Expression of truncated HER2 and its prognostic value in HER2-positive breast cancer patients

Purpose

The purpose of this work was to assess the truncated form of human epidermal growth factor receptor 2 (HER2) such as p95-HER2 expression in HER2-positive breast cancer (BC) patients who developed metastatic disease after adjuvant treatment with a trastuzumab-containing regimen.

Quantitative aspects of the analysis of the monoclonal antibody trastuzumab using high-performance liquid chromatography coupled with electrospray mass spectrometry

The analytical possibilities of quantification of the intact monoclonal antibody trastuzumab by high-performance liquid chromatography coupled with electrospray mass spectrometry (HPLC-ESI-MS) were investigated. To clarify the results obtained by LC-MS, complementary experiments were performed using direct UV-spectrophotometry and high-performance liquid chromatography coupled with ultraviolet detection (HPLC-UV). A polystyrene-divinylbenzene (POROS) column was applied with gradient elution using formic acid 0.08% (v/v) in water and formic acid 0.08% (v/v) in acetonitrile as mobile phase for chromatographic analysis. Quantification on LC-MS was performed by using the peak area of the total ion current (TIC) chromatograms of one charge state. Non-linearity and sensitivity loss were the major limitations observed with the LC-MS method, of which the non-linearity is most likely caused by detector saturation. The sensitivity loss during analysis could be reduced by lowering the MS source temperature. This parameter is critical in creating a robust LC-MS system for the quantitative analysis of trastuzumab.     

补肾活血汤联合曲妥珠单抗对肝肾阴虚型Her-2阳性晚期乳腺癌患者的影响分析

目的 分析补肾活血汤联合曲妥珠单抗对肝肾阴虚型人表皮生长因子受体2(Her-2)阳性晚期乳腺癌患者的影响.方法 选取2020年7月至2021年12月本院收治的80例肝肾阴虚型Her-2阳性晚期乳腺癌患者作为研究对象,根据随机数字表法分为对照组与研究组,各40例.对照组采用单一曲妥珠单抗治疗,研究组采用补肾活血汤联合曲妥...     

GDF-15在预测和监控表柔比星/环磷酰胺-多西他赛-曲妥珠单抗辅助治疗HER-2阳性乳腺癌患者产生心脏毒性中的作用

目的 评估表柔比星/环磷酰胺-多西他赛-曲妥珠单抗(EC-D-T)辅助治疗HER-2阳性乳腺癌患者的心脏毒性及生长分化因子15(GDF-15)对其心脏毒性发生风险的预测作用。方法 纳入2014年1月—2016年12月手术后接受EC-D-T辅助治疗的73例HER-2阳性乳腺癌患者。于辅助治疗前(M₀)、辅助治疗后第3(M₃)、6(M₆)、9(M₉)、12(M₁₂)和15个月(M₁₅)检测患者血清GDF-15、心肌肌钙蛋白I(cTnI)和氨基末端脑钠肽前体(NT-proBNP)水平。同时,患者在各时间点接受心脏超声检查并通过超声心动图评估左心室射血分数(LVEF)。结果 启动EC-D-T治疗后,LVEF水平逐渐降低。整个研究过程中,共21(28.8%)例患者发生了心脏毒性,同时,发生心脏毒性患者在M₀的GDF-15水平及各个时间点的cTnl水平显著高于未发生心脏毒性患者,而NT-proBNP水平和未发生心脏毒性患者相当。此外,单因素Logistic回归显示基线期GDF-15可能是接受EC-D-T治疗的HER-2阳性乳腺癌患者心脏毒性的影响因素,多因素Logistic回归分析表明仅有cTnl水平是接受EC-D-T治疗的HER-2阳性乳腺癌患者出现心脏毒性的独立预测因素,而NT-proBNP水平不可预测心脏毒性发生风险。结论 HER-2阳性乳腺癌患者接受EC-D-T治疗后的心脏毒性发生率高,而GDF-15可以预测及监控心脏毒性的发生风险。     

Duration of adjuvant trastuzumab in HER2 positive breast cancer: Overall and disease free survival results from meta-analyses of randomized controlled trials

BackgroundOne year of trastuzumab, chosen empirically, improves survival of women with early-stage, HER2-positive breast cancer but also adds substantially to cost, toxicity, and inconvenience. Longer treatment does not improve outcomes, but potentiates toxicities.MethodsMedline, Embase, and major conference proceedings were searched systematically in June 2017 to identify Randomized Controlled Trials (RCTs) comparing one year versus shorter durations of trastuzumab in adjuvant treatment of breast cancer. Reported Hazard-Ratios (HR) for Overall Survival (OS) and Disease-Free Survival (DFS), and Odds-Ratio for cardiac events, with respective 95% Confidence Intervals (CI) from each study was weighted using generic inverse-variance, and pooled in a meta-analysis. Inter-study heterogeneity and sub-group difference (based on hormone-receptors and node-positivity) were assessed using I², and chi² statistics, respectively.ResultsFour studies (n = 7614) satisfied inclusion criteria. Individual RCTs had diverse pre-specified upper-limits of 95% CI for declaring non-inferiority (range: <1.15 to <1.53). Pooled results demonstrated significant improvements in OS (HR 1.28, p = 0.04), and DFS (HR 1.24, p = 0.005) with 1 year of trastuzumab compared to shorter durations. Absence of multiplicity argument allowed for declaring superiority of 1 year of trastuzumab based on our results despite non-inferiority designs of individual trials. No influence on overall effect by duration of trastuzumab in experimental arm (9 weeks versus 6 months) was noted. No statistical interaction by hormone-receptor status and node-positivity on overall results was noticed [p(sub-group difference) 0.73, and 0.52, respectively]. Odds-Ratio for cardiac events was 2.65 (p < 0.001) favoring shorter duration.ConclusionOne year of trastuzumab prolongs overall, and disease-free survivals in women with early-stage HER2 positive breast cancer compared to shorter durations and this should remain as the standard of care. Cardiotoxicity increased significantly with the 1-year treatment.     

Long-term outcome of the REMAGUS 02 trial,a multicenter randomised phase II trial in locally advanced breast cancer patients treated with neoadjuvant chemotherapy with or without celecoxib or trastuzumab according to HER2 status

BackgroundThe REMAGUS-02 multicenter randomised phase II trial showed that the addition to neoadjuvant chemotherapy (NAC) of trastuzumab in patients with localised HER2-positive breast cancer (BC) increased the pathological complete response (pCR) rate and that the addition of celecoxib in HER2-negative cases did not increase the pCR rate. We report here the long-term follow-up results for disease-free survival (DFS) and overall survival (OS).Patients and methodsFrom 2004 to 2007, 340 stage II–III BC patients were randomly assigned to receive neoadjuvant EC-T (four cycles of epirubicin–cyclophosphamide followed by four cycles of docetaxel) +/− celecoxib in HER2-negative cases (n = 220) and ± trastuzumab in HER2-positive cases (n = 120). From September 2005, all patients with HER2-positive BC received adjuvant T (n = 106).ResultsMedian follow-up was nearly 8 years (94.4 months, 20–127 m). In the HER2-negative subgroup, addition of celecoxib was not associated with a DFS benefit. Favourable factors were smaller tumour size, expression of progesterone receptor status (PgR) and pCR. In the HER2-positive population, neoadjuvant trastuzumab was not associated with a DFS benefit. Axillary pCR was the only prognostic factor associated with DFS in this group [HR = 0.44, 95% CI = 0.2–0.97], p = 0.035]. To note, DFS and OS were significantly higher in the HER2-positive than in HER2-negative BC patients (HR = 0.58 [0.36–0.92], p = 0.021).ConclusionCelecoxib combined with NAC provided neither pCR nor survival benefit in patients with HER2-negative BC. Absence of PgR is a major prognostic factor. Neoadjuvant trastuzumab increased pCR rates without translation into a DFS or OS benefit compared with adjuvant trastuzumab only. Axillary pCR could be a more relevant surrogate of survival than in the breast in HER2-positive population. A retrospective comparison shows that patients with HER2-positive tumours have a better outcome than HER2-negative BC patients showing the impact of trastuzumab on the natural history of BC.     

Patients' preference of trastuzumab administration (subcutaneous versus intravenous) in HER2-positive metastatic breast cancer: Results of the randomised MetaspHer study

HannaH (NCT00950300) and PrefHer (NCT01401166) studies validated the subcutaneous (H-s.c.) formulation of trastuzumab as effective and safe as intravenous (H-i.v.) and highly preferred by patients in early breast cancer. The present randomised MetaspHer trial (NCT01810393) is the first study assessing patient's preference in metastatic setting.MethodsPatients with HER2-positive metastatic breast cancer who completed a first line chemotherapy with trastuzumab and achieved a long-term response lasting more than 3 years were randomised to receive 3 cycles of 600-mg fixed-dose adjuvant H-s.c., followed by 3 cycles of standard H-i.v., or the reverse sequence. Primary end-point was overall preference for H-s.c. or H-i.v. at cycle six, assessed by Patient Preference Questionnaire (PPQ). Secondary end-points included healthcare professional (HCP) satisfaction; safety and tolerability; quality of life.ResultsHundred and thirteen patients were randomised and treated. H-s.c. was preferred by 79/92 evaluable intent-to-treat patients (85.9%, 95% confidence interval [CI; 78.8–93.0]; p < 0.001), 13/92 preferred H-i.v. (14.1%, 95% CI [7.0–21.3]). HCPs were most satisfied with H-s.c. (56/88 available data, 63.6%, [53.6–73.7]). On the safety population, adverse events occurred in 73 (67.6%) and 49 (44.1%) patients during the H-s.c. and H-i.v. periods, respectively; 7 (6.5%) and 4 (3.6%) were grade ≥ III, 3 (2.8%) and 2 (1.8%) were serious.ConclusionThe safety was consistent with the known H-i.v. and H-s.c. profiles without safety concern raised. Definitively, patients preferred H-s.c. as reported in early stage by PrefHer study.     

Patients with HER2-positive Early Breast Cancer Receiving Adjuvant Trastuzumab: Clinicopathological Features,Efficacy, and Factors Affecting Survival

Background: The aim of the present study was to evaluate clinicopathological characteristics of our early stagebreast cancer patients who are epidermal growth factor receptor 2 (HER2) overexpressed/ amplified (HER2+),the efficacy of trastuzumab treatment and survival results. Materials and Methods: Patients with HER2- positiveearly stage breast cancer receiving adjuvant trastuzumab were investigated retrospectively. Clinicopathologicalfeatures of 210 patients and treatment outcome were analysed. To evaluate survival rates, the Kaplan-Meiermethod was used. Univariate and multivariate analyses were conducted with the Cox regression model. Results:Mean age of the patients was 51.8, 71.9% being postmenopausal. Some 37.6% of patients were node negative,and 31% had T1 tumor size and 52.4% were positive for estrogen receptor. Of 210 patients, 89.5% completedplanned 52 weeks adjuvant trastuzumab treatment. The median follow up was 27.5 months (6.0-86.0 ). Relapsefree survival (RFS) was 68.0 months (95% CI: 62.1-74.0) and overall survival (OS) was 74.8 months (95%CI: 69.5-80.1). The 3 year OS for all patients was 92.0% and RFS was 79.6%. During follow up, relapse wasdetected at the rate of 14.3%. Trastuzumab associated cardiotoxicity was found at the rate of 3.3%. In univariateanalyses, larger tumor size and grade III were significantly associated (p<0.05) with RFS. Multivariate analysesof covariates displaying p<0.05 identified grade III as an independent prognostic factor. Conclusions: In thepresent study, it was established that trastuzumab had a satisfactory safety profile and treatment efficacy as inother clinical studies and that among clinicopathological factors evaluated, only being grade 3 had a significanteffect on RFS. The occurrence of relapse with adjuvant trastuzumab makes it necessary to identify molecularpredictors, which will define this group better and help explain resistance to anti HER2 based therapies.     

Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer

Background

A novel antibody–drug conjugate (trastuzumab-DM1, T-DM1) is currently in clinical trials for patients with trastuzumab resistant HER2-positive breast cancer. Since no clinical data is available from gastric cancer, we studied T-DM1 on HER2-positive human gastric cancer cells and xenograft tumors.

Methods

Effects of T-DM1 were studied in four HER2-positive gastric cancer cell lines (N-87, OE-19, SNU-216 and MKN-7) in vitro. Xenograft tumors from N-87 and OE-19 were studied to determine the effect of T-DM1 in vivo.

Results

T-DM1 was found more effective than trastuzumab in N-87 and OE-19, and moderately effective in MKN-7 cells. On SNU-216 cells both trastuzumab and T-DM1 showed limited efficacy. In xenograft tumor experiments, complete pathological response was observed in all OE-19 xenografted mice and in half of the N-87 xenografted mice. The results were equally good irrespective of the tumor burden at therapy initiation, or preceding trastuzumab treatment. T-DM1 treatment showed direct effects (apoptotic cell death and aberrant mitosis) as well as it mediated antibody-dependent cellular cytotoxcity (ADCC).

Conclusions

T-DM1 showed a promising anti-tumor effect in HER2-positive gastric cancer cell lines in vitro and in vivo, even in tumors which had developed resistance to trastuzumab. T-DM1 therapy may warrant clinical trials for HER2-positive gastric cancer patients.