Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) versus chemotherapy in luminal B early breast cancer: lessons from the CORALLEEN trial

摘要

About 70% of all invasive breast cancers are hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative (1). Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) plus endocrine therapy represents nowadays the standard of care for pre- and post-menopausal women with HR-positive/HER2-negative advanced breast cancer both in the first- and second-line setting (2-5). Six studies have reported the efficacy of CDK4/6i in the neoadjuvant setting: PALLET, NeoPalAna, neoMONARCH, N007, CORALLEEN and NeoPAL (6-11). However, only the last two trials randomized patients between neoadjuvant endocrine treatment plus CDK4/6i vs. neoadjuvant chemotherapy (10,11). CORALLEEN, the study that is the main focus of this editorial, is a parallel arm, randomized, phase II trial conducted in 21 centers in Spain in which 106 postmenopausal women with HR-positive/HER2-negative, stage I–IIIA, luminal B by PAM50 (Prosigna) breast cancer were enrolled. A total of 52 patients received six cycles of ribociclib (600 mg daily for 21 days, every 4 weeks) plus letrozole (2.5 mg daily), while 54 patients received four cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks followed by 12 cycles of weekly paclitaxel (80 mg/m2). A PAM50 risk of relapse (ROR) prognostic score was evaluated for each patient at study entry. PAM50 ROR score was calculated by integrating gene expression data, tumor size and nodal status and three classes were assigned, namely low, intermediate and high ROR. Most patients had T2 tumors, no axillary node involvement, Ki67 expression level >14%, and a high-ROR disease at baseline (Table 1) (10). NeoPAL is also a non-comparative, phase II study in which 106 patients with HR-positive/HER2-negative, stage II–III, luminal B or node-positive luminal A PAM50-defined breast cancer were enrolled. A total of 53 patients received palbociclib (125 mg daily, 3 weeks on and 1 week off) plus letrozole (2.5 mg daily) for 19 weeks, while 53 patients received three cycles of FEC100 (5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2, every 3 weeks) followed by three cycles of docetaxel (100 mg/m2, every 3 weeks). Similarly, to the Spanish study, most patients in NeoPAL had T2, luminal B, Ki67 expression ≥14%, and high-ROR breast cancers. However, in the NeoPAL trial patients with luminal A, node-positive disease were also allowed (Table 1) (11). Two strengths of both trials were: (I) a strong chemotherapy regimen in the non CDK4/6i arm; (II) the patient selection through a prognostic gene signature (PAM50), thus obtaining a homogenous study population (10,11). In a cohort of 1,691 patients with available PAM50 results, patients with luminal A subtype had a lower cumulative probability of dying from breast cancer compared to those with luminal B (7.1% vs. 16.2% at 10 years) (12).