Shah Ami N, Cristofanilli Massimo
Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, 710 North Fairbanks Ct, Suite 8-250a, Chicago, IL, USA.
Curr Treat Options Oncol. 2017 Jan;18(1):6. doi: 10.1007/s11864-017-0443-7.
Single-agent endocrine therapy has been the standard therapeutic choice for the management of hormone receptor (HR)-positive, Her2-negative advanced breast cancer (ABC) for decades. However, the rapidly accumulating data regarding the biological role and safety of CDK4/6 inhibitors and the first-in-class approval of palbociclib have made these novel agents an essential component of treatment for HR-positive ABC. In the frontline setting, palbociclib in combination with endocrine therapy showed an improvement in progression-free survival (PFS) by 10 months to nearly 25 months when compared with endocrine therapy alone and a clinical benefit rate (CBR = stable disease >24 weeks + partial response + complete response) of 85%. Furthermore, clinically meaningful improvements in PFS were seen in combination with fulvestrant for patients with prior endocrine therapy, including premenopausal women. While neutropenia is experienced by most patients, it is typically uncomplicated and palbociclib is otherwise well tolerated. Recent analysis also demonstrated improved quality of life and reassuring evidence of no compromise in benefit from subsequent therapies after progression on palbociclib. Along with palbociclib, the CDK4/6 inhibitors ribociclib and abemaciclib are being evaluated in a variety of settings (metastatic, neoadjuvant, and adjuvant), alone and in combination with endocrine therapy, chemotherapy, and targeted therapies. Future research is needed to address challenges regarding the potential competition of these agents as the preferred partner in endocrine-sensitive disease, their use as single agents or in combination in the endocrine-refractory setting, and the clinical and molecular criteria for use as an alternative to chemotherapy. Unfortunately, despite efforts to determine predictive biomarkers for response, RB1 expression and HR-positive disease have been the only clear predictors of therapeutic benefit. Once more mature data become available, we hope to confirm a significant impact on long-term survival. Meanwhile, given the multiple therapies patients with ABC will receive, prolonged PFS with a well-tolerated oral regimen is a clinically meaningful endpoint. Palbociclib's impact on PFS, high CBR, and tolerability have made its use a preferred option for treating many HR-positive, Her2-negative ABC patients.
几十年来，单药内分泌治疗一直是激素受体（HR）阳性、人表皮生长因子受体2（Her2）阴性晚期乳腺癌（ABC）治疗的标准选择。然而，关于细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂生物学作用和安全性的快速积累的数据，以及哌柏西利的同类首创获批，使这些新型药物成为HR阳性ABC治疗的重要组成部分。在一线治疗中，与单纯内分泌治疗相比，哌柏西利联合内分泌治疗可使无进展生存期（PFS）延长10个月，接近25个月，临床获益率（CBR = 疾病稳定>24周 + 部分缓解 + 完全缓解）为85%。此外，对于既往接受过内分泌治疗的患者，包括绝经前女性，与氟维司群联合使用时，PFS有临床意义的改善。虽然大多数患者会出现中性粒细胞减少，但通常并不复杂，而且哌柏西利在其他方面耐受性良好。最近的分析还表明，生活质量有所改善，并且有令人放心的证据表明，在哌柏西利治疗进展后，后续治疗的获益不受影响。除了哌柏西利，CDK4/6抑制剂瑞博西尼和阿贝西利正在多种治疗场景（转移性、新辅助和辅助治疗）中进行评估，单独使用以及与内分泌治疗、化疗和靶向治疗联合使用。未来的研究需要解决这些药物作为内分泌敏感疾病首选联合用药的潜在竞争、它们在内分泌难治性情况下作为单药或联合用药的使用，以及作为化疗替代药物使用的临床和分子标准等挑战。不幸的是，尽管努力确定反应的预测生物标志物，但RB1表达和HR阳性疾病一直是治疗获益的唯一明确预测指标。一旦有更成熟的数据可用，我们希望能证实其对长期生存有显著影响。同时，考虑到ABC患者将接受多种治疗，采用耐受性良好的口服方案延长PFS是一个具有临床意义的终点。哌柏西利对PFS的影响、高CBR以及耐受性使其成为治疗许多HR阳性、Her2阴性ABC患者的首选药物。
