Editor's Note: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have brought transformative breakthroughs to the clinical treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer patients. The combination of CDK4/6 inhibitors and endocrine therapy has become the standard regimen for HR+/HER2- locally advanced and metastatic breast cancer. In the adjuvant treatment phase for early-stage breast cancer, CDK4/6 inhibitors have also shown positive results and have been approved for indications. The 2024 ASCO conference presented multiple advancements in the adjuvant treatment of HR+/HER2- early-stage breast cancer with CDK4/6 inhibitors. At the recent 5th Comprehensive Cancer Treatment Academic Conference of the Xinghai Medical Forum, Oncology Frontier invited Professor Hong Hu from Shenzhen People's Hospital, and Professor Yuntao Wei from Liaoning Cancer Hospital & Institute to elaborate on and discuss the research progress of CDK4/6 inhibitors in adjuvant therapy for HR+ early-stage breast cancer.

Review of Key Research Advances in CDK4/6 Inhibitors for Early HR+ Breast Cancer

Professor Hong Hu: The PENELOPE-B, PALLAS, monarchE, and NATALEE studies compared the efficacy of CDK4/6 inhibitors combined with endocrine therapy versus endocrine therapy alone for adjuvant treatment of HR+/HER2- early-stage breast cancer. Currently, the monarchE and NATALEE studies have yielded positive results, altering the clinical practice for early HR+ breast cancer, while the PENELOPE-B and PALLAS studies did not show statistical differences.

For early-stage HR+/HER2- breast cancer patients, previous treatment options were typically limited to intensified endocrine therapy or chemotherapy. The monarchE study provided a new treatment strategy. For high-risk early-stage HR+/HER2- breast cancer patients with positive lymph nodes, 2 years of abemaciclib (150 mg twice daily) combined with endocrine therapy significantly improved invasive disease-free survival (iDFS) compared to endocrine therapy alone. At the 2023 ESMO conference, the monarchE study released milestone 5-year data, with absolute benefits in iDFS and distant relapse-free survival (DRFS) reaching 7.6% and 6.7%, respectively. As most iDFS events were DRFS events, DRFS also showed continuous benefits, reducing the risk of distant recurrence or death by 32.5%. The subgroup treatment effect pattern (STEPP) analysis showed consistent iDFS benefits with abemaciclib combination therapy regardless of patients’ ER, PR, or Ki-67 expression levels, particularly in high-risk subgroups with Ki-67≥20% and ER+/PR-. iDFS increased by 9% and 11.3% in these subgroups compared to the control group, providing better outcomes for a significant portion of high-risk patients.

The NATALEE study is another landmark study aimed at a broad population of II-III stage HR+/HER2- early breast cancer patients, comparing the efficacy and safety of 400 mg ribociclib combined with endocrine therapy versus endocrine therapy alone. As of the second interim analysis, ribociclib plus NSAI significantly reduced the risk of invasive disease, recurrence, or death by 25% compared to NSAI alone. The 3-year iDFS rates were 90.4% for the ribociclib+NSAI group and 87.1% for the NSAI alone group. Ribociclib significantly reduced the risk of distant metastasis or death by 26% and the risk of disease recurrence or death by 28%. Compared to the monarchE study, the NATALEE study included node-negative (N0) patients, demonstrating excellent efficacy benefits in a broader population.

Efficacy Data and Population Selection for the N0 Subgroup in the NATALEE Study Reported at the 2024 ASCO Conference

Professor Yuntao Wei: For HR+/HER2- stage II-III early breast cancer patients, data show a 5-year recurrence rate of 15% to 30% overall, with a 10-year recurrence rate as high as 20% to 58%. For the N0 population, the 5-year and 10-year recurrence rates are approximately 10% and 20%, respectively. These data highlight the importance of implementing intensified treatment, particularly combined endocrine-targeted therapy, to further reduce recurrence risk and improve prognosis for these patients.

The recurrence in the N0 population is more likely related to endocrine resistance caused by tumor heterogeneity rather than directly from lymph node involvement, as seen in patients with lymph node involvement. It is worth noting that the real-world recurrence rate may be higher than shown in clinical studies. Therefore, endocrine intensified treatment, including strategy adjustments for the N0 population, holds significant clinical value and practical importance, similar to those with positive lymph nodes.

CDK4/6 inhibitors have performed well in treating HR+/HER2- advanced breast cancer, and their use in adjuvant intensified treatment for early breast cancer patients has also shown good efficacy. The NATALEE study, as one of the positive clinical studies, focuses not entirely on prolonging the duration of endocrine therapy but more on implementing intensified treatment strategies in specific patient groups. The N0 subgroup, a non-predefined subgroup, includes T2N0 (stage IIA with G3 or G2, Ki-67≥20% or high genomic risk), T3N0 (stage IIB), and T4N0 (stage IIIB) patients, excluding T1N0 patients. Data reported at the 2024 ASCO conference showed that the experimental group (ribociclib combined with endocrine therapy) had improvements in iDFS, DDF, and DRFS compared to the control group (endocrine therapy alone). These data indicate that for the N0 population, combined CDK4/6 inhibitor intensified therapy can reduce recurrence risk and further improve prognosis.

However, patient selection requires strict criteria, especially for the N0 subgroup, which includes T2 and above meeting specific conditions considered high-risk. Although this may differ from clinical practice assessments of high recurrence risk, existing data show the potential to reduce recurrence risk and have significant clinical guidance value. Furthermore, more precise identification of which patients can benefit the most requires further clinical data and research support, including the exploration and judgment of biomarkers. These efforts will provide more accurate clinical guidance, helping doctors formulate more precise treatment plans.

Professor Hong Hu

• Head of Breast Surgery, Doctor of Surgery at Shenzhen People’s Hospital
• Member of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association
• Standing Member of the Breast Tumor Integrated Rehabilitation Professional Committee of the Chinese Anti-Cancer Association
• Member of the Youth Group of the Breast Tumor Branch of the Chinese Medical Association
• Member of the Youth Expert Committee of the Chinese Society of Clinical Oncology (CSCO)
• Vice Chairman of the Breast Cancer Prevention and Treatment Professional Committee of the Guangdong Preventive Medicine Association
• Member of the Breast Disease Branch of the Guangdong Medical Association
• Standing Member of the Breast Cancer Personalized Diagnosis and MDT Professional Committee of the Beijing Cancer Prevention Society
• Vice Chairman of the Youth Committee of the Breast Disease Branch of the Shenzhen Medical Association
• Editorial Board Member of Clinical Breast Cancer
• Visiting Scholar at Lynn Sage Breast Center, Memorial Hospital of Northwestern University, USA
• Visiting Scholar at the Breast Plastic Surgery Department of Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo

Professor Yang Zhang

• Associate Chief Physician/Associate Professor of Breast Surgery at the Second Affiliated Hospital of Dalian Medical University
• Doctor of Medicine, Master’s Supervisor
• Chief Cosmetic Physician
• Visiting Scholar at Stanford University, USA
• Member of the Breast Cancer Professional Committee of the Liaoning Society for Cell Biology
• Secretary and Member of the Oncology Surgery Treatment and Translational Medicine Professional Committee of the Liaoning Society for Cell Biology
• Member of the Breast Tumor Precision Treatment and Cytology Research Professional Committee of the Liaoning Society for Cell Biology
• Member of the Tumor Minimally Invasive Treatment and Tissue Reconstruction Professional Committee of the Liaoning Society for Cell Biology
• Member of the Tumor Minimally Invasive Treatment Professional Committee of the Chinese Anti-Cancer Association
• Corresponding Editorial Board Member of the Chinese Journal of Endocrine Surgery