<p>Adjuvant therapy for HR+/HER2- early-stage breast cancer is increasingly personalized. While endocrine therapy remains foundational, CDK4/6 inhibitors have moved from exclusive use in the metastatic setting to use in high-risk, node-positive, early-stage and selective high-risk, node-negative, early-stage populations. Researchers at the recent <strong>2025 San Antonio Breast Cancer Symposium (SABCS 2025)</strong> presented new data on CDK4/6 inhibitor therapy use in this setting.</p> <p><br></p> <p><em>Following these presentations, featured expert Erica L. Mayer, MD, MPH, was interviewed by </em>Conference Reporter<em> Associate Editor-in-Chief Christopher Ontiveros, PhD. Clinical perspectives from Dr Mayer on these findings are presented here.</em></p>

Adjuvant systemic therapy becomes very personalized based on the patient’s stage, subtype of breast cancer, comorbidities, and preferences. For HR+ disease, the mainstay of treatment is adjuvant endocrine therapy, including taking an endocrine agent for 5 to 10 years. Adjuvant endocrine therapy is a fundamental part of systemic therapy and provides substantial reductions in the risk of disease recurrence.

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Over the past few years, targeted therapies have been introduced into the adjuvant space for HR+ disease as CDK4/6 inhibitors have transitioned from being exclusively used by patients with metastatic breast cancer to being used by patients with HR+/HER2- early-stage disease. Currently in the United States, 2 CDK4/6 inhibitors are US Food and Drug Administration (FDA) approved for early-stage disease in combination with endocrine therapy: abemaciclib, which is approved for high-risk node-positive disease, and ribociclib, which is approved for node-positive disease as well as high-risk node-negative disease. Further, some patients with HR+ disease will also receive adjuvant chemotherapy, and we can be more thoughtful and careful in the selection of patients for adjuvant chemotherapy through the use of genomic tools such as Oncotype DX (Exact Sciences Corporation) or MammaPrint (Agendia). This ensures that chemotherapy is only given in situations in which the disease is sensitive to chemotherapy and there will be a meaningful benefit for the patient who is receiving it.

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The FDA approval of abemaciclib in the adjuvant setting was based on the phase 3 monarchE study, which was a large global trial that randomized patients with high-risk, node-positive, early-stage breast cancer to receive adjuvant endocrine therapy alone or endocrine therapy with the addition of 2 years of the CDK4/6 inhibitor abemaciclib.

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Results from monarchE have been presented multiple times over several years. The initial study results, first presented in 2020, demonstrated a significant benefit in terms of reducing invasive disease-free survival risk in patients who received adjuvant abemaciclib. With each subsequent look at the data, the benefits observed in the abemaciclib arm have deepened, meaning that the curves have separated and have remained separated over the past few years with a clinically meaningful improvement in invasive disease-free survival in those who received abemaciclib. Data presented at the European Society for Medical Oncology (ESMO) Congress 2025 showed, after 7 years of follow-up, an overall survival benefit in patients who received adjuvant abemaciclib. It is difficult to demonstrate overall survival benefits in HR+/HER2- early breast cancer because patients receive many different lines of therapy and can have very heterogeneous outcomes, making these data even more meaningful.

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The benefits of adjuvant abemaciclib in monarchE were further supported in a presentation at SABCS 2025 in which investigators Javier Cortés, MD, PhD, and colleagues confirmed the benefits of adjuvant abemaciclib regardless of the degree of nodal involvement (poster PS1-08-08). I think that, for many individuals in the breast cancer community, these results help confirm the benefits of taking adjuvant abemaciclib across the spectrum of nodal burden of disease.

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The NATALEE trial is a large, global, phase 3 study that evaluated the CDK4/6 inhibitor ribociclib in the adjuvant setting. NATALEE was a little different from monarchE. First, the CDK4/6 inhibitor used in the study was ribociclib. Another important difference was that, although abemaciclib was used for 2 years in monarchE, ribociclib was used for 3 years in NATALEE. Finally, there was overlap in patient eligibility between monarchE and NATALEE, as both studies were open to node-positive patients, but NATALEE also included patients with node-negative disease with an additional high-risk feature such as a larger tumor, high-grade disease, or a high genomic score. As the NATALEE study timelines were also a little different from those in monarchE, the results of NATALEE were reported later, and NATALEE does not have as long of a follow-up as monarchE. However, very similarly, at the time of the first report from NATALEE, it was shown that this was a positive trial, and the benefits in patients who received adjuvant ribociclib have continued to deepen with greater data maturity.

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Also at the recent ESMO Congress, we saw data from a 5-year analysis from NATALEE. Importantly, the node-negative cohort of patients—a very prevalent group of patients clinically, who had experienced only a marginal signal of benefit at early follow-up in the trial—had deepened and statistically significant benefits at the 5-year follow-up analysis. This is very reassuring for the breast cancer community, as it further supports the role of ribociclib in the adjuvant setting, not only in patients with node-positive disease but also specifically in patients with node-negative disease who would not have been eligible for adjuvant abemaciclib, thereby reflecting a unique population eligible for ribociclib.

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The efficacy of adjuvant ribociclib was further supported by a subgroup analysis of the NATALEE trial by Sara Hurvitz, MD, et al presented at SABCS 2025 (poster PS3-09-08). In this analysis, investigators confirmed improvements in distant disease-free survival with adjuvant ribociclib in node-negative and -positive disease.

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Between both the monarchE and the NATALEE trials and the respective regulatory approvals of these agents, the global role of CDK4/6 inhibitors in the adjuvant setting for patients with stages II and III breast cancer is very much solidified.