过去十年以来，随着多种靶向治疗相继获批，晚期乳腺癌的治疗发生了巨大改观。其中，CDK4/6抑制剂为激素受体阳性HER2阴性乳腺癌绝经后女性（占大多数乳腺癌患者）带来了新的治疗方案。对于已经发生转移的晚期乳腺癌，除了联合内分泌治疗，临床实践模式已经开始从单药化疗转向前期联合靶向治疗。不过，对于许多情况，需要明确证据指导治疗方案选择。对于激素受体阳性HER2阴性晚期乳腺癌绝经后女性，虽然国际指南支持内分泌治疗±靶向治疗取代化疗，但是前期化疗仍然十分普遍，即使尚未发生内脏转移。而且，目前几乎没有对一线或二线化疗与内分泌治疗进行头对头比较的随机对照研究。
2019年9月4日，英国《柳叶刀》肿瘤学分册在线发表意大利那不勒斯腓特烈二世大学、博科尼大学管理学院、克雷莫纳地区医院、那不勒斯国家肿瘤研究所、那不勒斯地中海医院、乌迪内大学、阿维亚诺肿瘤学参考中心、圣马蒂诺综合医院、热那亚大学、都灵大学、的里雅斯特大学、美国贝勒医学院、西北大学、南卡罗来纳医科大学、西班牙乳腺癌研究协作组、奥古斯特皮森耶生物医学研究所、巴塞罗那医院、比利时列日大学、法国里昂贝拉尔癌症中心、古斯塔夫鲁西研究所的研究报告，对激素受体阳性HER2阴性晚期乳腺癌绝经后女性的内分泌治疗与化疗进行了比较。
该系统回顾与网络荟萃分析首先对PubMed、Embase、Cochrane临床研究登记中心、Web of Science以及相关国际肿瘤学会议在线档案进行系统的文献检索，收集所有发表于2000年1月1日～2017年12月31日、比较化疗±靶向治疗与内分泌治疗±靶向治疗一线或二线治疗激素受体阳性HER2阴性晚期乳腺癌绝经后女性的2期和3期随机对照研究。随后还增加了最近发表的相关随机对照研究。文献检索未对语言进行限制。最后通过贝叶斯网络荟萃分析，对所有治疗与阿那曲唑单药或哌柏西利＋来曲唑相比的无进展生存（主要结局）风险比、客观缓解率（次要结局）比值比进行比较。
结果，对2689篇已经发表的研究结果和140项研究50029例患者进行分析。
与阿那曲唑单药相比：
哌柏西利＋来曲唑：复发或死亡风险低58%（风险比：0.42，95%可信区间：0.25～0.70）
瑞波西利＋来曲唑：复发或死亡风险低57%（风险比：0.43，95%可信区间：0.24～0.77）
阿贝西利＋阿那曲唑或来曲唑：复发或死亡风险低58%（风险比：0.42，95%可信区间：0.23～0.76）
哌柏西利＋氟维司群：复发或死亡风险低63%（风险比：0.37，95%可信区间：0.23～0.59）
瑞波西利＋氟维司群：复发或死亡风险低52%（风险比：0.48，95%可信区间：0.31～0.74）
阿贝西利＋氟维司群：复发或死亡风险低56%（风险比：0.44，95%可信区间：0.28～0.70）
依维莫司＋依西美坦：复发或死亡风险低58%（风险比：0.42，95%可信区间：0.28～0.67）
阿培利司＋氟维司群：PIK3CA突变患者复发或死亡风险低61%（风险比：0.39，95%可信区间：0.22～0.66）
氟尿嘧啶＋表柔比星＋环磷酰胺：复发或死亡风险低53%（风险比：0.47，95%可信区间：0.26～0.93）
紫杉醇＋贝伐珠单抗：复发或死亡风险低61%（风险比：0.39，95%可信区间：0.18～0.88）
卡培他滨：复发或死亡风险低59%（风险比：0.41，95%可信区间：0.24～0.76）
艾立布林：复发或死亡风险低55%（风险比：0.45，95%可信区间：0.23～0.89）
与哌柏西利＋来曲唑相比：
氟维司群＋阿那曲唑：复发或死亡风险高53%（风险比：0.47，95%可信区间：0.27～0.83）
氟维司群标准剂量：复发或死亡风险高48%（风险比：0.52，95%可信区间：0.30～0.91）
阿那曲唑：复发或死亡风险高58%（风险比：0.42，95%可信区间：0.25～0.70）
来曲唑：复发或死亡风险高45%（风险比：0.55，95%可信区间：0.40～0.74）
依西美坦：复发或死亡风险高57%（风险比：0.43，95%可信区间：0.25～0.75）
他莫昔芬：复发或死亡风险高62%（风险比：0.38，95%可信区间：0.24～0.61）
化疗±靶向治疗方案：复发或死亡风险相似
与哌柏西利＋来曲唑相比：
紫杉醇＋贝伐珠单抗：客观缓解患者比例高8.95倍（比值比：8.95，95%可信区间：1.03～76.92）
其他治疗方案：客观缓解患者比例相似
三种CDK4/6抑制剂（哌柏西利、瑞波西利、阿贝西利）相比，复发或死亡风险相似：
哌柏西利＋来曲唑与瑞波西利＋来曲唑相比（风险比：0.98，95%可信区间：0.58～1.66）
哌柏西利＋来曲唑与阿贝西利＋阿那曲唑或来曲唑相比（风险比：1.01，95%可信区间：0.59～1.70）
阿贝西利＋阿那曲唑或来曲唑与瑞波西利＋来曲唑相比（风险比：0.97，95%可信区间：0.53～1.78）
哌柏西利＋氟维司群与阿贝西利＋氟维司群相比（风险比：0.83，95%可信区间：0.47～1.46）
哌柏西利＋氟维司群与瑞波西利＋氟维司群相比（风险比：0.77，95%可信区间：0.44～1.35）
阿贝西利＋氟维司群与瑞波西利＋氟维司群相比（风险比：0.93，95%可信区间：0.54～1.61）
因此，该研究结果表明，对于激素受体阳性HER2阴性晚期乳腺癌绝经后女性的一线或二线治疗，CDK4/6抑制剂＋内分泌治疗与标准内分泌治疗相比，复发或死亡风险显著较低、无进展生存显著较好。此外，化疗±靶向治疗方案与CDK4/6抑制剂＋内分泌治疗相比，无进展生存并未显著改善。该研究结果支持治疗指南推荐意见：将内分泌治疗＋靶向治疗的新联合方案用于激素受体阳性HER2阴性转移性乳腺癌女性一线或二线治疗。
对此，美国匹兹堡大学发表同期评论：CDK4/6抑制剂能否取代化疗地位？
Lancet Oncol. 2019 Sep 4. [Epub ahead of print]
Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis.
Mario Giuliano, Francesco Schettini, Carla Rognoni, Manuela Milani, Guy Jerusalem, Thomas Bachelot, Michelino De Laurentiis, Guglielmo Thomas, Pietro De Placido, Grazia Arpino, Sabino De Placido, Massimo Cristofanilli, Antonio Giordano, Fabio Puglisi, Barbara Pistilli, Aleix Prat, Lucia Del Mastro, Sergio Venturini, Daniele Generali.
University of Naples Federico II, Naples, Italy; Baylor College of Medicine, Houston, TX, USA; August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; SDA Bocconi School of Management, Milan, Italy; Azienda Socio Sanitaria Territoriale di Cremona, Cremona, Italy; Liège University, Liège, Belgium; Léon Bérard Cancer Center, Lyon, France; Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy; Clinica Mediterranea, Naples, Italy; Northwestern University, Chicago, IL, USA; Medical University of South Carolina, Charleston, SC, USA; University of Udine, Udine, Italy; IRCCS Centro di Riferimento Oncologico Aviano - National Cancer Institute, Aviano, PN, Italy; Institut Gustave Roussy, Villejuif, France; SOLTI Breast Cancer Research Group, Barcelona, Spain; Hospital Clinic de Barcelona, Barcelona, Spain; Ospedale Policlinico San Martino-IRCCS, Genova, Italy; University of Genova, Genova, Italy; University of Turin, Turin, Italy; University of Trieste, Trieste, Italy.
BACKGROUND: Although international guidelines support the administration of hormone therapies with or without targeted therapies in postmenopausal women with hormone-receptor-positive, HER2-negative metastatic breast cancer, upfront use of chemotherapy remains common even in the absence of visceral crisis. Because first-line or second-line treatments, or both, based on chemotherapy and on hormone therapy have been scarcely investigated in head-to-head randomised controlled trials, we aimed to compare these two different approaches.
METHODS: We did a systematic review and network meta-analysis with a systematic literature search on PubMed, Embase, Cochrane Central Register of Clinical Trials, Web of Science, and online archives of the most relevant international oncology conferences. We included all phase 2 and 3 randomised controlled trials investigating chemotherapy with or without targeted therapies and hormone therapies with or without targeted therapies as first-line or second-line treatments, or both, in postmenopausal women with hormone-receptor-positive, HER2-negative metastatic breast cancer, published between Jan 1, 2000, and Dec 31, 2017. Additional recently published randomised controlled trials relevant to the topic were also subsequently added. No language restrictions were adopted for our search. A Bayesian network meta-analysis was done to compare hazard ratios (HRs) for progression-free survival (the primary outcome), and to compare odds ratios (ORs) for the proportion of patients achieving an overall response (the secondary outcome). All treatments were compared to anastrozole and to palbociclib plus letrozole. This study is registered in the Open Science Framework online public database, registration DOI 10.17605/OSF.IO/496VR.
FINDINGS: We identified 2689 published results and 140 studies (comprising 50029 patients) were included in the analysis. Palbociclib plus letrozole (HR 0.42; 95% credible interval [CrI] 0.25-0.70), ribociclib plus letrozole (0.43; 0.24-0.77), abemaciclib plus anastrozole or letrozole (0.42; 0.23-0.76), palbociclib plus fulvestrant (0.37; 0.23-0.59), ribociclib plus fulvestrant (0.48; 0.31-0.74), abemaciclib plus fulvestrant (0.44; 0.28-0.70), everolimus plus exemestane (0.42; 0.28-0.67), and, in patients with a PIK3CA mutation, alpelisib plus fulvestrant (0.39; 0.22-0.66), and several chemotherapy-based regimens, including anthracycline and taxane-containing regimens, were associated with better progression-free survival than was anastrozole alone. No chemotherapy or hormone therapy regimen was significantly better than palbociclib plus letrozole for progression-free survival. Paclitaxel plus bevacizumab was the only clinically relevant regimen that was significantly better than palbociclib plus letrozole in terms of the proportion of patients achieving an overall response (OR 8.95; 95% CrI 1.03-76.92).
INTERPRETATION: In the first-line or second-line setting, CDK4/6 inhibitors plus hormone therapies are better than standard hormone therapies in terms of progression-free survival. Moreover, no chemotherapy regimen with or without targeted therapy is significantly better than CDK4/6 inhibitors plus hormone therapies in terms of progression-free survival. Our data support treatment guideline recommendations involving the new combinations of hormone therapies plus targeted therapies as first-line or second-line treatments, or in both settings, in women with hormone-receptor-positive, HER2-negative metastatic breast cancer.
DOI: 10.1016/S1470-2045(19)30420-6
Lancet Oncol. 2019 Sep 4. [Epub ahead of print]
CDK4/6 inhibitors: taking the place of chemotherapy?
Azadeh Nasrazadani, Adam M Brufsky.
University of Pittsburgh, Magee-Women's Hospital, Pittsburgh, PA, USA.
The treatment landscape for advanced breast cancer has shifted dramatically over the past decade with the successive approvals of a multitude of targeted therapies. Specifically, CDK4/6 inhibitors have introduced a new treatment framework in the management of postmenopausal patients with hormone-receptor-positive, HER2-negative disease, who comprise the majority of patients with breast cancer. Clinical practice patterns have begun to veer away from a single-agent chemotherapy approach in the metastatic setting and towards upfront combination therapies with targeted agents in addition to endocrine therapy. Clearly delineating evidence, however, is needed to guide selection of one regimen over another in many cases.
DOI: 10.1016/S1470-2045(19)30507-8
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