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Twenty-three patients with inoperable de novo hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) locally advanced breast cancer were treated with first-line ribociclib plus letrozole. At baseline, 15 (65.2%) of women had stage IIIA ductal carcinoma; median Ki-67 expression was 15% (range: 10-80%) and 13 patients (56,5%) had Ki 67 under 20%. After treatment, 68.5% of patients achieved overall response (only 1 clinical complete response); 73.9% were eligible for surgery. Following surgery, 88% experienced TNM downstaging and in number (56.3%) Ki-67 we obtained regression. At a median follow-up of 18 months, all patients were alive. To our knowledge, this is the first real-world observational report of ribociclib plus letrozole in this setting.