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Chemotherapy is used as neoadjuvant therapy for all subgroups of breast cancer, including ER-positive, and HER2-negative cases. However, studies have suggested that using aromatase inhibitors combined with CDK4/6-inhibitors might be an appropriate alternative in selected patients. Thus, the NEOLETRIB trial evaluates the response of ER-positive, HER2-negative luminal A/B breast cancer to the combination of letrozole and ribociclib in the neoadjuvant setting. Comprehensive molecular biology procedures, including sequential single-cell RNA-sequencing of tumor biopsies, are performed during 6 months of treatment with extensive biobanking of blood samples, tumor biopsies and gut microbiome specimens. Our findings will hopefully contribute to an improved selection of patients who may benefit from this drug combination and give new insights into the intra-tumoral changes during this treatment. Trial registration number:NCT05163106 (ClinicalTrials.gov) Article highlights Background & rationale Hormone receptor-positive breast cancer is the most common subtype and accounts for about 70–80% of all breast cancer patients. The rationale for using neoadjuvant therapy in the treatment of early breast cancer is to down-size large, otherwise inoperable tumors, with or without axillary lymph node metastasis, before definite surgery. Chemotherapy is still widely used as neoadjuvant therapy for all subgroups of breast cancer, including ER-positive, and HER2-negative cases. Neoadjuvant endocrine treatment with aromatase inhibitors and a CDK4/6 inhibitor in combination is currently tested in the neoadjuvant setting with promising results. Trial design The NEOLETRIB trial is a Phase-II, multicenter, single-arm, open-label, neoadjuvant trial. Objectives The trial aims to comprehensively study the tumor response to the highly potent drug combination of letrozole and ribociclib in women with locally advanced, ER-positive, luminal A/B breast cancer. In premenopausal women, goserelin will be added to letrozole and ribociclib. Comprehensive molecular biology procedures, including sequential single-cell RNA-sequencing of tumor biopsies, are performed during 6 months of treatment with extensive biobanking of blood samples, tumor biopsies and gut microbiome specimens. Conclusion The findings will hopefully contribute to an improved selection of patients who may benefit from this drug combination, and give new insights into the intra-tumoral changes during this treatment. [ABSTRACT FROM AUTHOR]