Editor’s Note: Hormone receptor–positive, HER2-negative (HR+/HER2−) breast cancer is the most common molecular subtype of breast cancer. Although patients with this subtype generally have a favorable prognosis, its high heterogeneity means that some individuals remain at risk of disease recurrence.In recent years, adjuvant treatment strategies have been continuously refined — evolving from standard endocrine therapy to the incorporation of CDK4/6 inhibitors — significantly improving patient outcomes.In this edition of Oncology Frontier, Professor Juliang Zhang from the Department of Breast, Thyroid, and Vascular Surgery, Xijing Hospital, Air Force Medical University, shares his insights on adjuvant intensified therapy for HR+/HER2− breast cancer. 

Part 1 — What is the Current Landscape of Adjuvant Intensified Therapy for Early HR+/HER2− Breast Cancer?

HR+/HER2− breast cancer is the most common molecular subtype in clinical practice. Although the reported incidence varies slightly among studies, it is widely recognized that this subtype accounts for about two-thirds of all breast cancer cases, making its treatment strategies a central focus in clinical oncology.

From a disease characteristics perspective, HR+/HER2− breast cancer typically has a relatively favorable prognosis and a wider range of therapeutic options compared with other subtypes. However, the subtype’s inherent heterogeneity means that even among patients diagnosed at an early stage and treated according to standard protocols, a significant proportion may still experience disease progression, ultimately developing metastatic breast cancer. Thus, the clinical focus remains on achieving optimal disease control at the early stage, aiming for cure and preventing progression.

In recent years, substantial progress has been made in the adjuvant intensified treatment of early HR+/HER2− breast cancer. The introduction of ovarian function suppression (OFS) combined with aromatase inhibitors, compared with traditional tamoxifen therapy, significantly improved survival outcomes. Subsequently, the duration of endocrine therapy has been extended — from the initial 5 years to 10 years or even longer — yielding further benefits.Meta-analyses have consistently demonstrated that prolonged and intensified endocrine therapy offers clear survival advantages for early HR+/HER2− breast cancer.In addition, the incorporation of CDK4/6 inhibitors into postoperative adjuvant therapy has marked a new era in this field. A growing body of clinical evidence confirms their efficacy in early HR+/HER2− breast cancer. For instance, abemaciclib in the monarchE trial and ribociclib in the NATALEE trial have both received approval for early-stage adjuvant indications. Meanwhile, the Chinese-developed CDK4/6 inhibitor dalpiciclib, evaluated in the DAWNA-A study, has shown promising early results though it has not yet obtained formal approval for adjuvant use. These pivotal studies have solidified the position of CDK4/6 inhibitors in adjuvant intensified therapy, providing patients with more options and greater potential benefits.

Part 2 — How Should High-Risk Patients Be Identified After Surgery, and Who Should Receive Adjuvant Therapy with CDK4/6 Inhibitors?

The concept of precision medicine is now deeply embedded in the management of breast cancer. Whether in advanced, early-stage, or even surgical decision-making, precise risk stratification has become the cornerstone of clinical practice.

For postoperative patients with early HR+/HER2− breast cancer, identifying high-risk individuals is essential for determining the need for adjuvant intensified therapy.

Currently, three major clinical studies with positive results — monarchE, NATALEE, and DAWNA-A — offer valuable guidance. Although the inclusion criteria varied across studies, all focused on patients with intermediate to high recurrence risk. Among them, the monarchE trial aligns most closely with existing clinical guidelines for high-risk stratification, providing a clear framework for patient selection.

According to current guidelines, high-risk patients include those with:(1) four or more positive lymph nodes; or (2) one to three positive lymph nodes combined with at least one additional high-risk feature, such as tumor size ≥5 cm, histologic grade 3, or Ki-67 proliferation index ≥20%.These criteria are widely recognized for their clinical practicality.Importantly, studies have shown that patients with one to three positive lymph nodes who also possess these additional high-risk features face recurrence risks similar to those with four or more positive lymph nodes. The monarchE study, acknowledging this, included such patients and demonstrated that CDK4/6 inhibitor therapy significantly reduced recurrence risk in this group.

Therefore, for patients meeting the monarchE inclusion criteria — whether with multiple lymph node metastases or fewer nodes but additional high-risk pathology — CDK4/6 inhibitors should be considered to minimize recurrence risk and improve long-term survival.

Beyond pathological indicators, certain clinical characteristics also signal higher risk. For instance, patients younger than 40 are often classified as having “young breast cancer,” a group associated with more aggressive disease biology and greater treatment challenges. Age itself serves as an independent risk factor, and these patients often warrant intensified adjuvant therapy. Similarly, the presence of lymphovascular invasion (LVI) indicates strong metastatic potential and is a factor clinicians closely monitor.

In addition, genomic assays provide complementary information for risk assessment. In the NATALEE trial, certain node-negative patients with high recurrence risk identified by gene profiling were enrolled and also benefited from CDK4/6 inhibitor therapy.

In summary, high-risk stratification remains fundamental in guiding adjuvant intensified therapy for HR+/HER2− breast cancer. As research advances, further refinements in risk assessment and treatment personalization can be expected.

Part 3 — With Multiple CDK4/6 Inhibitors Showing Positive Adjuvant Results, How Should Clinicians Choose the Most Suitable One?

This is a key practical question that often arises in clinical settings — what might be called a “fortunate dilemma,” as physicians now have several effective therapeutic options. Each CDK4/6 inhibitor differs in mechanism, study population, efficacy data, and adverse event profile. Therefore, individualized drug selection requires careful consideration.In clinical practice, I first focus on the clinical trial population on which the drug’s approval is based. If a patient’s characteristics closely match the inclusion criteria of a particular study, that medication becomes my first-line choice. The second factor is safety and tolerability. Different drugs vary in side effects, which directly influence adherence and treatment persistence. The third is insurance coverage and accessibility — whether a drug is included in medical reimbursement policies can significantly impact affordability and continuity of care, making it a crucial factor in real-world decisions.

From the current evidence, abemaciclib was the first CDK4/6 inhibitor approved for adjuvant intensified therapy in HR+/HER2− early breast cancer. It has been included in national insurance coverage for both early and advanced settings. The drug is initiated at full dosage for a two-year treatment duration, and the supporting data are robust. For example, the 5-year invasive disease-free survival (IDFS) improvement reached 7.6%, and the upcoming 7-year IDFS and overall survival data are highly anticipated.

Notably, abemaciclib has demonstrated consistent benefits across multiple subgroups. In the recently reported subgroup of younger patients, the 5-year IDFS benefit was 10.3%. In Chinese cohorts, the 5-year IDFS improvement was 6.8%, while in patients who received neoadjuvant chemotherapy (accounting for 32% of monarchE participants), the 4-year IDFS gain was 9.1%, translating to a ~40% reduction in recurrence risk. These steady, durable, and consistent clinical results greatly reinforce our confidence in this drug.

Overall, treatment for HR+/HER2− breast cancer has made remarkable progress in recent years. Therapeutic options continue to expand, and long-term patient outcomes are steadily improving. With the addition of CDK4/6 inhibitors in adjuvant settings, treatment strategies have become more precise and diversified. In clinical decision-making, we now consider not only pathological and molecular risk factors but also treatment tolerance, adherence, and reimbursement coverage — all of which are essential for tailoring optimal therapy to each patient.

This comprehensive approach enhances both the scientific rigor and patient-centeredness of treatment decisions. Looking ahead, as more real-world evidence and long-term follow-up data become available, our understanding of CDK4/6 inhibitors will deepen further, optimizing their use across diverse patient populations. We look forward to continuing progress in precision medicine, bringing more durable and meaningful survival benefits to patients with HR+/HER2− breast cancer.

Professor Juliang ZhangDepartment of Breast, Thyroid, and Vascular SurgeryXijing Hospital, Air Force Medical University.