Background: Adjuvant Endocrine Therapy (ET) is the cornerstone treatment of localized hormone-receptor positive (HR+) breast cancer, with demonstrated benefits on overall survival (30-40% relative decrease in mortality) but also on the risk of local and contralateral relapse (43-50% relative decrease). While the relative benefit of 5 years of ET is identical for small tumors as compared to larger ones, the absolute benefit is much lower, and the risk-benefit ratio becomes questionable given the frequent and impactful side effects of ET which are associated with non-adherence. If recent trials tested longer durations as compared to 5 years for high-risk cancers, older trials have tested shorter durations. Five years appeared at that time as the gold standard because of optimal benefit-risk ratios of tamoxifen among rather high-risk patients. However, shorter treatments of 2-3 years were already associated with substantial benefits and may be enough for very low risk patients. The purpose of this study is to demonstrate that adjuvant ET limited to 2 years of aromatase inhibitor (AI) in postmenopausal women at very low risk of recurrence as determined with a MammaPrint and BluePrint Ultra Low Risk Luminal test result can ensure very high survival without metastatic relapse and allows a reduction of side effects and a better quality of life. Methods: LESS (NCT05297617) is a prospective, national, multicenter, single-arm, interventional, non-threshold crossing phase II study evaluating a therapeutic de-escalation that limits adjuvant ET to 2 years of AI. Approximately 696 post-menopausal patients with an invasive unilateral, HR+, HER2-negative, without indication of adjuvant chemoT and genomically-assessed MammaPrint/BluePrint UltraLow risk Luminal A breast cancer tumors, will be enrolled. LESS will include two sub cohorts: the majority of patients with Grade 2, pT1c-2, pN0/N1mic tumors, and up to 80 patients ≥65 years with Grade 1, pT1, pN0 and Ki67<10% tumors. The primary endpoint is distant metastasis free survival (DMFS) defined as the time from date of registration to date of first event of distant recurrence, death, or second primary non-breast invasive cancer. Secondary endpoints include the assessment of quality of life parameters and psychological aspects related to this de-escalation. The null hypothesis (H0) that, in the study population after 2 years of adjuvant AI, DMFS at 5 years is lower or equal to 94.5% will be tested against the alternative - that it is above 94.5%. For an expected DMFS of 96.7% under the alternative hypothesis, a total of 37 DMFS events are required in order to provide approximately 85% power at a one-sided significance level of 0.05 to reject H0 using a logrank test. The 1st patient was included in October 2022, initiating the 2-year inclusion period and 10 years FU per patient. Clinical trial information: NCT05297617.