早期乳腺癌术后瑞波西利优化方案
学术
健康
2025-01-08 16:00
上海
激素受体阳性HER2阴性乳腺癌是最常见的乳腺癌亚型，占乳腺癌病例的70%～75%，该亚型大多数病例诊断时都是早期（I～III期），手术±放化疗后大多可治愈，5～10年内分泌治疗可进一步减少复发；不过，27%～37%的II期患者和46%～57%的III期患者出现复发，并且可能复发于诊断后长达20年内。对于此类乳腺癌，内分泌治疗±CDK4/6抑制剂哌柏西利、阿贝西利、瑞波西利相比，已被证实可显著改善晚期患者无进展生存，瑞波西利和阿贝西利还被证实可显著改善晚期患者总生存。对于早期患者，CDK4/6抑制剂的结果不一。PENELOPE-B和PALLAS研究未能证实哌柏西利可显著改善早期患者无浸润癌生存，无论复发风险较高或较低、淋巴结阳性或阴性。相反，monarchE研究证实阿贝西利可显著改善复发风险较高、淋巴结阳性早期患者无浸润癌生存，可是该研究并未入组复发风险较低、淋巴结阴性早期患者。NATALEE研究表明，对于早期（II或III期）激素受体阳性HER2阴性乳腺癌，包括复发风险较高或较低、淋巴结阳性或阴性患者，瑞波西利相比可显著改善无浸润癌生存、无远处癌生存、无复发生存。 不过，NATALEE研究仅对术后内分泌治疗24个月内早期用药进行评价，术后内分泌治疗24个月后延迟用药的作用尚不明确。由于激素受体阳性乳腺癌存在细胞休眠的生物学现象，阻断细胞增殖的CDK4/6抑制剂用药时机可能尤其重要。此外，瑞波西利治疗晚期乳腺癌的MONALEESA研究剂量为600毫克，NATALEE研究仅对400毫克瑞波西利进行评价，未对早期乳腺癌术后治疗直接比较600毫克与400毫克。 2025年1月7日，英国《自然》与美国乳腺癌研究基金会（BCRF）合作期刊《乳腺癌》在线发表美国哈佛大学医学院、麻省总医院癌症中心、贝斯以色列（和新英格兰）女执事医疗中心的LEADER研究报告，首次直接对瑞波西利600毫克间歇或者400毫克连续用药以及早期或者延迟用药治疗激素受体阳性HER2阴性早期乳腺癌患者的的有效性、耐受性和安全性进行前瞻比较。- LEADER (NCT03285412): CDK 4/6 Inhibitor, Ribociclib, With Adjuvant Endocrine Therapy for ER-positive Breast Cancer
- Official Title: Phase II Study of CDK 4/6 Inhibitor, LEE011 (Ribociclib), in Combination With Adjuvant Endocrine Therapy at Varying Duration for ER-positive Breast Cancer (LEADER)
该多中心随机对照二期临床研究于2018年2月2日至2019年9月27日从麻省总医院癌症中心和贝斯以色列女执事医疗中心入组I～III期激素受体阳性HER2阴性乳腺癌术后患者81例，按1比1随机分为两组给予瑞波西利：其中41例400毫克连续用药（早期用药占56%），其余41例600毫克间歇用药（每28天第1～21天，早期用药占75%）。主要目的为评价连续与间歇用药方案的安全性和耐受性。主要终点为12个月时完成全部12个周期之前停用瑞波西利的患者比例，次要终点包括无复发生存以及循环肿瘤DNA检测。 结果，仅发生6例严重不良事件，两组发生率相似，且无患者死亡。25例患者（31%）12个月时完成全部12个周期之前停用瑞波西利，两组停药比例相似。早期用药与延迟用药相比，瑞波西利停药比例较高：36%比21%。 导致停药的主要原因为以下不良事件，尤其600毫克间歇用药组：
中位随访20个月期间，400毫克连续组与600毫克间歇组相比，2年无复发生存率高：100%比97%（95%置信区间：88～99%）。 仅2例复发患者检出循环肿瘤DNA，中位时间为影像学复发前7.5个月。 因此，该研究结果表明，对于激素受体阳性HER2阴性早期乳腺癌术后患者，内分泌治疗联合瑞波西利的安全且耐受性良好，内分泌治疗24个月后联合瑞波西利400毫克连续用药可行、停药比例较低、2年无复发生存率较高，循环肿瘤DNA检出早于乳腺癌影像学复发中位7.5个月的临床证据可以被作为监测工具，故有必要进一步开展多中心大样本随机对照三期临床研究对这些结果进行验证。 声明：本文仅供乳腺癌专业工作者参考，并非科普读物，患者请遵医嘱及药品说明书。NPJ Breast Cancer. 2025 Jan 7;11:2. IF: 5.9Adjuvant endocrine therapy with cyclin-dependent kinase 4/6 inhibitor, ribociclib, for localized hormone receptor-positive/HER2- breast cancer (LEADER).Laura M. Spring, Lauren Scarpetti, Arielle J. Medford, Andrzej Niemierko, Amy Comander, Therese Mulvey, Lowell Schnipper, Steven J. Isakoff, Beverly Moy, Seth A. Wander, Jennifer Shin, Zanta Ephrem, Anneke R. Laposta, Elyssa Denault, Elizabeth Abraham, Gayle Calistro, Ekaterina Kalashnikova, Angel Rodriguez, Minetta C. Liu, Alexey Aleshin, Jeffrey Peppercorn, Leif W. Ellisen, Aditya Bardia.Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Natera Inc., Austin, TX, USA.Optimal timing and dosing of adjuvant cyclin-dependent kinase (CDK) 4/6 inhibitor in early breast cancer is controversial. This prospective phase II clinical trial investigated tolerability and safety of two ribociclib dosing schedules. Patients with stage I-III hormone receptor-positive (HR+)/HER2- breast cancer on adjuvant endocrine therapy (ET) were randomized to two ribociclib dosing schedules: 400 mg continuous vs 600 mg intermittent, with initiation in early (prior ET < 2 years) vs delayed (prior ET ≥ 2 years) setting. Primary objective was to evaluate safety and tolerability of continuous vs intermittent schedule. Primary endpoint was proportion of patients who discontinued ribociclib before completion of all 12 cycles (measured at 12 months). Recurrence free survival (RFS) and circulating tumor DNA (ctDNA) detection were also evaluated. 81 patients were enrolled. Only six serious adverse events occurred, with no significant difference between treatment arms and no subject deaths. Twenty-five patients (31%) discontinued ribociclib before completion of 12 months, with no significant difference between treatment arms. Ribociclib discontinuation was higher in early vs delayed initiation (36% vs 21%). At median follow-up of 20 months, two patients in the intermittent arm (600 mg; Arm 2) experienced disease recurrence (2-year RFS 97%, 95%CI 88-99%), vs none in the continuous arm (400 mg; Arm 1) (2-year RFS 100%). ctDNA was only identified in the two subjects with recurrent disease at median of 7.5 months prior to radiological recurrence. Ribociclib is a safe and well-tolerated adjunct to adjuvant ET in early-stage breast cancer. Delayed initiation of ribociclib at 400 mg continuous dosing was feasible, better tolerated and associated with promising outcomes. ctDNA detection preceded clinical evidence of recurrence and may be considered as a surveillance tool in breast cancer.DOI: 10.1038/s41523-024-00708-5
