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）。早期乳腺癌手术±放化疗后大多可治愈，其中激素受体阳性HER2阴性患者进行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。 对于激素受体阳性HER2阴性乳腺癌，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的无进展生存，瑞波西利和阿贝西利还被证实可显著改善晚期患者的总生存。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的无浸润癌生存，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的无浸润癌生存，该研究并未入组复发风险较低、淋巴结阴性早期患者。那么，无论复发风险较高或较低、淋巴结阳性或阴性，瑞波西利能否显著改善早期患者的无浸润癌生存？ 2024年3月21日，全球四大医学期刊之一、创刊于1812年的美国麻省医学会《新英格兰医学杂志》正式发表美国洛杉矶加利福尼亚大学大卫格芬医学院、田纳西肿瘤医院莎拉坎农研究所、哈佛大学医学院麻省总医院癌症中心、西雅图华盛顿大学弗雷德哈钦森癌症中心、奥兰多癌症研究所、全国乳腺癌联盟、德克萨斯大学MD安德森癌症中心、俄罗斯联邦卫生部乌法共和国肿瘤医院、莫斯科市第六十二肿瘤医院、波兰华沙居里夫人国家肿瘤研究院、卢布林省癌症中心、中国台湾大学医学院附设医院、中国医学科学院肿瘤医院、德国埃尔朗根纽伦堡大学纽伦堡大都市区医院、柏林赫利俄斯医院、爱尔兰都柏林大学圣文森特医院、加拿大温哥华不列颠哥伦比亚癌症中心、埃德蒙顿肿瘤学转化研究中心、韩国首尔大学附属医院癌症研究所、西班牙乳腺癌研究协作组、塞维利亚大学圣母罗西奥医院、澳大利亚墨尔本大学彼得麦卡伦癌症中心、巴西拉丁美洲肿瘤学协作组、法国巴黎肿瘤学转化研究中心、乌拉圭蒙得维的亚肿瘤学转化研究中心、瑞士诺华的NATALEE研究中期分析报告，首次对复发风险较高或较低、淋巴结阳性或阴性早期激素受体阳性HER2阴性乳腺癌术后内分泌治疗±瑞波西利的有效性和安全性进行了比较。NATALEE (NCT03701334): A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/HER2- Early Breast Cancer (A Phase III Multi-center, Randomized, Open-label Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as an Adjuvant Treatment in Patients With Hormone Receptor-positive, HER2-negative Early Breast Cancer (New Adjuvant TriAl With Ribociclib) 该国际多中心非盲随机对照三期临床研究于2019年1月10日至2021年4月20日从全球入组激素受体阳性HER2阴性早期（II或III期）乳腺癌术后患者5101例，按1∶1的比例随机分为两组，其中2549例给予瑞波西利（每天400毫克连续3周，随后停药1周，持续3年）联合非甾体芳香化酶抑制剂（来曲唑每天2.5毫克或阿那曲唑每天1毫克，持续≥5年），其余2552例单用非甾体芳香化酶抑制剂。男性和绝经前女性每28天给予戈舍瑞林治疗。主要终点为无浸润癌生存，次要终点包括无远处癌生存、无复发生存、总生存和安全性。采用分层对数秩检验进行统计学比较，预设单侧P小于0.0128（双侧P小于0.0256）为优效。 结果，截至预设中期分析数据截止日期2023年1月11日，中位随访34个月，共计426例患者发生浸润癌、复发或死亡。- 3年无浸润癌生存率：90.4%比87.1%（风险比：0.75，95%置信区间：0.62～0.91，双侧P=0.003，小于0.0256）
- 3年无远处癌生存率：90.8%比88.6%（风险比：0.74，95%置信区间：0.60～0.91）
- 3年无复发生存率：91.7%比88.6%（风险比：0.72，95%置信区间：0.58～0.88）
- 3年总生存率：97.6%比97.1%（风险比：0.76，95%置信区间：0.54～1.07）
3年瑞波西利400毫克起始剂量（该剂量低于晚期患者每天600毫克用药剂量，可能有助于早期患者长期坚持用药）＋非甾体芳香化酶抑制剂治疗方案未见任何新的安全问题。 因此，该研究中期分析结果表明，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，非甾体芳香化酶抑制剂±瑞波西利相比，3年无浸润癌生存、无远处癌生存、无复发生存显著改善，3年总生存略改善。 不过，大约40个月后，两组患者的生存曲线发生交叉，与monarchE研究阿贝西利坚挺的生存曲线相比，似乎不太好看。由于激素受体阳性HER2阴性早期乳腺癌复发风险长达20年，风物长宜放眼量，仍然需要更长的随访时间，才能看出究竟谁是早期乳腺癌内分泌治疗的最佳战友。 我们也期待达尔西利治疗激素受体阳性HER2阴性早期乳腺癌的SHR6390-III-303研究能够早日为国争光。N Engl J Med. 2024 Mar 21;390(12):1080-1091. IF: 158.5Ribociclib plus Endocrine Therapy in Early Breast Cancer.Slamon D, Lipatov O, Nowecki Z, McAndrew N, Kukielka-Budny B, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Ruiz-Borrego M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Afenjar K, Fresco R, Severin I, Ji Y, Ghaznawi F, Li Z, Zarate JP, Chakravartty A, Taran T, Hortobagyi G.David Geffen School of Medicine at the University of California, Los Angeles; Republican Clinical Oncology Dispensary, Ufa, Moscow City Oncology Hospital No. 62, Moscow, Russia; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw; Centrum Onkologii Ziemi Lubelskiej im. sw. Jana z Dukli, Lublin, Poland; Sarah Cannon Research Institute at Tennessee Oncology, Nashville; National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei City; University Hospital Erlangen, Comprehensive Cancer Center Erlangen-European Metropolitan Region of Nuremberg, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen; Interdisciplinary Breast Cancer Center, Helios Klinikum Berlin-Buch, Berlin, Germany; St. Vincent's Hospital, Dublin; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston; British Columbia Cancer Agency, Vancouver; Translational Research in Oncology, Edmonton, AB, Canada; Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea; Hospital Virgen del Rocío, Seville, and Grupo Espanol de Investigación en Cáncer de Mama, Spanish Breast Cancer Group, Madrid, Spain; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; Fred Hutchinson Cancer Center, University of Washington, Seattle; Latin American Cooperative Oncology Group, Porto Alegre, Brazil; Orlando Health Cancer Institute, Orlando, FL; National Breast Cancer Coalition, Washington, DC; TRIO, Paris; TRIO, Montevideo, Uruguay; Novartis Pharmaceuticals, East Hanover, NJ; Novartis Pharma, Basel, Switzerland; University of Texas M.D. Anderson Cancer Center, Houston.BACKGROUND: Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear.METHODS: In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy.RESULTS: As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P = 0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals.CONCLUSIONS: Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer.NATALEE ClinicalTrials.gov number: NCT03701334DOI: 10.1056/NEJMoa2305488
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