EGFR、TP53共突变的晚期非小细胞肺癌靶向治疗进展

TP53突变是表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变的晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)最常见的合并体突变,在靶向治疗过程中与疾病进展和较差的预后相关。为揭示TP53突变在EGFR突变的晚期NSCLC靶向治疗中的预后价值,探讨治疗方案,国内外医学界进行了深入的研究,但尚未达成共识。全文就近年来EGFR/TP53共突变的NSCLC靶向治疗的进展进行综述,为临床治疗研究提供新思路。     

TP53、EGFR共突变对NSCLC治疗的影响及对预后预测作用的进展

摘 要：随着二代基因检测技术的发展,人们发现与单个基因突变相比,多个体细胞共突变已被证明与预后较差有关。在这些共突变中,TP53突变最常见,但被认为是不可用药的靶点。近年来对TP53突变的预测价值进行了深入研究,由于结果不一致,尚未达到临床应用。本篇综述通过对近几年国内外关于TP53抑癌基因与EGFR共突变对非小细胞肺癌（non-small cell lung cancer,NSCLC）治疗及预后的影响进行小结,为EGFR伴随TP53突变NSCLC的靶向治疗提供新的思路。     

TP53-EGFR共突变对非小细胞肺癌预后及治疗的研究进展

非小细胞肺癌(Non-small cell lung cancer, NSCLC)是全球癌症相关死亡的主要原因。表皮生长因子受体酪氨酸激酶抑制剂(Epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI)是目前NSCLC患者靶向表皮生长因子受体(Epidermal growth factor receptor, EGFR)突变的标准一线治疗方法，然而原发性或获得性耐药会导致治疗中断和疾病进展。TP53突变是EGFR突变型NSCLC患者中最常见的共突变，研究表明TP53-EGFR共突变提示患者预后不良，对这类突变患者的治疗方案尚未达成共识。本文就TP53突变在晚期EGFR突变型NSCLC患者中的预后价值和TP53-EGFR共突变晚期NSCLC患者治疗的研究进展进行综述。     

EGFR复杂突变对酪氨酸激酶抑制剂治疗非小细胞肺癌疗效影响的研 究进展

表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI）是治疗EGFR基因突变的非小细胞肺癌（NSCLC）的靶向药物,因 其具有精准、高效、安全和使用便捷等优点而备受瞩目。但是,EGFR基因复杂突变（主要包括EGFR基因复合突变与EGFR基因 共突变）会影响NSCLC患者对EGFR-TKI治疗的敏感性。通过降低药物与肿瘤细胞之间的结合力或关键信号转导通路等多种作 用途径,可影响NSCLC患者的近期疗效及预后。根据现有证据分析影响TKI治疗NSCLC疗效的EGFR基因复杂突变类型的研 究发现,大多数EGFR基因复杂突变能够导致TKI疗效不佳,其作用机制可能与突变类型本身对药物的敏感性、介导病理类型更 加恶化或与导致DNA损伤修复障碍等作用相关。因此,提出多靶向药物联合治疗、EGFR-TKI联合化疗或联合血管靶向治疗等 方案,为EGFR基因复杂突变的NSCLC患者提供了新的增强EGFR-TKI疗效的临床治疗策略。     

TP53共突变对驱动基因阳性肺癌靶向治疗疗效的影响及对策

非小细胞肺癌(NSCLC)的发生发展常与致癌驱动基因变异有关。虽然靶向这些驱动基因的药物取得显著疗效,但TP53共突变已被证实是肺癌靶向治疗疗效差的重要因素。针对合并TP53突变的驱动基因变异肺癌患者,联合化疗或抗血管治疗等新策略取得了重要进展。鉴于此,该文总结了TP53共突变对驱动基因阳性肺癌靶向治疗疗效的影响,以及对这部分肺癌患者最佳治疗策略的探索。     

非小细胞肺癌EGFR突变类型与TKIs疗效关系的研究进展

摘 要：表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变状态的检测以及表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）的应用开创了晚期非小细胞肺癌患者个体化分子靶向治疗的新纪元。本文就EGFR的不同突变类型与TKIs临床疗效的关系进行综述,为临床上EGFR突变——尤其是少见EGFR突变类型的晚期非小细胞肺癌患者个体化治疗方案的选择提供理论依据。     

EGFR突变对NSCLC预后的影响

目的 探讨EGFR基因突变对非小细胞肺癌患者临床特征,预后的价值,揭示OS≥3生存的的影响因素。 目的 回顾性分析2013-01-01至2018-06-30南京医科大学附属肿瘤医院接受个体化治疗的349例NSCLC患者的临床资料。对应收集的石蜡包埋组织标本,采用HRM法,检测组织中EGFR基因第18、19、20、21外显子的突变状态,χ2分析EGFR基因突变与患者临床病理参数的相关性,Kaplan-Meier方法和χ2分析随访完整的249例EGFR基因突变情况对生存的影响,揭示OS≥3生存的的影响因素。 目的 在349例NSCLC肺癌患者中,EGFR基因突变率为50.4%,EGFR基因主要高突变人群是女性腺癌患者。在249例随访完整的患者中,女性,EGFR基因的总突变和21突变,能显著提高PFS和OS,差异具有统计学意义(P 目的 EGFR基因的总突变和21突变的患者均能明显延长生存期。尤其是TNM分期早,女性,21突变的患者,都可以针对性尝试靶向治疗,提高生存时间。     

EGFR/TP53/RB1三重突变的小细胞肺癌转化研究及治疗进展

表皮生长因子受体（epidermal growth factor receptor,EGFR）突变型非小细胞肺癌（non-small cell lung cancer,NSCLC）患者在接受EGFR酪氨酸激酶抑制剂（tyrosine kinase inhibitors, TKIs ）靶向治疗后能获得临床获益,但之后会不可避免地出现获得性耐药,而发生小细胞肺癌（small cell lung cancer,SCLC）组织学转化被认为是一种罕见的耐药机制。随着二代基因检测（next- generation sequencing,NGS）技术的快速发展及广泛应用,研究者发现存在EGFR/TP53/RB1三重突变的NSCLC经靶向治疗后更容易发生SCLC组织学转化,并且转化型SCLC疗效及预后较差。本文对近年来关于EGFR突变的NSCLC发生SCLC组织学转化的研究作一综述,涉及相关的转化机制、可能有效的新型药物及治疗策略,为EGFR/TP53/RB1三重突变的转化型SCLC患者提供更多潜在的临床治疗选择。      

EGFR敏感突变非小细胞肺癌脑转移患者临床特征综述

晚期非小细胞肺癌(NSCLC)常常合并脑转移,预后和生活质量较差。表皮生长因子受体(EGFR)是常见NSCLC的敏感基因突变类型,与其他分子类型相比,具有不同的分子生物学特征。随着靶向药物的广泛使用,EGFR敏感突变NSCLC脑转移的预后及颅内外控制有很大提高。为了更好地认识EGFR敏感突变NSCLC脑实质转移的特点,本文从脑转移的发病率、发病时间、发病部位、病灶数目及大小、发病症状、靶向治疗疗效和疾病转归等方面综述了EGFR突变阳性NSCLC脑实质转移的临床特征及治疗,为脑实质转移局部治疗的介入时机以及局部治疗技术选择提供参考。     

EGFR突变与非小细胞肺癌酪氨酸激酶抑制剂靶向治疗

肺癌的高发病率和高病死率，以及化疗对晚期肺癌疗效的十分有限，使之成为世界性医学难题。最近发现，表皮生长因子受体（epidermal growth factor receptor，EGFR）酪氨酸激酶抑制剂（tyrosine kinases inhibitors，TKIs）的分子靶向治疗可以使晚期非小细胞肺癌瘤体缩小；然而，以Gefitinib和Erlotinib为代表的TKIs治疗敏感性与EGFR基因突变显著相关。研究证实，EGFR最常见发生的19区缺失突变和21区点突变导致相应氨基酸序列和EGFR结构的改变，是其增加药物敏感性的主要机制。此外，EGFR基因扩增和CA重复序列的多态性、EGFR通路下游信号（如p-AKT等）激活、HER2和（或）HER3表达的增加、K—RAS基因突变等因素皆影响其对TKIs的治疗敏感性。鉴于此，进一步研究EGFR基因不同突变的功能，寻找能预测TKIs治疗敏感性的因素，并作为TKIs敏感患者的筛选指标，对于提高晚期肺癌患者TKIs靶向治疗疗效具有重要意义。     

EGFR19/21基因突变与NSCLC组织中p53蛋白表达的关系及对预后的影响

目的 探讨表皮生长因子受体19/21(EGFR19/21)基因突变与非小细胞肺癌(NSCLC)患者肿瘤组织中p53蛋白表达的关系及对患者预后的影响.方法 收集98例NSCLC患者的NSCLC组织标本,采用Taqman-ARMS法检测肿瘤组织中EGFR19/21基因的突变情况,采用免疫组化检测p53蛋白的表达情况,并根据EGFR19/21基因检测结果将患者分为突变组(n=44)和野生型组(n=54),分析EGFR19/21基因突变与p53蛋白表达及患者预后的关系.结果 EGFR19/21基因突变组NSCLC患者p53蛋白的阳性表达率为38.64％,低于野生型组NSCLC患者的59.26％,差异有统计学意义(P﹤0.05).不同年龄、性别、肿瘤直径、TNM分期、淋巴结转移情况、分化程度、病理类型、ECOG评分NSCLC患者的EGFR19/21基因突变发生率比较,差异均无统计学意义(P﹥0.05);Cox比例风险回归分析结果显示,TNM分期高、发生淋巴结转移、分化程度为低分化、p53蛋白阳性表达是影响NSCLC患者预后的独立危险因素(P﹤0.05),EGFR19/21突变是影响NSCLC患者预后的保护因素(P﹤0.05).结论 EGFR19/21基因突变的NSCLC患者,其p53蛋白呈现低表达,EGFR19/21野生型患者的预后较突变型差.     

Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in non-small cell lung cancers in relation to smoking history

Mutations in the tyrosine kinase domain of the epidermal growth factor receptor EGFR are common in non-small cell lung cancer (NSCLC) of never smokers, whereas HER2 mutations are rare. We have analyzed EGFR and HER2 mutations and the expression of the two products of the CDKN2A gene (p14(arf) and p16(INK4a)) in 116 NSCLC that have been previously analyzed for TP53 and KRAS mutations in relation to smoking history of patients. EGFR mutations were detected in 20 of 116 (17%) tumors, whereas five (4.3%) tumors contained HER2 mutations. No tumor contained both mutations. Of tumors with EGFR or HER2 mutation, 72% were adenocarcinomas, 68% were from never smokers, and 32% were from former smokers. EGFR but not HER2 mutations were mutually exclusive with KRAS mutation. Among never smokers, 11 of 16 tumors with EGFR mutation also had TP53 mutation, in contrast with two of 17 tumors without EGFR mutation (P = 0.0008). Expression of p14(arf), but not p16(ink4a), was more frequently down-regulated in never smokers (62.5%) than ever smokers (35%; P = 0.008). All tumors with EGFR or HER2 mutations and wild-type TP53 showed down-regulation of p14(arf) expression. These observations suggest that functional inactivation of the p14(arf)/p53 connection is required in tumors with EGFR or HER2 mutations, consistent with the notion that these proteins are part of a fail-safe mechanism protecting cells against untimely or excessive mitotic signals.     

Development of a rapid and practical mutation screening assay for human lung adenocarcinoma

Mortality after initial diagnosis of lung cancer is higher than from any other cancer. Although mutations in several genes, such as EGFR and K-ras, have been associated with clinical outcome, technical complexity, cost and time have rendered routine screening prohibitive for most lung cancer patients prior to treatment. In this study, using both novel and established technologies, we developed a clinically practical assay to survey the status of three frequently mutated genes in lung cancer (EGFR, K-ras and TP53) and two genes (BRAF and β-catenin) with known hotspot mutations in many other cancers. A single 96-well plate was designed targeting a total of 14 fragments (16 exons) from EGFR, K-ras, TP53, BRAF and β-catenin. In 96 lung adenocarcinoma patients, the mutation frequencies of three major genes (EGFR, K-ras and TP53) were between 21-24%. Fifty-six out of 96 (58%) patients had a mutation in at least one of the five genes. K-ras mutations positively correlated with smoking pack-years (p=0.035). EGFR mutations were frequent in never-smokers (p=0.0007), Asians (p=0.0204) and non-stage I lung cancer (p=0.016). There was also a trend towards an association between the presence of any mutation and improved recurrence-free survival (p=0.070). We demonstrate that our novel multigene mutation assay technology can rapidly and cost-effectively screen for mutations in lung adenocarcinoma. This screening assay can be used in the clinical setting for the large-scale validation of prognosis and/or predicting therapeutic response so that the majority of lung cancer patients can benefit from leveraging up-to-date knowledge on how mutation profiles may influence treatment options.     

Influence of epidermal growth factor receptor (EGFR) gene mutations on the expression of EGFR, phosphoryl-Akt, and phosphoryl-MAPK, and on the prognosis of patients with non-small cell lung cancer

BACKGROUND AND OBJECTIVES: In this paper we examined the influence of epidermal growth factor receptor (EGFR) gene mutations on EGFR expression, downstream mediators, and survival in patients with non-small cell lung cancer (NSCLC). METHODS: We retrospectively analyzed the tumors of 53 patients with completely resected pathological stage I-IIIA NSCLC for the presence of EGFR gene mutations, the expression of EGFR mRNA and protein, phosphoryl-Akt, and phosphoryl-mitogen-activated protein kinase (MAPK) using immunostaining, and patients' prognosis. RESULTS: EGFR mutations were associated with elevations in EGFR mRNA (P = 0.004) and protein (P = 0.029) expression, but not with the expression of phosphoryl-Akt or phosphoryl-MAPK. The 5-year survival rate for all patients who exhibited an EGFR mutation was similar to those who were free of such mutations (71% vs. 56%, P = 0.252). However, the 5-year survival rate of patients with either a stage I adenocarcinoma or large cell carcinoma who had an EGFR mutation was significantly greater than for those who did not have such a mutation (92% vs. 57%, P = 0.037). CONCLUSIONS: EGFR gene mutations were significantly associated with higher EGFR expression, but not with p-Akt or p-MAPK status. In early stage NSCLC, the presence of an EGFR gene mutation bode well for the patient's prognosis.     

EGFR突变状态对NSCLC脑转移和放疗及靶向治疗疗效影响

脑转移为肺癌患者死亡的主要原因之一。尽管予以手术、放疗为主的标准治疗,预后仍然欠佳。近年来,随着对肺癌分子机制研究的深入,EGFR突变可能成为酪氨酸激酶抑制剂(TKI)治疗NSCLC脑转移有效的关键靶点。为此,笔者就EGFR突变对非小细胞肺癌脑转移发生及预后影响的进展进行综述。     

非小细胞肺癌EGFR基因突变的临床意义研究

  目的   探讨非小细胞肺癌EGFR基因外显子突变与其临床病理特征的关系。   方法   利用ADx-ARMS?EGFR基因突变检测试剂盒,检测214例未接受过Gefitinib治疗的非小细胞肺癌患者组织中EGFR基因外显子18、19、20和21突变。   结果   非小细胞肺癌组织中EGFR基因总突变率为45.8%（98/214）,外显子18、19、20和21的突变率分别为0.93%（2/214）、22.0%（47/214）、2.3%（5/ 214）和20.6%（44/214）。另有2例19和21外显子双重突变。EGFR基因在肺腺癌组织中的总突变率为50.3%（93/185）明显高于肺鳞状细胞癌17.2%（5/29）（P=0.001）。EGFR基因在女性患者中的突变率57.0%（57/100）高于男性36.0%（41/114）（P=0.002）,EGFR基因在NSCLC淋巴结转移患者中的突变率（66.7%）显著高于无淋巴结转移患者（39.5%）（P < 0.05）,但EGFR基因突变率与肺癌患者的年龄、肿瘤分级和临床分期均无显著性差异（P>0.05）。   结论   中国肺癌尤其是肺腺癌患者存在EGFR基因的较高突变率,EGFR外显子19、21突变结合肺癌的临床病理特征有望成为评估TKI治疗非小细胞肺癌疗效的分子标志。      

Impact of HER2 and EGFR gene status on gefitinib-treated patients with nonsmall-cell lung cancer

We previously examined the relationship between epidermal growth factor receptor (EGFR) status and clinical outcomes of nonsmall-cell lung cancer (NSCLC) patients treated with gefitinib. In our study, we additionally examined HER2 status and investigate the impact of genetic status as predictors in Japanese NSCLC patients treated with gefitinib. The HER2 copy number status was determined by fluorescence in situ hybridization assay and mutation of HER2 exon 20 was determined by direct sequencing in 74 patients to investigate the relationship between molecular statuses including HER2 and EGFR and the clinical outcomes of patients treated with gefitinib. The high HER2 copy number was identified in 32 (43.2%) of 74 NSCLC patients and no HER2 exon 20 mutations were found. The high HER2 copy number was significantly associated with the sensitivity to gefitinib (p = 0.0045) and a prolonged progression-free survival (PFS) (p = 0.0089) in a univariate analysis, but not in a multivariate analysis. Multivariate analyses exhibited that the drug-sensitive EGFR mutation was an independent predictive factor of a better sensitivity to gefitinib (OR = 41.9, p = 0.002), prolonged overall survival (HR = 0.32, p = 0.019) and PFS (HR = 0.31, p = 0.0045). The high EGFR copy number might have a weak association with better response and prognosis without statistical significance. In conclusion, the drug-sensitive EGFR mutation, rather than HER2 and EGFR copy numbers, is a determinant of favorable clinical outcomes in gefitinib-treated patients with NSCLC, although the high HER2 copy number, to some extent, may influence the gefitinib effect.     

Association of epidermal growth factor receptor (EGFR) gene mutations with EGFR amplification in advanced non-small cell lung cancer

Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the response to EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Increased EGFR copy number has also been associated with sensitivity to these drugs. However, given that it is often difficult to obtain sufficient amounts of tumor tissue for genetic analysis from patients with advanced NSCLC, the relationship between these two types of EGFR alterations has remained unclear. We have now evaluated EGFR mutation status both by direct sequencing and with a high-sensitivity assay, the Scorpion-amplification-refractory mutation system, and have determined EGFR copy number by fluorescence in situ hybridization (FISH) analysis in paired tumor specimens obtained from 100 consecutive patients with advanced NSCLC treated with chemotherapy. EGFR mutations or FISH positivity (EGFR amplification or high polysomy) were apparent in 18% (18/100) and 32% (32/100) of patients, respectively. The Scorpion-amplification-refractory mutation system was more sensitive than direct sequencing for the detection of EGFR mutations. Furthermore, EGFR mutations were associated with EGFR amplification (P = 0.009) but not with FISH positivity (P = 0.266). Our results therefore suggest the existence of a significant association between EGFR mutation and EGFR amplification in patients with advanced NSCLC.     

Molecular Characteristics of the Uncommon EGFR Exon 21 T854A Mutation and Response to Osimertinib in Patients With Non-Small Cell Lung Cancer

BackgroundEpidermal growth factor receptor (EGFR) T854A is an uncommon exon 21 mutation in patients with non-small cell lung cancer (NSCLC). It was first reported in samples collected after first generation EGFR tyrosine kinase inhibitor (TKI) treatment as an acquired resistant mutation to first generation EGFR-TKI. The efficacy of osimertinib, a third generation EGFR-TKI, in these patients was not clear.MethodsIn this study, a total of 8932 NSCLC patients with NGS data were retrospectively analyzed to investigate the molecular characteristics and clinical outcomes of patients with EGFR T854A mutation.ResultsEight of 8932 patients (0.09%) had EGFR T854A mutation, and 5 of them (62.5%) were treatment-naïve. Interestingly, all EGFR T854A mutations were co-occurred with EGFR L858R mutation in cis. TP53 was the most common concomitant mutation and no other driver mutation was found. Five of the 8 patients received treatment of osimertinib. Four patients achieved partial response, and one had stable disease, resulting in an overall objective response rate of 80% and disease control rate of 100%. The median progression-free survival of patients who received osimertinib was 10 months. Moreover, EGFR C797S mutation was detected in 1 patient after resistant to osimertinib treatment.ConclusionPresence of EGFR T854A mutation was rare in NSCLC patients and our retrospective study provides clinical evidence that osimertinib may be an effective treatment to improve survival outcomes in patients with EGFR T854A.