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对于早期乳腺癌，手术被认为是主要治疗，术后治疗被称为辅助治疗、术前治疗被称为新辅助治疗。2016年，美国临床肿瘤学会参考加拿大安大略癌症治疗指南，首次发表HER2阳性乳腺癌辅助靶向治疗和HER2阴性乳腺癌最佳辅助化疗方案选择临床实践指南。2018年，由于卡培他滨CREATE-X研究、帕妥珠单抗APHINITY研究、奈拉替尼ExteNET研究结果相继公布，美国临床肿瘤学会对该指南进行更新并更名为：早期乳腺癌最佳辅助化疗和靶向治疗的选择。2020年，美国临床肿瘤学会根据恩美曲妥珠单抗KATHERINE研究结果对该指南推荐意见进行快速更新并更名为：早期乳腺癌最佳辅助化疗和靶向治疗。2021年，美国临床肿瘤学会根据阿贝西利monarchE研究3年随访结果对该指南推荐意见再次快速更新。随着阿贝西利monarchE研究4年和5年随访结果、瑞波西利NATALEE研究预设首次中期分析结果公布，又向美国临床肿瘤学会发出更新指南的信号。 2024年5月20日，美国临床肿瘤学会官方期刊《临床肿瘤学杂志》在线发表哈佛大学医学院达纳法伯癌症研究所、斯坦福大学医学院、美国临床肿瘤学会、德克萨斯大学MD安德森癌症中心的美国临床肿瘤学会早期乳腺癌最佳辅助化疗和靶向治疗指南CDK4/6抑制剂推荐意见快速更新。 根据monarchE研究2020年2年随访结果，2年阿贝西利150毫克每天2次被推荐联合内分泌治疗用于淋巴结阳性、激素受体阳性、HER2阴性乳腺癌术后复发风险较高并且Ki-67评分≥20%的患者。根据monarchE研究2021年3年和2022年4年随访结果，美国食品药品监督管理局于2023年3月3日扩大阿贝西利批准范围，取消Ki-67检测要求，承认monarchE研究对全部入组患者观察到的获益。2024年发表的monarchE研究结果中位随访54个月，表明阿贝西利联合内分泌治疗与单用内分泌治疗相比，浸润癌或死亡风险进一步降低32%（风险比：0.680，95%置信区间：0.599～0.772）而且降低幅度持续扩大，5年无浸润癌生存率提高7.6个百分点、无远处复发生存率提高6.7个百分点。虽然阿贝西利治疗组报告死亡人数较少，但是尚未达到统计学显著性。 
根据NATALEE研究截至2023年1月11日预设首次中期分析结果，3年瑞波西利400毫克每天1次持续3周停药1周联合标准内分泌治疗（来曲唑2.5毫克每天1次或阿那曲唑1毫克每天1次持续≥5年）与单用内分泌治疗相比，用于II期至III期、激素受体阳性、HER2阴性早期乳腺癌女性和男性。男性和绝经前女性接受性腺抑制剂戈舍瑞林作为内分泌治疗一部分。对于IIA期乳腺癌（T2N0）患者，还需要至少满足以下条件之一：肿瘤分级为2级且Ki-67≥20%、基因组风险高、3级。主要研究终点无浸润癌生存显著改善，也向美国临床肿瘤学会进一步修订2020年指南发出信号。 指南专家组进行文献检索，未发现对该患者人群采用瑞波西利或阿贝西利的其他III期临床研究。 NATALEE研究将5101例患者按1∶1随机分为两组：其中2549例给予瑞波西利400毫克联合内分泌治疗、其余2552例单用内分泌治疗。 中位随访27.7个月时，瑞波西利联合内分泌治疗与单用内分泌治疗相比：- 浸润癌或死亡风险：降低25%（风险比：0.75，95%置信区间：0.62～0.91，P=0.003）
- 3年无浸润癌生存率：提高3.3个百分点（90.4%比87.1%）
- 远处癌或死亡风险：降低26%（风险比：0.74，95%置信区间：0.60～0.91）
- 3年无远处癌生存率：提高2.2个百分点（90.8%比88.6%）
中位随访30个月时，瑞波西利联合内分泌治疗与单用内分泌治疗相比：- 总死亡风险：降低尚未达到统计学显著性（风险比：0.76，95%置信区间：0.54～1.07）并计划进行更长期随访
瑞波西利联合内分泌治疗组≥15%的患者发生以下特别令人关注的≥3级不良事件且与单用内分泌治疗组相比发生率较高：- 肝脏相关不良事件（8.3%比1.5%）是造成瑞波西利停用率最高的任何级别不良事件（8.9%）
瑞波西利联合内分泌治疗与单用内分泌治疗相比，发生率较高的其他任何级别不良事件： 根据美国临床肿瘤学会的方法，采用GRADE工具对研究报告进行评分，发现该研究证据质量很高。 推荐意见1：阿贝西利2年联合内分泌治疗≥5年可提供给符合monarchE研究入组标准的患者：激素受体阳性、HER2阴性、淋巴结阳性早期乳腺癌已切除且复发风险高，定义为腋窝淋巴结阳性≥4枚或者1～3枚且至少具有以下特征之一：肿瘤分级为3级、肿瘤大小≥5厘米或Ki-67指数≥20%。虽然美国食品药品监督管理局的措辞很宽泛，但是指南专家组推荐阿贝西利主要用于符合monarchE研究入组标准的患者（证据质量：高；推荐强度：强）。 推荐意见2：根据NATALEE研究，指南专家组推荐可以向解剖学II或III期乳腺癌已经满足研究入组标准并且复发风险较高患者提供瑞波西利3年辅助治疗（400毫克每天1次，持续3周，停药1周）持续3年联合内分泌治疗治疗（证据质量：高；推荐强度：有条件）。 指南专家组认为，CDK4/6抑制剂辅助治疗可能无法为全部符合现有研究入组标准患者提供有临床意义的获益，尤其入组NATALEE研究的低风险患者。例如，对于大多数淋巴结阴性乳腺癌患者，瑞波西利的风险可能大于获益，但是某些风险最高的淋巴结阴性乳腺癌患者除外。不过，专家组承认缺乏足够数据具体说明哪些亚组患者需要或不需要治疗。因此，指南专家组推荐决定是否建议治疗时考虑每位患者的获益、风险、成本和偏好。 对于同时满足monarchE和NATALEE标准的患者，指南专家组还指出，这两种CDK4/6抑制剂相比，阿贝西利的随访时间较长、随着时间推移获益幅度不断扩大、疗程较短、已被美国食品药品监督管理局批准用于辅助治疗。在这种情况下，指南专家组赞成首选阿贝西利，而保留对阿贝西利有禁忌证（例如以前存在严重腹泻）或不耐受阿贝西利的患者选用瑞波西利。指南专家组将瑞波西利推荐意见的强度描述为有条件，有待将来的疗效数据和监管批准更新。虽然正式的成本效益分析超出本次更新范围，但是对于一些考虑这两种药品成本的决策者，可能提供参考信息。长期随访结果也将进一步为辅助治疗决策提供参考信息。J Clin Oncol. 2024 May 20. IF: 45.3 Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer-Cyclin-Dependent Kinase 4 and 6 Inhibitors: ASCO Guideline Rapid Recommendation Update. Freedman RA, Caswell-Jin JL, Hassett M, Somerfield MR, Giordano SH; Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer Guideline Expert Panel. Dana-Farber Cancer Institute, Boston, MA; Stanford University School of Medicine, Stanford, CA; American Society of Clinical Oncology, Alexandria, VA; MD Anderson Cancer Center, Houston, TX. BACKGROUND In 2020, ASCO published a guideline on the selection of optimal adjuvant chemotherapy and targeted therapy for breast cancer. This is a rapid recommendation update of that guideline that addresses, in turn, the adjuvant use of the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors abemaciclib and ribociclib in patients with stage II and III breast cancer. Abemaciclib With Endocrine Therapy in the Treatment of High-Risk Early Breast Cancer A 2022 update occasioned by the publication of monarchE recommended 2 years of abemaciclib (150 mg twice daily) plus endocrine therapy (ET) for patients with node-positive, hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer at high risk of recurrence and a Ki-67 score of ≥20% as determined by a US Food and Drug Administration (FDA)-approved test. The FDA expanded the approval of abemaciclib on March 3, 2023; this expanded approval eliminates the Ki-67 testing requirement, acknowledging the benefits observed across the intention-to-treat (ITT) population of the monarchE study. Recently published data at a median follow-up of 54 months demonstrate a sustained hazard ratio (HR) of 0.680 (95% CI, 0.599 to 0.772) for invasive disease-free survival (IDFS) for abemaciclib plus ET, with a deepening of benefit over time and 5-year absolute improvement in IDFS of 7.6% and distant relapse-free survival of 6.7% compared with ET alone. Although fewer deaths have been reported in the abemaciclib-treated arm, statistical significance has not been reached. Ribociclib With ET in the Treatment of Early Breast Cancer Slamon et al recently published the first results of a prespecified interim analysis of data from NATALEE, an open-label, multicenter, randomized phase III trial that evaluated the addition of 3 years of ribociclib (400 mg once daily, 3 weeks on followed by 1 week off) to standard ET (letrozole 2.5 mg once per day or anastrozole 1 mg once per day for ≥5 years) versus ET alone among women and men with stage II to III, hormone receptor-positive, HER2-negative early breast cancer (EBC). Premenopausal women and men received gonadal suppression as part of their ET. For those with stage IIA disease (T2N0), at least one of the following was also required: grade 2 disease plus Ki-67 ≥20% or high genomic risk or grade 3 disease. Significant improvements in the primary study end point of IDFS constituted a signal for further amending the 2020 ASCO guideline. METHODS A literature search was conducted to identify phase III trials on the use of ribociclib or abemaciclib in this patient population. No additional trials were identified. Evidence Review for Adjuvant Ribociclib NATALEE randomly assigned patients (1:1) to ribociclib 400 mg plus ET (n = 2,549) or ET alone (n = 2,552). At a median follow-up of 27.7 months, adjuvant ribociclib plus ET significantly improved IDFS compared with ET alone (HR, 0.75 [95% CI, 0.62 to 0.91]; P = .003). The 3-year IDFS rates were 90.4% versus 87.1%, with a 3.3% absolute IDFS benefit at 3 years with ribociclib-based therapy. Ribociclib plus ET significantly improved distant disease-free survival (DDFS) compared with ET alone (HR, 0.74; 95% CI, 0.60 to 0.91); 3-year DDFS rates were 90.8% versus 88.6%. At a median follow-up of 30 months, overall survival was not significantly different between treatment arms (HR, 0.76; 95% CI, 0.54 to 1.07), with longer-term follow-up planned. The following grade 3 or higher adverse events (AEs) of special interest occurred in ≥15% of patients in the ribociclib plus ET arm and were numerically higher in the ribociclib plus ET arm compared with the ET arm: neutropenia (43.8% v 0.8%) and liver-related AEs (8.3% v 1.5%). Liver-related AEs were the most frequent AE of any grade leading to ribociclib discontinuation (8.9%). Any-grade QT prolongation occurred in 5.2% of those receiving ribociclib plus ET and 1.2% for those receiving ET alone. For AEs of any grade, nausea (23% v 7.5%), headache (22% v 16.5%), and fatigue (21.9% v 12.7%) were numerically higher in the ribociclib plus ET arm compared with the ET arm. Appraisal of the trial report using the GRADE instrument was performed as per ASCO's methodology and found a high certainty of the evidence. UPDATED RECOMMENDATIONS Recommendation 1 Abemaciclib for 2 years plus ET for ≥5 years may be offered to patients meeting the criteria of the ITT monarchE population with resected, hormone receptor-positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence, defined as having ≥4 positive axillary lymph nodes (ALNs) or as having 1-3 positive ALNs plus at least one of the following features: grade 3 disease, tumor size ≥5 cm, or Ki-67 index ≥20%. Although the FDA's language is broad, the Panel promotes the use of abemaciclib primarily in those who would have been eligible for monarchE based on that trial's eligibility criteria (Evidence quality: High; Strength of recommendation: Strong). Recommendation 2 The Panel recommends, based on the phase III NATALEE trial, that adjuvant ribociclib (400 mg once daily, 3 weeks on followed by 1 week off) for 3 years plus ET may be offered to patients with anatomic stage II or III breast cancer who would have met criteria for study entry and have a high risk of recurrence (Evidence quality: High; Strength of recommendation: Conditional). Qualifying Statements for Recommendations 1 and 2 on the Use of Adjuvant Abemaciclib and Ribociclib The Panel believes that adjuvant CDK4/6 inhibitor therapy may not provide meaningful clinical benefit to all patients who would have been eligible for the available trials, especially the lower-risk patients who were included in the NATALEE trial. For example, for most patients with node-negative disease, the risks of ribociclib may outweigh the benefits, with the exception of some patients with the highest risk, node-negative disease. However, the Panel acknowledges that there are insufficient data to specify which subgroups of patients do or do not warrant therapy. The Panel thus recommends considering the benefits, risks, costs, and preferences for each individual patient when deciding whether to recommend therapy. Among patients meeting criteria for both monarchE and NATALEE, the Panel also notes that, of the two CDK4/6 inhibitors, abemaciclib has longer follow-up, a deepening benefit over time, a shorter duration of therapy, and FDA approval in the adjuvant setting. In this case, the Panel favors using abemaciclib, reserving use of ribociclib in patients who have a contraindication to (eg, preexisting high-grade diarrhea) or intolerance of abemaciclib. The Panel characterized the strength of the ribociclib recommendation as conditional, pending future efficacy data and regulatory updates. Although a formal cost-effectiveness analysis was out of scope for this update, it could be informative for some decision makers considering the costs of both medications. Results from longer-term follow-up will further inform adjuvant therapy decision making. Evidence supporting unchanged recommendations and sections on cost implications and more are found in the full guideline publication, and apply to this Rapid Update. Additionally, for guideline tools and resources, including a complete summary table, visit www.asco.org/breast-cancer-guidelines. PMID: 38768407 DOI: 10.1200/JCO.24.00886
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