Molecularly targeted therapies for advanced or metastatic non-small-cell lung carcinoma

Non-small-cell lung cancer(NSCLC)remains the leading cause of cancer-related death in both men and women in the United States.Platinum-based doublet chemotherapy has been a standard for patients with advanced stage disease.Improvements in overall survival and quality of life have been modest.Improved knowledge of the aberrant molecular signaling pathways found in NSCLC has led to the development of biomarkers with associated targeted therapeutics,thus changing the treatment paradigm for many NSCLC patients.In this review,we present a summary of many of the currently investigated biologic targets in NSCLC,discuss their current clinical trial status,and also discuss the potential for development of other targeted agents.

Evolution of breast cancer therapeutics: Breast tumour kinase's role in breast cancer and hope for breast tumour kinase targeted therapy

There have been significant improvements in the detection and treatment of breast cancer in recent decades. However, there is still a need to develop more effective therapeutic techniques that are patient specific with reduced toxicity leading to further increases in patients' overall survival; the ongoing progress in understanding recurrence, resistant and spread also needs to be maintained. Better understanding of breast cancer pathology, molecular biology and progression as well as identification of some of the underlying factors involved in breast cancer tumourgenesis and metastasis has led to the identification of novel therapeutic targets. Over a number of years interest has risen in breast tumour kinase(Brk) also known as protein tyrosine kinase 6; the research field has grown and Brk has been described as a desirable therapeutic target in relation to tyrosine kinase inhibition as well as disruption of its kinase independent activity. This review will outline the current "state of play" with respect to targeted therapy for breast cancer, as well as discussing Brk's role in the processes underlying tumour development and metas-tasis and its potential as a therapeutic target in breast cancer.

Efficacy and safety of dacomitinib as first-line treatment for advanced non-small cell lung cancer patients with epidermal growth factor receptor 21L858R mutation:A multicenter,case-series study in China

Objective:To provide real-world evidence for the application of first-line dacomitinib treatment for epidermal growth factor receptor(EGFR)21L858R mutant non-small cell lung cancer(NSCLC)patients in China and to explore the factors influencing the efficacy and safety.Methods:A longitudinal,consecutive case-series,multicenter study with mixed prospective and retrospective data was conducted.The primary endpoint was progression-free survival(PFS),and the secondary endpoints included duration of treatment(DOT),overall survival(OS),objective response rate(ORR),disease control rate(DCR)and safety.Results:A total of 155 EGFR 21L858R mutant patients treated with first-line dacomitinib were included.The median follow-up time for these patients was 20.4 months.Among 134 patients with evaluable lesions,the ORR was 70.9%and the DCR was 96.3%.The median PFS was 16.3[95%confidence interval(95%CI),13.7−18.9]months.Multivariate Cox regression analysis suggested that the baseline brain metastasis(BM)status[with vs.without BM:hazard ratio(HR),1.331;95%CI,0.720−2.458;P=0.361]and initial doses(45 mg vs.30 mg:HR,0.837;95%CI,0.427−1.641;P=0.604)did not significantly affect the median PFS.The median DOT was 21.0(95%CI,17.5−24.6)months and the median OS was not reached.Genetic tests were performed in 64 patients after progression,among whom 29(45.3%)patients developed the EGFR 20T790M mutation.In addition,among the 46 patients who discontinued dacomitinib treatment after progression,31(67.4%)patients received subsequent third-generation EGFR-tyrosine kinase inhibitors.The most common grade 3−4 adverse events were rash(10.4%),diarrhea(9.1%),stomatitis(7.1%)and paronychia(4.5%).The incidence of grade 3−4 rash was significantly higher in the 45 mg group than that in the 30 mg group(21.9%vs.7.5%,P=0.042).Conclusions:First-line dacomitinib treatment demonstrated promising efficacy and tolerable adverse events among EGFR 21L858R mutant NSCLC patients in China.

Targeted therapies for patients with advanced NSCLC harboring wild-type EGFR:what's new and what's enough

Historically,non-small cell lung cancer(NSCLC) is divided into squamous and nonsquamous subtypes based on histologic features.With a growing number of oncogenic drivers being identified in squamous and nonsquamous NSCLC,this malignancy has been recently divided into several distinct subtypes according to the specific molecular alterations.This new paradigm has substantially highlighted the treatment of advanced NSCLC,shifting it from standard chemotherapy according to specific histologic subtypes to targeted therapy according to specific oncogenic drivers.The application of epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs) in NSCLC patients harboring activating EGFR mutations has been a representative model of precise medicine in the treatment of NSCLC.As the role of EGFR-TKIs in routine management of patients with advanced NSCLC has been well established,this review provides an overview of alternative targeted therapy in the treatment of NSCLC,including EGFR-TKIs for patients with wild-type EGFR NSCLC,as well as other targeted agents either clinical available or in early- to late-stage development.

Accuracy of endoscopic ultrasound-guided needle aspiration specimens for molecular diagnosis of non-small-cell lung carcinoma

BACKGROUND Endoscopic ultrasonography-guided fine-needle aspiration(EUS-FNA)and endobronchial ultrasound-guided transbronchial needle aspiration(EBUS-TBNA)are highly sensitive for diagnosing and staging lung cancer.In recent years,targeted therapy has shown great significance in the treatment of non-small cell lung carcinoma(NSCLC).Using these minimally invasive techniques to obtain specimens for molecular testing will provide patients with a more convenient diagnostic approach.AIM To evaluate the feasibility and accuracy of tissue samples obtained using EUSFNA and EBUS-TBNA for molecular diagnosis of NSCLC.METHODS A total of 83 patients with NSCLC underwent molecular testing using tissues obtained from EUS-FNA or EBUS-TBNA at the Tianjin Medical University Cancer Hospital from January 2017 to June 2019.All enrolled patients underwent chest computed tomography or positron emission tomography/computed tomography prior to puncture.We detected abnormal expression of EGFR,KRAS,MET,HER2,ROS1 and anaplastic lymphoma kinase protein.Two patients failed to complete molecular testing due to insufficient tumor tissue.The clinical features,puncture records,molecular testing results and targeted treatment in the remaining 81 patients were summarized.RESULTS In a total of 99 tissue samples obtained from 83 patients,molecular testing was successfully completed in 93 samples with a sample adequacy ratio of 93.9%(93/99).Biopsy samples from two patients failed to provide test results due to insufficient tumor tissue.In the remaining 81 patients,62 cases(76.5%)were found to have adenocarcinoma,11 cases(13.6%)had squamous cell carcinoma,3 cases(3.7%)had adenosquamous carcinoma and 5 cases(6.2%)had NSCLC-not otherwise specified.The results of molecular testing showed EGFR mutations in 21 cases(25.9%),KRAS mutations in 9 cases(11.1%),ROS-1 rearrangement in 1 case(1.2%)and anaplastic lymphoma kinase-positive in 5 cases(6.2%).Twentyfour patients with positive results received targeted therapy.The total effectiveness rate of targeted therapy was 66.7%(16/24),and the disease control rate was 83.3%(20/24).CONCLUSION Tissue samples obtained by EUS-FNA or EBUS-TBNA are feasible for the molecular diagnosis of NSCLC and can provide reliable evidence for clinical diagnosis and treatment.

Efficacy Differences of First-line EGFR-TKIs Alone vs in Combination with Chemotherapy in Advanced Lung Adenocarcinoma Patients with Sensitive EGFR Mutation and Concomitant Non-EGFR Genetic Alterations

Background and objective:Epidermal growth factor receptor(EGFR)mutations are often associated with non-EGFR genetic alterations,which maybe a reason for the poor efficacy of EGFR tyrosine kinase inhibitors(TKIs).Here we conducted this study to explore whether EGFR-TKIs combined with chemotherapy would benefit advanced lung adenocarcinoma patients with both sensitive EGFR mutation and concomitant non-EGFR genetic alterations.Materials and methods:Cases of advanced lung adenocarcinoma with EGFR mutation combined with concomitant nonEGFR genetic alterations were retrospectively collected.And the patients were required to receive first-line EGFR-TKIs and chemotherapy combination or EGFR-TKIs monotherapy.Demographic,clinical and pathological data were collected,and the electronic imaging data were retrieved to evaluate the efficacy and time of disease progression.Survival data were obtained through face-to-face or telephone follow-up.The differences between the two groups in objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS)and overall survival(OS)were investigated.Results:107 patients were included,including 63 cases in the combination group and 44 cases in the monotherapy group.The ORR were 78%and 50%(P=0.003),and DCR were 97%and 77%(P=0.002),respectively.At a median follow-up of 13.7 mon,a PFS event occurred in 38.1%and 81.8%of patients in the two groups,with median PFS of18.8 mon and 5.3 mon,respectively(P<0.000,1).Median OS was unreached in the combination group,and 27.8 mon in the monotherapy group(P=0.31).According to the Cox multivariate regression analysis,combination therapy was an independent prognostic factor of PFS.Conclusion:In patients with EGFR-mutant advanced lung adenocarcinoma with concomitant non-EGFR genetic alterations,combination of TKIs and chemotherapy was significantly superior to EGFR-TKIs monotherapy,which should be the preferred treatment option.

工程化外泌体在肺癌治疗中的研究进展

非小细胞肺癌最佳的治疗方式为早期手术治疗,而大部分肺癌发现时已为晚期。治疗方式以药物及放射治疗为主。但上述治疗方式出现耐药或疗效不显著是不可避免的,因此,针对肺癌的治疗迫切需要更多的手段。研究证实,工程化外泌体在心血管系统疾病、肿瘤、组织再生与修复等领域具有良好的临床应用潜能。本文总结了国内外工程化外泌体在肺癌治疗中的应用。

奥希替尼在老年非小细胞肺癌患者靶向治疗中的应用效果及对T细胞水平的影响

目的 探讨奥西替尼在老年非小细胞肺癌患者靶向治疗中的效果及对免疫水平的影响。方法 回顾性选择2018年1月至2020年12月老年非小细胞肺癌患者116例研究,根据治疗方法不同分为2组,各58例。对照组采用常规放化疗治疗,观察组在对照组基础上联合奥西替尼治疗,3个月治疗后评估患者效果,比较2组总有效率、T细胞水平(CD3^(+)、CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+))、肿瘤标志物水平、不良反应发生率。结果 观察组治疗3个月总有效率为44.8%高于对照组25.9%(P<0.05);2组治疗后3个月CD3^(+)、CD4^(+)、CD4^(+)/CD8^(+)水平均低于治疗前(P<0.05);CD8^(+)水平高于治疗前(P<0.05);观察组治疗后3个月CD3^(+)(58.95±4.21)%、CD4^(+)(32.59±3.11)%、CD4^(+)/CD8^(+)(1.21±0.22)高于对照组(P<0.05);CD8^(+)(26.81±3.32)%低于对照组(P<0.05);观察组干预3个月后CA125(91±8)U/ml、CYFRA21-1(1.26±0.24)μg/L及癌胚抗原(CEA)水平(34±5)μg/L均低于对照组(P<0.05);2组不良反应发生率差异无统计学意义(P>0.05)。结论 奥西替尼用于老年非小细胞肺癌患者靶向治疗中,能获得较好的总有效率,对患者T细胞水平影响较小,可降低肿瘤标志物水平,未增加不良反应发生率,值得临床推广应用。

肺癌分子靶向治疗EGFR-TKI患者证候及中医处方用药研究进展

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)是肺癌治疗领域的里程碑,中医药与分子靶向治疗EGFR-TKI相结合是肺癌综合治疗的新模式。辨证论治是中医的特色,中医药的精准配合,可以贯穿于分子靶向治疗EGFR-TKI的全程。通过查阅、归纳及分析近年来不同专家学者对分子靶向治疗EGFR-TKI相关肺癌患者不同治疗阶段的中医证候及中医处方用药研究的文献,总结肺癌分子靶向治疗EGFR-TKI患者在不同治疗阶段的证候分布及中医处方用药特点,促使中医辨证论治更加精准,旨在进一步提高临床上中医药配合分子靶向治疗EGFR-TKI的效果。

Molecular markers and pathogenically targeted therapy innon-small cell lung cancer

Lung cancer is one of the most common human cancers and the number one cancer killer in the United States.In general,lung cancer includes small cell lung cancer(SCLC)and non-small cell lung cancer(NSCLC),but NSCLC accounts for approximately 90%of lung cancer.The early diagnosis and therapy of lung cancer still presents a big challenge because validated screening tools,which can improve current early detection to reduce mortality from lung cancer,do not exist.Over the last decade,molecular genetic abnormalities have been described in NSCLC,including chromosomal aberrations,overexpression of oncogenes,and deletion and/or muta-tions in tumor suppressor genes.These molecular markers in NSCLC demonstrated close associations with the development of lung cancer such as Ras,the epidermal growth factor receptor(EGFR,or c-erbB-1),HER2(c-erbB-2),c-Met,and Bcl-2.Therefore,this information may be applied for early cancer detection,classification,novel targeted therapy,and prognosis in NSCLC.Recent clinical data have revealed that targeted therapy might be the second-line therapy as an alternative approach.Currently,the targeted therapies are mainly focused on two lung cancer pathways,the EGFR and the vascular endothelial growth factor(VEGF)pathways.Some clinical trials are very encouraging,but some of them are not.However,these trials have not identified a subgroup of NSCLC with biomarkers.Therefore,it is very important to select NSCLC patients with biomarkers to match targeted agents so that we can further identify effectiveness of targeted therapy in the future.

G719X/L861Q/S768I突变非小细胞肺癌诊断及靶向治疗进展

肺癌在全球癌症死亡原因中占比最高,对人类健康造成了极大威胁。30%-40%的非小细胞肺癌(non-small cell lung cancer,NSCLC)的发生是由于表皮生长因子受体(epidermal growth factor receptor,EGFR)发生点突变、外显子插入、外显子缺失导致。除常见的19号外显子缺失突变和21号外显子L858R突变外,18号外显子G719X突变、21号外显子L861Q突变、20号外显子S768I突变是最主要的罕见突变。目前,针对主要罕见突变的诊断方法主要是下一代测序技术(next-generation sequencing,NGS)、数字聚合酶链式反应(digital polymerase chain reaction,dPCR)、微滴式数字PCR(droplet digital PCR,ddPCR)等。关于G719X/L861Q/S768I突变NSCLC的靶向治疗,第一代EGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)疗效较差,第二代和第三代EGFR-TKIs疗效相当,新型第三代EGFR-TKIs和联合治疗展现出不错的治疗前景。本文对G719X/L861Q/S768I突变NSCLC诊断及靶向治疗进展进行了归纳,以期为后续临床用药及研究提供参考。

EGFR外显子20插入突变:研究现状与治疗新策略

作为非小细胞肺癌(non-small cell lung cancer,NSCLC)中重要的致癌驱动基因,表皮生长因子受体外显子20插入突变(epidermal growth factor receptor exon 20 insertion,EGFR ex20ins)具有独特蛋白构象,并且对传统EGFR酪氨酸激酶抑制剂(EGFR-tyrosine kinase inhibitors,EGFR-TKIs)原发耐药。近年来,靶向EGFR ex20ins的药物探索从未停止。莫博赛替尼与埃万妥单抗率先被美国食品药品监督管理局(Food and Drug Administration,FDA)获批用于EGFR ex20ins突变NSCLC患者,随后舒沃替尼等药物取得突破,联合治疗方案的探索也有所收获。多管齐下有望克服EGFR ex20ins耐药。因此,深入了解EGFR ex20ins的分子机制并评估新型药物的有效性与差异性至关重要。本文将对相关最新研究成果进行全面总结,以期为EGFR ex20ins突变患者精准治疗提供有价值的参考。

粒细胞样髓源性抑制细胞在非小细胞肺癌中的研究进展

粒细胞样髓源性抑制细胞(granulocytic myeloid-derived suppressor cells,G-MDSCs)是MDSCs的主要亚群之一,在多数癌症中广泛富集,通过表达精氨酸酶1(arginase-1,Arg-1)及活性氧(reactive oxygen species,ROS)等机制抑制淋巴T细胞杀伤功能,重塑肿瘤免疫微环境,促进肿瘤的发生发展。近年来,越来越多的研究发现G-MDSCs与非小细胞肺癌患者的预后和免疫治疗疗效具有显著相关性,使用特异性靶向G-MDSCs的募集、分化和功能的药物能够有效抑制肿瘤的进展。本文主要就G-MDSCs在非小细胞肺癌中的免疫抑制作用及其相关通路靶向药物的研究进展进行综述。

不可切除胰腺癌的分子靶向药物治疗进展

胰腺癌作为消化系统最常见的恶性肿瘤之一,其发病率及死亡率正逐年上升,大多数胰腺癌患者因分期较晚而失去了手术机会。尽管以吉西他滨、氟尿嘧啶为主的化疗方案在一定程度上延长了患者的生存期,但仍有部分患者因无法耐受化疗而失去治疗机会。随着精准医疗时代的来临,分子靶向药物治疗展现出的优异疗效使其成为对抗肿瘤的重要治疗手段之一,但由于胰腺癌高度的异质性及复杂的免疫微环境,针对胰腺癌的分子靶向治疗并未取得显著效果,因此亟需探寻新的治疗靶点及药物攻克这一难题。本综述基于胰腺癌常见分子靶点及肿瘤免疫相关靶点探究在不可切除胰腺癌中分子靶向药物治疗研究的最新进展,为胰腺癌患者提供新的治疗策略。

EGFR突变可切除的NSCLC围手术期辅助靶向治疗研究进展及问题探讨

肺癌在全球范围内仍是导致癌症死亡的首要原因,非小细胞肺癌(non-small cell lung cancer,NSCLC)是肺癌的主要病理类型,占80%左右。在所有NSCLC患者中,约30%初诊时为可切除的早中期NSCLC。近期表皮生长因子受体-酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors,EGFR-TKIs)在EGFR突变可切除的NSCLC围手术期辅助靶向治疗中取得重大突破,并被指南推荐应用于临床。本文在总结EGFR突变可切除NSCLC围手术期辅助靶向治疗临床研究进展的基础上,针对临床研究中的关键问题进行探讨。

子宫内膜癌TCGA分子分型与治疗新进展

2013年美国癌症基因组图谱(The Cancer Genome Atlas,TCGA)完成了子宫内膜癌(endometrial carcinoma,EC)分子分型,将患者分为POLE(DNA polymerase epsilon)突变型、微卫星不稳定高突变(microsatellite instability-high,MSI-H)型、低拷贝数(copy number low,CN-L)型和高拷贝数(copy number high,CN-H)型,后西方学者改良为更贴合临床应用的ProMisE及Trans-PORTEC分型。POLE突变型患者预后较好,复发率较低,可合理减少患者手术范围,术后降级治疗,当患者合并MSI-H或CN-H时仍归为POLE突变型;MSI-H型患者肿瘤突变负荷高,免疫治疗临床获益显著;CN-L型患者最常见,预后仅次于POLE突变型患者,该类患者为保留生育功能行激素治疗缓解率较高;CN-H型患者预后最差,肿瘤具有侵袭性特征及高复发风险,对于该类患者术后需积极补充治疗,避免治疗不足,此外靶向治疗对CN-H患者疗效较好。TCGA分子分型突破了子宫内膜癌传统病理组织学分型评估预后的局限性,为子宫内膜癌的病理特征、预后及临床诊疗决策提供了全新见解。

基于妇科肿瘤耐药治疗中工程化外泌体的应用研究进展

妇科恶性肿瘤严重威胁着女性健康,在女性各类疾病中其发病率和死亡率均位居前列,关键原因在于传统化疗对复发、耐药患者的疗效欠佳。近年来,探讨肿瘤细胞化疗的耐药机制,开发新型药物逆转耐药已成为妇科肿瘤研究者关注的热点。外泌体(exosome)是一种来源于细胞内溶酶体微粒内陷的多囊泡体,具有低免疫原性、先天靶向性及获得靶向性和高传递效率等生物学特性。因此,外泌体可作为一种理想的、天然的纳米递送药物载体,不仅可以降低肿瘤细胞对化疗药物的耐药性,提高药物治疗效果,还可以减少化疗药物对全身的毒副反应。本文就外泌体作为妇科肿瘤耐药治疗中药物载体的研究进展进行综述,以期对妇科肿瘤的临床治疗提供帮助。

非小细胞肺癌表皮生长因子受体靶向治疗的研究进展

肺癌是致死率最高的恶性肿瘤,非小细胞肺癌(NSCLC)是最主要的病理类型。表皮生长因子受体(EGFR)的突变驱动NSCLC的发展,而表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)是晚期EGFR突变NSCLC患者的标准一线治疗。然而,分子结构、伴随突变和耐药机制等多个维度的不同机制,导致了EGFR亚组的预后差异。本文主要综述NSCLC中EGFR不同突变类型的分子结构基础与治疗反应差异。

克唑替尼治疗伴有ROS1基因融合晚期肺鳞癌1例并文献复习

非小细胞肺癌(non-small cell lung cancer,NSCLC)分为非鳞状细胞癌和鳞状细胞癌,大约有30%新诊断的NSCLC为鳞状细胞癌[1]。ROS1基因融合主要发生在不吸烟的年轻女性晚期肺腺癌患者中,突变概率仅为1%~2%[2-4],伴有ROS1基因融合的肺鳞癌患者极为罕见[5-9]。多项数据表明[10-13],克唑替尼对ROS1基因融合的NSCLC表现出良好的治疗效果,被推荐为伴有ROS1基因融合的晚期NSCLC的一线治疗方案[14-15]。本文报道1例伴有ROS1基因融合的晚期肺鳞癌患者经克唑替尼治疗后肿瘤病灶得到良好控制,病情稳定时间为9个月,提示伴有ROS1基因融合的肺鳞癌对克唑替尼治疗敏感,为临床中对伴有ROS1基因融合肺鳞癌患者的诊疗提供一定的参考。

导致子宫内膜疾病的激素通路及调节因素

子宫内膜的发育和功能高度依赖于类固醇激素的周期分泌及其同源受体的表达,其中最重要的是雌、孕激素及其受体。雌、孕激素使子宫内膜有增殖期和分泌期,维持正常的月经周期并为妊娠做准备,雌、孕激素失调会导致子宫内膜癌、子宫内膜增生和子宫内膜异位症等一系列疾病,引起严重的健康问题。病理状态下,雌激素与雌激素受体相互作用促进子宫内膜过度增殖,这与子宫内膜病变发生风险升高密切相关,而孕激素能有效抑制雌激素的增殖作用,但当孕激素受体表达异常或出现孕酮抵抗时会导致孕激素功能失调。子宫内膜相关疾病的有效治疗有赖于对激素通路的认识,综述导致子宫内膜疾病的激素通路及其调节因素,以期为临床研制出能有效预防及改善治疗结局的新药提供借鉴。