Editor’s Note: The "Northern Breast Cancer Salon Annual Progress Review" was held in Beijing from January 3 to 5, 2025, providing a comprehensive overview of the latest developments in the diagnosis, treatment, and research of breast cancer over the past year. Dr. Shusen Wang from the Sun Yat-sen University Cancer Center presented a summary of the advances in endocrine therapy for advanced breast cancer in 2024. After the conference, Oncology Frontier invited Professor Wang for an in-depth interpretation of these significant developments.

Oncology Frontier: Could you briefly summarize the major advances in endocrine therapy for advanced breast cancer in 2024?

Dr. Shusen Wang: The field of endocrine therapy for hormone receptor-positive (HR+) advanced breast cancer saw several significant breakthroughs in 2024. These can be categorized as follows:

Reassessing the Role of CDK4/6 Inhibitors + Endocrine Therapy (ET) in First-Line Treatment

For HR+ advanced breast cancer patients with aggressive disease, such as those with visceral metastases or rapid progression, chemotherapy has been a widely used treatment option. However, studies presented at the 2024 ESMO and SABCS conferences, including the ABIGAIL and PADMA trials, explored the positioning of chemotherapy versus CDK4/6 inhibitors + ET as first-line treatments.

The ABIGAIL study demonstrated that in HR+/HER2- advanced breast cancer with aggressive features, abemaciclib + ET achieved a higher objective response rate (ORR) compared to paclitaxel followed by ET. Similarly, the PADMA study showed that in high-risk HR+/HER2- metastatic breast cancer (mBC) patients, palbociclib + ET significantly improved time to treatment failure (TTF) and PFS compared to single-agent chemotherapy (± maintenance ET). These findings, combined with data from the RIGHT Choice study, reaffirm the role of CDK4/6 inhibitors + ET as a standard treatment option, even in aggressive HR+ advanced breast cancer.

The SONIA study also challenged the timing of CDK4/6 inhibitors in first-line treatment. This Phase III trial, initiated in 2017, compared the efficacy and safety of CDK4/6 inhibitors + ET in first-line versus second-line settings. Patients were randomized 1:1 into two groups: one receiving CDK4/6 inhibitors + aromatase inhibitors (AIs) in the first line and fulvestrant upon progression, and the other receiving AIs in the first line and CDK4/6 inhibitors + fulvestrant in the second line.

Initial results, presented at the 2023 ASCO conference, were published in Nature in November 2024. With a median follow-up of 37.3 months, the study reported no statistically significant differences in second progression-free survival (PFS2) between the groups (31.0 vs. 26.8 months; HR = 0.87) or overall survival (OS: 45.9 vs. 53.7 months). Additionally, no quality-of-life improvements were observed.

These findings have implications for clinical practice and encourage a deeper evaluation of treatment strategies for HR+/HER2- advanced breast cancer. Despite the lack of significant differences in PFS2 or OS, the results do not undermine the standard role of CDK4/6 inhibitors + ET in first-line treatment. This is because the SONIA study compared second-line CDK4/6 inhibitors + fulvestrant with fulvestrant monotherapy, which is not aligned with current clinical practice. Furthermore, at the time of the study’s initiation, evidence for first-line CDK4/6 inhibitor use was limited. Now, with more robust data showing OS benefits from first-line CDK4/6 inhibitor + ET, the standard remains unchanged.

The study also highlighted the differences between first- and second-line use of CDK4/6 inhibitors + ET. First-line use incurs higher overall costs and results in more adverse events due to longer treatment durations. However, with improved management of side effects and increased accessibility of CDK4/6 inhibitors in China, adverse events have become less of a barrier in clinical practice. For patients with indolent disease who achieve prolonged remission, single-agent endocrine therapy remains an adequate option.

Our center, in collaboration with 12 research centers nationwide, conducted a Phase III trial comparing metronomic capecitabine + aromatase inhibitors (AIs) versus AIs alone as first-line treatment for HR+/HER2- advanced breast cancer. The study, published in Journal of Clinical Oncology (JCO) on January 2, 2025, demonstrated that metronomic capecitabine + AI significantly improved PFS and OS with good tolerability and safety. While the study began before the approval of CDK4/6 inhibitors for first-line treatment in China, it offers an alternative for patients who cannot access or tolerate CDK4/6 inhibitors or face financial constraints.

Ongoing research is investigating whether survival outcomes can be further improved by building on the CDK4/6 inhibitor + ET combination. The PI3K/AKT/mTOR (PAM) pathway is frequently mutated in breast cancer. The INAVO120 study suggests that combining inavolisib, a PI3K inhibitor, with palbociclib and fulvestrant improves PFS in patients with PIK3CA-mutated breast cancer. This promising strategy may further expand treatment options for HR+/HER2- advanced breast cancer.

Oncology Frontier: What role does the PI3K/AKT/mTOR pathway play in breast cancer treatment, and what were the key advancements in 2024?

Dr. Shusen Wang: The PI3K/AKT/mTOR (PAM) pathway plays a critical role in the development and progression of breast cancer. Genetic alterations in this pathway are highly prevalent in breast cancer, with abnormal activation of PI3K and AKT or loss of PTEN leading to dysregulated PAM signaling. Such abnormalities are associated with resistance to endocrine therapy, chemotherapy, and targeted therapies, making the development of drugs targeting the PAM pathway a major focus over the past decade. In recent years, new findings have emerged in this area.

The mTOR inhibitor everolimus has been approved for HR+/HER2- advanced breast cancer for several years. However, the publication of the INAVO120 trial results demonstrated that combining the PI3Kα inhibitor inavolisib with palbociclib and fulvestrant significantly improved progression-free survival (PFS) in HR+/HER2- advanced breast cancer patients. Similarly, the CAPItello-291 trial showed that the AKT inhibitor capivasertib, combined with fulvestrant, significantly improved PFS compared to placebo in HR+/HER2- advanced breast cancer patients (7.2 vs. 3.6 months; HR=0.60, P<0.001). In patients with AKT pathway alterations, the benefit was even greater (7.3 vs. 3.1 months; HR=0.50, P<0.001).

Over the past few years, drug development targeting the PAM pathway has achieved considerable success. I believe these therapies will soon be integrated into clinical practice, offering more treatment options for patients with PAM pathway alterations.

Oncology Frontier: What key developments or breakthroughs do you anticipate in the treatment of HR+ advanced breast cancer in the coming years? Additionally, what are your views on improving access and affordability for these treatments?

Dr. Shusen Wang: HR+/HER2- advanced breast cancer accounts for approximately 70% of breast cancer cases, making it the most common subtype. These patients generally respond well to endocrine therapy, and there are numerous endocrine agents and combination regimens currently available.

I am particularly optimistic about the therapeutic potential of oral SERDs (selective estrogen receptor degraders). Preliminary clinical results have shown promise for combinations like oral SERDs with CDK4/6 inhibitors. For example, the EMBER-3 study, presented at the 2024 SABCS conference, evaluated imlunestrant as an endocrine monotherapy and in combination with abemaciclib for HR+/HER2- advanced breast cancer. The results showed that imlunestrant + abemaciclib improved PFS in ESR1-mutant patients, as well as in those previously treated with CDK4/6 inhibitors or those with PI3K pathway alterations. These findings suggest that such combinations warrant further clinical exploration.

HR+/HER2- advanced breast cancer is a highly heterogeneous disease. Understanding its molecular biology and classifying different subtypes based on their biological characteristics will be crucial. Future advancements will likely focus on biomarker-driven individualized therapies.

In terms of drug accessibility, China has made remarkable progress over the past few decades. Both internationally and domestically developed drugs are increasingly accessible to Chinese patients. Additionally, affordability has improved significantly due to the inclusion of many new drugs in the national health insurance program. Negotiated price reductions and insurance reimbursements have substantially alleviated the financial burden on patients.

In summary, with ongoing efforts from the pharmaceutical industry and collaboration between healthcare professionals and government agencies, we will continue to refine patient selection to maximize the benefits of these therapies. I am confident that individualized treatment for HR+/HER2- advanced breast cancer will continue to advance, supported by improved affordability and accessibility.

About Dr. Shusen Wang

• Current Positions: Chief Specialist for Breast Cancer, Sun Yat-sen University Cancer Center Professor, Chief Physician, and Doctoral Supervisor
• Professional Affiliations: Member, Breast Cancer Quality Control Professional Committee, National Cancer Quality Control Center Member, Expert Committee for Breast Cancer Screening and Early Diagnosis and Treatment Guidelines, China Member, Expert Committee for Rational Use of Breast Cancer Drugs, National Health Commission Vice Chair, Breast Cancer Committee, Chinese Research Hospital Association Vice Chair, Endocrine Tumor Committee, Chinese Anti-Cancer Association Standing Member, Breast Cancer Committee, Chinese Anti-Cancer Association Standing Member, Breast Cancer Committee, Chinese Society of Clinical Oncology Chair, Chemotherapy Committee, Guangdong Anti-Cancer Association Chair, Breast Cancer Committee, Guangdong Thoracic Tumor Prevention and Research Association Vice Chair, Breast Cancer Committee, Guangdong Anti-Cancer Association Vice Chair, Breast Cancer Specialty Committee, Guangdong Medical Association