Ⅳ期EGFR阳性肺腺癌综合治疗1例并文献复习

报告1例Ⅳ期表皮生长因子受体(epidermal growth factor receptor,EGFR)阳性肺腺癌患者,在治疗过程中局部治疗及多次活体组织检查(以下简称活检)在综合治疗中起重要作用。患者,女,76岁,2017年2月以"持续背部疼痛1个月余,发现左肺占位1周"为主诉来郑州大学第一附属医院就诊。外院PET-CT检查示左肺上叶占位代谢活跃,考虑肺癌,胸11椎体、胸12椎体及腰2椎体代谢活跃,考虑转移。行肺占位穿刺活检,穿刺病理示:肺腺癌,EGFR第19外显子缺失突变。诊断为"左肺腺癌cT2aN0M1cⅣB期"。一线治疗方案:"靶向治疗+局部治疗"(吉非替尼+椎体转移癌微波消融并椎体成形术+唑来膦酸),无进展生存(progression-free survival,PFS)8个月。2017年10月疾病出现局部进展,再次行穿刺活检,病理示:肺腺癌,EGFR第19外显子缺失突变。治疗方案:"靶向治疗+局部治疗"(吉非替尼+左肺癌射频消融术),PFS为4个月。2018年2月疾病出现快速进展,第3次穿刺活检肺新发转移结节,病理示:肺腺癌,EGFR第19外显子缺失突变。EGFR第20外显子T790M错义突变。二线治疗方案:靶向药物(甲磺酸奥希替尼),PFS为18个月。2019年8月疾病出现快速进展,肺多发结节,脑多发结节。第4次穿刺活检病理示:EGFR第19外显子缺失突变。EGFR第20外显子T790M错义突变。三线治疗方案:化学药物治疗(培美曲塞二钠+洛铂+重组人血管内皮抑制素)2个周期。患者目前仍在随访中。     

奥希替尼治疗获得性表皮生长因子受体-酪氨酸激酶抑制剂耐药T790M突变肺腺癌晚期1例

报告1例使用奥西替尼治疗表皮生长因子受体(epithelial growth factor receptor,EGFR)基因19外显子缺失突变耐药后T790M突变肺腺癌晚期患者。患者,女,72岁,无明显诱因出现左侧胸闷、气喘5 d于当地医院治疗,查胸部CT示双侧胸腔积液,右肺中叶占位,并纵隔淋巴结肿大。为求进一步治疗遂来郑州大学第一附属医院,入院完善相关检查,PET-CT示右肺中叶软组织肿块代谢较活跃,考虑肺癌,建议结合病理诊断;双侧锁骨上区、纵隔及右肺门多发淋巴结肿大,代谢活跃,考虑转移。不符合手术指征,未进行手术治疗,第1次CT引导下经皮肺穿刺活检确诊肺腺癌,基因检测示EGFR基因第19外显子缺失突变,于2017年11月29日开始服用吉非替尼,至2018年12月4日停止服用。期间复查CT发现右上肺结节较前增大,第2次CT引导下经皮肺穿刺活检结果示肺腺癌,基因检测示EGFR基因18外显子缺失突变,合并EGFR基因第20外显子T790M突变,于2018年12月4日开始服用奥希替尼至今,复查未见异常。     

1例晚期非小细胞肺癌患者的全程管理

山西省肿瘤医院呼吸一病区收治1例IV期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者。患者,男,50岁,于2012年10月初无明显诱因出现刺激性咳嗽、咳痰。正电子发射计算机断层显像(positron emission tomography-computed tomography,PET-CT)提示:右肺上叶癌,右锁区、纵隔及右肺门肿大淋巴结转移。全身多发骨质破坏。病理(右肺穿刺物)检查示腺癌。变性高效液相色谱(denaturing high performance liquid chromatography,DHPLC)示EGFR19外显子突变。一线治疗给予培美曲塞二钠联合顺铂全身化疗6周期,无进展生存期(progression-free survival,PFS)为8个月;二线治疗予吉非替尼,PFS为42个月;三线治疗继续口服吉非替尼,PFS为4个月;四线治疗予口服AZD9291,PFS为11个月;五线治疗予吉非替尼联合阿帕替尼,PFS为2个月;六线治疗行右上肺楔形切除术,术后病理示:BRAF V600E突变,出现头颅转移,给予培美曲塞二钠+顺铂全身化疗2周期,并予同步左侧额叶、左侧顶叶转移灶大分割调强放疗,PFS为3个月;液滴式数字聚合酶链式反应(droplet digital polymerase chain reaction,ddPCR):T790M(+),七线治疗口服奥希替尼联合培美曲塞单药化疗2周期,疗效评估为部分缓解(partial response,PR),目前仍在随访中。     

1例EGFR T790M突变阳性晚期肺腺癌的治疗策略及文献复习

回顾性分析中南大学湘雅医学院附属株洲医院1例晚期肺腺癌患者的临床资料,并进行相关文献复习。该患者经胸腔穿刺术及左侧淋巴结活检确诊为肺腺癌,头部MRI及上腹部增强CT示头、肝、脾、胰腺及左侧肾上腺多发转移,表皮生长因子受体扩增阻滞突变系统(epidermal growth factor receptor-amplification refractory mutation system,EGFR-ARMS)检测提示EGFR 21外显子突变(L858R),给予第1代EGFR抑制剂(tyrosine kinase inhibitors,TKIs;吉非替尼)治疗11个月后,病情出现进展,再次基因检测EGFR T790M突变为阳性,二线给予第3代EGFR-TKIs(奥西替尼)治疗,病情得到缓解。说明初次EGFR-TKIs治疗后,部分晚期肺腺癌患者耐药后仍然可在EGFR-TKIs治疗中受益。以奥西替尼为代表的第3代EGFR-TKIs治疗耐药后出现T790M突变的患者疗效显著,给晚期肺癌患者带来更多的生存获益。     

奥希替尼治疗T790M突变的晚期肺腺癌1例并文献复习

在肺癌的驱动基因中,表皮生长因子(epidermal growth factor receptor,EGFR)是其最常见的驱动基因之一。在EGFR突变阳性的患者中,一线使用表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors,EGFR-TKIs)(例如吉非替尼、埃克替尼、阿法替尼等)口服治疗,已经体现出良好的疗效。但大多数患者在服用初始一线的TKIs治疗后出现T790M突变,引起耐药,导致疾病进展。嘉兴市第二医院呼吸与危重症医学科收治的1例EGFR突变阳性患者,在使用吉非替尼片口服治疗1年后,出现疾病进展。行基因检测后提示T790M突变阳性,改奥希替尼口服。目前患者疗效评价为部分缓解。奥希替尼对于出现T790M突变患者的治疗,有着稳定的疗效。早期及时将临床、病理和分子诊断学技术联合起来对患者治疗进行全程管理,可以为晚期非小细胞肺癌患者的治疗提供强有力的保障。     

奥希替尼治疗经埃克替尼一线治疗后进展并继发T790M突变的肺腺癌1例

徐州医科大学附属常熟医院收治1例埃克替尼治疗进展后继发T790M突变的肺腺癌接受二线奥希替尼治疗的女性患者。该患者70岁,反复咳嗽咳痰15年,加重半月;CT提示右肺中叶实变影,大量胸腔积液;病理报告:(胸水细胞块)转移性腺癌,倾向肺来源;血液基因检测示EGFR 19Del合并TP53突变;口服埃克替尼125 mg,每天3次,10个月后疾病进展,再次血液基因检测T790M突变,口服奥希替尼80 mg,每天1次,随访至今(9个月),疾病达到部分缓解(partial response,PR)。因此,晚期非小细胞肺癌患者治疗前应明确基因状态,对于阳性患者给与表皮生长因子受体-酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors,EGFR-TKIs)治疗,可以使患者获得更长的总生存期和更好的生活质量。     

吉非替尼联合AP化疗治疗晚期肺腺癌患者的疗效分析

目的:探究吉非替尼联合AP化疗治疗Ⅲb/Ⅳ期表皮生长因子受体(EGFR)突变阳性晚期肺腺癌患者的效果。方法:选取我院2014年8月～2016年8月收治的Ⅲb/Ⅳ期EGFR突变阳性晚期肺腺癌患者64例,采用随机数字表法分为对照组和观察组各32例。对照组给予AP化疗治疗,观察组于对照组基础上给予吉非替尼治疗。比较两组临床疗效。结果:观察组治疗总有效率、中位无进展生存期均明显高于对照组(P0.05);治疗前,两组血清CA242、CA125、CEA水平比较,差异无统计学意义(P0.05);治疗后,观察组血清CA242、CA125、CEA水平均低于对照组(P0.05);两组白细胞减少、皮疹、肺炎、恶心呕吐发生率比较,差异无统计学意义(P0.05)。结论:吉非替尼、AP化疗联合治疗Ⅲb/Ⅳ期EGFR突变阳性晚期肺腺癌,可降低患者血清肿瘤标志物水平,延长其中位无进展生存期,疗效显著,且安全性高。     

非小细胞肺癌接受埃克替尼治疗进展后继发性T790M突变

目的:探讨非小细胞肺癌(non-small cell lung cancer,NSCLC)患者接受埃克替尼治疗进展后的继发性T790M突变情况。方法:应用突变扩增阻滞系统(amplification refractory mutation system,ARMS)方法检测209例EGFR 19del或L858R突变NSCLC患者接受埃克替尼治疗进展后T790M突变状态,并分析临床特征。结果:209例NSCLC样本中,19del有123例,L858R有86例,接受埃克替尼治疗耐药后检测T790M突变型患者占45.93%(96/209),耐药后T790M突变与19del/L858R之间差异有统计学意义(P0.034)。结论:EGFR常见突变的NSCLC患者,19del患者接收埃克替尼治疗后更易出现T790M突变,应予以重视。     

肺肉瘤样癌二例

例1,男,72岁,因咳嗽、右侧胸痛1月余入院。胸部CT平扫示:右上肺软组织块影,大小约5.3cm×2.5cm×2cm,轻度分叶,密度不均,周围胸膜增厚,无明显毛刺,两侧肺门见肿大淋巴结,拟诊断为右上肺周围型肺癌(图1,2)。完善相关实验室检查后行右上肺叶切除术,术中病灶位于右上肺,大小约5cm×     

1例EGFR敏感突变局部晚期肺鳞癌病例报告及文献复习

报告1例信阳市中心医院经病理确诊、EGFR检测敏感突变的局部晚期肺鳞癌,该患者为一老年男性,不能耐受同步放化疗后序贯接受表皮生长因子受体-酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors,EGFR-TKIs)治疗,效果显著,无进展生存期(progression-free survival,PFS)达19个多月,后期病情进展后再次行基因检测(液态活检),发现T790M突变,给予第3代TKI奥希替尼治疗后仍然有效。对于III期不可切除的局部晚期肺鳞癌,EGFR基因检测非常重要,同步放化疗后序贯EGFR-TKIs分子靶向药物的治疗模式,可延长此类患者的生存时间和提高生活质量。     

Combine therapy of gefitinib and fulvestrant enhances antitumor effects on NSCLC cell lines with acquired resistance to gefitinib

Gefitinib, an EGFR receptor tyrosine kinase inhibitor, is approved for clinical use in the treatment of non-small cell lung cancer (NSCLC), but the emergence of mutations resistant to these inhibitors, such as T790M, has become a clinical problem. According to statistics, female patients, the presence of adenocarcinoma or non-smokers experienced a higher response rate. This may be involved in interaction between the estrogen receptor (ER) and the epidermal growth factor receptor (EGFR). To test whether inhibition of the ER signaling pathway affects the antitumor effect of gefitinib, gefitinib and an ER antagonist, fulvestrant, were administered to NSCLC cell lines with acquired resistance to gefitinib. Compared with treatment of either fulvestrant or gefitinib alone, drug combination obviously decreased proliferation of H1976, H1650 and PC-9 cells coming from adenocarcinoma. Rapid activations of EGFR pathway by E2β were observed in H1975 cells with T790M mutation. Additionally, EGFR and ERs expression were down-regulated respectively in response to estrogen and EGF but up-regulated in response to fulvestrant and gefitinib in vitro. These results suggest that there is a functional cross-signaling between the EGFR/ER pathways in NSCLC with acquired resistance to gefitinib, possibly providing rationale for combining gefitinib with anti-estrogen therapy for advanced NSCLC treatment.     

江西地区非小细胞肺癌EGFR基因突变分析

目的探讨江西地区非小细胞肺癌(NSCLC)患者表皮生长因子受体(EGFR)基因突变类型、突变率及其与临床特征的关系。方法收集2014年3月至2015年6月南昌大学第一附属医院非小细胞肺癌患者石蜡包埋组织78例,采用等位基因特异性扩增-聚合酶链反应(ARMS-PCR)方法,对非小细胞肺癌患者肿瘤组织EGFR基因18~21外显子突变进行检测,并分析其突变类型、突变发生率及其与临床特征之间的关系。结果在78例非小细胞肺癌患者中,共有27例发生EGFR基因突变,总突变率为34.6%。其中,第18、19、20、21号外显子突变率分别2.6%(2/78),12.8%(10/78),3.9%(3/78),14.1%(11/78)。一例既有21号外显子突变,又有20号外显子突变,其中,19号外显子的突变均为第746~750密码子的碱基缺失,21号外显子突变类型以L858R为主,且19号外显子的突变率与21号外显子的突变率无统计学差异(P0.05),女性EGFR基因的突变率显著高于男性,不吸烟者显著高于吸烟者,腺癌患者显著高于鳞癌患者(P0.05),而EGFR基因的突变率与非小细胞肺癌患者的年龄、临床分期无相关性(P0.05)。结论江西地区的非小细胞肺癌EGFR基因突变以19、21号外显子为主,常见于女性、不吸烟、腺癌的非小细胞肺癌患者。     

Response to gefitinib/crizotinib combination in a pulmonary sarcomatoid carcinoma patient harboring concurrent EGFR mutation and MET amplification

Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non‐small cell lung cancer (NSCLC) with an extremely poor prognosis making it a therapeutic challenge. However, the development of genetic variation molecular diagnosis and targeted agents has brought the treatment of such malignancies to the precision era. Co‐existing mutations of EGFR and MET have been reported in NSCLC, but rarely found in PSC. We herein present a rare case of a 74‐year‐old female patient diagnosed with PSC, carrying an activating mutation in exon 21 L858R of EGFR and a concurrent MET amplification prior to treatment. Combined application of gefitinib and crizotinib, inhibitors targeting EGFR and MET, respectively, was prescribed. The patient experienced a partial response and was stable for 9.7 months off therapy. The observation stresses the importance of genetic testing and paves the way for combined targeted strategies in PSC.     

Combined tamoxifen and gefitinib in non-small cell lung cancer shows antiproliferative effects

Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is approved for clinical use in the treatment of non-small cell lung cancer (NSCLC). According to statistics, NSCLC patients who are female, have adenocarcinoma, or never smoked have a higher response rate to gefitinib treatment. This phenomenon could be due to the interaction between the estrogen receptor (ER) and EGFR. To test whether inhibition of the EGFR signaling pathway affects the antitumour effect of gefitinib, NSCLC cell lines were treated with gefitinib and tamoxifen, an ER antagonist. Cotreatment with gefitinib plus tamoxifen decreased the proliferation and increased the apoptosis of A549 and H1650 adencarcinoma cell lines, when compared with either drug alone. However, there was no effect on H520 cells (squamous cell carcinoma). Rapid activation of the EGFR pathway by both EGF and β-E2 was observed in A549 cells. Additionally, EGFR and ERβ expression was down-regulated in response to estrogen and EGF, respectively, but up-regulated in response to tamoxifen and genfitib, respectively. These results suggest that there is a functional cross-signaling between the EGFR and the ER pathways in NSCLC, possibly providing a rationale to combine gefitinib with anti-estrogen therapy for lung cancer treatment.     

吉非替尼治疗伴有EGFR基因检测的非小细胞肺癌的文献综合分析

[目的]了解吉非替尼治疗非小细胞肺癌肺癌的疗效及生物学特性与治疗疗效的相关性.[方法]在Pubmed和Sciencedirect网站收集了6个伴有EGFR基因检测的非小细胞肺癌使用吉非替尼治疗的前瞻性临床试验进行分析.[结果]分别对吉非替尼治疗的患者特征、患者EGFR基因突变、疗效及不良反应的数据进行列表并对比分析.有EGFR基因突变患者的CR、PR、SD、PD、RR、DCR、中位无进展生存期、中位总生存期的各项结果均优于总体患者的结果,有EGFR基因突变患者疗效情况比总体患者疗效情况好,提示吉非替尼对有EGFR基因突变患者治疗效果更佳,是吉非替尼治疗NSCLC的优势人群.[结论]吉非替尼的优势人群为亚裔、女性、非吸烟者,吉非替尼的疗效比含铂化疗方案疗效佳,并且吉非替尼对有EGFR基因突变患者治疗效果更佳.     

Successful treatment of refractory lung adenocarcinoma harboring a germline BRCA2 mutation with olaparib: A case report

BACKGROUNDIn recent years, targeted therapy and immunotherapy have become important treatment strategies for patients with non-small cell lung cancer (NSCLC). However, the clinical evidence for successful off-label use of targeted drugs for patients with NSCLC following progression on multiple lines of treatment is still lacking.CASE SUMMARYWe describe a 62-year-old male patient with a right lung adenocarcinoma who harbored an EGFR exon 19 deletion mutation. He received gefitinib combined with six cycles of vinorelbine, cisplatin, and recombinant human endostatin as the first-line therapy. Then gefitinib was administered in combination with recombinant human endostatin as maintenance therapy, resulting in a progression-free survival (PFS) of 14 mo. Chemoradiotherapy was added following progression (enlarged brain metastases) on maintenance treatment. Unfortunately, the brain lesions were highly refractory and progressed again after 15 mo, at which time next-generation sequencing (NGS) of 1021 cancer-related genes was performed using peripheral blood to identify potential actionable mutations. NGS revealed that the patient harbored a BRCA2 germline mutation, the EGFR exon 19 deletion mutation disappeared, and no additional targetable genetic variant was detected. Therefore, the patient received olaparib combined with gefitinib and recombinant human endostatin, with a rapid and long-lasting clinical response (PFS = 13.5 mo).CONCLUSIONThis is a rare case of lung adenocarcinoma in a patient with a BRCA2 germline mutation who had long-term benefit from olaparib combination treatment, suggesting that NGS-based genetic testing may render the possibility of long-term survival in NSCLC patients after disease progression.     

Durable response to pulsatile icotinib for central nervous system metastases from EGFR-mutated non-small cell lung cancer: A case report

BACKGROUND Central nervous system(CNS) metastases are a catastrophic complication of nonsmall cell lung cancer(NSCLC), including brain and leptomeningeal carcinomatosis, and are always accompanied by a poor prognosis. Despite the continuous development of existing treatments, the therapy of CNS metastases remains challenging.CASE SUMMARY We report a patient who was definitively diagnosed with brain and leptomeningeal metastases from NSCLC with a targeted mutation in epidermal growth factor receptor(EGFR). A standard dosage of icotinib(125 mg three times daily) was implemented but ineffective. CNS lesions developed despite stable systemic control, so pulsatile icotinib(1125 mg every 3 d) was administered. This new strategy for administration has lasted 25 mo so far, and resulted in complete remission of neurological symptoms, almost vanished lesions, and longer survival with no notable side effects.CONCLUSION This is the first successful example of pulsatile icotinib for treating isolated CNS progression from EGFR mutation-positive NSCLC, providing a new alternative for the local treatment of CNS metastases.