In the 2025 San Antonio Breast Cancer Symposium in General Session 1 we are presenting an exploratory analysis of the ALTTO trial, aiming to investigate the optimal adjuvant endocrine therapy in patients with ER+/HER2- disease. So this is an unmet need so far because we know that aromatase inhibitors are superior to tamoxifen in patients with hormone receptor positive disease overall, however, the evidence on the optimal adjuvant endocrine therapy in the special group of patients with HER2+/ HR+ disease has been debated over the past years. This is what we wanted to look into in the ALTTO trial which is the largest adjuvant study in HER2+ breast cancer.

What was the study design?

The ALTTO trial was designed to look at the optimal adjuvant anti-HER2 therapy, comparing trastuzumab alone with lapatinib alone, a sequence of the two anti-HER2 agents or a combination of these two anti-HER2 agents. It’s a very large study that included more than 8,000 patients and within this study we included in our exploratory analysis patients with hormone receptor positive disease to look into the endocrine therapies that the patients have received as part of this study.

We included out of the 8,381 patients included in the ALTTO trial, we included 2,615 in this specific analysis. Specifically we excluded those patients in the lapatinib alone arm, those with hormone receptor negative disease and those with hormone receptor positive disease who did not receive adjuvant endocrine therapy, who received ovarian function suppression alone as the only adjuvant endocrine therapy, or those patients who switched from one endocrine therapy to the other during the follow-up. We also excluded this population to avoid a potential risk of immortal time bias because the patients had to be disease free at the time of the switch, considering the study was not designed, it was not randomised to one switched strategy to the other.

So in this exploratory analysis we compared the outcomes of patients who received up-front aromatase inhibitors versus up-front tamoxifen.

What were the results?

At the median follow-up of almost ten years, it was a median follow-up of 9.9 years, we observed that patients who received an aromatase inhibitor experienced a significantly better disease free survival as compared to patients who received tamoxifen alone. Specifically, there was a 3.6% absolute difference in ten-year disease free survival favouring AI over tamoxifen with a hazard ratio of 0.65. This benefit was observed regardless of patient, tumour or treatment characteristics and specifically we observed also benefit of AI over tamoxifen also in the cohort of premenopausal patients at the time of study initiation, meaning that an aromatase inhibitor appears to be the best adjuvant endocrine therapy regardless of menopausal status.

We also observed a significant improvement of time to distant recurrence favouring AI over tamoxifen with a 2.6 absolute difference in time to distant recurrence at ten years and an adjusted hazard ratio of 0.65 again. However, we did not observe any difference in overall survival between the two different options with only a slight trend favouring AI over tamoxifen.

So, overall, we believe that this data, despite coming from an exploratory analysis, so this trial was not designed to look specifically into the endocrine therapy but it’s a large study with more than 2,600 patients included, almost ten years of follow-up, centrally reviewed, hormone receptor status, HER2 status, we believe that this data provides important evidence to suggest that AI, aromatase inhibitor, is probably the preferred endocrine therapy also among patients with HR+/HER2+ disease, regardless of menopausal status. So in premenopausal women, of course, this should be combined with ovarian function suppression.

What is the importance of these results?

The importance of these results is that they provide evidence on the potential optimal adjuvant endocrine therapy in this space. Not a lot of studies have investigated endocrine therapy in the field of HER2+/ HR+ early breast cancer. Despite being an exploratory analysis, we believe that there are several strengths in this analysis. This still an analysis within a randomised trial, more than 2,600 patients included, centrally reviewed receptor status and almost ten years median follow-up. So we believe that this data provides evidence that AI should be probably considered as the preferred adjuvant endocrine therapy also among patients with HR+/HER2+ disease, including premenopausal women, together with ovarian function suppression.

What is next for this study?

Another important additional piece of information coming from this analysis is to raise awareness on the importance to investigate endocrine therapy in the field of HER2+/ HR+ disease. In the HER2+ space we do have a lot of very effective anti-HER2 therapies that are entering clinical practice and are also moving into the early breast cancer setting. Thinking about ADCs, for example trastuzumab deruxtecan, however, in patients with HR+/HER2+ disease, endocrine therapy is still a critical component of systemic therapy to be offered to these patients. So we really need more attention towards this patient population and also to have future prospective studies looking specifically into new endocrine therapy combinations in this space.

We do have data already coming from the HER2-/HR+ field – oral SERDs, CDK4/6 inhibitors – there is space to develop these new molecules also in the HER2+/HR+ field.