Editor’s Note:
The monarchE study is a randomized, open-label, multicenter Phase III clinical trial designed to compare the efficacy and safety of abemaciclib combined with endocrine therapy versus endocrine therapy alone in HR+, HER2-high-risk early-stage breast cancer patients. Since the disclosure of relevant data in March 2020, the study results have been updated multiple times, establishing the standard position of abemaciclib combined with endocrine therapy. At the 2023 ESMO Congress, Professor Nadia Harbeck, the lead investigator of the monarchE study from the University of Munich, Germany, announced the milestone data results of the 5-year follow-up. In this regard, Professor Zhimin Shao, the lead investigator of the monarchE study, director of the Institute of Oncology and Institute of Breast Cancer Research at Fudan University, and director of the Department of Surgery at Fudan University Affiliated Tumor Hospital, provided an introduction and interpretation of the monarchE study results.
Distinguished Professor of the Ministry of Education’s Changjiang Scholars Program, National Distinguished Youth, Distinguished Professor of Fudan University. Currently serving as the director of the Institute of Oncology and the Institute of Breast Cancer Research at Fudan University, director of the Department of Surgery, and honorary chairman of the Breast Cancer Committee of the Chinese Anti-Cancer Association. He is also the director of the Targeted Therapy Committee of the Chinese Anti-Cancer Association, a council member of the Chinese Society of Clinical Oncology (CSCO), deputy director of the Oncology Branch of the Chinese Medical Association, chairman of the Breast Cancer Committee of the Clinical Precision Medicine Professional Committee of the Chinese Physicians Association, vice chairman of the Breast Cancer Committee of the Shanghai Anti-Cancer Association, honorary chairman of the Oncology Specialized Committee of the Shanghai Medical Association, and the 8th Chairman of the Asian Breast Cancer Association. He is mainly engaged in clinical and basic research on breast cancer, establishing early screening and diagnosis and treatment processes suitable for the Chinese population, and defining the “Fudan subtype” and precise treatment strategies for triple-negative breast cancer. He has published nearly 500 papers on breast cancer research, including over 400 SCI-indexed papers, authored 10 monographs, and served as the chief editor of the “Chinese Journal of Cancer.” He has received numerous awards, including the second prize of the National Science and Technology Progress Award, the first and second prizes of the Ministry of Education’s Science and Technology Progress Award, the first prize of the Ministry of Health’s Science and Technology Progress Award, and the first, second, and third prizes of the Shanghai Science and Technology Progress Award.
HR+, HER2- Early Breast Cancer Diagnosis and Treatment Urgently Need Optimization
It is estimated that 90% of breast cancers are diagnosed at an early stage. Among them, HR+, HER2- breast cancer is the most common subtype, accounting for 60-70% of newly diagnosed breast cancer cases each year [1,2]. Endocrine therapy has been clinically proven for many years and, due to its widespread drug availability and good patient compliance, has become the cornerstone of comprehensive treatment for HR+, HER2- early breast cancer. However, approximately 30% of high-risk patients may experience recurrence and metastasis [3], progressing to incurable metastatic disease. Moreover, for these high-risk breast cancer patients, the risk of recurrence within 5 years after surgery is three times higher than that of non-high-risk patients [4]. Therefore, there is a clinical need for innovative treatment approaches to reduce the risk of recurrence for these patients.
monarchE 5-Year Data Update, Continued Reduction in Early Breast Cancer Recurrence Risk
monarchE is the first clinical study to obtain positive results in adjuvant treatment of HR+, HER2-high-risk early breast cancer. The study focused on HR+, HER2-high-risk early breast cancer patients and explored the clinical value of abemaciclib combined with endocrine therapy in adjuvant treatment. High recurrence risk was defined as pathologically positive axillary lymph nodes (ALN) ≥4 or 1-3 positive ALNs with at least one of the following high-risk features: primary tumor ≥5cm, histological grade 3, Ki-67 ≥20%.
The study included 5637 patients from more than 600 centers in 38 countries, randomly assigned in a 1:1 ratio to the abemaciclib combined with endocrine therapy group or the endocrine therapy alone group, with a treatment period of 2 years. All patients continued to receive adjuvant endocrine therapy for at least 5 years based on clinical indications. The primary endpoint was invasive disease-free survival (IDFS, STEEP criteria), and key secondary endpoints included IDFS in the high Ki-67 (≥20%) population, distant recurrence-free survival (DRFS), overall survival (OS), safety, patient-reported outcomes, and pharmacokinetics.
The data presented at the ESMO Congress are based on pre-planned analyses of 5-year results. As of July 3, 2023, the median follow-up time was 4.5 years (54 months). All patients had completed the course of abemaciclib, with over 80% of patients followed for at least two years after treatment.
The results showed that in the intention-to-treat (ITT) population, abemaciclib combined with endocrine therapy continued to provide benefits: compared to endocrine therapy alone, patients receiving abemaciclib combined with endocrine therapy had an absolute 5-year IDFS benefit of 7.6%, with a significantly reduced risk of IDFS events by 32% (83.6% vs. 76.6%, HR 0.680, 95% CI: 0.599-0.772); the 5-year DRFS benefit was 6.7%, with a 32.5% reduction in the risk of DRFS events (HR 0.675, 95% CI: 0.588-0.774).
The data showed that 2 years of adjuvant therapy with abemaciclib significantly reduced the risk of metastasis. The number of patients in the endocrine therapy alone group who experienced metastasis and survived was nearly twice that of the abemaciclib combined with endocrine therapy group (n = 269 vs. 138), suggesting that abemaciclib provides more possibilities for clinical cure in HR+, HER2-high-risk early breast cancer patients.
Subgroup analysis showed consistent IDFS benefit trends in all subgroups, including menopausal status, histological grade, previous chemotherapy, and the number of positive lymph nodes, consistent with previous reported results.
In terms of safety, the updated data is consistent with previous results, with similar rates of any-grade treatment-emergent adverse events (TEAE), ≥3-grade TEAE, and severe adverse events between the abemaciclib combined with endocrine therapy group and the endocrine therapy alone group.
Professor Zhimin Shao’s Comments
HR+, HER2- early breast cancer generally has a better prognosis, and although endocrine therapy is effective, high-risk patients still have a higher risk of recurrence. Therefore, reducing the risk of disease recurrence and metastasis is a top priority for optimizing the diagnosis and treatment of these patients. In recent years, various treatment modalities, such as CDK4/6 inhibitors, immunotherapy, ADC, and others, have been explored to further optimize the diagnosis and treatment of HR+, HER2-high-risk early breast cancer, improving the long-term prognosis of patients. Among them, the targeted combined endocrine therapy model represented by CDK4/6 inhibitors has pioneered a new pattern in the diagnosis and treatment of HR+, HER2-high-risk early breast cancer.
The monarchE study has first confirmed that CDK4/6 inhibitors can significantly reduce the risk of disease recurrence or metastasis in HR+, HER2-high-risk early breast cancer patients, representing a significant breakthrough in breast cancer diagnosis and treatment. The 5-year mark is an important time point for clinically assessing the prognosis of cancer patients, and patients who remain recurrence-free for 5 years after early tumor surgery often have a more optimistic long-term prognosis. The milestone significance of this updated 5-year efficacy data demonstrates the robust and sustained IDFS and DRFS benefits of abemaciclib in treating HR+, HER2- early breast cancer patients, further solidifying the standard adjuvant treatment position of abemaciclib and providing more opportunities for clinical cure for this patient population.
Although the monarchE study has not observed an overall survival (OS) benefit at present, the 5-year data update has further confirmed that 2 years of adjuvant therapy with abemaciclib significantly reduces the risk of metastatic recurrence. It is believed that with longer follow-up, the IDFS and DRFS benefits are expected to translate into OS benefits.
Currently, regulatory agencies such as the NMPA and FDA have approved abemaciclib combined with endocrine therapy for adjuvant treatment of HR+, HER2-, lymph node-positive high-risk early breast cancer patients, and this treatment is also listed as the preferred treatment option in authoritative guidelines at home and abroad. It is believed that abemaciclib will benefit more and more clinical patients, and more real-world data will further confirm its effectiveness.
Based on the breakthrough progress achieved in the monarchE study, there are still some challenges to be explored in the future for HR+, HER2- early breast cancer. With the continuous exploration and understanding of the molecular biology characteristics of breast cancer, precision treatment based on molecular subtyping has become an inevitable trend in the future development of breast cancer. For the most common type – HR+, HER2- breast cancer, there is increasingly more evidence in evidence-based medicine that it also has molecular heterogeneity. Our team’s recent research shows that HR+, HER2- breast cancer can be subdivided into four subtypes, and these four subtypes have certain differences in biological behavior and clinical characteristics, and they also have different efficacy for different treatment strategies. This has important guiding significance for clinical treatment, and in the future, “umbrella trials” will be needed to further achieve more precise diagnosis and treatment to maximize patient benefits.
