Abstract：
CDK4/6 inhibitors are oral agents inhibiting key molecules of the cell cycle regulation. In patients with endocrine receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer, the combination of CDK4/6 inhibitors with endocrine therapy is an effective treatment in the metastatic setting. Now, two studies in the adjuvant setting - MonarchE (2 years of abemaciclib) and NATALEE (3 years of ribociclib) - report positive invasive disease-free survival. Here, we re-evaluate these seminal trials. First, an excess drop-out or loss-to-follow up occurred early in the control arms of both studies. Since both trials are open-label, there is concern that the patients who drop-out do not do so at random but based on socioeconomic factors and alternative options. Is it possible that the results merely appear favorable due to loss to follow up? Based on re-constructed Kaplan-Meier curves, we concluded the results of these studies remain fragile, being prone to informative censoring. Secondly, adverse events were notably higher in both trials, and some of them, like COVID-19 related deaths in NATALEE, raise serious concerns. Third, the potential costs associated with CDK4/6 inhibition given as adjuvant therapy are unprecedented. The NATALEE strategy, in particular, could affect up to 35 % of patients with newly diagnosed breast cancer, which is the cancer with the highest incidence worldwide. Without confirmatory data based on a placebo-controlled trial, or better identification of patients that would benefit from the addition of CDK4/6 inhibitors in the adjuvant setting, we argue against their routine use as adjuvant therapy in ER+ /HER2- early breast cancer.
摘要：
CDK4/6抑制剂是抑制细胞周期调控的关键分子的口服药剂。在内分泌受体阳性（ER+）的患者中，人表皮生长因子受体2阴性（HER2-）乳腺癌，CDK4/6抑制剂联合内分泌治疗在转移性疾病中是一种有效的治疗方法.现在,辅助治疗的两项研究——MonarchE(2年的abemaciclib)和NATALEE(3年的ribociclib)——报告侵袭性无病生存阳性.这里,我们重新评估这些开创性的试验.首先,在两项研究的对照组早期都发生了过度退出或失访.由于两个试验都是开放标签，值得关注的是,退出的患者并不是随机选择,而是基于社会经济因素和其他选择.Isitpossiblethattheresultsmerelyappearfavorableduetolosstofollowup?Basedonre-constructedKaplan-Meiercurves,我们得出结论，这些研究的结果仍然脆弱，容易进行信息性审查。其次,两项试验的不良事件均明显较高,其中一些，就像NAT中与COVID-19相关的死亡一样，引起严重关注。第三，与CDK4/6抑制相关的潜在成本作为辅助治疗是前所未有的.娜塔莉的战略,特别是,可能影响高达35%的新诊断乳腺癌患者，这是全球发病率最高的癌症。没有基于安慰剂对照试验的验证数据，或更好地识别将受益于在佐剂设置中添加CDK4/6抑制剂的患者，我们反对常规使用它们作为ER+/HER2-早期乳腺癌的辅助治疗.
