Abstract GS1-03: Adjuvant aromatase inhibitor or tamoxifen in patients with hormone receptor-positive/HER2-positive early breast cancer: An exploratory analysis from the ALTTO (BIG 2-06) trial

Abstract Background: The optimal adjuvant endocrine therapy (ET) for patients (pts) with hormone receptor-positive (HR+)/HER2-positive (HER2+) early breast cancer (EBC) remains controversial. The present analysis investigated the efficacy of different types of ET in pts with centrally tested HR+/HER2+ EBC treated with modern chemotherapy (CT) and trastuzumab (T)-based regimens at 10-year follow-up. Patients and methods: ALTTO (BIG 2-06) is an international phase 3 trial in pts with HER2+ EBC randomized to 4 adjuvant anti-HER2 treatments with CT: T alone, lapatinib (L) alone, their sequence (T->L) or their combination (T+L). Pts in the L alone arm, pts with HR-/HER2+ disease and pts with HR+ tumours who did not start adjuvant ET were excluded from the analysis. HER2 and HR status were centrally tested for all pts. Disease-free survival (DFS), time to distant recurrence (TTDR) and overall survival (OS) were compared between pts who received a selective estrogen receptor modulator (SERM) vs. those who received an aromatase inhibitor (AI). To avoid the risk of immortal time bias, pts with HR+/HER2+ disease who switched from one ET to another during the follow-up were excluded. A pre-planned subgroup analysis according to menopausal status at baseline was performed. Among premenopausal women, a comparison was made between SERM alone, SERM + ovarian function suppression (OFS) and AI±OFS (depending on post-CT menopausal status). Multivariable Cox proportional hazards regression models were used to model survival outcomes with adjuvant ET as the predictor. Other covariates in the model were CT timing (concurrent/sequential), tumour grade (G1/2, G3, GX), age (continuous) and tumour size (T, continuous) and a strata variable of axillary lymph node (N0, N1-3, N>=4 nodes, N/A). SERM were used as the reference category for adjusted hazard ratios (aHR). Results: This analysis included 2,651 pts with HR+/HER2+ of whom 1,518 (57.3%) received SERM (99.5% tamoxifen) and 1,133 (42.7%) AI. Among 1,259 premenopausal pts, 903 (71.7%) received SERM alone, 238 (18.9%) SERM+OFS and 118 (9.4%) AI±OFS. Median follow-up was 9.9 years (IQR 7.0-10.0 years). Overall, 10-year DFS was 80.1% and 76.5% in the AI and SERM groups, respectively (aHR 0.65; 95% CI 0.52-0.82). Compared to pts treated with SERM, those who received AI had fewer local (0.9% vs. 2.4%) and distant (9.3% vs. 12.1%) recurrences. In subgroup analyses, AI was superior to SERM irrespective of pts (age, menopausal status, body mass index), tumor (T, N, G, HR+ levels, HER2 FISH ratio) and treatment (anti-HER2 arm, CT type and timing) characteristics. In the AI and SERM groups, 10-year TTDR was 85.7% and 83.1% (aHR 0.65; 95% CI 0.50-0.85), and 10-year OS was 88.9% and 89.1% (aHR 0.73; 95% CI 0.53-1.00), respectively. Among premenopausal pts only, 10-year DFS was 90.0%, 77.3% and 77.6% with AI±OFS, SERM+OFS and SERM, respectively (AI±OFS vs. SERM: aHR 0.44; 95% CI 0.23-0.85; SERM+OFS vs. SERM: aHR 0.87; 95% CI 0.61-1.23). In the AI±OFS, SERM+OFS and SERM groups, 10-year TTDR was 92.8%, 82.9% and 85.1% (AI±OFS vs. SERM: aHR 0.57; 95% CI 0.27-1.18; SERM+OFS vs. SERM: aHR 0.94; 95% CI 0.62-1.41), and 10-year OS was 95.6%, 88.7% and 91.3% (AI±OFS vs. SERM: aHR 0.68; 95% CI 0.27-1.73; SERM+OFS vs. SERM: aHR 0.98; 95% CI 0.58-1.66), respectively. Conclusions: In this large 10-year follow-up analysis of pts with centrally tested HR+/HER2+ EBC treated with modern CT+anti-HER2-based therapy in the ALTTO trial, the use of AI was associated with significantly improved DFS and TTDR without differences in OS. The DFS benefit of AI was observed in both premenopausal and postmenopausal pts. These data may help optimizing adjuvant ET choices in pts with HR+/HER2+ EBC and shed light on the need of designing ad hoc clinical trials in this setting. Citation Format: M. Lambertini, F. Samy, E. Agostinetto, L. Arecco, P. Freire, A. Sonnenblick, G. Arpino, L. Del Mastro, A. Choudhury, N. Harbeck, I. Vaz-Luis, V. Kaklamani, A. Wolff, A. Partridge, S. Loi, S. Fielding, M. Piccart, S. Di Cosimo, E. de Azambuja. Adjuvant aromatase inhibitor or tamoxifen in patients with hormone receptor-positive/HER2-positive early breast cancer: An exploratory analysis from the ALTTO (BIG 2-06) trial [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 GS1-03.