Editor’s Note: The "Northern Breast Cancer Salon Annual Progress Review" was held from January 3 to 5, 2025, in Beijing. The conference comprehensively reviewed the latest advances in the diagnosis, treatment, and research of breast cancer over the past year, in-depth discussions on the latest research findings for different breast cancer subtypes, and their impact on clinical practice. The meeting also focused on the updates of the CSCO BC guidelines, providing scientific guidance for clinical practice in breast cancer. Dr. Jin Yang from The First Affiliated Hospital of Xi'an Jiaotong University presented a report on the "Advances in Endocrine Therapy for Early Breast Cancer," and afterward, he was invited by Oncology Frontier to provide an in-depth introduction and outlook on precision treatment strategies for early breast cancer endocrine therapy.Oncology Frontier: Could you briefly summarize the important advances in endocrine therapy for early breast cancer in 2024?
Dr. Jin Yang: Overall, the progress in endocrine therapy for HR+/HER2- early breast cancer in 2024 can be described as “seeking new breakthroughs within precision.” We witnessed positive explorations in neoadjuvant therapy for HR+/HER2- early breast cancer patients, as well as investigations into novel treatment models. In postoperative adjuvant therapy, there was further refinement in endocrine therapy for premenopausal populations. For example, the RESPONDX study on identifying populations for precision endocrine treatment and the in-depth analysis of invasive lobular carcinoma in the SOFT&TEXT clinical trials were noteworthy. Additionally, 2024 focused on the use of CDK4/6 inhibitors for adjuvant therapy in high-risk HR+/HER2- early breast cancer patients, with key updates such as the 4-year follow-up data from the NATALEE study, subgroup analyses and translational clinical research from the monarchE trial, as well as the latest results from the 6-year survival follow-up in the OlympiA study.
Oncology Frontier: The use of CDK4/6 inhibitors in adjuvant therapy for early breast cancer has gained increasing attention. Based on the results of the NATALEE trial, can we expect major changes in the adjuvant treatment strategies for HR+/HER2- early breast cancer patients? Besides CDK4/6 inhibitors, what other new endocrine treatment drugs or strategies have shown potential in HR+ early breast cancer treatment in 2024?
Dr. Jin Yang: The use of CDK4/6 inhibitors in postoperative adjuvant therapy for early HR+/HER2- breast cancer undoubtedly provides an effective treatment strategy for high-risk early HR+/HER2- breast cancer populations. Abemaciclib was the first CDK4/6 inhibitor explored in adjuvant intensification therapy. The monarchE trial carefully selected a highly high-risk patient population and achieved positive results. Currently, multiple subgroup analyses of the monarchE study have been published, including genomic and transcriptomic analyses of primary tumors and the prognostic value of ctDNA detection in the monarchE study for high-risk early breast cancer adjuvant therapy.
Particularly at the 2024 ASCO conference, ctDNA detection data revealed that ctDNA could effectively identify patients with a high risk of recurrence and help guide prognosis management to some extent. However, we found that in the high-risk group, the proportion of patients who underwent ctDNA testing was not very high. Therefore, there still exists an unmet clinical need among these patients. It is worth noting that, in the baseline ctDNA positive and negative populations, the overall prognosis of patients differed by four times. In the continued dynamic monitoring of ctDNA, we found that patients who converted from negative to positive or remained positive had a very poor prognosis, indicating that we need to explore new adjuvant intensification treatment strategies for these patients in the future.
The NATALEE trial is a representative clinical trial for postoperative adjuvant intensification therapy. The 4-year iDFS data from the NATALEE study were updated at the 2024 ESMO conference, showing that the combination of ribociclib and endocrine therapy continues to provide therapeutic benefits compared to the control group. The absolute benefit of iDFS increased from 3.1% at 3 years to 4.9% at 4 years (88.5% vs. 83.6%, HR=0.715, P<0.0001), with a consistent benefit trend observed across all subgroups of patients.
This suggests that ribociclib, as the second drug to be explored for postoperative adjuvant intensification therapy, provides iDFS benefits for more high-risk early breast cancer patients as the NATALEE study follows up. Unlike the monarchE trial, the NATALEE study enrolled a broader patient population, including all stages from IIA to IIIC, with specific requirements for T2N0 patients (G3 or G2 with Ki-67 ≥20% or genomic high-risk). Of the study participants, 28% were N0 patients, with 20% from stages IIA and IIB. The 4-year DDFS data from the NATALEE study, presented at the 2024 SABCS conference, showed that ribociclib-based adjuvant intensification therapy significantly benefited patients in terms of DDFS (HR=0.715, 95% CI: 0.604-0.847, P<0.0001). This gives us more confidence because, after DDFS benefits, the likelihood of OS benefits is higher, and we look forward to the early release of OS data from this study.
Looking back at the past year, ribociclib has made continuous progress in the treatment of early breast cancer patients. On March 21, 2024, the NATALEE study’s full text was published in the New England Journal of Medicine (NEJM). Based on the results of the NATALEE study, ribociclib received FDA approval in September 2024, in combination with aromatase inhibitors (AIs) for adjuvant therapy in high-risk HR+/HER2- stage II and III early breast cancer patients, including some patients with lymph node-negative (N0) disease. In October, the NCCN guidelines were updated to incorporate ribociclib with AIs as a first-line adjuvant therapy option (Category 1 recommendation). In November, the European Medicines Agency (EMA) formally approved ribociclib combined with endocrine therapy for adjuvant therapy in high-risk HR+/HER2- early breast cancer patients in stages II-III, including all N1 and N0 patients with high-risk factors. This has brought more hope to the treatment of high-risk early breast cancer patients.
The clinical features, pathological parameters, and multi-gene testing data of different patients vary. In clinical treatment, we comprehensively consider data from various aspects to make treatment decisions. Both the monarchE and NATALEE clinical trials targeted early HR+/HER2- breast cancer patients. Although the enrolled patient populations, treatment durations, and types of CDK4/6 inhibitors used differ, they share two key findings: both achieved iDFS benefits, and both treatment groups showed continued benefits after stopping therapy, maintaining a relatively good quality of life. Based on the results of these two studies, we can confirm that CDK4/6 inhibitors for adjuvant intensification therapy have already established their role in high-risk early HR+/HER2- breast cancer patients, and this benefit has now extended to the intermediate- and high-risk groups. Therefore, we will continue to apply this therapeutic strategy in clinical practice. Furthermore, as the characteristics of the enrolled populations in these two studies are not fully consistent, longer follow-up is needed to observe disease progression patterns and OS benefits in these groups. At the same time, these groups still face new challenges when recurrence occurs after adjuvant intensification therapy.
Oncology Frontier: The SOLTI VALENTINE study, presented at the 2024 SABCS conference, showed that HER3-DXd has good efficacy in HR+/HER2- early breast cancer. What is your evaluation of this study? What advantages do you see in HER3-DXd as an innovative treatment compared to traditional therapies?
Dr. Jin Yang: For HR+/HER2- early breast cancer, previous research mainly focused on the neoadjuvant chemotherapy field. With the application of CDK4/6 inhibitors in adjuvant therapy, the combination of CDK4/6 inhibitors and endocrine therapy has become a new research focus for HR+/HER2- early breast cancer. At the 2024 SABCS conference, we also saw the addition of HER3-DXd. The SOLTI VALENTINE study results showed that the HER3-DXd monotherapy group, HER3-DXd combined with endocrine therapy group, and the chemotherapy group had no significant differences in pCR and ORR.
However, a closer analysis of the reduction of Ki67 on Day 1 of Cycle 2 (C2D1) and the tissue samples from the surgery showed that the HER3-DXd monotherapy and HER3-DXd plus endocrine therapy groups had a significantly better Ki67 reduction compared to the chemotherapy group. In addition, the changes in PAM50 risk scores (from high/medium-risk at baseline to low-risk at surgery) and changes in PAM50 subtypes (from Luminal B to Luminal A/Normal-like with less proliferation at surgery) are also noteworthy. Additionally, in terms of adverse reactions, the HER3-DXd monotherapy and HER3-DXd plus endocrine therapy groups had fewer side effects compared to the chemotherapy group.
Professor Zhao Zhiming’s team at Fudan University’s Shanghai Cancer Center also conducted relevant research. The FASCINATE-N study, led by Professor Zhao, focuses on early and locally advanced patients in a precision neoadjuvant treatment platform guided by the “Fudan Typing” approach, with HR+/HER2- (SNF), TN (FUSCC), and HER2+ three cohorts. The study aims to evaluate treatment efficacy in different subtypes of breast cancer. Based on the precise SNF breast cancer typing, we also saw that ADC (antibody-drug conjugate) drugs brought therapeutic efficacy to HR+/HER2- advanced breast cancer patients.
These studies offer the following insights: 1) There is still room for exploration of ADC drugs in the treatment of HR+ early breast cancer. 2) ADC drugs have considerable potential for exploration in populations insensitive to neoadjuvant endocrine therapy and chemotherapy, but their exploration should be based on precise identification of the relevant research cohorts. 3) Compared to chemotherapy, ADC drugs are safer. In summary, ADC drugs also have potential in HR+/HER2- early breast cancer patients.
Dr. Jin Yang
Director of the Cancer Center, First Affiliated Hospital of Xi’an Jiaotong University Director of the Precision Oncology Research Center MD, Chief Physician/Professor, Doctoral Supervisor Vice Chairman of the Oncology Drug Clinical Research Committee, China Medical Education Association Standing Committee Member of the Breast Cancer Professional Committee, Chinese Research Hospital Association Committee Member of the Breast Cancer Professional Committee, Chinese Anti-Cancer Association Committee Member of the Breast Oncology Committee, Chinese Medical Doctor Association Vice Chairman of the Breast Oncology Group of the Tumor Biomarker Professional Committee, Chinese Anti-Cancer Association Standing Committee Member of the Medical Oncology Branch, Shaanxi Medical Association Chairman of the Anti-Cancer Drug Professional Committee, Shaanxi Anti-Cancer Association Chairman of the Cancer Rehabilitation and Precision Oncology Committee, Xi’an Cancer Recovery Association Shaanxi Provincial Labor Model Award Author of more than 50 papers, 47 of which are indexed in SCI Leader of five projects funded by the National Natural Science Foundation of China Recipient of two Shaanxi Provincial Science and Technology Progress Awards and two University Science and Technology Progress Awards
