Compared with A549 cells, A549/DDP cells increased expression of ERCC1 （P 〈 0.05）. Moreover, A549/DDP cells showed morphological and phenotypic changes consistent with EMT： with spindle-shaped morphology, and decreased expression of E-cadherin and increased expression of vimentin. Immunohistochemistry showed significant positive correlation between the expression of ERCCI and vimentin （r = 0.496, 0.332, P 〈 0.05）, and significant negative correlation between the ERCCI and E-cadherin （r = -0.403, -0.295, P 〈 0.05） in neoadjuvant chemotherapy group and simple surgery group. In addition, compared with simple surgery group, the expression of ERCC1 （P = 0.003） and vimentin （P = 0.004） was significantly increased, and the expression of E-cadherin was decreased in neoadjuvant chemotherapy group （P = 0.032）. Cenclusion： A549/DDP cells acquired cisplatin-resistance and occurred EMT simultaneously; the phenomenon of chemoresistance and EMT was caused more easily in neoadjuvant chemotherapy group. As such, we further confirmed the close correlation between chemoresistance and EMT of NSCLC, and provided theoretical basis for the targeting therapy with EMT regulatory factor for chemoresistant NSCLC patients.