An Economic Evaluation of Adjuvant Trastuzumab Therapy in HER2-Positive Early Breast Cancer

Objective:  One-year adjuvant trastuzumab therapy increases disease-free and overall survival in the adjuvant treatment of early HER2-positive breast cancer. This study aims to assess the long-term cost-effectiveness of adjuvant trastuzumab treatment in Beijing, Shanghai, and Guangzhou.
Methods:  A Markov health-state transition model was constructed to simulate the natural development of breast cancer based on HERceptin Adjuvant (HERA) trial, estimate costs and disease progression over a lifetime perspective with annual transition cycles, and evaluate the cost-effectiveness of 1-year adjuvant trastuzumab treatment group compared with the standard adjuvant chemotherapy. From the perspective of a China health insurance system, cost was calculated based on a survey from clinical expert panels.
Results:  On the basis of HERA data, the model results showed that the utilization of adjuvant trastuzumab treatment in early breast cancer can prolong 2.87 life years, compared with the standard chemotherapy group. The incremental cost for an additional life-year gained (LYG) was US$7564, US$7933, and US$7929 in Beijing, Shanghai, and Guangzhou, respectively. If measured by quality-adjusted life-year, the incremental cost-effectiveness ratio was US$7676, US$8049, and US$8046, respectively.
Conclusion:  The results suggest that the 1-year adjuvant trastuzumab treatment is cost-effective. Both clinical and economic benefits were superior for the 1-year adjuvant trastuzumab treatment group compared with the standard adjuvant chemotherapy group.     

6 versus 12 months of adjuvant trastuzumab in HER2+ early breast cancer: A systematic review and meta-analysis

Background:Adjuvant trastuzumab improves survival outcomes of human epidermal receptor 2 positive early breast cancer patients. Currently, administration of 12 months adjuvant trastuzumab is the standard therapy. However, whether 6 months treatment is non-inferior to the standard 12 months treatment remains controversial.Methods:Relevant records were searched in PubMed, Cochrane Library, Web of Science, and EMBASE through Jan 14, 2020. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were meta-analyzed. The primary endpoint was DFS with a non-inferiority hazard margin of 1.2 and the second was OS with 1.43.Results:Three randomized clinical studies met the inclusion criteria, including 3974 patients in 6 months group and 3976 in 12 months group. HR for DFS was 1.18 (95% CI 0.97–1.44, P = .09), with the non-inferiority margin comprised in the 95% CI. HR for OS was 1.14 (95% CI 0.98–1.32, P= .08), whereas the upper limit of 95% CI did not exceed the non-inferiority hazard margin.Conclusion:Our analysis failed to show that 6 months treatment was non-inferior to 12 months treatment in improving the DFS. Although the non-inferiority of the 6-month adjuvant trastuzumab treatment was found for OS, considering that breast cancer patients should receive additional systematic therapies when disease progression or relapse happens, we suggest that 12 months adjuvant trastuzumab treatment should remain the standard therapeutic strategy for patients with early human epidermal receptor 2 positive breast cancer.     

Estimated Life-Years Saved in Women with HER2-Positive Metastatic Breast Cancer Receiving First-Line Trastuzumab and Pertuzumab in the United States

BackgroundHER2 positive (HER2+) metastatic breast cancer (MBC) is associated with high mortality. Trastuzumab was approved for use in 1998, but the life-years saved from first-line use are unknown, as are the potential US population benefits from adding pertuzumab.ObjectivesThe first aim was to estimate the number of life-years saved by using first-line trastuzumab between 1999 and 2013 in HER2+ women with MBC. In addition, based on these estimates, the second aim was to project the life-years that could be saved by adding pertuzumab to trastuzumab in first-line therapy.MethodsWe constructed a simulation model accounting for incidence, testing rates, therapy utilization, and overall survival. The model was run for 1999 to 2013 (15 years) to estimate the life-years saved from using trastuzumab plus chemotherapy instead of chemotherapy alone. The model was also run from 2013 to 2027 (15 years) to project the life-years that might be saved by adding pertuzumab. Uncertainty was incorporated using Monte-Carlo methods.ResultsThe estimated number of women with HER2+ MBC varied over time, with the peak of 9700 in 2005 and the low of 7700 in 2018. The cumulative incremental life-years saved because of first-line trastuzumab use from 1999 to 2013 was estimated to be 156,413 (95% simulation interval 114,840–195,201). The projection for pertuzumab from 2013 to 2027 was 137,959 (95% simulation interval 56,011–225,069). Exploratory analyses of value showed that pertuzumab, trastuzumab, and chemotherapy is associated with a $1.10 billion gain compared with chemotherapy alone, and adding pertuzumab is associated with a $0.06 billion gain compared with trastuzumab with chemotherapy.ConclusionsThis simulation model suggests that substantial progress has been made in treating HER2+ women over the past 15 years, and the future may witness similar gains with the introduction of pertuzumab.     

南方红豆杉水提物抑制 Ras/MAPK信号通路调控HER2阳性胃癌移植瘤生长实验研究

目的:初步探讨南方红豆杉水提物抑制Ras/MAPK信号通路上相关靶点蛋白调控裸鼠HER2阳性胃癌移植瘤生长及其机制。方法：建立荷瘤裸鼠模型，将80只BALB/c裸鼠接种人HER2阳性胃癌NCI-N87细胞株并随机分组给药及取瘤，采用Western Blot检测HER2、KRAS蛋白表达情况，RT-PCR定量检测其mRNA表达水平。结果：Western blot检测HER2、KRAS蛋白，与空白组比，各给药组HER2、KRAS蛋白表达均显著下调，低剂量联合组HER2蛋白下调显著（0.554+0.110 vs 1.482+0.101；P＜0.01），中剂量红豆杉组KRAS蛋白表达下调显著（1.015+0.033 vs 0.630+0.049；P＜0.01）。2、RT-PCR检测HER2、KRAS蛋白，中剂量红豆杉组HER2及KRAS mRNA表达下调（P＜0.01），联合后下调明显。结论：南方红豆杉水提物可部分下调HER2、KRAS mRNA及蛋白表达水平，联合赫赛汀可增强其抑制作用。     

Locoregional therapy with α‐emitting trastuzumab against peritoneal metastasis of human epidermal growth factor receptor 2‐positive gastric cancer in mice

Peritoneal metastasis of gastric cancer (PMGC) is incurable and thus has an extremely poor prognosis. We have found, however, that locoregionally administered trastuzumab armed with astatine‐211 (²¹¹At‐trastuzumab) is effective against human epidermal growth factor receptor 2 (HER2)‐positive PMGC in a xenograft mouse model. We first observed that ²¹¹At‐trastuzumab can specifically bind and effectively kill NCI‐N87 (N87) cells, which are HER2‐positive human metastatic GC cells, both in vitro and in s.c. tumors. We established a PMGC mouse model using N87 xenografts stably expressing luciferase to test α‐particle radioimmunotherapy with ²¹¹At‐trastuzumab against PMGC. Biodistribution analysis in this PMGC mouse model revealed that the i.p. administration of ²¹¹At‐trastuzumab (1 MBq) was a more efficient means of delivery of ²¹¹At into metastatic tumors than i.v. injection; the maximum tumor uptake with i.p. administration was over 60% injected dose per gram of tissue (%ID/g) compared to approximately 18%ID/g with i.v. injection. Surprisingly, a single i.p. injection of ²¹¹At‐trastuzumab (1 MBq) was sufficient to completely eradicate intraperitoneally disseminated HER2‐positive GC xenografts in two of six treated mice by inducing DNA double‐strand breaks, and to drastically reduce the tumor burden in another three mice. No bodyweight loss, leukocytopenia, or significant biochemical changes in liver or kidney function were observed in the treatment group. Accordingly, locoregionally administered ²¹¹At‐trastuzumab significantly prolonged the survival time of HER2‐positive PMGC mice compared with control treatments. Our results provide a proof‐of‐concept demonstration that locoregional therapy with ²¹¹At‐trastuzumab may offer a new treatment option for HER2‐positive PMGC.     

HER2-positive advanced breast cancer: optimizing patient outcomes and opportunities for drug development

Effective targeting of the human epidermal growth factor receptor 2 (HER2) has changed the natural history of HER2 overexpressing (HER2+) metastatic breast cancer. The initial success of trastuzumab improving time to progression and survival rates led to the clinical development of pertuzumab, ado-trastuzumab emtansine and lapatinib. These biologic therapies represent significant additions to the breast medical oncology armamentarium. However, drug resistance ultimately develops and most tumours progress within 1 year. Ongoing studies are evaluating novel therapeutic approaches to overcome primary and secondary drug resistance in tumours, including inhibition of PI3K/TOR, HSP90, IGF-IR and angiogenesis. Mounting experimental data support the clinical testing of immune checkpoint modulators and vaccines. The central nervous system remains a sanctuary site for HER2+ breast cancer and further studies are needed for the prevention and treatment of brain metastases in this population. Despite efforts to identify predictors of preferential benefit from HER2-targeted therapies (e.g., truncated HER2, PTEN loss and SRC activation), HER2 protein overexpression and/or gene amplification remains the most important predictive factor of response to HER2-targeted therapies. In this article, we review the optimal sequence of HER2-targeted therapies and describe ongoing efforts to improve the outcome of HER2+ advanced breast cancer through rational drug development.     

RUNX3调控胃癌细胞对曲妥珠单抗耐药的机制：基于超效高液相色谱-四极杆/静电场轨道阱质谱的代谢组学分析

目的 探讨Runt相关转录因子3（RUNX3）在胃癌曲妥珠耐药细胞中的代谢调控作用,阐释敲除RUNX3逆转耐药的代谢机制。方法 基于超高效液相色谱-四极杆/静电场轨道阱质谱联用技术,对曲妥珠耐药胃癌细胞（NCI N87R）及RUNX3敲除细胞（NCI N87R/RUNX3）进行代谢组分析;采用多变量结合单变量分析方法及二级质谱离子匹配打分筛选差异变量;使用MetaboAnalyst 5.0数据库进行通路富集分析;基于OmicsNet数据库构建差异代谢物-基因调控关系;通过试剂盒检测还原性/氧化性谷胱甘肽（GSH/GSSG）及还原性/氧化性辅酶II（NADPH/NADP）的比值。结果 RUNX3敲除前后NCI N87R细胞的代谢特征显著改变,鉴定到81个对分类有显著贡献的差异代谢物,其中43个代谢物在NCI N87R/RUNX3细胞中增加,38个代谢物减少。RUNX3敲除导致耐药细胞8条通路显著改变（P<0.01）,包括谷氨酰胺、糖酵解、甘油磷脂酸-烟酰胺及谷胱甘肽代谢等。试剂盒检测结果显示,NCI N87R/RUNX3胞内GSH/GSSG及NADPH/NADP降低（P<0.01）;差异代谢物-基因网络揭示了代谢分子与基因之间的调控关系。结论 RUNX3通过调控能量代谢及氧化-还原稳态逆转胃癌细胞对曲妥珠单抗耐药,提示RUNX3可能是胃癌曲妥珠单抗耐药的潜在治疗靶标。     

ABP 980: promising trastuzumab biosimilar for HER2-positive breast cancer

Introduction: Approval of the HER2-targeted antibody trastuzumab dramatically improved outcomes for patients with HER2-positive breast cancer. Multiple trastuzumab biosimilars, including ABP 980, are in clinical development. Biosimilars are not identical to the reference biologic, but exhibit equivalence and safety in analytical and clinical studies.

Areas covered: A brief introduction to trastuzumab, overview of trastuzumab biosimilars, and detailed review of ABP 980 preclinical and clinical studies are included. We searched PubMed and 2016–2017 ASCO and ESMO conference proceedings for ‘ABP 980’ or ‘trastuzumab biosimilar’. ‘ABP 980 and breast cancer’ or ‘trastuzumab biosimilar and breast cancer’ were used to search clinicaltrials.gov for phase III trials. Analytical studies of ABP 980 pharmacokinetics (PK) or pharmacodynamics (PD), phase I studies of ABP 980 safety and PK/PD, and phase III studies of clinical efficacy vs trastuzumab are included.

Expert opinion: Questions remain regarding long-term impact of biosimilars on overall healthcare costs, insurance coverage of multiple approved biosimilars, and extensive clinical safety and efficacy follow-up. By producing a competitive market, trastuzumab biosimilars are anticipated to improve access to standard of care therapies, although real-world evidence remains to be obtained. Increased global access to HER2-targeted therapy may eventually alter the landscape of breast cancer and survival rates.     

超声心动图评价乳腺癌患者曲妥珠单抗靶向药物治疗后早期心脏毒性的价值

目的探讨超声心动图评价乳腺癌患者曲妥珠单抗靶向药物治疗后早期心脏毒性的价值。方法对40例首次接受曲妥珠单抗靶向治疗的乳腺癌患者于治疗前后进行超声心动图检查,包括常规参数、组织多普勒参数及左心房容积指数(LAVI)。结果治疗后Sm、Em、Em/Am降低,Am与E/Em均升高,LAVI治疗后亦升高,且E/Em与LAVI呈正相关(r=0.82,P0.05)。结论乳腺癌患者接受曲妥珠单抗治疗后,早期心脏毒性主要表现为舒张功能减退。组织多普勒、E/Em、LAVI可作为评价早期左心功能损伤的指标。