HER2-positive breast cancer: current and future treatment strategies

In the year 2006, breast cancer was estimated to affect >200,000 American women and cause nearly 56,000 deaths. Furthermore, breast cancer is the most common cancer diagnosed and second most common cause of cancer-related deaths in women. The current treatment armamentarium for breast cancer includes chemotherapy, endocrine therapy and biological therapy. Treatment has become more individualised based on characteristics of the tumour including overexpression of the human epidermal growth factor receptor (HER)-2. Between 20 and 30% of all breast cancers overexpress HER2, which means 40,000 - 60,000 patients will have this type of cancer.Previously, overexpression of HER2 was a negative prognostic and predictive risk factor for survival; however, with the advent of trastuzumab, patients' prognosis is improving in all treatment settings. Much controversy exists in the use of trastuzumab, including (i) the sequence of adjuvant trastuzumab (concurrent with chemotherapy or sequential); (ii) the treatment duration (<1 year, 1 year or 2 years); and (iii) the treatment choice upon disease progression (whether to continue or not with trastuzumab and add another cytotoxic agent). Current trials are ongoing to help answer these questions.Furthermore, there has been interest in predicting which HER2-positive patients would require anthracycline therapy, and which could avoid anthracycline therapy and its toxicities. Novel therapeutics, such as lapatinib, an oral tyrosine kinase inhibitor, which blocks both the epidermal growth factor receptor and HER2 receptor has recently been approved by the US FDA. Whereas pertuzumab, a humanised monoclonal antibody, directed against heterodimerisation of HER2 and HER3 has entered phase II and III clinical trials.     

Pertuzumab in HER2-positive breast cancer

Abstract

Background:

Lack of response in some patients and relapse during the course of therapy in the treatment of HER2-positive early breast cancer and metastatic breast cancer continue to challenge researchers and clinicians towards a better understanding of the fundamental mechanisms of trastuzumab action and new therapies for HER2. The aim of this review is to discuss current and future treatment options with pertuzumab in the light of new insights into HER2-positive breast cancer.     

Pertuzumab: in the first-line treatment of HER2-positive metastatic breast cancer

The humanized monoclonal antibody pertuzumab is the first in a new class of drugs, the human epidermal growth factor receptor (HER) dimerization inhibitors. Given that pertuzumab binds to a different epitope of the HER2 extracellular domain than trastuzumab, combination therapy with pertuzumab plus trastuzumab may result in more comprehensive blockade of HER2 signalling than can be achieved with trastuzumab alone. The efficacy of adding pertuzumab to trastuzumab plus docetaxel for the first-line treatment of HER2-positive metastatic breast cancer was demonstrated in the randomized, double-blind, multinational, phase III CLEOPATRA trial. Both independently assessed progression-free survival (primary endpoint) and investigator-assessed progression-free survival were significantly improved in patients receiving pertuzumab plus trastuzumab and docetaxel compared with those receiving placebo plus trastuzumab and docetaxel. The prespecified interim analysis of survival revealed a strong trend towards a survival benefit associated with pertuzumab, although this was not considered statistically significant. The objective response rate was higher with pertuzumab than with placebo. Intravenous pertuzumab had an acceptable tolerability profile when added to trastuzumab and docetaxel in the CLEOPATRA trial.     

HER-2阳性晚期乳腺癌的治疗策略

人表皮生长因子受体-2过表达型乳腺癌进展快,预后差。近年来,针对人表皮生长因子受体-2介导的信号传导途径开发了一系列分子靶向药物,特别是抗人表皮生长因子受体-2单克隆抗体曲妥珠单抗以及小分子酪氨酸激酶抑制药拉帕替尼及其临床应用,极大提高了人表皮生长因子受体-2阳性晚期乳腺癌的疗效,并改变了这类乳腺癌一线和二线治疗的临床实践。     

Pharmacodynamics,pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations

Introduction: Despite the availability of several potent HER2-directed targeted agents, primary and acquired resistance continues to influence patient outcomes in HER2-positive breast cancer. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor in late-phase clinical development.

Areas covered: This review article focuses on neratinib in the treatment of HER2-positive breast cancer – early and metastatic stage – and HER2-mutant breast cancer, with particular emphasis on the pharmacokinetics and pharmacodynamics of the drug.

Expert opinion: The phase III ExteNET trial shows that neratinib improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer, and in particular HER2+/HR+ tumors. Survival data are awaited. The investigational role of neratinib in high-risk patients or conversely in de-escalation dual regimens with other anti-HER2 therapies and without chemotherapy are of interest. Phase II trials show that neratinib has efficacy, either as monotherapy or in combination with other chemotherapeutic or endocrine agents, in patients with HER2-positive metastatic breast cancer and in tumors harboring HER2 mutations. The role of neratinib in therapeutic algorithms of HER2-positive patients, as well as delaying CNS events, awaits the results of ongoing trials such as NALA. Diarrhea, the main toxicity of neratinib, can be effectively managed with early loperamide prophylaxis.     

Recent advances in novel targeted therapies for HER2-positive breast cancer

The monoclonal antibody trastuzumab has improved the outcomes of patients with breast cancer that overexpresses the human epidermal growth factor receptor 2 (HER2). However, despite this advancement, many tumors develop resistance and novel approaches are needed. Recently, a greater understanding of cellular biology has translated into the development of novel anti-HER2 agents with varying mechanisms of action. The small molecule tyrosine kinase inhibitor lapatinib has demonstrated activity in HER2-positive metastatic breast cancer (MBC) and in the preoperative setting. Pertuzumab is a monoclonal antibody with a distinct binding site from trastuzumab, which inhibits receptor dimerization. In recent studies, the addition of pertuzumab to combination therapy has led to improvements in progression-free survival in patients with HER2-positive MBC and higher response rates in the preoperative setting. An alternative approach is the use of novel antibody-drug conjugates such as trastuzumab-emtansine, which recently demonstrated activity in MBC. Neratinib, a pan-HER tyrosine kinase inhibitor, which irreversibly inhibits HER1 and HER2, also has proven activity in MBC. A range of compounds is being developed to attempt to overcome trastuzumab resistance by targeting heat shock protein 90, a molecular chaperone required for the stabilization of cellular proteins. Furthermore, agents are being developed to inhibit the mammalian target of rapamycin, a downstream component of the PTEN/PI3K pathway, which has been implicated in trastuzumab resistance. Finally, there are emerging data indicating that combinations of anti-HER2 agents may circumvent resistance mechanisms and improve patient outcomes. In this review, recent data on these emerging agents and novel combinations for HER2-positive breast cancer are discussed.     

跨线曲妥珠单抗治疗HER2阳性乳腺癌疗效分析

目的:评价应用曲妥珠单抗治疗后进展的人类表皮生长因子受体2(human epidermal growth factor receptor2,HER2)阳性乳腺癌继续曲妥珠单抗治疗的疗效。方法:回顾性分析中国癌症基金会赫赛汀援助项目中接受曲妥珠单抗治疗进展的HER2阳性乳腺癌患者的临床资料,以疾病进展后是否继续应用曲妥珠单抗治疗为分组标准,通过组间显著性差异比较评价跨线曲妥珠单抗治疗疗效。结果:在符合纳入标准的195例HER2阳性晚期乳腺癌患者中,一线继续曲妥珠单抗治疗可延长患者无进展生存期(progression free survival,PFS)及总生存期(overall survival,OS)(继续曲妥珠单抗或不用2组PFS分别为9个月和6个月,P=0.027; OS分别为20个月和16个月,P=0.031),二线继续曲妥珠单抗治疗可延长PFS(用或不用2组PFS分别为9个月和5个月,P=0.026),对OS无明显影响,三线继续曲妥珠单抗治疗对PFS、OS均无明显改善。基于辅助阶段存在曲妥珠单抗原发耐药,一线继续曲妥珠单抗治疗可延长PFS,而对OS无明显影响。对于一线治疗存在曲妥珠单抗原发耐药的患者,二线继续曲妥珠单抗治疗对PFS、OS均无明显改善。结论:经曲妥珠单抗治疗进展的HER2阳性乳腺癌患者,跨线曲妥珠单抗治疗有较好的临床获益。     

Trastuzumab: in HER2-positive metastatic gastric cancer

Trastuzumab is a recombinant humanized IgG? monoclonal antibody directed against the extracellular domain of the human epidermal growth factor receptor type 2 (HER2) that inhibits HER2-dependent tumour cell proliferation and survival. Proliferation of gastric cancer cells overexpressing HER2 is inhibited by trastuzumab in vitro and in vivo. HER2-positive expression (defined as immunohistochemistry 3+ or fluorescence in situ hybridization-positive) was observed in 22.1% of almost 4000 metastatic gastric cancers in patients who were screened for randomization in the open-label, multicentre, phase III ToGA trial. In patients with HER2-positive metastatic gastric cancer (n?=?584), median overall survival (primary endpoint) was significantly longer for recipients of intravenous trastuzumab plus chemotherapy (comprising cisplatin and either fluorouracil or capecitabine) than in those receiving chemotherapy alone in the ToGA trial. Furthermore, the overall response rate was significantly higher and the median time to disease progression and median time of progression-free survival were also significantly longer with trastuzumab plus chemotherapy than with chemotherapy alone. In general, combination therapy with trastuzumab and chemotherapy was relatively well tolerated in patients with metastatic gastric cancer with no reports of new or unexpected adverse events.     

Trastuzumab emtansine (T-DM1) for HER2-positive breast cancer

Abstract

Background:

Trastuzumab emtansine (T-DM1), a novel drug developed for the treatment of HER2-positive breast cancer, is a human epidermal growth factor receptor (HER2) targeted antibody drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine). It has been shown that, in preclinical studies, it has anti-tumor activity in trastuzumab refractory cancer cells. In this review, we aim to show the clinical data about trastuzumab-DM1 (T-DM1) therapy and to discuss the therapy advantages for the management of patients with HER2-positive breast cancer.     

HER2阳性乳腺癌靶向治疗药物的临床研究进展

乳腺癌已成为全球最常见的癌症,人表皮生长因子受体2（HER2）阳性乳腺癌恶性程度较高,早期易复发和转移,总体预后较差。HER2阳性乳腺癌的治疗因靶向药物的不断问世而呈现更多可能,这类药物包括单克隆抗体（曲妥珠单抗、帕妥珠单抗）、酪氨酸激酶抑制剂（奈拉替尼、拉帕替尼、吡咯替尼、图卡替尼）、抗体药物偶联物（T-DM1、DS-8201）。对HER2阳性乳腺癌靶向治疗药物的最新临床试验结果进行综述,以期为该类乳腺癌的临床用药提供参考。     

Trastuzumab and chemotherapy after the treatment failure of lapatinib for HER2-positive metastatic breast cancer

We describe a patient with human epidermal growth factor receptor type 2 (HER2/c-erbB-2)-positive metastatic breast cancer who survived for approximately 6 years after the initiation of combination therapy with trastuzumab and varying types of chemotherapeutic agents. The patient was a 48-year-old postmenopausal female who underwent partial mastectomy with axillary node dissection for cancer of the right breast in March 1994. She developed lung metastases 2 years thereafter, but survived free of relapse for 8 years following chemotherapy and pulmonary lobectomy. The patient failed to respond to lapatinib, a HER1 (EGFR)/HER2 tyrosine kinase inhibitor, received during the course of her treatment but then again responded to subsequently administered trastuzumab. Primary treatment with trastuzumab and paclitaxel was initiated in April 2004 when the patient developed hepatic metastases 8 years after undergoing surgery for lung metastases. Long-term combination therapy with continued trastuzumab and a variety of chemotherapeutic agents was administered for 6 years without any significant adverse events. We discuss the treatment strategies for HER2-positive breast cancer and the role of lapatinib, a recently approved anticancer drug.     

Efficacy and safety of a combination of HER2-targeted agents as first-line treatment for metastatic HER2-positive breast cancer: a network meta-analysis

Background: Using network meta-analysis, we assessed the efficacy and safety of a combination regimen of HER2-targeted agents as first-line treatment for metastatic HER2-positive breast cancer.

Methods: We searched the Medline, Embase, and Cochrane Library electronic databases (through December 2016) for phase II/III randomized controlled trials that compared regimens of one or two HER2-targeted agents combined with trastuzumab or chemotherapy. A network meta-analysis including direct and indirect analyses was conducted in WinBUGS using fixed and random effects. Study quality was assessed following the Grading of Recommendations, Assessment, Development and Evaluations method. The primary outcome was overall survival.

Results: The network meta-analysis incorporated nine HER2-targeted regimens with 9 direct comparisons and 28 indirect comparisons for the main outcomes (8 studies; n = 3976). Combining direct and indirect effects showed significant increased efficacy of trastuzumab and docetaxel plus pertuzumab (TDP) over other regimens as first-line treatment. With indirect comparison of overall safety, TDP, TDM-1, and TDM-1 plus pertuzumab demonstrated a lower risk of grade 3–4 adverse events compared to other regimens.

Conclusions: TDPs are a preferred first-line treatment for HER2-positive metastatic breast cancer compared with other target agent regimens.     

Targeted agents for HER2-positive breast cancer in older adults: current and future perspectives

ABSTRACT

Introduction: One-third of breast cancer (BC) cases worldwide occur in women aged 65 years and older, with 10 to 15% overexpressing the human epidermal growth factor receptor 2 (HER2). Although several HER2-targeted therapies have been developed, the lack of data regarding their use in older patients hampers evidence-based decision-making for this population.

Areas Covered: We review current evidence on the efficacy and safety of HER2-targeted therapies in older adults with BC, focusing on approved therapies such as trastuzumab, lapatinib, pertuzumab, ado-trastuzumab-emtansine, and neratinib. Additionally, we discuss drugs under development to target the HER2-receptor, and to overcome resistance to existing therapies. Finally, we highlight the cardiotoxicity of HER2-targeted drugs among older adults.

Expert Opinion: Older adults are underrepresented in trials of HER2-targeted therapies in BC. We propose strategies to increase recruitment of older adults in clinical trials in order to increase the evidence base to treat this growing population.     

帕妥珠单抗联合曲妥珠单抗、多西他赛一线治疗HER2阳性转移性乳腺癌的成本-效用分析

目的评价帕妥珠单抗联合曲妥珠单抗、多西他赛(PTD)方案相比曲妥珠单抗联合多西他赛(TD)方案一线治疗人表皮生长因子受体2(HER2)阳性转移性乳腺癌的经济性。方法从我国卫生体系角度出发,利用CLEOPATRA临床试验披露的生存数据和相关文献数据构建分区生存模型,模型模拟时限设为20年,循环周期为3周,贴现率为5%。模型的产出指标包括两种治疗方案的成本及质量调整生命年(QALYs)。意愿支付(WTP)阈值设为2020年我国1~3倍人均国内生产总值(GDP),即72000~216000元/QALY。采用单因素敏感性分析及概率敏感性分析评价模型参数变化对结果稳健性的影响。结果基础分析结果显示,在20年的模拟时限内,PTD方案较TD方案可带来更高的健康获益(3.28 QALYs vs.2.50 QALYs),但总成本更高(1219376.83元vs.784007.84元);与TD方案相比,PTD方案的增量成本-效果比为554625.46元/QALY,超过WTP阈值。单因素敏感性分析结果显示,疾病无进展生存状态的效用值对结果的影响最大。概率敏感性分析结果显示,使用我国2020年3倍人均GDP作为WTP阈值时,PTD方案具有经济性的概率为1%;当WTP阈值升至550000元/QALY时,PTD方案具有经济性的概率可达50%。结论与TD方案相比,PTD方案一线治疗HER2阳性转移性乳腺癌不具有经济性。     

Adjuvant trastuzumab regimen for HER2-positive early-stage breast cancer: a systematic review and meta-analysis

ABSTRACT

Objective: Breast cancer remains to be the globally leading female cancer. About 15% to 20% of breast cancers have human epidermal growth factor receptor 2 (HER2)-positive tumors – a more aggressive breast cancer subtype with shortened survival. In the light of new and updated trial data on trastuzumab therapy for HER2-positive early-stage breast cancer (EBC), we conducted a systematic review and meta-analysis to update the pooling of its relative treatment effects.

Methods: Systematic search was performed through Pubmed and Scopus to identify studies comparing survival outcomes and risks of heart toxicity effects of adjuvant trastuzumab with chemotherapy versus chemotherapy alone for HER2-positive EBC patients.

Results: Based on the eight included studies in the review, combining trastuzumab with chemotherapy continues to show lowered death and relapse risks by one-third. The decision to initiate trastuzumab, however, needs to be prudently deliberated as two to three times more cardiotoxicity risk was shown to be associated with its use.

Conclusion: Administering adjuvant trastuzumab in a weekly cycle concurrently with anthracycline-taxane chemotherapy regimen appears to be a preferable option to optimize its favorable effect in improving DFS and to prevent significantly higher risk for cardiotoxic effects.     

乳腺癌中ApoM差异表达及其对HER2阳性且HR阳性乳腺癌细胞株的生物学影响

目的 探讨载脂蛋白M(ApoM)在乳腺癌中差异表达及其对人表皮生长因子受体2(HER2)阳性且激素受体(HR)阳性的乳腺癌细胞株BT-474和ZR-75-1的生物学影响.方法 检测55例乳腺癌患者癌组织和癌旁组织中ApoM表达水平.应用慢病毒载体构建ApoM过表达体系并转染HER2阳性且HR阳性的乳腺癌细胞株BT-47...     

Drug interaction potential of trastuzumab emtansine (T-DM1) combined with pertuzumab in patients with HER2-positive metastatic breast cancer

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprised of trastuzumab and the cytotoxic agent DM1 (derivative of maytansine) linked by a stable linker N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC). T-DM1 targets an epitope located at subdomain IV of human epidermal growth factor receptor 2 (HER2). Pertuzumab is a monoclonal antibody that targets an epitope located at subdomain II of HER2, distinct from the epitope recognized by T-DM1. The pharmacokinetics (PK), safety, and efficacy of T-DM1 combined with pertuzumab were studied in a phase 1b/2 trial in 67 patients with HER2-positive, locally advanced or metastatic breast cancer (MBC). The therapeutic protein-drug interaction (TP-DI) potential of T-DM1 plus pertuzumab was evaluated. The PK of T-DM1-related analytes and pertuzumab were compared with historical PK data. The results show that the exposure of T-DM1 and DM1, as estimated by noncompartmental analyses, was comparable with that reported by historical single-agent studies in patients with HER2-positive MBC. T-DM1 clearance and volume of distribution in the central compartment, as estimated by population PK analysis, were also comparable between this study and historical single-agent studies in patients with HER2-positive MBC. Summary statistics of pertuzumab trough and maximal exposure (concentrations at predose and 15-30 minutes after the end of infusion at cycle 1 and at steady state) were similar with those observed in a representative historical single-agent study with the same dosing regimen. The visual predictive check plot by population simulation further confirmed that T-DM1 did not alter pertuzumab PK. Based on these data and the PK and pharmacodynamic properties of T-DM1 and pertuzumab, the risk of TP-DI appears to be low when T-DM1 and pertuzumab are given together.