Abstract PS5-07-10: Young HOPE/JCOG2402: A Randomized Phase III Study of Response-Guided Therapy Following Neoadjuvant Endocrine Therapy to Optimize Adjuvant Treatment in Premenopausal HR+/HER2- Breast Cancer

Abstract Background: In Asia, the incidence of breast cancer (BC) is increasing, with premenopausal patients accounting for 30-40% of all cases. The TAILORx and RxPONDER trials demonstrated that premenopausal women with hormone receptor (HR)-positive/HER2-negative BC and intermediate risk (defined as node-negative with high clinical risk and Oncotype DX Recurrence Score RS of 16-20, node-negative with RS 21-25, or node-positive with RS ≤25) derive benefit from adding chemotherapy (CT) to endocrine therapy (ET). The ADAPT trial suggested that patients achieving endocrine response (Ki-67≤10%) after neoadjuvant endocrine therapy (NET) had excellent outcomes without CT, regardless of menopausal status. Thus, ET response may serve as a biomarker to identify premenopausal patients who could safely omit CT. We hypothesize that premenopausal HR+/HER2- BC patients with intermediate risk (pN0 with RS16-25 or pN1 with RS ≤25) who achieve an ET response after NET can safely omit CT. The Young HOPE/JCOG2402 study is a randomized, phase III, non-inferiority trial. Methods: Patients are randomized (1:1) to either an upfront surgery arm or a NET arm, stratified by clinical nodal status (cN0/cN1), histologic grade (HG 1-2 vs. 3), and institution. Key eligibility criteria include: 1) ECOG PS 0-1; 2) premenopausal status with spontaneous menstruation within 12 months; 3) ER and/or PgR-positive and HER2-negative BC with ≥10% ER expression; 4) cN0 with clinical high-risk tumor (HG 1 with 3 cm T≤5 cm, HG 2 with 2 cm T≤5 cm, or HG 1 with 1 cm T≤5 cm) or cN1 with cT 5 cm and HG 1-2; and 5) adequate organ function. In the NET arm, patients receive NET for 3 months followed by surgery. Those with pN0 with RS 16-25 or pN1 with RS ≤25 achieving an ET response (Ki-67 ≤10%) will omit CT. In the upfront surgery arm, CT is administered for pN0 with RS ≥16 or pN+ disease. ET consists of an aromatase inhibitor (AI) plus ovarian function suppression (OFS), with tamoxifen permitted per investigator discretion. Radiotherapy will be administered per investigator discretion per protocol guidelines. The primary endpoint is event-free survival (EFS). Secondary endpoints include overall survival, relapse-free survival, distant relapse-free survival, patient-reported outcomes (EORTC QLQ-C30, QLQ-BR42), ET-alone proportion, and ET response rate. Based on prior data (TAILORx, RxPONDER, ADAPT), 5-year EFS in the upfront surgery arm is estimated at 92%. The non-inferiority margin is 3.4% (HR 1.45) with one-sided α=0.05 and 70% power, requiring enrollment of 928 patients. Target accrual is 950 patients over 5 years and 7 years follow-up. Translational research will be conducted alongside this trial. Patient accrual is scheduled to begin in 2025. Citation Format: M. Ono, Y. Sagara, Y. Kikawa, M. Kawamura, I. Nishibuchi, M. Yoshida, Y. Koi, N. Uehiro, T. Tsukioki, Y. Tanabe, Y. Naito, H. Tsuda, N. Mitome, K. Sasaki, T. Shibata, F. Hara, T. Fujisawa, H. Iwata, T. Shien. Young HOPE/JCOG2402: A Randomized Phase III Study of Response-Guided Therapy Following Neoadjuvant Endocrine Therapy to Optimize Adjuvant Treatment in Premenopausal HR+/HER2- Breast Cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-07-10.