赫赛汀对乳腺癌SK-BR3细胞Notch-1信号通路的影响及意义

探讨赫赛汀对乳腺癌SK-BR3细胞Notch-1蛋白的影响及其作用机制,认识Notch-1信号通路在乳腺癌细胞形成赫赛汀耐药中的意义。方法：选用HER-2过表达乳腺癌SK-BR3细胞及HER-2非过表达乳腺癌MDA-MB-231细胞,免疫细胞化学法和Western blot法检测两细胞株中Notch-1蛋白的表达;应用赫赛汀处理SK-BR3细胞,Western blot法检测HER-2、Notch-1通路活性分子Notch-1IC的蛋白表达;RT-PCR法检测Notch-1靶基因HES-1 mRNA的表达;免疫共沉淀法检测SK-BR3细胞中Notch-1与HER-2是否存在相互作用。结果：Notch-1IC核定位水平及Notch-1IC蛋白表达水平在HER-2过表达乳腺癌细胞（9.37±0.64）中明显低于HER-2非过表达乳腺癌细胞（21.665±1.11）,P<0.01;赫赛汀处理SK-BR3细胞后,与未处理组比较,细胞内Notch-1IC蛋白及HES-1 mRNA水平均明显增高（P<0.01,P<0.01）,HER-2蛋白表达水平在处理前后未发生明显变化（F=0.973,P>0.05）;免疫共沉淀结果显示Notch-1与HER-2蛋白之间存在共沉淀。结论：Notch-1蛋白在HER-2过表达乳腺癌细胞中活性下降;HER-2与Notch-1结合,可能负性调控Notch-1;赫赛汀活化的Notch-1信号通路,可能与细胞耐药发生有关。     

Short-duration versus 1-year adjuvant trastuzumab in early HER2 positive breast cancer: A meta-analysis of randomized controlled trials

BackgroundOne year of adjuvant trastuzumab treatment is the standard of care for early stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients; however, controversy remains regarding the optimal schedule of trastuzumab because the selection of the 1-year schedule was arbitrary. After the remarkable results of the PERSEPHONE trial as well as the updated final results of the PHARE trial, we performed an updated meta-analysis to reassess the efficacy and safety of shorter durations of trastuzumab.MethodsA literature search of databases was conducted to identify randomized controlled trials reporting the efficacy and cardiotoxicity of shorter-duration and standard 1-year trastuzumab treatment. The hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS), and the odds ratios (ORs) of cardiac events were also estimated and pooled.ResultsSix studies were eligible, including a total of 11,496 patients. Both DFS (HR = 1.13; 95% confidence interval [CI] = 1.03–1.25; p = 0.01) and OS (HR = 1.16; 95% CI = 1.01–1.32; p = 0.03) were significantly improved with conventional 1-year trastuzumab treatment compared with shorter treatments. The more pronounced survival benefits observed in patients with negative estrogen receptor (ER) tumor and nodal involvement should be interpreted cautiously because of the lack of interaction between the survival benefit and ER, as well as the nodal status (interaction test, ER status: p = 0.26; nodal status: p = 0.60). One year of trastuzumab treatment resulted in a substantial DFS benefit compared with shorter schedules when administered concurrently with chemotherapy (HR = 1.22; 95% CI = 1.09–1.38; p = 0.0008; p = 0.02 for the interaction test). Patients in the shorter duration group experienced significantly fewer cardiac events (OR = 0.52; 95% CI = 0.43–0.62; p < 0.00001).ConclusionsThough correlated with an increasing risk of cardiotoxicity, 1 year of adjuvant trastuzumab treatment conferred substantial survival benefits and should remain as the preferred treatment for early stage HER2-positive breast cancer. Shorter durations of trastuzumab may serve as an alternative choice for patients with cardiac disease and those at lower risk of recurrence.     

Poly (ADP-ribose) polymerase inhibition enhances trastuzumab antitumour activity in HER2 overexpressing breast cancer

AimPoly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in Breast Cancer (BRCA) deficient breast cancer, but not in molecularly unselected patient populations. Two lines of research in this field are needed: the identification of novel subsets of patients that could potentially benefit from PARP inhibitors and the discovery of suitable targeted therapies for combination strategies.MethodsWe tested PARP inhibition, alone or combined with the anti-HER2 antibody trastuzumab on HER2+ breast cancer. We used two PARP inhibitors in clinical development, olaparib and rucaparib, as well as genetic downmodulation of PARP-1 for in vitro studies. DNA damage was studied by the formation of γH2AX foci and comet assay. Finally, the in vivo anti-tumour effect of olaparib and trastuzumab was examined in nude mice subcutaneously implanted with BT474 cells.ResultsIn a panel of four HER2 overexpressing breast cancer cell lines, both olaparib and rucaparib significantly decreased cell growth and enhanced anti-tumour effects of trastuzumab. Cells exposed to olaparib and trastuzumab had greater DNA damage than cells exposed to each agent alone. Mechanistic exploratory assays showed that trastuzumab downmodulated the homologous recombination protein proliferating cell nuclear antigen (PCNA). Combination treatment in the BT474 xenograft model resulted in enhanced growth inhibition, reduced tumour cell proliferation, and increased DNA damage and apoptosis.ConclusionTaken together, our results show that PARP inhibition has antitumour effects and increases trastuzumab activity in HER2 overexpressing breast cancer. These findings make this novel combination a promising strategy for clinical development.     

Population pharmacokinetics of trastuzumab in patients With HER2+ metastatic breast cancer

Purpose: To characterize the population pharmacokinetics of trastuzumab in patients with metastatic breast cancer. Methods: A nonlinear mixed effect model was based on pharmacokinetic data from phase I, II, and III studies of 476 patients. The phase I study enrolled patients with advanced solid tumors. The phase II and III studies enrolled patients with HER2-positive metastatic breast cancer. Patients in the pivotal phase II and III studies were treated with a 4 mg/kg loading dose of trastuzumab followed by 2 mg/kg weekly for up to 840 days. The model adequately predicted observed trastuzumab concentrations. Model stability and performance were verified using bootstrap simulations. Percentiles, mean, and standard deviation of observed levels were compared with their distributions from 100 replicates of datasets simulated under the model. Results: A two-compartment linear pharmacokinetic model best described the data and accounted for the long-term accumulation observed following weekly administration of trastuzumab. Population estimates from the base model for clearance (CL) and volume of distribution of the central compartment (V₁) of trastuzumab were 0.225 L/day, and 2.95 L, respectively. Estimated terminal halflife (t_1/2) based on the population estimate was 28.5 days. Interpatient variabilities in clearance and volume were 43 and 29%, respectively. The number of metastatic sites, plasma level of extracellular domain of the HER2 receptor, and patient weight were significant baseline covariates for clearance, volume, or both (P<0.005). However, these covariate effects on trastuzumab exposure were modest and not clinically important in comparison with the large inter-patient variability of CL. Concomitant chemotherapy (anthracycline plus cyclophosphamide, or paclitaxel) did not appear to influence clearance. Conclusion: This population pharmacokinetic model can predict trastuzumab exposure in the long-term treatment of patients with metastatic breast cancer and provide comparison of alternative dosage regimens via simulation.     

Central nervous system metastases in a cohort of metastatic breast cancer patients treated with trastuzumab

Background  Several analyses suggest an increase of brain metastases in HER2 over-expressing breast cancers treated with trastuzumab as compared to historical series of unselected patients. Patients and methods  We analyzed the incidence of central nervous system (CNS) metastases in 78 patients with HER2 over-expressing breast cancer treated with trastuzumab between July 2000 and June 2006 at the Oncology Department of University Federico II in Naples. We also characterized and compared patients with and without CNS involvement. Results  The median follow-up was 35.3 months (95%CI 26.3–44); median overall survival was 56 months (95%CIs 46-nr); 5 patients showed CNS involvement before trastuzumab therapy while 31 developed CNS metastases during trastuzumab treatment. The median overall survival after CNS metastases was 25.4 months (95%CIs 15.2-nr); patients with CNS lesions showed worse overall survival than patients without CNS lesions (39.1 vs. 75 months, p = 0.005). Conclusion  CNS metastases are common events in patients with metastatic HER2 over-expressing breast cancer treated with trastuzumab; the impact on survival is detrimental even if survival after CNS metastases is longer than historical reports. Appropriate investigation of the role of CNS imaging screening and the prophylactic treatment strategies for CNS represents a priority research in this setting. E. Montagna and G. Cancello have contributed equally to this work.     

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.     

miR-375靶向YAP1调控上皮-间质转化参与乳腺癌细胞曲妥珠单抗的耐药

背景与目的:曲妥珠单抗作为人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)常用靶向抗体药物,其耐药问题日益凸显.探讨miR-375靶向Yes相关蛋白1(Yes-associated protein 1,YAP1)介导上皮-间质转化(epithelial-...     

Notch-1信号通路在甲状腺癌中作用的研究进展

Notch信号通路参与调控机体细胞的增殖、分化、凋亡等,人类Notch信号通路包括了四种受体及五种配体,其中Notch-1受体在甲状腺癌中发挥重要作用。然而,Notch-1在甲状腺乳头状癌中的作用仍存在争议,大多数学者认为Notch-1信号通路能够促进乳头状癌细胞增殖、侵袭转移,且其表达水平与甲状腺乳头状癌侵袭性相关。而对于甲状腺滤泡状癌、髓样癌及未分化癌细胞,活化Notch-1信号通路可抑制他们的增殖。众多研究表明Notch-1信号通路有望成为甲状腺癌重要治疗靶点。本文就Notch-1在甲状腺癌发生、发展中的作用进行综述。     

Superimposable outcomes for sequential and concomitant administration of adjuvant trastuzumab in HER2-positive breast cancer: Results from the SIGNAL/PHARE prospective cohort

AimAdjuvant clinical trials in early human epidermal growth factor receptor 2 (HER2)-positive breast cancer have assessed either sequential or concomitant incorporation of trastuzumab with chemotherapy; only the North Central Cancer Treatment Group (NCCTG)-N9831 trial prospectively compared both modalities. In routine trastuzumab has been incorporated into a concurrent regimen with taxane chemotherapy instead of sequential modality on the basis of a positive risk-benefit ratio. This present study assessed sequential versus concomitant administration of adjuvant trastuzumab.MethodsA population combining patients from Protocol for Herceptin^® as Adjuvant therapy with Reduced Exposure (PHARE) a randomised phase III clinical trial (NCT00381901) and SIGNAL (RECF1098) a prospective study specifically designed for Genome-wide Association Studies (GWAS) analyses was studied. In this cohort with 58 months of median follow-up, the comparison in the HER2-positive group of adjuvant trastuzumab and chemotherapy modalities was based on a propensity score methodology. Treatment modalities were based on physician's choice and comparisons adjustment were made by a propensity score methodology. Overall Survival (OS) and Disease-Free Survival (DFS) were estimated using the Kaplan–Meier method, and comparisons between groups were based on the log rank test.ResultsThe SIGNAL/PHARE cohort included 11,728 breast cancer cases treated in adjuvant setting; some 5502 of them with HER2-positive tumour: 34.5% (1897/5502) were treated by sequential and 65.5% (3605/5502) by concomitant modality of administration for taxane-chemotherapy and trastuzumab. The adjusted comparison found similar OS (HR = 1.01; 95% CI: 0.86–1.19) and similar DFS (HR = 1.08; 95% CI: 0.96–1.21).ConclusionThese results suggest that the sequential administration of trastuzumab given after the completion of adjuvant chemotherapy might be as valid as the concomitant administration of trastuzumab and taxane chemotherapy in the adjuvant setting.     

Inhibition of HER1 signaling pathway enhances antitumor effect of endocrine therapy in breast cancer

Epidermal growth factor receptor (EGFR)/HER1 is expressed at high levels in at least 20% of breast cancers. This high expression correlates with a poor prognosis in patients with breast cancer. Experimental and clinical findings suggest that aberrant activation of tyrosine receptor kinases, such as HER1 pathway, play a causal role in the development of antiestrogen resistance in breast cancer. Recent preclinical and clinical evidence shows that inhibition of growth factor signaling pathways suppresses the growth of malignant cells without serious toxicities. To test the hypothesis that inhibition of the HER1 signaling pathway enhances the antitumor effect of endocrine therapy, a promising signal transduction inhibitor (STI) of HER1 tyrosine kinase, gefitinib, and an estrogen receptor (ER) antagonist, fulvestrant, were administered to human breast cancer cells. Our experimental results have revealed that gefitinib additively enhances the antitumor effect of fulvestrant in estrogen receptor (ER)-positive breast cancer cells under estrogen-supplemented conditions. An additive increase in the protein expression level of a cyclin-dependent kinase inhibitor, p21 may play a key role of this additive cytostatic effect. The rationale and future perspectives of the combined use of STIs with endocrine therapy in breast cancer are discussed.     

曲妥珠单抗耐药机制及HER2阳性乳腺癌耐药后的治疗策略

曲妥珠单抗治疗人表皮生长因子受体2(Human epidermal growth factor receptor 2,HER2)阳性乳腺癌的效果确切,但高耐药率限制了其临床应用。本文对HER2阳性乳腺癌曲妥珠单抗耐药机制进行回顾与总结,并分析耐药后HER2阳性乳腺癌的治疗策略,以期为进一步的研究及临床治疗方案制定提供参考。     

Trastuzumab and breast cancer: developments and current status

The emergence of trastuzumab has drastically changed therapy for breast cancer. Trastuzumab (Herceptin; Genentech) is a recombinant humanized monoclonal antibody that targets an epitope in the extracellular domain of the human epidermal growth factor receptor 2 (HER2) protein. HER2 is a member of a family of four transmembrane receptor tyrosine kinases that regulate cell growth, survival, and differentiation via multiple signal transduction pathways. Overexpression of HER2 or amplification of the HER2 gene occurs in 20%–30% of human breast cancers. Preclinical models have demonstrated that this antibody has significant antitumor activity as a single agent, and it also has a synergy with certain chemotherapeutic drugs. Phase II and III clinical trials performed in women with metastatic breast cancers that overexpress HER2 have shown trastuzumab to have clinical activity when used as monotherapy, while also improving survival when used as a first-line therapy in combination with chemotherapy. At present, clinical investigations are focusing attention on the efficacy of trastuzumab in both the adjuvant and neoadjuvant setting, as well as in the metastatic setting. In this review, we describe the developments and current status of trastuzumab-based treatment for breast cancer.     

Limited human epidermal growth factor receptor 2 discordance in metastatic breast cancer patients treated with trastuzumab,a population based study

BackgroundAccurate assessment of the human epidermal growth factor receptor 2 (HER2) in breast cancer is essential for proper treatment decisions. HER2 positivity confirmation rates in breast cancer trials by central testing pathology laboratories were reported to be approximately 85%. The aim of our study was to assess in a population based sample concordance of HER2 status in metastatic breast cancer (MBC) patients locally tested HER2 positive and treated with trastuzumab. Moreover cost-effectiveness of in situ hybridisation (ISH) in patients with an immunohistochemical score 3+ (IHC3+) was explored.MethodsMBC patients treated between 2005 and 2009 with trastuzumab-based therapy in North East Netherlands were identified by a survey of hospital pharmacies. Primary tumour samples were retested centrally for HER2 status using 1 immunohistochemical (IHC) method and two methods using ISH on tissue micro-arrays. Potential discordant patients were retested on whole tumour slides. HER2 positivity was defined as: (1) ISH amplification (according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) clinical practice Guideline Update) and (2) when ISH failed an IHC score of 3+. Cost-effectiveness was estimated using potential ISH and treatment costs.ResultsHER2 status could be retested in 174 of 194 (90%) patients. The HER2 concordance rate was 87%. The 21 discordant patients were in the 67% due to primary HER2 testing with only IHC. Overall survival of HER2 discordant and concordant patients was not significantly different (18 versus 25 months, p = 0.131). Structural ISH in the case of IHC3+ has an estimated potential saving of €87,710 per 100 patients.ConclusionHER2 concordance in a population based study is comparable to those described in selected populations. Discordance is mostly due to testing with only IHC. ISH in the case of IHC3+ is cost-effective.     

Clinical development of trastuzumab in Breast Cancer

The HER-2/neu protein is thought to be a unique and useful target for antibody therapy of cancers overexpressing the HER-2/neu gene. The recombinant humanized anti-HER-2 monoclonal antibody, trastuzumab (Herceptin) is now available for clinical use in the U.S.A. It is also expected to be available in Japan in the near future. In this paper, the details of this novel biologic agent are reviewed in conjunction with a phase I study performed in Japan.     

Evaluation of HER2 status: For the treatment of metastatic breast cancers by humanized anti-HER2 monoclonal antibody (trastuzumab) (Pathological committee for optimal use of trastuzumab)

For the treatment of patients with metastatic breast cancer by humanized anti- human epidermal growth factor receptor type 2 (HER2) antibody (trastuzumab), it is important to evaluate HER2 status adequately. "A guideline for HER2 testing" and "HER2 atlas" produced by the "Pathological committee for optimal use of trastuzumab" are introduced in this report. Appropriate evaluations of biological markers are essential for targeting therapy.     

Efficacy and safety of subcutaneous trastuzumab and intravenous trastuzumab as part of adjuvant therapy for HER2-positive early breast cancer: Final analysis of the randomised,two-cohort PrefHer study

AimTo assess efficacy (event-free survival, EFS) and safety in patients followed up for 3 years in the PrefHer study (NCT01401166).Patients and methodsPost surgery and post chemotherapy in the (neo)adjuvant setting, patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer were randomised to receive four cycles of the subcutaneous form of trastuzumab (Herceptin^® SC [H SC] via single-use injection device [Cohort 1] or delivery via a hand-held syringe from an SC Vial [Cohort 2]; 600 mg fixed dose) followed by four of the intravenous form of trastuzumab (Herceptin^® [H IV]; 8 mg/kg loading, 6 mg/kg maintenance doses) in the adjuvant setting or vice versa every 3 weeks. Patients could have received H before randomisation. H was then continued to complete a total of 18 cycles, including any cycles received before randomisation.ResultsA total of 488 patients were randomised across both cohorts. After median follow-up of 36.1 months, 3-year EFS across both groups in the evaluable intention-to-treat population (467 patients) was 90.6% overall, 89.9% in Cohort 1, and 91.1% in Cohort 2. No new safety signals were identified during long-term follow-up, with only one cardiac serious adverse event in the safety population (483 patients).ConclusionsThree-year EFS data following H SC and H IV treatment are consistent with those reported by previous trials for H in the adjuvant setting. The overall safety profile during adjuvant treatment was as expected.     

Efficacy and safety of trastuzumab plus capecitabine in heavily pretreated patients with HER2-positive metastatic breast cancer

Purpose We retrospectively evaluated the efficacy and safety of combination therapy of trastuzumab plus capecitabine in heavily pretreated patients with HER2-positive metastatic breast cancer (MBC). Methods Patients with HER2-positive MBC who had been administered the combination therapy between July 2003 and July 2006 at the Cancer Institute Hospital, Tokyo, were retrospectively reviewed. Capecitabine (828 mg/m²) was given twice daily for 3 weeks followed by a 1-week rest period; this was repeated every 4 weeks. Trastuzumab was given at 4 mg/kg as an initial loading dose intravenously, followed by 2 mg/kg weekly. We investigated objective response rate (ORR), clinical benefit rate (CBR), and time-to-treatment failure (TTF) according to the Response Evaluation Criteria in Solid Tumors guidelines. Adverse events were graded according to the National Cancer Institute, Common Toxicity Criteria, version 3.0. Results A total of 49 patients were assessed and median follow-up time of patients was 16.2 months (1.4–43.5 months). ORR was 16% (95% confidence interval: 7–30%) and CBR was 47% (95% confidence interval: 32–62%). Median TTF was 5.4 months. Common adverse effects were hand–foot syndrome, liver dysfunction, and bone marrow suppression. Grade 3 adverse events were observed in nine patients (18%). One patient (2%) suffered from symptomatic chronic heart failure, which improved after discontinuation of trastuzumab. Conclusions The combination therapy of trastuzumab plus capecitabine is effective and tolerable for heavily pretreated patients with HER2-positive MBC.     

曲妥珠单抗治疗４５例ＨＥＲ-２阳性乳腺癌安全性的初步观察

目的　探讨ＨＥＲ-２阳性乳腺癌患者应用曲妥珠单抗治疗的安全性。方法　４５例ＨＥＲ-２阳性乳腺癌患者接受３周１次的曲妥珠单抗治疗,首次以负荷剂量８ｍｇ／ｋｇ给药,然后每３周给予６ｍｇ／ｋｇ静脉滴注,观察其毒副反应,特别是对心脏功能的影响。结果　４５例中接受治疗＞１年为４例（８.９％）,６～１２个月为１７例（３７.８％）,＜６个月为２４例（５３.３％）。有２例在第１次用药时出现寒战和发热;６例患者治疗后左心射血分数下降,其中２例下降超过１０％;１９例治疗过程中出现轻度ＳＴ-Ｔ波改变,但未出现心力衰竭。结论　曲妥珠单抗对ＨＥＲ-２阳性国人乳腺癌患者心脏功能有一定影响,应在治疗中注意监测观察,但总体安全性良好。     

Adjuvant trastuzumab with chemotherapy is effective in women with small, node-negative, HER2-positive breast cancer

BACKGROUND:

Several large, randomized trials established the benefits of adjuvant trastuzumab with chemotherapy. However, the benefit for women with small, node‐negative HER2‐positive (HER2+) disease is unknown, as these patients were largely excluded from these trials. Therefore, a retrospective, single‐institution, sequential cohort study of women with small, node‐negative, HER2+ breast cancer who did or did not receive adjuvant trastuzumab was conducted.

METHODS:

Women with ≤2 cm, node‐negative, HER2+ (immunohistochemistry 3+ or fluorescence in situ hybridization ≥2) breast cancer were identified through an institutional database. A “no‐trastuzumab” cohort of 106 trastuzumab‐untreated women diagnosed between January 1, 2002 and May 14, 2004 and a “trastuzumab” cohort of 155 trastuzumab‐treated women diagnosed between May 16, 2005 and December 31, 2008 were described. Survival and recurrence outcomes were estimated by Kaplan‐Meier methods.

RESULTS:

The cohorts were similar in age, median tumor size, histology, hormone receptor status, hormone therapy, and locoregional therapy. Chemotherapy was administered in 66% and 100% of the “no trastuzumab” and “trastuzumab” cohorts, respectively. The median recurrence‐free and survival follow‐up was: 6.5 years (0.7‐8.5) and 6.8 years (0.7‐8.5), respectively, for the “no trastuzumab” cohort and 3.0 years (0.5‐5.2) and 3.0 years (0.6‐5.2), respectively, for the “trastuzumab” cohort. The 3‐year locoregional invasive recurrence‐free, distant recurrence‐free, invasive disease‐free, and overall survival were 92% versus 98% (P = .0137), 95% versus 100% (P = .0072), 82% versus 97% (P < .0001), and 97% versus 99% (P = .18) for the “no trastuzumab” and “trastuzumab” cohorts, respectively.

CONCLUSIONS:

Women with small, node‐negative, HER2+ primary breast cancers likely derive significant benefit from adjuvant trastuzumab with chemotherapy. Cancer 2011;. © 2011 American Cancer Society.     

Compassionate use of humanized anti-HER2/neu protein, trastuzumab for metastatic breast cancer in Japan

The HER-2/neu protein is thought to be a unique and useful target for antibody therapy of cancers overexpressing the HER-2/neu gene. The recombinant humanized anti-HER-2 monoclonal antibody, trastuzumab (Herceptin) was approved for clinical use in the US in 1998. In Japan, it was approved and later became available in June, 2001. We have treated 41 patients with metastatic breast cancer with trastuzumab purchased from the US. In this paper, the details of the patients we experienced are reviewed.