In patients with HR-positive/HER2-positive early breast cancer, adjuvant anti-HER2 therapy constitutes the cornerstone of systemic treatment. However, robust high-level evidence has long been lacking to guide the choice between aromatase inhibitors (AIs) and tamoxifen (SERMs) for adjuvant endocrine therapy in this population.At the 2025 San Antonio Breast Cancer Symposium (SABCS), Professor Matteo Lambertini from IRCCS Ospedale Policlinico San Martino, University of Genova, Italy, presented key results from the ALTTO (BIG 2-06) trial regarding endocrine therapy selection in HER2-positive early breast cancer.
Oncology Frontier invited Professor Mao Xiaoyun from The First Affiliated Hospital of China Medical University to introduce and comment on these findings.
Study Overview
The ALTTO (BIG 2-06) Trial
The ALTTO (BIG 2-06) study is an international, multicenter, open-label, phase III randomized clinical trial designed to optimize adjuvant anti-HER2 therapy in patients with HER2-positive early breast cancer.
Between January 2007 and July 2011, a total of 8,381 patients were enrolled across 946 centers worldwide. The trial compared four adjuvant anti-HER2 strategies:
- Lapatinib alone
- Trastuzumab alone
- Sequential trastuzumab followed by lapatinib
- Concurrent trastuzumab plus lapatinib
Among these patients, 2,651 had hormone receptor–positive disease. A prespecified subgroup analysis stratified patients by menopausal status. In premenopausal patients, endocrine therapy strategies were further categorized as:
- SERM alone
- SERM plus ovarian function suppression (OFS)
- Aromatase inhibitor (AI) ± OFS
A multivariable Cox proportional hazards model was used to adjust for chemotherapy timing, tumor grade, age, tumor size, and nodal status, with the SERM group serving as the reference.
Patient Characteristics
- Premenopausal patients: 1,259 SERM alone: 903 SERM + OFS: 238 OFS + AI: 118
- Postmenopausal patients: 1,392 AI: 1,015 SERM: 377
The median follow-up duration was 9.9 years.
Key Results
Disease-Free Survival (DFS)
- 10-year DFS rate AI group: 80.1% SERM group: 76.5% Adjusted HR (aHR): 0.65 (95% CI: 0.52–0.82, P < 0.001)
Compared with SERM therapy, AI treatment was associated with:
- Lower local recurrence (0.9% vs 2.4%)
- Lower distant recurrence (9.3% vs 12.1%)
Subgroup Analyses
The DFS benefit of AIs over SERMs was consistent across multiple subgroups, including:
- Age
- Menopausal status
- BMI
- Tumor characteristics (size, grade, nodal status, ER expression level, HER2 FISH ratio)
- Treatment patterns (anti-HER2 regimen, chemotherapy type and timing)
Distant Recurrence–Free Survival and Overall Survival
- 10-year distant recurrence–free survival: AI: 85.7% SERM: 83.1% aHR = 0.65 (95% CI: 0.50–0.85)
- 10-year overall survival (OS): AI: 88.9% SERM: 89.1% aHR = 0.73 (95% CI: 0.53–1.00) No statistically significant difference
Menopausal Status–Specific Findings
- Postmenopausal patients: 10-year DFS: AI: 81.5% SERM: 75.0% aHR = 0.65 (95% CI: 0.50–0.85)
- Premenopausal patients: 10-year DFS: SERM alone: 77.6% SERM + OFS: 77.3% OFS + AI: 90.0%
Compared with SERM alone:
- OFS + AI significantly reduced recurrence risk aHR = 0.44 (95% CI: 0.23–0.85)
- SERM + OFS showed no significant benefit aHR = 0.87 (95% CI: 0.61–1.23)
No statistically significant differences were observed among the three groups in time to distant recurrence (TTDR) or overall survival.
Expert Commentary
In the traditional understanding of HR+/HER2+ breast cancer, the HER2 pathway has been viewed as the dominant driver of tumor progression, and clinical practice has therefore focused primarily on anti-HER2 targeted therapy. However, the optimal endocrine strategy in early-stage HR+/HER2+ disease—whether to intensify therapy to further improve outcomes or to de-escalate treatment to avoid overtreatment—has remained controversial.
The ALTTO (BIG 2-06) study provides the largest dataset to date with the longest follow-up comparing endocrine therapy strategies in this population, offering valuable clinical insight. The results demonstrate that AI-based therapy improves disease-free survival and delays distant recurrence, although no overall survival advantage was observed. Importantly, both premenopausal and postmenopausal patients derived DFS benefit from AI therapy compared with SERM alone.
It should be noted, however, that the primary objective of ALTTO was to compare different anti-HER2 adjuvant regimens. The endocrine therapy analysis represents a post-hoc exploratory evaluation within the HR+/HER2+ subgroup and was not a prespecified primary endpoint. The lack of a dedicated endocrine therapy trial design—including predefined stratification and standardized endocrine treatment protocols—means that the level of evidence supporting AI superiority over SERMs is inherently lower than that of a purpose-built randomized endocrine trial.
Nevertheless, the findings support AI-based endocrine therapy as a preferred option in HR+/HER2+ early breast cancer, particularly suggesting that AI combined with OFS may provide greater benefit in premenopausal patients. These conclusions warrant confirmation in future prospective trials specifically designed to address endocrine treatment optimization in this population.
Professor Mao Xiaoyun
Chen Guangzhou
