Quercetin inhibits truncated isoform of dopamine-and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer

Trastuzumab resistance is one of the causes of poor prognosis in patients with human epidermal growth factor receptor 2(HER2)-positive(HER2+)breast cancer(BC).The truncated isoform of dopamine-and cAMPregulated phosphoprotein(t-DARPP)has been reported to be involved in trastuzumab therapy resistance and promoting tumor progression.To evaluate the t-DARPP expression in BC,paired tumors and surrounding normal tissues were analyzed by real-time polymerase chain reaction and confirmed higher DARPP-32 kDa family mRNA expression in HER2+BC tumor tissues.We established 2 patient-derived xenografts(PDX)mice models to test the efficacy of trastuzumab,named model 1(non-responder)and model 2(responder).t-DARPP and p95-HER2 protein-protein interactions were detected in PDX tumor tissue from non-responders using Förster resonance energy transfer assays.Instead,there is no response from the responder.Furthermore,mechanistic studies using transwell and western blot assays demonstrated that t-DARPP could upregulate epithelial-mesenchymal transition signaling proteins,enhance p95-HER2 expression and promote cell migration.We found that quercetin effectively reduced t-DARPP expression in HER2+BC cells.In t-DARPP ShRNA-suppressed cells,quercetin synergistically enhanced trastuzumab-induced apoptotic cell death and G2/M phase arrest.In conclusion,the combination of quercetin and trastuzumab treatment by targeting t-DARPP in HER2+BC patients has the potential as a biomarker for mitigating drug resistance.

Mechanisms of resistance to trastuzumab in HER2-positive gastric cancer

Gastric cancer is one of the most prevalent cancers worldwide,and human epidermal growth factor receptor 2(HER2)-positive cases account for approximately 20%of the total cases.Currently,trastuzumab+chemotherapy is the recommended first-line treatment for patients with HER2-positive advanced gastric cancer,and the combination has exhibited definite efficacy in HER2-targeted therapy.However,the emergence of drug resistance during treatment considerably reduces its effectiveness;thus,it is imperative to investigate the potential mechanisms underlying resistance.In the present review article,we comprehensively introduce multiple mechanisms underlying resistance to trastuzumab in HER2-positive gastric cancer cases,aiming to provide insights for rectifying issues associated with resistance to trastuzumab and devising subsequent treatment strategies.

Pyrotinib is effective in both trastuzumab-sensitive and primary resistant HER2-positive breast tumors

Objective: Primary resistance to trastuzumab frequently occurs in human epidermal growth factor receptor 2(HER2)-positive(+) breast cancer patients and remains a clinical challenge. Pyrotinib is a novel tyrosine kinase inhibitor that has shown efficacy in the treatment of HER2+ breast cancer. However, the efficacy of pyrotinib in HER2+ breast cancer with primary trastuzumab resistance is unknown.Methods: HER2+ breast cancer cells sensitive or primarily resistant to trastuzumab were treated with trastuzumab, pyrotinib, or the combination. Cell proliferation, migration, invasion, and HER2 downstream signal pathways were analyzed. The effects of pyrotinib plus trastuzumab and pertuzumab plus trastuzumab were compared in breast cancer cells in vitro and a xenograft mouse model with primary resistance to trastuzumab.Results: Pyrotinib had a therapeutic effect on trastuzumab-sensitive HER2+ breast cancer cells by inhibiting phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT) and rat sarcoma virus(RAS)/rapidly accelerated fibrosarcoma(RAF)/mitogen-activated protein kinase(MAPK)/extracellular-signal regulated kinase(ERK)pathways. In primary trastuzumab-resistant cells, pyrotinib inhibited cell growth, migration, invasion, and HER2 downstream pathways, whereas trastuzumab had no effects. The combination with trastuzumab did not show increased effects compared with pyrotinib alone. Compared with pertuzumab plus trastuzumab, pyrotinib plus trastuzumab was more effective in inhibiting cell proliferation and HER2 downstream pathways in breast cancer cells and tumor growth in a trastuzumab-resistant HER2+ breast cancer xenograft model.Conclusions: Pyrotinib-containing treatments exhibited anti-cancer effects in HER2+ breast cancer cells sensitive and with primary resistance to trastuzumab. Notably, pyrotinib plus trastuzumab was more effective than trastuzumab plus pertuzumab in inhibiting tumor growth and HER2 downstream pathways in HER2+ breast cancer with primary resistance to trastuzumab. These findings support clinical testing of the therapeutic efficacy of dual anti-HER2 treatment combining an intracellular small molecule with an extracellular antibody.

Sequential neoadjuvant chemotherapy using pegylated liposomal doxorubicin and cyclophosphamide followed by taxanes with complete trastuzumab and pertuzumab treatment for HER2-positive breast cancer: A phase Ⅱ single-arm study

Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin(PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2(HER2)-positive early breast cancer(BC).Methods: In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD(30-35 mg/m^(2)) and cyclophosphamide(600 mg/m^(2)), followed by four cycles of taxanes(docetaxel,90-100 mg/m^(2) or nab-paclitaxel, 260 mg/m^(2)), concomitant with eight cycles of trastuzumab(8 mg/kg loading dose,then 6 mg/kg) and pertuzumab(840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response(tp CR, yp T0/is yp N0). Secondary endpoints included breast p CR(bp CR),objective response rate(ORR), disease control rate, rate of breast-conserving surgery(BCS), and safety(with a focus on cardiotoxicity).Results: Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42(53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval(95% CI), 48.5%-71.2%] patients achieved tp CR, and 49(62.8%) achieved bp CR. ORRs were 76.9%(95% CI, 66.0%-85.7%) and 93.6%(95% CI,85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine(11.5%) patients experienced asymptomatic left ventricular ejection fraction(LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP(NT-pro BNP), troponin I, or high-sensitivity troponin.Conclusions: This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety profile,especially a low risk of cardiac events, suggesting it as an attractive treatment approach with a favorable risk-benefit balance.

A phase Ⅰ study of Hemay022, an irreversible dual EGFR/HER2 tyrosine kinase inhibitor in Chinese patients with HER2-positive advanced breast cancer

Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics,tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles.Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea(85.7%), vomiting(28.6%), nausea(25.0%) and decreased appetite(17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response(CR), and three achieved partial response(PR). The objective response rate(ORR) and disease control rate(DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival(PFS) was3.98 months.Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase Ⅲ trial(No. NCT05122494).

A multicenter study on efficacy of dual-target neoadjuvant therapy for HER2-positive breast cancer and a consistent analysis of efficacy evaluation of neoadjuvant therapy by Miller-Payne and RCB pathological evaluation systems(CSBrS-026)

Objective: The aim of this study was to investigate the factors influencing pathological complete response(pCR)rate in early breast cancer patients receiving neoadjuvant dual-target [trastuzumab(H) + pertuzumab(P)] therapy combined with chemotherapy. Additionally, the consistency of the Miller-Payne and residual cancer burden(RCB)systems in evaluating the efficacy of neoadjuvant therapy for early human epidermal growth factor receptor-2(HER2)+ breast cancer was analyzed.Methods: The clinicopathological data of female patients with early-stage HER2+ breast cancer who received dual-target neoadjuvant therapy at 26 hospitals of the Chinese Society of Breast Surgery(CSBrS) from March 2019 to December 2021 were collected. Patients were allocated to four groups: the HER2 immunohistochemistry(IHC)3+/hormone receptor(HR)-, IHC3+/HR+, IHC2+ in situ hybridization(ISH)+/HR-and IHC2+ ISH+/HR+groups. The overall pCR rate for patients, the pCR rate in each group and the factors affecting the pCR rate were analyzed. The consistency between the Miller-Payne and RCB systems in assessing the efficacy of neoadjuvant therapy was analyzed.Results: From March 1, 2019, to December 31, 2021, 77,376 female patients with early-stage breast cancer were treated at 26 hospitals;18,853(24.4%) of these patients were HER2+. After exclusion of unqualified patients, 2,395 patients who received neoadjuvant dual-target(H+P) therapy combined with chemotherapy were included in this study. The overall pCR rate was 53.0%, and the patients' HR statuses and different HER2+ statuses were significantly correlated with the pCR rate(P<0.05). The consistency of the pathological efficacy assessed by the Miller-Payne and RCB systems was 88.0%(κ=0.717, P<0.001).Conclusions: Different HER2 expression statuses and HR expression statuses are correlated with the pCR rate after dual-target neoadjuvant therapy in HER2+ breast cancer patients. There is a relatively good consistency between Miller-Payne and RCB systems in evaluating the pathologic efficacy of neoadjuvant therapy for HER2+breast cancer.

Antibody-Coupled Drugs in HER2-Positive Gastric Cancer

Antibody drug conjugates (ADCs) are a new class of drugs that combine chemosynthetic drugs with antibody drugs through a linker. Antibody drug conjugates combine the targeting characteristics of traditional antibody drugs with the cytotoxic characteristics of small molecule drugs, while reducing the side effects of both drugs, making them a kind of “biological missile” and representing a relatively new and evolving class of anti-cancer drugs. Antibody-coupled drugs are currently used in many solid tumors, and this article reviews the clinical application of antibody-coupled drugs in HER2-positive gastric cancer.

Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2(HER2)-positive early-stage breast cancer: A real-world retrospective study in Chinese patients

Objective: To assess the long-term effectiveness and safety of trastuzumab in adjuvant therapy for Chinese patients with early-stage human epidermal growth factor 2(HER2)-positive breast cancer in a real-world setting.Methods: This retrospective observational study analyzed the medical records of HER2-positive breast cancer patients between 2000 and 2012 at the Chinese Academy of Medical Sciences. Patients who received adjuvant chemotherapy alone or adjuvant chemotherapy followed by/combined with trastuzumab were included. The Kaplan-Meier method was used to estimate disease-free survival(DFS) and overall survival(OS). Hazard ratios(HR) and 95% confidence intervals(95% CI) were calculated using the Cox regression model.Results: Of the 1,348 patients analyzed, 909 received chemotherapy alone and 439 received chemotherapy plus trastuzumab. The 3-year, 5-year and 10-year DFS rates were 83.70%, 76.38% and 68.94%, respectively, in the chemotherapy-alone cohort, and 90.21%, 86.19% and 83.45% in the chemotherapy plus trastuzumab cohort. The3-year, 5-year and 10-year OS rates were 96.10%, 91.40% and 81.88% in the chemotherapy-alone cohort, and98.17%, 94.91% and 90.01% in the chemotherapy plus trastuzumab cohort. The chemotherapy plus trastuzumab group had a significantly lower risk of disease recurrence and death than the chemotherapy-alone group(DFS:HR=0.50, 95% CI, 0.37-0.68;P<0.001;OS: HR=0.53, 95% CI, 0.34-0.81;P=0.004) after adjusting for covariates.In the 439 patients treated with trastuzumab, multivariate analysis suggested that lymph node positivity, higher T stages, and hormone receptor-negative status were significantly associated with higher risks of disease recurrence,and lymph node positivity and hormone receptor-negative status were significantly associated with higher risks of death. Grade 3/4 adverse events(incidence ≥1%) were more common in patients receiving trastuzumab(54.44% vs.15.73%).Conclusions: Early-stage HER2-positive breast cancer patients treated with trastuzumab plus adjuvant chemotherapy have a significant survival benefit compared with chemotherapy-alone in real-world settings. Lymph node positivity, hormone receptor-negative status, and higher T stages may be associated with higher risks of recurrence, and effective therapy for patients with these factors is required.

Effect of trastuzumab combined with paclitaxel neoadjuvant chemotherapy on the cell proliferation and invasion in HER-2-positive breast cancer lesions

Objective: To study the effect of trastuzumab combined with paclitaxel neoadjuvant chemotherapy on the cell proliferation and invasion in human epidermal growth factor receptor-2 (HER-2)-positive breast cancer lesions. Methods: Patients who were diagnosed with HER-2-positive breast cancer in the Central Hospital of Enshi Autonomous Prefecture Hubei Province between April 2015 and January 2017 were selected and randomly divided into two groups, the combined group received trastuzumab combined with paclitaxel chemotherapy, and the control group accepted paclitaxel chemotherapy. The surgically removed breast cancer lesions were collected to determine the expression of cell proliferation genes, cell invasion genes and angiogenesis molecules. Results: USP39, EphA2, NUAK1, Gab2, Raptor, ICAM-1, HIF-1α, VEGF, ANGPLT-2 and ANGPLT-4 mRNA expression in tumor lesion of combined group were significantly lower than those of control group while CCN5, ALEX1, ATG2B, ATG4D, E-cadherin and EBP50 mRNA expression were significantly higher than those of control group. Conclusion: Trastuzumab combined with paclitaxel neoadjuvant chemotherapy can inhibit the cell proliferation and invasion and decrease the angiogenesis in HER-2-positive breast cancer lesions.

德曲妥珠单抗对比化疗方案二线治疗HER-2低表达晚期乳腺癌的经济学评价

目的 从我国卫生体系角度出发,评价德曲妥珠单抗方案对比医生选择化疗(TPC)方案二线治疗人表皮生长因子受体2(HER-2)低表达晚期乳腺癌的经济性。方法 基于DESTINY-Breast04临床试验数据构建动态Markov模型,模拟时限为10年,循环周期为3周。以成本、质量调整生命年(QALY)、增量成本-效果比(ICER)作为模型产出指标,采用5%的贴现率,以3倍2023年我国人均国内生产总值(GDP)作为意愿支付(WTP)阈值,采用成本-效用分析法分析激素受体阳性队列和所有患者队列中两种治疗方案的经济性,再通过不确定性分析验证基础分析结果的稳健性。结果 基础分析结果显示,德曲妥珠单抗方案与TPC方案相比,在激素受体阳性队列和所有患者队列中的ICER值分别为1 045 655.76、906 404.99元/QALY,均高于WTP阈值(268 074元/QALY)。单因素敏感性分析结果显示,疾病无进展状态效用值、德曲妥珠单抗价格、疾病进展状态效用值等参数对模型结果影响较大。概率敏感性分析结果显示,当WTP阈值为3倍2023年我国人均GDP时,德曲妥珠单抗方案具有经济性的概率为0。情境分析结果显示,在考虑援助计划时,德曲妥珠单抗方案具有经济性的概率为0;当德曲妥珠单抗价格降低70%时,该方案具有经济性的概率显著提高至82.80%。结论 在以3倍2023年我国人均GDP作为WTP阈值时,德曲妥珠单抗方案相对于TPC方案二线治疗HER-2低表达晚期乳腺癌不具有经济性;按地区适当降低德曲妥珠单抗的价格,可以提高其经济性。

曲妥珠单抗联合化疗致人表皮生长因子受体2阳性乳腺癌患者心脏毒性的影响因素分析

目的:探讨曲妥珠单抗联合化疗致人表皮生长因子受体2(Human Epidermal Growth Factor Receptor-2,HER-2)阳性乳腺癌患者心脏毒性的影响因素。方法:选取2020年12月-2022年12月徐州市中心医院诊治的152例HER-2阳性乳腺癌患者为研究对象。所有患者均采用曲妥珠单抗联合化疗(AC→PH)方案治疗,治疗期间每3个月使用超声监测心功能,统计心脏毒性发生情况。收集患者的临床资料,包括年龄、体质量指数、肿瘤分期、合并症(高血压病、糖尿病、高脂血症)、雌激素受体(Estrogen Receptor,ER)/孕激素受体(Progesterone Receptor,PR)的表达情况、吸烟史、饮酒史、同期行放疗及右丙亚胺使用情况,采用单因素分析、多因素Logistic回归分析患者发生心脏毒性的危险因素。结果:152例患者中心脏毒性发生率为26.31%,发生心脏毒性的患者常见的心电图改变有:T波改变、窦性心率过缓/过速、ST段异常等。单因素分析显示,年龄≥60岁、合并高血压病、合并高脂血症、同期行放疗、联合使用右丙亚胺是发生心脏毒性的影响因素(P <0.05)。多因素Logistic回归分析显示,年龄[95%置信区间(CI):2.429~5.135]、合并高血压病(95%CI:1.625~3.962)、合并高脂血症(95%CI:2.054~5.362)、同期行放疗(95%CI:1.759~4.637)是曲妥珠单抗联合化疗致HER-2阳性乳腺癌患者心脏毒性的危险因素(P<0.05),而联合使用右丙亚胺(95%CI:3.772~6.015)可显著减少心脏毒性的发生(P <0.05)。结论:年龄≥60岁、合并高血压病/高脂血症、同期行放疗是曲妥珠单抗联合化疗致HER-2阳性乳腺癌患者心脏毒性发生的危险因素,使用右丙亚胺是HER-2阳性乳腺癌患者发生心脏毒性的保护因素;化疗期间应将年龄≥60岁、合并高血压病和高脂血症、同期行放疗的患者列为心脏毒性的重点防治人群,联合应用右丙亚胺有助于减少心脏毒性发生。

曲妥珠单抗生物仿制药对比原研药治疗复发或转移性HER-2阳性乳腺癌的药物经济学评价

目的从卫生体系角度评估曲妥珠单抗生物仿制药(汉曲优)与原研药(赫赛汀)治疗复发或转移性人表皮生长因子受体2(HER-2)阳性乳腺癌的经济性。方法根据NCT03084237试验数据构建分区生存模型,模拟周期为3周,模拟时限为10年。以成本和质量调整生命年(QALY)为产出指标,采用成本-效用分析法评价上述2种方案的经济性。采用单因素敏感性分析和概率敏感性分析检验模型的稳健性。结果曲妥珠单抗生物仿制药组与原研药组的成本分别为111516.72、111122.30元,效用分别为1.52、1.36 QALYs,增量成本-效果比(ICER)为2465.12元/QALY,小于以3倍中国2023年人均国内生产总值(GDP)作为的意愿支付(WTP)阈值(268200元/QALY)。单因素敏感性分析结果表明,曲妥珠单抗生物仿制药费用与曲妥珠单抗原研药费用对ICER有较大影响。概率敏感性分析结果显示,当WTP阈值大于14902元/QALY时,曲妥珠单抗生物仿制药组具有经济性的概率为100%。结论当WTP阈值为3倍中国2023年人均GDP(268200元/QALY)时,与曲妥珠单抗原研药相比,曲妥珠单抗生物仿制药治疗复发或转移性HER-2阳性乳腺癌具有较好的经济性。

HER2 heterogeneity is a poor prognosticator for HER2-positive gastric cancer

BACKGROUND The clinical significance of intratumoral human epidermal growth factor receptor 2(HER2)heterogeneity is unclear for HER2-positive gastric cancer,although it has been reported to be a significant prognosticator for HER2-positive breast cancer,which has received trastuzumab-based chemotherapy.AIM To clarify the clinical significance of intratumoral HER2 heterogeneity for HER2-positive gastric cancer,which has received trastuzumab-based chemotherapy.METHODS Patients with HER2-positive unresectable or metastatic gastric cancer who received trastuzumab-based chemotherapy as a first line treatment were included.The patients were classified into two groups according to their intratumoral HER2 heterogeneity status examined by immunohistochemistry(IHC)on endoscopic biopsy specimens before treatment,and their clinical response to chemotherapy and survival were compared.RESULTS A total of 88 patients were included in this study,and HER2 heterogeneity was observed in 23(26%)patients(Hetero group).The overall response rate was significantly better in patients without HER2 heterogeneity(Homo group)(Homo vs Hetero:79.5%vs 35.7%,P=0.002).Progression-free survival of trastuzumab-based chemotherapy was significantly better in the Homo group(median,7.9 vs 2.5 mo,HR:1.905,95%CI:1.109-3.268).Overall survival was also significantly better in the Homo group(median survival time,25.7 vs 12.5 mo,HR:2.430,95%CI:1.389-4.273).Multivariate analysis revealed IHC HER2 heterogeneity as one of the independent poor prognostic factors(HR:3.115,95%CI:1.610-6.024).CONCLUSION IHC of HER2 heterogeneity is the pivotal predictor for trastuzumab-based chemotherapy.Thus,HER2 heterogeneity should be considered during the assessment of HER2 expression.

The efficacy of tucatinib-based therapeutic approaches for HER2-positive breast cancer

Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in approximately 15–20% of breast cancer cases. HER2 is a member of the epidermal growth factor receptor (EGFR) family with tyrosinase kinase activity, and its overexpression is linked to poor prognosis and shorter progression-free survival (PFS) and overall survival (OS). Among various treatment options, HER2-targeting monoclonal antibodies and tyrosine kinase inhibitors (TKIs) have mostly been applied in recent decades to treat HER2-positive (HER2^(+)) breast cancer patients. Although positive clinical outcomes were documented in both advanced disease and neoadjuvant settings, the development of resistance mechanisms to such approaches has been one of the major challenges with the continuous usage of these drugs. In addition, patients who experience disease progression after treatment with multiple HER2-targeted therapies often have limited treatment options. The Food and Drug Administration (FDA) has recently approved a new TKI (i.e., tucatinib) for use in combination with immunotherapy and/or chemotherapeutic agents for the treatment of advanced-stage/metastatic HER2^(+) breast cancer. This review highlights recent updates on the efficacy of tucatinib-based therapeutic approaches in experimental models as well as in the clinical settings of HER2^(+) breast cancer.

曲妥珠单抗新辅助化疗治疗HER-2阳性乳腺癌中体重指数与病理完全缓解的关系

目的 分析体重指数(BMI)与人表皮生长因子受体2(HER-2)阳性乳腺癌曲妥珠单抗新辅助化疗病理完全缓解(pCR)的关系。方法 收集2018年5月至2022年6月曲妥珠单抗新辅助治疗HER-2阳性乳腺癌患者136例临床资料,分析不同BMI的HER-2阳性乳腺癌临床病理特征,采用单因素及多因素Logistic分析BMI与pCR的关系。结果 136例HER-2阳性乳腺癌患者中,获得pCR 43例(31.62%)。BMI≥24组T分期(Ⅲ~Ⅳ期)、孕激素受体(PR)(阳性)、细胞核增殖抗原(Ki-67)(≥14)、淋巴结转移(阳性)高于BMI<24组(P<0.05)。pCR组与非pCR组年龄、月经状态、Ki-67比较(P>0.05);pCR组T分期(Ⅲ~Ⅳ期)、ER(阴性)、PR(阴性)、淋巴结转移(阳性)、BMI(≥24)低于非pCR组(P<0.05)。孕激素受体(PR)、淋巴结转移、BMI是影响ER-2阳性乳腺癌pCR的危险因素(P<0.05)。结论 曲妥珠单抗新辅助化疗治疗HER-2阳性乳腺癌pCR与PR、淋巴结转移、BMI明显相关,结合BMI与HER-2阳性乳腺癌临床病理特征的关系,BMI是HER-2阳性乳腺癌曲妥珠单抗新辅助化疗pCR的独立危险因素。

Thioridazine reverses trastuzumab resistance in gastric cancer by inhibiting S-phase kinase associated protein 2-mediated aerobic glycolysis

BACKGROUND Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2(HER-2)-positive gastric cancer(GC).However,the efficacy of this treatment is hindered by substantial challenges associated with both primary and acquired drug resistance.While S-phase kinase associated protein 2(Skp2)overexpression has been implicated in the malignant progression of GC,its role in regulating trastuzumab resistance in this context remains uncertain.Despite the numerous studies investigating Skp2 inhibitors among small molecule compounds and natural products,there has been a lack of successful commercialization of drugs specifically targeting Skp2.AIM To discover a Skp2 blocker among currently available medications and develop a therapeutic strategy for HER2-positive GC patients who have experienced progression following trastuzumab-based treatment.METHODS Skp2 exogenous overexpression plasmids and small interfering RNA vectors were utilized to investigate the correlation between Skp2 expression and trastuzumab resistance in GC cells.Q-PCR,western blot,and immunohistochemical analyses were conducted to evaluate the regulatory effect of thioridazine on Skp2 expression.A cell counting kit-8 assay,flow cytometry,a amplex red glucose/glucose oxidase assay kit,and a lactate assay kit were utilized to measure the proliferation,apoptosis,and glycolytic activity of GC cells in vitro.A xenograft model established with human GC in nude mice was used to assess thioridazine's effectiveness in vivo.RESULTS The expression of Skp2 exhibited a negative correlation with the sensitivity of HER2-positive GC cells to trastuzumab.Thioridazine demonstrated the ability to directly bind to Skp2,resulting in a reduction in Skp2 expression at both the transcriptional and translational levels.Moreover,thioridazine effectively inhibited cell proliferation,exhibited antiapoptotic properties,and decreased the glucose uptake rate and lactate production by suppressing Skp2/protein kinase B/mammalian target of rapamycin/glucose transporter type 1 signaling pathways.The combination of thioridazine with either trastuzumab or lapatinib exhibited a more pronounced anticancer effect in vivo,surpassing the efficacy of either monotherapy.CONCLUSION Thioridazine demonstrates promising outcomes in preclinical GC models and offers a novel therapeutic approach for addressing trastuzumab resistance,particularly when used in conjunction with lapatinib.This compound has potential benefits for patients with Skp2-proficient tumors.

曲妥珠单抗生物类似药与原研药治疗HER-2阳性乳腺癌的疗效与成本—效果比比较

目的 比较曲妥珠单抗生物类似药与原研药治疗人表皮生长因子受体2(HER-2)阳性乳腺癌的疗效与成本—效果比。方法 选取2020年1月—2022年12月靖江市人民医院收治的HER-2阳性乳腺癌患者74例,遵循1∶1原则随机分为生物类似药组和原研药组,各37例。生物类似药组采用曲妥珠单抗生物类似药治疗,原研药组采用曲妥珠单抗原研药治疗,3周为1个疗程,2组均持续治疗6个疗程。比较2组疗效,治疗前后肿瘤标志物[癌胚抗原(CEA)、糖类抗原125(CA125)、糖类抗原153(CA153)]水平、肿瘤长径、卡氏(KPS)评分及成本—效果比。结果 生物类似药组与原研药组客观缓解率比较差异不显著(59.46%vs.62.16%,χ^(2)=0.057,P=0.812)。治疗6个疗程后,2组CEA、CA125、CA153水平低于治疗前(P均<0.01),但生物类似药组与原研药组组间比较差异不显著(P>0.05);2组肿瘤长径较治疗前缩短,KPS评分较治疗前提高(P均<0.01),但生物类似药组与原研药组组间比较差异不显著(P>0.05);生物类似药组成本/疗效优于原研药组,经济效益更高。结论 曲妥珠单抗原研药与生物类似药均可改善患者病情,促使肿瘤长径缩短,降低肿瘤标志物水平,且二者疗效相当,但曲妥珠单抗生物类似药的成本—效果比更优,其经济效益更显著。

靶向HER2胞外结构域Ⅳ的单克隆抗体在乳腺癌中的应用进展

人表皮生长因子受体2(HER2)阳性乳腺癌侵袭性强且易转移,抗HER2靶向药物的应用能显著改善HER2阳性乳腺癌患者的预后。在已上市的HER2靶向药物中,靶向HER2胞外结构域Ⅳ的大分子单克隆抗体是治疗HER2阳性乳腺癌的基础靶向药物,主要包括曲妥珠单抗、伊尼妥单抗和马吉妥昔单抗。曲妥珠单抗用于乳腺癌全线治疗,循证医学证据充分,实践经验充足且安全性可控;伊尼妥单抗与曲妥珠单抗在HER2阳性转移性乳腺癌和新辅助/辅助治疗中疗效相似,且安全性可控;马吉妥昔单抗聚焦于携带CD16A-158F等位基因的患者,是晚期乳腺癌后线治疗的选择。临床上需根据患者具体病情选择最适合的药物。

白蛋白结合型紫杉醇与多西紫杉醇在人表皮生长因子受体-2阳性乳腺癌患者新辅助化疗中的疗效对比研究

目的:分析曲妥珠单抗+帕妥珠单抗分别联合不同类型紫杉醇应用于人表皮生长因子受体-2(HER2)阳性乳腺癌的疗效。方法:纳入90例拟行新辅助化疗的HER2阳性乳腺癌患者,根据曲妥珠单抗+帕妥珠单抗分别联合不同类型紫杉醇,将患者分为两组,44例采用多西紫杉醇方案化疗分为对照组,46例采用白蛋白结合型紫杉醇方案化疗分为观察组。以21 d为1个周期,治疗6个周期后,比较两组近期疗效、化疗前后Ki-67阳性率、基质金属蛋白酶-9(MMP-9)相对表达量、组织多肽特异性抗原(TPS)水平、生存情况、不良反应。结果:两组客观缓解率、疾病控制率比较差异无统计学意义(均P>0.05),两组总体病理完全缓解率比较差异有统计学意义(P<0.05)。治疗6个周期后,两组Ki-67阳性率、MMP-9相对表达量、TPS水平均降低,且观察组低于对照组(均P<0.05)。观察组中位生存期长于对照组(P<0.05)。两组不良反应比较差异无统计学意义(均P>0.05)。结论:相较于多西紫杉醇,白蛋白结合型紫杉醇可提高HER2阳性乳腺癌患者总体病理完全缓解率,降低Ki-67阳性率、MMP-9相对表达量和TPS水平,延长患者生存期。

HER2-positive adenocarcinoma arising from heterotopic pancreas tissue in the duodenum:A case report

BACKGROUND Adenocarcinoma originating from heterotopic pancreas tissue is a rare disease.Furthermore,to our knowledge,no HER2-positive cases in the duodenum have been reported in the scientific literature nor has the efficacy of trastuzumab treatment for the disease been reported.CASE SUMMARY A 65-year-old woman whose clinical diagnosis was unresectable advanced duodenal cancer with HER2 overexpression responded well to trastuzumab chemotherapy.The main tumor in the duodenum reduced drastically.The patient underwent pancreaticoduodenectomy and lymph node dissection.A small number of cancer cells remained in the submucosal layer of the duodenum and pancreas head.After histological and immunohistochemical examination,the patient was diagnosed with duodenal adenocarcinoma originating from heterotopic pancreas tissue.CONCLUSION Trastuzumab treatment is effective in HER2-positive adenocarcinoma originating from heterotopic pancreas tissue in the duodenum.