Xinghai Forum: Professors Yang Zhang and Kejing Zhang Discuss CDK4/6 Inhibitors in Adjuvant Therapy for HR+ Breast Cancer

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 Yang Zhang from The Second Hospital of Dalian Medical University, Professor Kejing Zhang from Xiangya Hospital of Central South University to elaborate on and discuss the research progress of CDK4/6 inhibitors in adjuvant therapy for HR+ early-stage breast cancer.

Prognostic Value of ctDNA Testing in MonarchE Trial Patients and Its Value in Early Breast Cancer Monitoring, Treatment Guidance, and Prognostic Judgment

Professor Kejing Zhang: At the 2024 ASCO conference, progress data on ctDNA testing were released for multiple cancers, including breast cancer, urothelial carcinoma, lung cancer, and colorectal cancer. In the field of breast cancer, although the therapeutic significance of ctDNA testing is still being explored, preliminary data show its potential in predicting patient prognosis.

The MonarchE study results indicate that combining intensified endocrine therapy and CDK4/6 inhibitors significantly improves the prognosis of high-risk early HR+/HER2- breast cancer patients. However, clear biomarker analyses for identifying the most suitable population for this intensified treatment are still lacking.

To explore the prognostic value of ctDNA testing in MonarchE trial patients, researchers analyzed samples from a specific patient subgroup (n=1397). Compared to the overall study population, this subgroup had a higher iDFS event rate (31% vs 18%). Of these patients, 65% (n=910) successfully underwent ctDNA testing. Notably, only a small fraction (70 patients) had detectable ctDNA at baseline.

Among these 910 patients, the iDFS event rate reached 27%. Importantly, 87% of ctDNA-positive patients experienced iDFS events, a much higher rate than ctDNA-negative patients. This finding suggests that ctDNA-positive patients have a poorer prognosis, requiring focused attention and treatment adjustments. Patients with persistent ctDNA positivity had even worse outcomes, with iDFS below 10%, while those who turned negative after treatment had a slightly better prognosis. Additionally, ctDNA-positive patients were more likely to develop distant metastases, while ctDNA-negative patients were more prone to local recurrence, indicating the value of ctDNA testing in predicting metastatic risk.

However, current research does not reveal the proportion of ctDNA-positive patients who turn negative after CDK4/6 inhibitor adjuvant intensified therapy. Future studies might further explore the role of ctDNA testing in guiding treatment decisions and whether additional therapeutic measures are needed to improve patient prognosis.

Overall, ctDNA testing shows some clinical application value in predicting the prognosis of breast cancer patients, whether triple-negative or HR+. For ctDNA-positive patients, more active and precise treatment strategies are needed. As research progresses, we look forward to better utilizing ctDNA testing to guide breast cancer patient treatment.

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Scientific Monitoring and Management of Adverse Events in CDK4/6 Inhibitor Adjuvant Therapy

Professor Yang Zhang: With the publication of clinical research data at the 2024 ASCO conference, including the inclusion of N0 patients in CDK4/6 inhibitor treatment, the importance of CDK4/6 inhibitors in adjuvant intensified therapy for early HR+/HER2- breast cancer is further highlighted. As the use of CDK4/6 inhibitors becomes widespread, the management of adverse reactions is increasingly important. The 2022 consensus on managing adverse reactions associated with breast cancer CDK4/6 inhibitors provides more guidance for clinical practice.

Common adverse reactions to CDK4/6 inhibitors include bone marrow suppression, gastrointestinal adverse reactions, liver function abnormalities, and skin and subcutaneous tissue reactions. To ensure treatment efficacy and quality of life for patients, clinicians need to fully communicate with patients at the beginning of treatment, informing them in advance of possible adverse reactions and emphasizing the importance of smoothly transitioning through the first 2 to 3 treatment cycles.

For hematological toxicity, hematological tests are typically performed at the start of each treatment cycle, on day 15 of the first two cycles, and whenever clinically indicated. Neutropenia during treatment is often managed by temporarily discontinuing the drug to allow bone marrow recovery. For patients with grade 3 febrile neutropenia or grade 4 neutropenia, granulocyte colony-stimulating factor (G-CSF) may be considered for symptomatic treatment. For grade 1-2 neutropenia, treatment continues with close monitoring, and no dose adjustment is needed. For grade 3 neutropenia, the first occurrence requires drug suspension, weekly monitoring of complete blood counts until recovery to grade 1-2, then resuming the next cycle at the same dose. If intolerable at the current dose, the drug is suspended, blood counts are monitored weekly until recovery to grade 1-2, and the next cycle begins at a reduced dose. Grade 3 febrile neutropenia or grade 4 neutropenia warrants drug suspension until recovery to grade 1-2, with G-CSF considered for symptomatic treatment and resuming the next cycle at a reduced dose. Besides neutropenia, other common hematological adverse reactions include leukopenia, thrombocytopenia, and lymphopenia, managed similarly, with most reactions reversible upon drug suspension. Most patients can smoothly transition through the initial phase and continue subsequent treatment.

Diarrhea is the most common gastrointestinal adverse reaction to CDK4/6 inhibitors. Adequate patient education helps manage diarrhea, guiding patients to record bowel movement frequency and stool characteristics for early detection and timely medical intervention. Mild to moderate simple diarrhea requires increased fluid intake, dietary adjustments, small frequent meals, and avoiding irritating foods. Loperamide is the standard treatment for diarrhea, initiated at the first sign of loose stools, or other antidiarrheal drugs and probiotics may be used.

QT interval prolongation, although rare, warrants high vigilance. Symptoms like dizziness, fainting, or arrhythmias require immediate medical attention as they could lead to severe or fatal outcomes.

Venous thromboembolism (VTE) is a serious adverse reaction during CDK4/6 inhibitor treatment. Continuous monitoring for symptoms and signs of pulmonary embolism, such as shortness of breath, hypoxia, chest pain, rapid breathing, or increased heart rate, is essential. If these symptoms occur, anticoagulant therapy is initiated, and drug discontinuation is considered. After symptom improvement, the treatment plan is reassessed, possibly including dose reduction or resumption at the original dose.

Besides these adverse reactions, some patients may experience other less obvious reactions, which can often be improved with appropriate symptomatic treatment.

It is noteworthy that the use of CDK4/6 inhibitors includes a significant number of elderly patients, who may have a higher risk of adverse reactions, particularly grades 3 to 4, such as thrombosis and interstitial pneumonia. These reactions could have a greater impact on the quality of life of elderly patients, necessitating more attention in future treatment.

• Associate Chief Physician, Master’s Supervisor at Xiangya Hospital Breast Surgery Department
• Postdoctoral Fellow at Hangzhou Institute of Medicine, Chinese Academy of Sciences
• Member of the Youth Group of the Breast Cancer Branch of the Chinese Medical Association
• Standing Member of the Yangtze River Academic Breast Cancer Alliance
• Standing Member of the Breast Cancer Professional Committee of the Hunan International Medical Promotion Association
• Member of the Breast Cancer Professional Committee of the Hunan Anti-Cancer Association
• Member of the Breast and Thyroid Health Management Professional Committee of Hunan Province
• Young Editorial Board Member of the Chinese Journal of General Surgery

• Chief Physician, Director of the Fourth Ward of Breast Surgery at Liaoning Cancer Hospital
• Member of the Breast Disease Professional Committee of the Chinese Medical Education Association
• Member of the Beijing Breast Disease Prevention and Treatment Association
• Member of the Breast Reconstruction and Cosmetic Surgery Professional Committee of the Liaoning Life Science Association
• Member of the Breast Cancer Professional Committee of the Liaoning Society for Cell Biology