Aromatase Inhibitors Favored as Adjuvant ET in HR+/HER2+ Early Breast Cancer

An exploratory analysis of the phase 3 ALTTO/BIG 2-06 (NCT00490139) trial suggests that aromatase inhibitors may be the optimal adjuvant endocrine therapy (ET) choice in patients with hormone receptor-positive (HR+), HER2-positive (HER2+) early breast cancer, offering advantages over selective estrogen receptor modulators (SERMs) in minimizing disease recurrence.¹

This long-term analysis, the results of which were presented at the 2025 San Antonio Breast Cancer Symposium (SABCS), examined the comparative efficacy of different types of ET used to treat patients treated with chemotherapy and anti–HER2-based therapy in the ALTTO trial, measuring disease-free survival (DFS) as a primary end point and time to distant recurrence and overall survival (OS) as secondary end points. With a median follow-up of 9.9 years, findings revealed that the use of an aromatase inhibitor was associated with improved DFS and TTDR without compromising OS, proving superiority to SERMs such as tamoxifen (Nolvadex).

Specifically, among all patients, the 10-year DFS among those receiving an aromatase inhibitor was 80.1% compared with 76.5% receiving a SERM (adjusted HR [aHR], 0.65; 95% CI, 0.52–0.82). Subgroup analyses showed that this DFS benefit persisted regardless of patient characteristics—including menopausal status—as well as tumor and treatment characteristics. Comparing DFS for those receiving aromatase inhibitors with those receiving SERMs, the respective aHRs for postmenopausal and premenopausal patients were reported as 0.65 (95% CI, 0.50–0.85) and 0.45 (95% CI, 0.24–0.86).

In terms of recurrence, patients receiving an aromatase inhibitor had fewer local (0.9% vs 2.4%) and distant recurrences (9.3% vs 12.1%) vs those treated with SERMs. The respective 10-year TTDRs among aromatase inhibitor- and SERM-treated patients were 85.7% and 83.1% (aHR, 0.65; 95% CI, 0.50–0.85).

“There was a 3.6% absolute gain in [DFS] at 10 years with [aromatase inhibitors] over SERM… and a 2.6% absolute gain in [TTDR] at 10 years,” Matteo Lambertini, MD, PhD, presenting author, shared during the presentation.

Importantly, the improvements in DFS and TTDR by aromatase inhibitors were achieved without significantly compromising OS, as evidenced by the similar 10-year OS of 88.9% and 89.1% (aHR, 0.73; 95% CI, 0.53–1.00) with aromatase inhibitors and SERMs, respectively. The lack of significant difference in OS between the 2 types of ETs underscores the role of aromatase inhibitors in reducing the incidence of disease recurrence and enhancing long-term outcomes for this patient group.

“We hope that this data may help optimize adjuvant [ET] choices in patients with [HR+/HER2+] early breast cancer and shed light on the need to design ad hoc clinical trials in this special setting,” Lambertini, associate professor and consultant in Medical Oncology at the University of Genova - IRCCS San Martino Hospital in Italy, said.¹

Findings in Premenopausal Patients

An additional prespecified analysis provided more detailed insights for premenopausal patients. This analysis compared the efficacy of 3 different ET options: aromatase inhibitors with or without ovarian function suppression (OFS), SERM only, and SERM plus OFS. The respective 10-year DFS in the 3 groups were 90.0%, 77.3%, and 77.6%.

“So, we did not observe an additional benefit of adding OFS… to SERM,” said Lambertini regarding these figures. Lambertini also noted that no significant differences in TTDR or OS were observed between the 3 options, although survival outcomes among those receiving aromatase inhibitors were numerically superior despite not meeting statistical significance.

ALTTO Trial: Patient Characteristics

This analysis encompassed 10 years of follow-up in the ALTTO trial, a randomized global phase 3 trial that ran between 2007 and 2021.² The ALTTO trial evaluated various adjuvant anti-HER2 treatments with chemotherapy in over 8000 patients with HER2+ early breast cancer: trastuzumab (Herceptin) alone, lapatinib (Tykerb) alone, a sequence of trastuzumab followed by lapatinib, and the combination of trastuzumab plus lapatinib.

This analysis included 2651 patients with centrally tested HR+/HER2+ disease and excluded those who received lapatinib alone, those with HR-negative/HER2+ disease, HR+ patients who did not start adjuvant ET, and those with HR+/HER2+ who had switched ETs during the follow-up period. Slightly less than half (42.7%) of the analytic cohort received an aromatase inhibitor for adjuvant ET, while the remainder (57.3%) received a SERM, predominantly tamoxifen (99.5%).

DISCLOSURES: Lambertini declared interests with Roche, Eli Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead Sciences, MSD, Exact Sciences, Pierre Fabre, Menarini, Nordic Pharma, Takeda Pharmaceuticals, Ipsen, Sandoz, Libbs, and Daiichi Sankyo.

REFERENCES

1. Lambertini, M. 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. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9–12, 2025; San Antonio, Texas. Abstract GS1-03.

2. ALTTO (adjuvant lapatinib and/or trastuzumab treatment optimisation) study; BIG 2-06/N063D (ALTTO). ClinicalTrials.gov. Updated March 21, 2025. Accessed December 9, 2025. https://clinicaltrials.gov/study/NCT00490139