Background: Human Epidermal growth factor Receptor-2 positive (HER2+) breast cancer (BC) heterogeneity can be captured at the mRNA level by the PAM50 classification. The HER2 “Enriched” (HER2-E) intrinsic subtype is encountered more often in HER2+ Hormone Receptor negative (HR-) tumors compared to HER2+ HR+ tumors and is particularly sensitive to HER2 blockade. HER2+ HR- and HER2-E achieve high pathological complete response (pCR) rates with neoadjuvant chemotherapy (CT) and dual anti-HER2 blockade with trastuzumab and pertuzumab. Additionally, the patients with pCR have improved outcomes. However, standard CT with common drugs such as anthracyclines has significant short and long-term toxicities, including cardiac events and secondary leukemias. Thus, tailoring the neoadjuvant treatment among carefully selected patients in order to reduce toxicity while preserving efficacy is a priority in early HER2-positive BC. Methods: DECRESCENDO is a large, multicentric, single-arm, phase 2 de-escalation study evaluating the efficacy of neoadjuvant CT with paclitaxel 80mg/m2 weekly or docetaxel 75mg/m2 every 3 weeks (Q3W) with pertuzumab and trastuzumab (P+T) 600/600mg fixed-dose combination (FDC) for subcutaneous (SC) injection Q3W for patients with early HER2+, HR- (ER<1% and PR<1%) BC. After surgery, the patients with pCR (defined as Residual Cancer Burden (RCB)=0, per local assessment) will receive 14 additional cycles of P+T FDC SC. Patients with RCB≥1 will receive adjuvant T-DM1 (preceded by anthracycline-based CT if RCB≥2). Eligible patients must be candidates for neoadjuvant treatment, with a tumor between 15 and 50mm, N0, ECOG PS 0-1, with LVEF ≥55%. 1,065 patients will be enrolled in 12 countries. A baseline tumor sample is required to retrospectively assess the intrinsic tumor subtype. The primary objective is to evaluate 3-year recurrence-free survival (RFS) in patients with HER2-E tumors who achieve pCR after neoadjuvant treatment. The key secondary objective is to evaluate 3-year RFS in all patients with pCR. If a 3-year RFS ≥94% with the lower boundary of a 1-sided 95% CI ≥92% is observed in the target group, the study treatment will be considered an acceptable alternative to strategies that include the addition of other chemotherapies such as anthracyclines, alkylating agents and platinum salts. A flexible care sub-study will enroll 121 patients with pCR in Belgium, France, Ireland, Israel and Italy to receive adjuvant P+T FDC SC in a location outside the hospital, such as at home or workplace. The aim is to compare patient preference for administration of P+T FDC SC outside the hospital vs in the hospital. The first patient was enrolled in January 2022. The trial is co-led by the Breast International Group (BIG) and Institut Jules Bordet. Clinical trial information: NCT04675827.