Abemaciclib for the treatment of breast cancer

Introduction: There have been numerous clinical trials of CDK4/6 inhibitors performed on various carcinomas including breast cancer. One such inhibitor tested and which has ongoing clinical trials for breast cancer is abemaciclib. Abemaciclib is a molecular-targeted agent that targets basic cell cycle regulatory mechanisms.

Areas covered: This review discusses the available clinical data and ongoing clinical trials of abemaciclib in breast cancer.

Expert opinion: Abemaciclib has demonstrated a clear anti-tumour effect and manageable toxicity against HR-positive, HER2-negative breast cancer in many clinical trials and is expected to be an important standard therapy. However, currently, besides oestrogen receptor expression, there is a definite lack of predictive biomarkers for response and/or tolerance to abemaciclib, which is important for patient selection. Another problem is that its contribution to overall survival (OS) has not been shown. And while two large the phase 3 study highlighted the anti-tumour effect of abemaciclib, the OS results are awaited. Furthermore, the effect on brain metastases is expected to be unique to abemaciclib as the response of brain metastasis in HR-positive breast cancer patients has been confirmed in a few cases with case collection still ongoing.     

Emerging data on the efficacy and safety of fulvestrant,a unique antiestrogen therapy for advanced breast cancer

Introduction: Fulvestrant is an antiestrogen therapy with a unique mechanism of action. Unlike the selective estrogen receptor modulator tamoxifen, fulvestrant has no known estrogen agonist activity and is considered a pure antiestrogen. Its primary mechanism of action is thought to result from downregulation of the estrogen receptor (ER). Considerable data have demonstrated the efficacy of fulvestrant in postmenopausal women with ER-positive advanced breast cancer, both in the first-line setting and following disease progression on tamoxifen or aromatase inhibitors. Recent studies report improved benefit with alternative dosing strategies. At all administration schedules, fulvestrant has an excellent safety profile with no significant adverse effects.

Areas covered: This article provides a review of the mechanism of action of fulvestrant and the preclinical and clinical data evaluating its use as a form of endocrine therapy. The reader will gain insight into the pharmacologic properties of the drug and its role in the treatment of advanced hormone receptor-positive breast cancer in postmenopausal women.

Expert opinion: Based on data demonstrating the efficacy of fulvestrant, including prolonged clinical benefit in many patients, this well-tolerated antiestrogen is an important therapy for breast cancer. The optimal position of fulvestrant in the sequence of endocrine therapies for postmenopausal women and its role in combination regimens are not yet resolved.     

Dissecting the determinants of cyclin-dependent kinase 2 and cyclin-dependent kinase 4 inhibitor selectivity

Cyclin dependent kinases are a key family of kinases involved in cell cycle regulation and are an attractive target for cancer chemotherapy. The roles of four residues of the cyclin-dependent kinase active site in inhibitor selectivity were investigated by producing cyclin-dependent kinase 2 mutants bearing equivalent cyclin-dependent kinase 4 residues, namely F82H, L83V, H84D, and K89T. Assay of the mutants with a cyclin-dependent kinase 4-selective bisanilinopyrimidine shows that the K89T mutation is primarily responsible for the selectivity of this compound. Use of the cyclin-dependent kinase 2-selective 6-cyclohexylmethoxy-2-(4'-sulfamoylanilino)purine (NU6102) shows that K89T has no role in the selectivity, while the remaining three mutations have a cumulative influence. The results indicate that certain residues that are not frequently considered in structure-aided kinase inhibitor design have an important role to play.     

Lapatinib: a tyrosine kinase inhibitor with a clinical role in breast cancer

Lapatinib is a dual (ErbB-1 and ErB-2) receptor tyrosine kinase inhibitor (TKI) that was recently approved by the FDA for the treatment of advanced breast cancer. It shows synergy with trastuzumab, and has demonstrated clinical activity in trastuzumab-resistant tumour. This paper reviews the drug development of lapatinib from preclinical studies to the pivotal Phase III trial and ongoing clinical studies. Areas of interest include the advantages of small molecule TKIs versus antibodies in targeting HER receptors and the efficacy of lapatinib in the treatment of cerebral metastases. The surprisingly high response rate in inflammatory breast cancer raises the possibility of other novel predictive biomarkers. The potential for combination and sequencing with other biological and cytotoxic agents is both exciting and challenging.     

Fulvestrant: a unique antiendocrine agent for estrogen-sensitive breast cancer

Importance of the field: The role of estrogen deprivation for the treatment of breast cancer has been understood since the 1800s. Pharmacologic advances in the field in the past decades, including tamoxifen and the aromatase inhibitors, have contributed significantly to the reduced mortality of estrogen-sensitive breast cancer. However, this subtype of breast cancer still presents with relapses and, once metastatic, progression to hormone-refractory state and loss of disease control remain an expected disease course. Fulvestrant, a pure estrogen receptor downregulator, is a new addition to the antiestrogen therapeutic armamentarium since its FDA approval in 2002. Its unique mechanism of action offers potential advantages over other estrogen targeted therapies.

Areas covered in this review: Published scientific literature, including presented abstracts, on fulvestrant from 1985 to the present were reviewed with selected publications included.

What the reader will gain: This review addresses current issues and therapies for estrogen-sensitive breast cancer, highlights the role of fulvestrant in current treatment guidelines and outlines some of the ongoing investigations of this compound.

Take home message: Fulvestrant is an effective and well-tolerated drug for treatment of metastatic estrogen-sensitive breast cancer. Work is underway to enhance its clinical benefit to patients as a single agent and in combination with other therapies.     

Aromatase inhibitors: a safety comparison

For almost three decades, tamoxifen has been the mainstay of hormonal therapy in breast cancer patients, but now the third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, are emerging as potential alternatives, associating greater clinical efficacy with a more favourable overall safety profile than tamoxifen. AIs are associated with a lower incidence of thromboembolic events and vaginal bleeding compared with tamoxifen, although they are known to affect bone turnover and possibly lipid metabolism. As the available AIs have similar efficacy, it is likely that safety and tolerability profiles will have an impact on agent selection in clinical practice. Therefore, it is important that differences in the safety profiles of the third-generation AIs are understood.     

A current and comprehensive review of cyclin-dependent kinase inhibitors for the treatment of metastatic breast cancer

Background: Resistance to endocrine treatment generally occurs over time, especially in the metastatic stage. In this paper, we aimed to review the mechanisms of cyclin-dependent kinase (CDK) 4/6 inhibition and clinical usage of new agents in the light of recent literature updates.

Scope: A literature search was carried out using PubMed, Medline and ASCO and ESMO annual-meeting abstracts by using the following search keywords; “palbociclib”, “abemaciclib”, “ribociclib”, “cyclin-dependent kinase inhibitors” and “CDK 4/6” in metastatic breast cancer (MBC). The last search was on 10 June 2017.

Findings: CDKs and cyclins are two molecules that have a key role in cell cycle progression. Today, there are three highly selective CDK4/6 inhibitors in clinical development – palbociclib, ribociclib and abemaciclib. Palbociclib and ribociclib were recently approved by the US FDA in combination with letrozole for the treatment of MBC in a first-line setting, as well as palbociclib in combination with fulvestrant for hormone-receptor (HR)-positive MBC that had progressed while on previous endocrine therapy according to the PALOMA-1, MONALEESA-2 and PALOMA-3 trials, respectively. In the recently published randomized phase III MONARCH 2 trial, abemaciclib plus letrozole had longer progression-free survival and higher objective response rates with less serious adverse events in advanced HR-positive breast cancer previously treated with hormonal treatment.

Conclusion: CDK4/6 inhibition is a new and promising target for patients with hormone-receptor-positive MBC. Both palbociclib and ribociclib showed significant additive benefit for patients receiving first-line treatment for HR-positive, epidermal growth factor receptor-2-negative advanced breast cancer. Palbociclib and abemaciclib also had significant activity in combination with fulvestrant for patients with MBC that progressed on previous endocrine therapy.     

EGFR和ErbB2双重酪氨酸激酶

拉帕替尼是一种人源2型表皮生长因子受体(HER2)和表皮生长因子受体(EGFR)双重酪氨酸激酶抑制剂,与卡培他滨联用治疗女性HER2阳性的乳腺癌。我们利用MEDLINE进行关键词为拉帕替尼的文献检索,对其药理作用、药动学、临床疗效及安全性,药物相互作用等进行综述。     

Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6

A pharmacological approach to inhibition of cyclin-dependent kinases 4 and 6 (Cdk4/6) using highly selective small molecule inhibitors has the potential to provide novel cancer therapies for clinical use. Achieving high levels of selectivity for Cdk4/6, versus other ATP-dependent kinases, presents a significant challenge. The pyrido[2,3-d]pyrimidin-7-one template provides an effective platform for the inhibition of a broad cross-section of kinases, including Cdks. It is now demonstrated that the modification of pyrido[2,3-d]pyrimidin-7-ones to include a 2-aminopyridine side chain at the C2-position provides inhibitors with exquisite selectivity for Cdk4/6 in vitro. This selectivity profile is recapitulated in cells where the most selective inhibitors create a G(1) block at concentrations up to 100-fold the IC(50) for cell proliferation. On the basis of its selectivity profile and pharmacokinetic profile, compound 43 (PD 0332991) was identified as a drug candidate for the treatment of cancer.     

Managing neoplastic bone disease with ibandronic acid: a preclinical and clinical data update

Background: Bisphosphonates are the standard of care for treating and preventing the complications of bone metastases. Ibandronic acid is available in effective and well-tolerated oral (50 mg daily) and intravenous (6 mg via ≥ 15 min infusion every 3 – 4 weeks) formulations. Objectives: This paper reviews the latest preclinical and clinical data supporting the use of ibandronic acid for the prevention and treatment of the skeletal complications of neoplastic bone disease, focusing on metastatic breast cancer. The aim was to update a review of ibandronic acid published in 2004 by the current author. Conclusions: Ibandronate remains the only bisphosphonate with approved oral and intravenous formulations; ibandronate should be considered when designing a bisphosphonate-containing regimen for patients with bone metastases from breast cancer.     

立博昔利布:细胞周期蛋白依赖性激酶4/6抑制剂类抗癌新药

立博昔利布是一种口服的小分子细胞周期蛋白依赖性激酶4/6抑制剂,通过抑制肿瘤细胞由G1期向S期转换达到抑制肿瘤发展的目的。立博昔利布和来曲唑联用已于2017年3月13日在美国获批,作为激素受体阳性/人表皮生长因子2受体阴性的晚期和转移性乳腺癌患者的治疗药物。临床研究表明该药对晚期和转移性肿瘤有明显的抑制作用;与来曲唑联用较单独使用来曲唑能显著延长患者的无恶化生存期。该药不良反应发生率较高,但是耐受性较好。介绍该药的药效学、药动学、临床观察和不良反应研究进展。     

Neuroprotective action of flavopiridol,a cyclin-dependent kinase inhibitor,in colchicine-induced apoptosis

Flavopiridol was developed as a drug for cancer therapy due to its ability to inhibit cell cycle progression by targeting cyclin-dependent kinases (CDKs). In this study, we show that flavopiridol may also have a neuroprotective action. We show that at therapeutic dosage (or at micromolar range), flavopiridol almost completely prevents colchicine-induced apoptosis in cerebellar granule neurones. In agreement with this, flavopiridol inhibits both the release of cyt c and the activation of caspase-3 induced in response to colchicine treatment. We demonstrate that in this cellular model for neurotoxicity, neither re-entry in the cell cycle nor activation of stress-activated protein kinases, such as c-Jun N-terminal kinase (JNK) or p38 MAP kinase, is involved. In contrast, we show that colchicine-induced apoptosis correlates with a substantial increase in the expression of cdk5 and Par-4, which is efficiently prevented by flavopiridol. Accordingly, a cdk5 inhibitor such as roscovitine, but not a cdk4 inhibitor such as 3-ATA, was also able to protect neurons from apoptosis as well as prevent accumulation of cdk5 and Par-4 in response to colchicine. Our data suggest a potential therapeutic use of flavopiridol in disorders of the central nervous system in which cytoskeleton alteration mediated by cdk5 activation and Par-4 expression has been demonstrated, such as Alzheimer's disease.     

乳腺单纯性黏液腺癌的临床病理分析

目的研究乳腺单纯黏液腺癌的临床病理特征,比较它和浸润性导管癌的区别,并分析病理特征和预后的关系。方法回顾性分析了23例可手术乳腺单纯性黏液腺癌患者和同期863例对照的浸润性导管癌的临床病理资料。结果单纯性导管癌占全部同期乳腺癌的2.6%以下,患者中位年龄51岁(23岁~86岁),肿块中位大小2.5 cm;单纯性黏液腺癌患者中位年龄62岁(36~83岁),肿块中位大小3.0 cm。浸润性导管癌和单纯性黏液腺癌之间的患者年龄、肿块大小、腋淋巴结状态转移数、ER状态和HER-2状态存在显著的差异,后者的临床病理特征明显优于前者。而且ER PR 组和ER PR-组在单纯性黏液腺癌中的比例显著提高。中位随访17.6月(1~24个月)内,无一例单纯性黏液腺癌发生复发转移。对照的863例浸润性导管癌患者中,2例死亡,6例复发转移。结论单纯性黏液腺癌临床病理学特征显著优于浸润性导管癌,提示了其预后的优势,而且ER阳性比例高,年龄大,内分泌治疗可能更加行之有效。     

阿贝西利联合氟维司群二线治疗激素受体阳性的晚期乳腺癌的药物经济学评价

目的 从中国卫生体系角度评价阿贝西利联合氟维司群对比单用氟维司群二线治疗激素受体(hormone receptor,HR)阳性的晚期乳腺癌的经济性。方法 利用MONARCH 2临床试验公布的生存数据及相关成本和效用数据构建分区生存模型,模型循环周期设为4周,模拟时限为20年,贴现率设为5%。模型的产出指标为成本和质量调整生命年(quality-adjusted life year,QALY),模型评价指标为增量成本-效果比(incremental cost-effectiveness ratio,ICER)。意愿支付阈值(willingness-to-pay threshold,WTP)为2021年中国1~3倍人均GDP(80 976元/QALY~242 928元/QALY)。进行不确定性分析以评价模型结果的稳健性。结果 基础分析结果显示,阿贝西利联合氟维司群同单用氟维司群相比可带来更多的健康获益,但同时总成本更高。增量效用及增量成本分别0.88 QALYs和306 014.57元,两方案相比的ICER值为348 507.45元/QALY。不确定性分析证实了模型结果具有稳健性。当阿贝西利价格降低70%时,阿贝西利联合氟维司群在中国3倍人均GDP下具有经济性的概率>50%。结论 阿贝西利联合氟维司群同单用氟维司群相比在二线治疗HR阳性的晚期乳腺癌患者时不具有成本-效果优势,但在北京、上海等较发达地区,阿贝西利联合氟维司群具有经济学优势。     

Indications and safety of proton pump inhibitor drug use in patients with cancer

Introduction: Although the exact prevalence of proton pump inhibitor (PPI) use in cancer patients is not known, it is generally perceived to be widespread. PPIs are generally well tolerated and carry an excellent safety profile. However, increasing and longer term PPI use has raised concerns about the risk of pneumonia, bone fractures and enteric infections, and a possible interaction with clopidogrel that could increase the risk of cardiovascular events.

Areas covered: We conducted a PubMed search of English language articles addressing the safety and adverse events associated with PPI use with particular emphasis in cancer patients.

Expert opinion: PPIs, frequently used in cancer patients, are generally well tolerated and carry an excellent safety profile. PPI-induced acid suppression may increase the risk of Clostridium difficile or other enteric infections, nutritional deficiencies and community acquired pneumonia, all particularly important in cancer patients. The indications for PPI use in cancer patients should be carefully reviewed prior to use.     

贝伐单抗治疗转移性乳腺癌有效性与安全性的Meta分析

目的：系统评价贝伐单抗治疗转移性乳腺癌的有效性与安全性,以期为临床提供循证参考。方法：计算机检索PubMed、EMbase、The Cochrane Library（2017年第8期）、CBM、CNKI、VIP和WanFang Data,检索时间均从建库至2017年8月。由 2 名研究者独立筛选文献、提取资料并评价纳入研究的偏倚风险后,采用RevMan 5.3统计软件进行Meta分析。结果：共纳入6项RCT,共计4 235例患者。Meta分析结果显示：与对照组相比,贝伐单抗组PFS [HR=0.71,95%CI（0.60,0.84）,P<0.000 1]明显延长,客观缓解率ORR[RR=1.42,95%CI（1.27,1.59）,P<0.000 01]、1年生存率[RR=1.06,95%CI（1.02,1.11）,P=0.003]显著提高。而OS[HR=0.92,95%CI（0.84,1.02）,P=0.11]、死亡率[RR=0.88,95%CI（0.75,1.04）,P=0.14]较对照组差异无统计学意义。安全性方面,贝伐单抗组较对照组高血压[RR=1.75,95%CI（1.34,2.28）,P<0.000 01]、蛋白尿[RR=1.75,95%CI（1.34,2.28）,P<0.000 01]发生率增加,同时增加出血、感觉障碍发生风险,差异均有统计学意义。结论：当前证据表明,与传统化疗相比,贝伐单抗联合化疗在转移性乳腺癌治疗中可显著延长PFS,增加客观缓解率、1年生存率,同时降低死亡率。不良反应以高血压、蛋白尿发生最为常见。受纳入研究数量和质量的限制,上述结论尚需开展更多高质量研究予以验证。     

Helicobacter pylori eradication therapy: indications,efficacy and safety

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) have been proved highly effective treatments for primary and secondary prevention of cardiovascular diseases. Despite widespread and long-term use of statins, there is still a debate concerning their association with cancer at various sites, including breast. As of today, the accumulated epidemiological evidence does not support the hypothesis that statin use affects the risk of developing breast cancer when taken at low doses for managing hypercholesterolemia. However, current evidence cannot exclude an increased risk of breast cancer with statin use in subsets of individuals, for example, the elderly. On the other hand, some studies show that statins might be useful to prevent recurrence and improve survival in patients already suffering from certain breast cancer types. They could also be combined with certain anticancer drugs and potentiate their effects, ameliorate their side effects or prevent the development of resistance. Further research is warranted to clarify these issues.