管腔B型（激素受体阳性且HER2阴性）乳腺癌，大约占全部乳腺浸润癌的70%。根据21基因OncotypeDX、11基因EndoPredict、50基因PAM50等多基因复发风险预测工具，可以指导某些低风险管腔B型早期乳腺癌术后患者避免辅助化疗。
2019年12月11日，英国《柳叶刀》肿瘤学分册和美国圣安东尼奥乳腺癌论坛SABCS同时发表西班牙乳腺癌研究协作组SOLTI的CORALLEEN研究报告，根据PAM50，比较了细胞周期蛋白依赖型激酶CDK4和CDK6抑制剂瑞博西利＋来曲唑内分泌新辅助治疗或标准多药联合新辅助化疗对于管腔B型早期乳腺癌术前绝经后女性的生物活性和临床效果。
CORALLEEN: Neoadjuvant Multi-agent Chemotherapy or Letrozole Plus Ribociclib in Luminal B/HER2-negative Breast Cancer: A Phase 2 Clinical Trial of Multi-agent Chemotherapy or Letrozole Plus Ribociclib (LEE011) as Neoadjuvant Treatment for Postmenopausal Patients With Luminal B/HER2-negative Breast Cancer (NCT03248427)
该平行多中心随机对照非盲二期临床研究于2017年7月27日～2018年12月7日从西班牙21家医院入组年龄≥18岁、美国东部肿瘤研究协作组ECOG体力状态评分0～1、经磁共振测定可手术原发肿瘤直径≥2厘米、经PAM50和组织学确认为激素受体阳性HER2阴性管腔B型的I～IIIA期乳腺癌绝经后女性106例。通过网络系统按1∶1的比例将患者随机入两组：
靶向治疗组52例：每天1次口服瑞博西利600毫克连续3周停用1周＋每天1次口服来曲唑2.5毫克，共计28天×6轮
标准化疗组54例：每21天1次静脉注射多柔比星60毫克/㎡＋环磷酰胺600毫克/㎡，共计21天×4轮；随后每周1次静脉注射紫杉醇80毫克/㎡，共计7天×12轮
术前新辅助治疗持续时间总计24周。根据肿瘤大小和淋巴结转移，对随机分组进行分层。术前新辅助治疗第0天、第15天和手术时，按计划采集肿瘤标本。主要研究终点：修订意向治疗人群（全部随机分组接受研究药物并且治疗前后测定复发风险评分的患者）手术时PAM50低复发风险患者比例。PAM50复发风险分类整合了用于预测结局的基因表达数据、肿瘤大小和淋巴结状态。
结果，中位随访200.0天（四分位：191.2～206.0）。治疗前复发风险较高、中等的患者分别占87%、13%。
靶向治疗组与标准化疗组相比：
治疗前复发风险较高的患者比例：85%比89%
治疗前复发风险中等的患者比例：15%比11%
手术时复发风险较低的患者比例：46.9%比46.1%（95%置信区间：32.5～61.7、32.9～61.5）
发生率最高的3～4级不良事件：
靶向治疗组：中性粒细胞减少（43%）和丙氨酸转氨酶浓度升高（20%）
标准化疗组：中性粒细胞减少（60%）和中性粒细胞减少伴发热（13%）
研究期间，两组患者均无死亡。
因此，该研究结果表明，对于某些高风险早期激素受体阳性HER2阴性乳腺癌患者，CDK4和CDK6抑制剂＋内分泌治疗即使不化疗也可以降低疾病的分子分期。
对此，美国芝加哥西北大学范伯格医学院罗伯特卢里综合癌症中心发表同期评论：管腔型乳腺癌分子降期时代来临。
Lancet Oncol. 2019 Dec 11. [Epub ahead of print]
Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicentre, randomised, phase 2 trial.
Aleix Prat, Cristina Saura, Tomás Pascual, Cristina Hernando, Montserrat Munoz, Laia Paré, Blanca González Farré, Pedro L Fernández, Patricia Galván, Núria Chic, Xavier González Farré, Mafalda Oliveira, Miguel Gil-Gil, Miriam Arumi, Neus Ferrer, Alvaro Montano, Yann Izarzugaza, Antonio Llombart-Cussac, Raquel Bratos, Santiago González Santiago, Eduardo Martínez, Sergio Hoyos, Beatriz Rojas, Juan Antonio Virizuela, Vanesa Ortega, Rafael López, Pamela Céliz, Eva Ciruelos, Patricia Villagrasa, Joaquín Gavilá.
SOLTI Breast Cancer Research Group, Barcelona, Spain; Hospital Clinic of Barcelona, Barcelona, Spain; August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain; Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain; Hospital Clínico Universitario of Valencia, Valencia, Spain; Hospital Germans Trials i Pujol, Badalona, Spain; Hospital General de Catalunya, Barcelona, Spain; Institut Català d'Oncologia Hospitalet, Hospitalet de Llobregat, Spain; Hospital Universitari Son Espases, Palma de Mallorca, Spain; Hospital Universitario Virgen del Rocío, Sevilla, Spain; Hospital Universitario Fundación Jimenez Díaz, Madrid, Spain; Hospital Arnau de Vilanova, Valencia, Spain; Centro Oncológico Internacional MD Anderson, Madrid, Spain; Hospital San Pedro de Alcántara, Cáceres, Spain; Consorcio Hospitalario Provincial of Castellón, Castellón de la Plana, Spain; Hospital Rey Juan Carlos, Madrid, Spain; Centro Integral Oncológico Clara Campal, Madrid, Spain; Hospital Virgen de la Macarena, Sevilla, Spain; Fundación Privada Asil de Granollers, Barcelona, Spain; Complejo Universitario de Santiago de Compostela, Spain; Hospital 12 de Octubre, Madrid, Spain; Instituto Valenciano de Oncología, Valencia, Spain.
BACKGROUND: In hormone receptor-positive, HER2-negative early stage breast cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition in combination with endocrine therapy could represent an alternative to multiagent chemotherapy. We aimed to evaluate the biological and clinical activity of neoadjuvant ribociclib plus letrozole in the luminal B subtype of early stage breast cancer.
METHODS: CORALLEEN is a parallel-arm, multicentre, randomised, open-label, phase 2 trial completed across 21 hospitals in Spain. We recruited postmenopausal women (≥18 years) with stage I-IIIA hormone receptor-positive, Eastern Cooperative Oncology Group Performance Status 0-1, HER2-negative breast cancer and luminal B by PAM50 with histologically confirmed, operable primary tumour size of at least 2 cm in diameter as measured by MRI. Patients were randomly assigned (1:1) using a web-based system and permuted blocks of 25 to receive either six 28-days cycles of ribociclib (oral 600 mg once daily for 3 weeks on, 1 week off) plus daily letrozole (oral 2.5 mg/day) or four cycles of doxorubicin (intravenous 60 mg/m2) and cyclophosphamide (intravenous 600 mg/m2) every 21 days followed by weekly paclitaxel (intravenous 80 mg/m2) for 12 weeks. The total duration of the neoadjuvant therapy was 24 weeks. Randomisation was stratified by tumour size and nodal involvement. Samples were prospectively collected at baseline (day 0), day 15, and surgery. The primary endpoint was to evaluate the proportion of patients with PAM50 low-risk-of-relapse (ROR) disease at surgery in the modified intention-to-treat population including all randomly assigned patients who received study drug and had a baseline and at least one post-baseline measurement of ROR score. The PAM50 ROR risk class integrated gene expression data, tumour size, and nodal status to define prognosis. This trial was registered at ClinicalTrials.gov, NCT03248427.
FINDINGS: Between July 27, 2017 to Dec 7, 2018, 106 patients were enrolled. At baseline, of the 106 patients, 92 (87%) patients had high ROR disease (44 [85%] of 52 in the ribociclib and letrozole group and 48 [89%] of 54 in the chemotherapy group) and 14 (13%) patients had intermediate-ROR disease (eight [15%] and six [11%]). Median follow-up was 200.0 days (IQR 191.2-206.0). At surgery, 23 (46.9%; 95% CI 32.5-61.7) of 49 patients in the ribociclib plus letrozole group and 24 (46.1%; 32.9-61.5) of 52 patients in the chemotherapy group were low-ROR. The most common grade 3-4 adverse events in the ribociclib plus letrozole group were neutropenia (22 [43%] of 51 patients) and elevated alanine aminotransferase concentrations (ten [20%]). The most common grade 3-4 adverse events in the chemotherapy group were neutropenia (31 [60%] of 52 patients) and febrile neutropenia (seven [13%]). No deaths were observed during the study in either group.
INTERPRETATION: Our results suggest that some patients with high-risk, early stage, hormone receptor-positive, HER2-negative breast cancer could achieve molecular downstaging of their disease with CDK4/6 inhibitor and endocrine therapy.
FUNDING: Novartis, Nanostring, Breast Cancer Research Foundation-AACR Career Development Award
DOI: 10.1016/S1470-2045(19)30786-7
Lancet Oncol. 2019 Dec 11. [Epub ahead of print]
Time for a shift in molecular down staging in luminal breast cancer.
Massimo Cristofanilli.
Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
DOI: 10.1016/S1470-2045(19)30806-X
联系客服
