Trastuzumab emtansine in breast cancer

Introduction: Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (HER2)–targeted antibody–drug conjugate (ADC) composed of trastuzumab, a stable linker (MCC), and the cytotoxic agent DM1 (derivative of maytansine). Administration of T-DM1 leads to limited systemic exposure of free DM1, with no evidence of DM1 accumulation after repeated dosing.

Areas covered: Phase I and Phase II clinical trials with T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown substantial clinical activity and a favorable safety profile. A randomized, open-label, first-line trial comparing trastuzumab and docetaxel with single agent T-DM1 showed a significant improved progression-free survival for T-DM1.

Expert opinion: T-DM1 has successfully completed second-line Phase III development for advanced HER2-positive breast cancer. The Phase III EMILIA study demonstrated an overall survival benefit for T-DM1 compared to the combination of lapatinib and capecitabine in taxane-trastuzumab pretreated patients. T-DM1 may offer delivery on a personalized basis of very potent cytotoxic agents in a cellular selective manner.     

Clinical perspective: Antibody-drug conjugates for the treatment of HER2-positive breast cancer

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表皮生长因子受体突变非小细胞肺癌耐药机制的研究进展

目前，肺癌的发病率及病死率仍居全球各类癌症的首位。肺癌确诊时常为中晚期，放化疗疗效不理想，术后复发与转移率较高。靶向治疗，如表皮生长因子受体(epidermal growth factor receptor,EGFR)酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)的应用，显著提高了伴EGFR突变的中晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的临床疗效。但由于耐药的发生，NSCLC患者预后仍然欠佳。本文对EGFR突变的NSCLC患者对TKIs耐药机制的研究进展作一综述，以期为临床探索新的解决策略提供依据。     

Cyclin-dependent kinase 15 upregulation is correlated with poor prognosis for patients with breast cancer

ObjectiveTo investigate the clinical significance of cyclin-dependent kinase (CDK) 15 in breast cancer.MethodsThis prospective observational study enrolled 154 patients with breast cancer. Tumor tissues and paired paracancerous normal tissues were collected. Additionally, 85 samples of benign breast lesions were obtained from patients with mammary gland hyperplasia. Patient characteristics were recorded, and CDK15, human epidermal growth factor receptor (HER)2, estrogen receptor, progesterone receptor, and Ki67 immunohistochemical expression were determined.ResultsThe rate of strong CDK15 expression was 63.6% (98/154) in breast cancer tissues, which was remarkably higher than that in benign breast lesions (34.1%, 29/85). Similarly, the ratio of strong CDK15 expression was markedly higher in tumor tissues (63.6%, 98/15) than in paracancerous normal tissues (27.3%, 42/154). Pearson’s analysis showed that the CDK15 expression score was positively correlated with HER2 and Ki67. Patients with high CDK15 expression showed markedly higher ratios of TNM stage III to IV, lymph node metastasis, and increased tumor diameters but a significantly lower rate of ductal carcinoma in situ. The median survival time of these patients was significantly shorter. Kaplan–Meier curve analysis showed that low CDK15 expression predicted longer survival times.ConclusionUpregulated CDK15 predicted poor clinical outcomes in breast cancer.     

循环肿瘤细胞的磁分离法建立及在肺癌EGFR-TKI治疗中的应用

目的探索磁分离循环肿瘤细胞(circulating tumor cells,CTCs)联合竞争性等位基因特异性Taq ManPCR(Cast PCR)检测表皮生长因子受体(EGFR)基因突变的可行性。方法收集12例晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者血液样本各7.5 m L,两步法磁分离CTCs,免疫荧光染色检测上皮细胞黏附分子(Ep CAM)和细胞角蛋白(Cytokeratin)后,流式细胞术检测CTCs数量及纯度;Cast PCR检测CTCs及循环DNA中EGFR基因del EGFR19、T790M和L858R突变;用EGFR基因突变检测试剂盒(ADx-ARMS法)检测癌组织的上述位点突变。结果高表达与不表达Ep CAM的CTCs分别在6例和12例NSCLC患者中被检测出;del EGFR19、T790M和L858R突变例数分别在2例、8例和5例NSCLC患者的CTCs中被检测出,其总检出率为83.3%(10/12);2例患者的循环DNA中检出L858R突变;ADx-ARMS法检测12例NSCLC患者癌组织中上述3种突变分别是2例、5例和3例,总检出率为75.0%(9/12)。CTCs与癌组织的突变具有一致性(Kappa=0.75,P=0.007),循环DNA与癌组织的突变一致性无统计意义(Kappa=0.06,P=0.546)。结论磁分离CTCs联合Cast PCR能有效检测EGFR基因突变,值得在NSCLC患者的EGFR酪氨酸激酶抑制剂(EGFR-TKI)治疗中推广应用。     

Platelet/lymphocyte ratio is a significant prognostic factor for targeted therapy in patients with EGFR-mutated non-small-cell lung cancer

ObjectiveTo analyze the prognostic significance of the pretreatment platelet/lymphocyte ratio (PLR) for targeted therapy in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC).MethodsWe conducted a retrospective study of 96 patients with EGFR-mutated advanced NSCLC who were treated at Dongguan People’s Hospital, Southern Medical University from May 2014 to December 2017. All patients received EGFR-targeted therapy until disease progression, unacceptable toxicity, or other factors. Approximately 3 days before the initial treatment, data including a detailed clinical history, physical examination, radiographic results, pathological diagnosis, and laboratory parameters including complete blood cell counts and albumin levels were evaluated.ResultsPatients in the PLR ≥ 190 group had shorter progression-free survival (PFS) than those in the PLR < 190 group. Furthermore, the 1-year PFS rate was worse in the PLR ≥ 190 group than in the PLR< 190 group. Multivariate analysis indicated the possible role of PLR as a prognostic factor for patients with advanced NSCLC who received EGFR-targeted therapy.ConclusionsPretreatment PLR may be an independent prognostic factor for patients with NSCLC receiving EGFR tyrosine kinase inhibitor treatment. Further studies are needed to identify the impact of PLR on EGFR-mutated NSCLC.     

曲妥珠单抗联合卡培他滨+顺铂化疗方案治疗HER2阳性晚期胃癌的疗效研究

目的探究曲妥珠单抗联合卡培他滨+顺铂化疗方案治疗人类表皮生长因子受体2(HER2)阳性晚期胃癌的临床效果与安全性。方法选择126例HER2阳性晚期胃癌患者进行前瞻性研究,随机分为研究组和对照组,各63例。对照组采用卡培他滨+顺铂化疗方案,研究组在对照组治疗方案基础上加用曲妥珠单抗治疗,观察比较两组患者临床治疗效果、肿瘤标记物水平、毒副反应发生情况及严重程度。结果两组患者随访时间3~18个月,中位随访时间9.40个月。研究组治疗总有效率与控制率均明显高于对照组(χ^2分别=5.43、5.42,P均<0.05);研究组无进展生存期(PFS)与总生存期(OS)均长于对照组,差异均有统计学意义(t分别=12.80、13.27,P均<0.05)。研究组治疗后的癌胚抗原(CEA)、人单核细胞趋化蛋白-1(MCP-1)、白细胞介素1β(IL-1β)与血管内皮生长因子(VEGF)水平均明显低于对照组治疗后,差异均有统计学意义(t分别=38.43、9.30、14.38、7.94,P均<0.05),两组患者恶心呕吐、肝功能损害、骨髓抑制、手足综合征等严重程度比较,差异均无统计学意义(Z分别=0.10、0.39、1.15、1.28,P均>0.05)。结论曲妥珠单抗联合卡培他滨+顺铂化疗方案治疗HER2阳性晚期胃癌效果肯定,能有效提升患者近期疗效与远期疗效,毒副作用小,安全性高。     

Gefitinib, a novel, orally administered agent for the treatment of cancer

Traditional cytotoxic anticancer therapies do not differentiate between tumour and host cells, and research efforts have been focused on finding new agents that target tumour tissue. Gefitinib ('Iressa', ZD1839) is an orally active epidermal growth factor receptor tyrosine kinase inhibitor that blocks signal pathways implicated in solid tumour growth and metastasis. In phase II trials, gefitinib 250 mg/day demonstrated efficacy in the control of advanced non-small-cell lung cancer (NSCLC) in patients who had undergone prior chemotherapy. Response rates were 18.4 and 11.8%, and disease control rates were 54.4 and 42.2%, at 250 mg/day in two multicentre trials - IDEAL 1 and 2. Gefitinib also caused rapid relief from the symptoms of NSCLC in approximately 40% of patients, while displaying a generally good tolerability profile that most commonly included mild, reversible gastrointestinal and skin adverse events. Gefitinib 250 mg/day has been approved for use in advanced, previously treated NSCLC in several countries including the USA, Japan and Australia. As a monotherapy and combination therapy, it is being investigated for the treatment of several common tumour types in addition to NSCLC. The pharmacokinetics of gefitinib have shown it to be suitable for once daily dosing, with a terminal half-life of approximately 48 h in patients with cancer. Steady-state exposure is achieved after 10 days dosing, and exposure is dose proportional up to 250 mg/day. Gefitinib is cleared principally by the biliary route and in part by metabolism. This review summarizes relevant data from studies of gefitinib that inform its clinical administration.     

Gefitinib (ZD1839, Iressa) in non-small-cell lung cancer: a review of clinical trials from a daily practice perspective

Gefitinib (ZD1839) is the most widely studied targeting agent in the area of non-small-cell lung cancer (NSCLC). Gefitinib is an orally active epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor. In order to assess the role of gefitinib in the management of NSCLC patients, we systematically reviewed published clinical trials from a daily practice perspective. A systematic research was made in the international medical literature. Gefitinib demonstrated a good tolerance and an encouraging efficacy in pretreated NSCLC patients in preclinical studies. These results were then confirmed in two phase II trials (IDEAL 1 and 2) involving more than 400 patients mostly pretreated with a platinum-containing regimen and docetaxel. All these results were reinforced by those of retrospective studies on patients enrolled in a compassionate use programme. Thus, two phase III trials in chemo-naive patients were initiated (INTACT 1 and 2). Unfortunately, the use of gefitinib with standard combination chemotherapy provided no survival benefit nor response rate or progression-free survival improvement over placebo. Furthermore, we also reviewed the results of studies interested in the characterization of predictive clinical or biological markers for response to gefitinib and discussed the results obtained with other EGFR inhibitors. The efficacy of gefitinib in the first-line setting of each stage of NSCLC has to be further studied through clinical trials. Furthermore, translational studies characterizing the molecular features involved in the response to anti-EGFR-targeted therapies are needed.     

三阴性乳腺癌578例临床病理特点及预后分析

目的 探讨女性三阴性乳腺癌(TNBC)的临床病理特点及影响预后因素.方法 回顾性分析中国医学科学院肿瘤医院外科1990 年12 月至2008 年12 月收治的578 例TNBC 资料.结果 578 例TNBC 占同期乳腺癌的18.6%,全组患者均经手术治疗,病理类型以浸润性导管癌为主(86.0%).全组总的5 年及10 年生存率分别为75.6%和56.3%.单因素分析显示年龄、组织学分化程度、脉管瘤栓、N 分期、T 分期以及TNM 分期是影响预后的主要因素(P ＜0.05).多因素分析显示组织学分化程度、淋巴结状态是影响预后的独立因素.结论 TNBC 具有较强的侵袭性,预后较差,淋巴结状况和组织学分化程度是影响TNBC 预后的独立因素.     

HER-2、CA153及HE4联合检测对乳腺癌的诊断价值

目的探讨联合检测血清人表皮生长因子2(HER-2)、癌抗原153(CA153)及人附睾蛋白4(HE4)对乳腺癌的诊断价值。方法选取该院收治的乳腺癌患者60例(乳腺癌组),乳腺良性疾病患者80例(乳腺良性疾病组)及同期的体检健康妇女60例(对照组)为研究对象。比较3组患者血清HER-2、CA153及HE4水平,并分析3项指标单独及联合检测对乳腺癌的诊断价值。结果乳腺癌组患者血清HER-2、CA153及HE4水平[(27.64±7.49)mg/mL、(48.25±11.36)U/mL、(183.46±27.39)pmol/L]显著高于乳腺良性疾病组和对照组[(13.57±3.51)mg/mL、(20.14±6.24)U/mL、(81.35±21.46)pmol/L;(10.26±2.37)mg/mL、(14.37±3.92)U/mL、(43.77±14.51)pmol/L],差异有统计学意义(P<0.05)。乳腺癌组HER-2、CA153及HE4表达阳性率(30.0%、48.3%、36.7%)显著高于乳腺良性疾病组和对照组(5.0%、13.8%、8.8%;0.0%、3.3%、1.7%),差异有统计学意义(P<0.05),且乳腺癌患者CA153表达阳性率(48.3%)显著高于HER-2和HE4(30.0%、36.7%),差异有统计学意义(P<0.05)。乳腺癌患者Ⅳ期血清HER-2、CA153及HE4水平[(40.27±12.45)mg/mL、(78.25±17.36)U/mL、(193.82±32.66)pmol/L]显著高于Ⅰ~Ⅱ期和Ⅲ期[(12.48±3.14)mg/mL、(25.73±7.48)U/mL、(142.16±21.37)pmol/L;(22.63±6.38)mg/mL、(43.61±13.62)U/mL、(153.49±25.61)pmol/L],Ⅲ期血清HER-2、CA153及HE4水平[(22.63±6.38)mg/mL、(43.61±13.62)U/mL、(153.49±25.61)pmol/L]显著高于Ⅰ~Ⅱ期[(12.48±3.14)mg/mL、(25.73±7.48)U/mL、(142.16±21.37)pmol/L],差异有统计学意义(P<0.05)。血清HER-2、CA153及HE4联合检测的灵敏度(71.9%)及准确度(80.0%)均显著提高(P<0.05)。结论血清HER-2、CA153及HE4联合检测可提高对乳腺癌的检出率,且还可作为病情严重程度和治疗监测的辅助检查指标。     

Clinical development of CT-P6 in HER2 positive breast cancer

ABSTRACT

Introduction: CT-P6 (trastuzumab-pkrb, Herzuma) is a trastuzumab biosimilar approved for use in HER2 positive breast cancer and HER2 positive gastric cancer. CT-P6 has been shown to exhibit similar safety and efficacy profiles to its reference product, trastuzumab. Preclinical and clinical studies have been performed to prove equivalence between CT-P6 and the trastuzumab originator.

Areas Covered: In this review, we examine the evidence comparing CT-P6 with its reference product, trastuzumab. Both monoclonal antibodies function to target cells that overexpress HER2 on the cell surface. Preclinical pharmacologic modeling of CT-P6 shows a similar mechanism of action to trastuzumab, similar pharmacologic properties and a phase I trial in healthy volunteers showed similar pharmacokinetics. A multicenter phase III randomized clinical trial in patients with early breast cancer showed equivalent safety and efficacy between CT-P6 and trastuzumab. One-year follow-up of patients showed identical rates of cardiotoxicity.

Expert Opinion: Preclinical and clinical studies showed CT-P6 pharmacologic profile, safety and efficacy are equivalent to trastuzumab. As such, it is a safe and effective alternative for use in patients with HER2 positive breast cancer and gastric cancer. Its implementation into clinical practice can potentially increase patient access and help financially alleviate overburdened health-care systems.     

Front-line Therapy in Advanced Non–Small Cell Lung Cancer With Sensitive Epidermal Growth Factor Receptor Mutations: A Network Meta-analysis

PurposeSeveral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were firmly established as front-line treatment for non–small cell lung cancer (NSCLC) that harbored an activating EGFR mutation. Gefitinib or erlotinib was considered the standard of care. TKI-based combination therapy has been investigated and has shown encouraging results.MethodsThe PubMed and EMBASE databases, the Cochrane Central Register of Controlled Trials, and meeting abstracts were screened for relevant studies between January 2000 and February 2019. Prospective randomized controlled trials were included that investigated EGFR TKIs (alone or in combination) in untreated patients with NSCLC whose tumors had sensitive EGFR mutations. A frequentist random effects network meta-analysis model was conducted to assess objective response rate, progression-free survival, and overall survival. P-score was used to rank treatment effects.FindingsSeventeen trials involving 9 treatments and 4373 patients were included. Heterogeneity existed in the network analysis. For progression-free survival, the top 3 treatments were osimertinib, standard of care plus chemotherapy, and standard of care plus bevacizumab; corresponding p-scores were 0.88, 0.79, and 0.75, respectively. For overall survival, the top 3 treatments were standard of care plus chemotherapy, osimertinib, and dacomitinib; corresponding p-scores were 0.89, 0.85, and 0.64. TKI-based combination therapy caused more toxicity than a TKI alone.ImplicationsOsimertinib seemed to be a better option as upfront therapy for EGFR-mutant NSCLC in terms of efficacy and tolerability.     

阿那曲唑联合依维莫司治疗乳腺癌的效果及对血清HER-2/neu、p185水平的影响

目的探究阿那曲唑联合依维莫司用于治疗乳腺癌的临床疗效及其对患者血清中人类表皮生长因子受体2蛋白(HER-2/neu)、p185水平的影响。方法选取2013年1月至2018年12月广元市第一人民医院治疗的符合纳入标准的患者1000例,按照随机数字表法分为对照组(n=500)和观察组(n=500)。对照组给予口服阿那曲唑片,观察组在对照组的基础上给予口服依维莫司片。治疗3个月后,观察比较2组患者的临床疗效及不良反应发生率,比较2组患者雌激素、HER-2/neu、p185水平。结果观察组的临床缓解率为60.60%,要明显高于对照组(54.20%),差异有统计学意义(χ^2=4.190,P=0.041)。治疗前,2组患者的雌二醇(E2)、黄体生成素(LH)、HER-2/neu、p185水平比较,差异无统计学意义(P>0.05)。经过3个月的治疗,观察组的E2、LH、HER-2/neu、p185水平均明显低于对照组(t=8.148,P=0.000;t=85.170,P=0.000;t=20.209,P=0.000;t=16.109,P=0.000)。治疗过程中,对照组和观察组患者不良反应发生率分别为8.60%和7.60%,差异无统计学意义(χ^2=0.340,P=0.562)。结论阿那曲唑联合依维莫司治疗乳腺癌具有良好的临床疗效,可抑制肿瘤细胞的生长发育,降低患者体内雌激素水平,且安全性高。     

T790M突变与TKI获得性耐药的晚期肺腺癌患者预后的相关性

目的 前瞻性分析T790M突变与一代TKI获得性耐药的晚期肺腺癌患者预后的相关性。方法 选择符合条件入组的肺腺癌患者93例,经二代测序(NGS)测出表皮生长因子受体(EGFR)敏感突变及T790M的突变状态,分二线或三线使用奥希替尼作为EGFR-TKI治疗方案,对照选择化疗和或放疗治疗方案。评估二三线治疗的客观缓解率(ORR), 疾病控制率(DCR)和无疾病进展生存期(PFS)。结果 T790M阳性和阴性患者组中的ORR差异无统计学意义( P=0.084),而DCR差异有统计学意义(P=0.01)。将治疗线数分开,二线使用奥希替尼在T790M的两种不同状态下,ORR和DCR差异均有统计学意义(ORR :P =0.022;DCR:P =0.016)。三线使用奥希替尼在T790M的两种不同状态下,同样发现差异也具有统计学意义(ORR: P=0.016;DCR: P=0.011)。通过Mann-WhitneyU检验提示,T790M的突变状态与PFS显著相关,其中所有人群中(P<0.01)、二线治疗人群中(P=0.022)和三线治疗人群中( P=0.016)。对所有的患者进行KM生存分析,观测到总体的PFS与T790M的突变状况有关(P<0.01)。在T790M阳性组中,患者基因检测中出现EGFR19外显子和21外显子的PFS差异有统计学意义(P=0.05)。多因素Cox比例风险回归分析,21外显子 vs 19外显子(HR=0.551, 95%CI =0.357~0.853, P=0.007);T790M阳性 vs T790M阴性( H R=2.972, 95% C I=1.643~5.379, P<0.01)。肿瘤直径≥5 cm vs 肿瘤直径<5 cm (HR=0.575, 95%CI =0.373~0.085, P=0.012)。结论 T790M突变阳性患者预后优于T790M突变阴性患者。对于T790M阳性的患者二线或三线使用奥希替尼未观测到PFS差异。晚期肺腺癌T790M阳性患者可在一代EGFR-TKI药物耐药后应用三代EGFR-TKI治疗。     

Biosimilars for breast cancer

ABSTRACT

Introduction: Cancer treatment has evolved significantly with the introduction of biologic agents, especially in the breast cancer (BC) area. The use of trastuzumab for HER2 amplified BCsignificantly improves survival in both metastatic and early stage disease. Although the efficacy of biologics is undeniable, their high costs increased the expenses of cancer care, becoming a problem to health-care systems, mainly in low and middle-income, but also for high-income countries. In an attempt to lower the costs and allow a greater access of biologics to cancer patients, biosimilars are rapidly being developed as an alternative to the reference biologics.

Areas covered: A literature review based on the MEDLINE/PubMed search about biosimilars allied with the FDA and EMA’s latest statements of this topic were conducted to summarize the development and the use of currently available biosimilars for BC, with a focus on trastuzumab.

Expert opinion: Biosimilars are drugs that have similar efficacy and safety profile to those of the original biological product with equivalent immunogenicity and, as these agents hold the potential to improve patient´s access to monoclonal antibodies because their production costs are estimated to be 20–30% lower compared to the reference product, they are progressively being incorporated into clinical practice.     

Adx-ARMS法与PCR-Sanger测序法检测非小细胞肺癌微小标本EGFR基因突变的比较

目的比较ADx-ARMS法和PCR-Sanger测序法检测肺癌微小标本EGFR基因突变的差异,评价微小标本用于非小细胞肺癌(NSCLC)患者EGFR突变检测的临床应用价值。方法收集2012~2013年95例NSCLC患者98份微小标本;用ADxARMS法和PCR-Sanger测序法检测上述标本EGFR基因18、19、20、21外显子基因突变,分析其与患者临床、病理特征的关联性。结果 ADx-ARMS法突变总检出率为51.0%(50/98),PCR-Sanger测序法突变总检出率为25.3%(24/95)。突变多见于女性(65.1%)、非吸烟(64.0%)、腺癌(51.9%)患者。EGFR-TKI疗效研究结果表明,ADx-ARMS法和PCR-Sanger测序法检测结果均为野生型患者的无进展生存期(PFS)为2.0个月,明显短于两种方法检测均为突变型和仅ADx-ARMS法检测为突变型患者的9.1个月和10.0个月(P0.01)。结论对于难以获得手术切除标本的患者,微小标本可作为其进行EGFR突变检测的适用材料;ADx-ARMS法较PCR-Sanger测序法更适用于微小标本的基因检测。     

人表皮生长因子受体3在乳腺癌组织中的表达及临床意义

目的探讨人表皮生长因子受体(HER)3基因在乳腺癌组织中的表达及其与临床病理学特征和预后的相关性。方法采用免疫组织化学法检测126例乳腺癌组织中HER3的表达,分析其表达与患者年龄、月经情况、TNM分期、肿瘤大小、淋巴结转移、雌激素受体(ER)、孕激素受体(PR)、HER2及预后的关系。结果 (1)乳腺癌组织中HER3的阳性表达率为30.2%。HER3阳性表达在乳腺癌绝经患者中占43.3%,高于未绝经者的18.2%(P0.05);淋巴结转移阳性的乳腺癌患者HER3阳性表达率为40.0%,高于无淋巴结转移患者的21.2%,差异有统计学意义(P0.05);HER2阳性的乳腺癌患者HER3阳性表达率为42.5%,高于HER2阴性者的24.4%,差异有统计学意义(P0.05)。(2)HER3阳性患者的五年无病生存率更低(P0.05)。(3)HER3与HER2均阳性的乳腺癌患者淋巴结转移率较高(P0.05)。结论 HER3的表达可能在乳腺癌的发生和发展过程中起重要作用,并影响其预后,HER3可能成为判断乳腺癌预后的指标及临床治疗的靶点。