Editor’s Note: The 16th Shanghai Breast Cancer Symposium and Annual Meeting of the Shanghai Anti-Cancer Association Breast Cancer Committee, hosted by the Chinese Anti-Cancer Association Breast Cancer Professional Committee (CBCS) and the Shanghai Anti-Cancer Association, and organized by the Breast Cancer Professional Committee of the Shanghai Anti-Cancer Association, was held from December 20 to 21, 2024, in Shanghai. On the afternoon of December 21, the 2025 CBCS & CSOBO Breast Cancer Diagnosis and Treatment Guidelines and Standards (Essentials), known as the "Little Red Book," was officially released. Oncology Frontier invited Dr. Jian Zhang, a key member of the guideline development team and expert from Fudan University Shanghai Cancer Center, to discuss updates on medical treatments for various breast cancer subtypes in the new edition.

Oncology Frontier: The latest Little Red Book introduces significant updates in second-line and subsequent treatments for HR+/HER2- metastatic breast cancer (MBC). Could you share more details about these updates?

Dr. Jian Zhang:The release of the 2025 edition of the Little Red Book has garnered significant attention, particularly for its updates on treatment strategies for HR+/HER2- metastatic breast cancer (MBC). One of the major enhancements is the integration of more precise medication strategies, especially for patients previously treated with CDK4/6 inhibitors. We have incorporated advanced sequencing technologies to better guide future clinical practices.

This shift is driven by the anticipated release of several new drugs in 2025, including PI3K inhibitors, AKT inhibitors, mTOR inhibitors, and inhibitors targeting ESR1 mutations. During the guideline revision, we made corresponding updates to second-line and later-line treatment strategies. For patients who have not received CDK4/6 inhibitors and experienced failure with nonsteroidal (or steroidal) aromatase inhibitors (AIs), the recommendation for using steroidal (or nonsteroidal) AIs has been adjusted from an optional strategy to a considered strategy.

For patients without prior CDK4/6 inhibitor use (excluding those who failed on Fulvestrant), a new optional strategy was added—Palbociclib combined with Inavolisib and Fulvestrant for PIK3CA mutations. A note was added specifying that this regimen is suitable only for patients who progress within 12 months after completing endocrine therapy. Inavolisib is not yet approved in China, so its use requires caution. For patients with PIK3CA mutations, Alpelisib was previously the only treatment option. However, following the results of the INAVO 120 clinical trial, combining Palbociclib, Inavolisib, and Fulvestrant has shown promising outcomes for patients with PIK3CA mutations, leading to its recommendation as an optional treatment.

For patients previously treated with CDK4/6 inhibitors, the original optional strategy of “AKT inhibitors combined with switch endocrine therapy (ET)” has been updated to Capivasertib combined with Fulvestrant for PIK3CA, AKT1, or PTEN mutations, with a note specifying inclusion of PTEN short fragment mutations, copy number alterations, and rearrangements. The previous option “Alpelisib combined with switch ET” has been revised to PI3K inhibitors combined with switch ET. The previous option “Elacestrant” has been updated to oral SERDs for ESR1 mutations and PARP inhibitors for gBRCA1/2 or PALB2 mutations.

Currently, drugs like Inavolisib and Capivasertib are not fully available in China, but in the future, treatment choices for patients with mutations in PIK3CA, AKT1, PTEN, and ESR1 can be better tailored based on genetic testing results.

Additionally, the updates introduced the HDAC inhibitor Entinostat combined with ET as a new consideration for patients previously treated with CDK4/6 inhibitors. Based on the results of the DESTINY-Breast04 and DESTINY-Breast06 studies, a new note was added. For patients with HER2-low or ultra-low expression who have been treated with CDK4/6 inhibitors and have not undergone chemotherapy, Trastuzumab Deruxtecan (T-DXd; DS-8201) can be cautiously considered despite not yet being approved for this indication in China. This highlights T-DXd’s potential value even in ultra-low HER2 expression cases, with future approvals expected.

Oncology Frontier: The updated treatment guidelines for HER2+ MBC highlight T-DXd and TKIs as preferred options for patients with brain metastases. What advantages do these drugs offer over localized treatments, and how do you view the timing and sequencing of systemic versus localized treatments?

Dr. Jian Zhang:For patients with HER2-positive breast cancer and brain metastases, our previous treatment strategies primarily focused on exploring TKI therapies. Many experts in the breast cancer field, including Professor Min Yan, have conducted studies in this area, such as the PERMEATE study. However, the emergence of ADC drugs has brought new possibilities. Recent studies have shown that Trastuzumab Deruxtecan (T-DXd) demonstrates promising efficacy in both stable and active brain metastases. Clinical data presented at this year’s ESMO conference from the DB-12 study further confirmed the efficacy of T-DXd.

Therefore, in the updated Little Red Book, we recommend prioritizing T-DXd and TKIs for HER2-positive advanced breast cancer patients with brain metastases. Additionally, the treatment guidelines have been updated to state that biosimilars and subcutaneous formulations of anti-HER2 targeted drugs can be used according to their approved indications in China.

Moreover, for HER2-positive advanced breast cancer patients, based on the results of the EMERALD clinical study, the first-line chemotherapy regimen now includes options with Eribulin. This reflects the ongoing emergence of new drugs in clinical treatment, offering patients more therapeutic opportunities.

Oncology Frontier: The updated Little Red Book introduces new first-line and second-line/later-line treatment recommendations for advanced triple-negative breast cancer (TNBC), including PD-1 inhibitors and Trop-2 ADCs. What are your thoughts on these updates and the supporting evidence from evidence-based medicine?

Dr. Jian Zhang:Triple-negative breast cancer (TNBC) is one of the most challenging subtypes of breast cancer, naturally attracting widespread attention. In the 2025 edition of the Little Red Book, we recommend first-line chemotherapy combined with immune checkpoint inhibitors for PD-L1-positive TNBC patients. However, it is important to note that the companion diagnostic criteria vary across different immune checkpoint inhibitors. For example, the combination of pembrolizumab and chemotherapy is approved for patients with a CPS score ≥10, while toripalimab combined with chemotherapy specifically targets patients with PD-L1 positivity (CPS ≥1).

Given these differences, we emphasized in the updated guidelines that not all immunotherapy regimens are suitable for every patient. In the new edition, we clearly marked a key note: “Some PD-1 antibody treatments are not yet approved for clinical use in China; clinical practice should proceed with caution.” This clarification aims to guide clinicians in making scientifically sound and safe treatment decisions.

Additionally, in the first-line treatment of advanced TNBC patients with PD-L1 positivity, the updated recommendations now include toripalimab along with supporting references. In the later-line treatment setting, under the Trop-2 targeted therapy section, sacituzumab govitecan has been added along with relevant references.

Dr. Jian Zhang

• Chief Physician and Doctoral Supervisor, Department of Medical Oncology, Fudan University Shanghai Cancer Center
• Head of Phase I Clinical Trials, Fudan University Shanghai Cancer Center
• Director of Clinical Research Center and Executive Deputy Director of Medical Oncology, Fudan University Shanghai Cancer Center Fujian Hospital
• Chair, Clinical Research Committee on Antitumor Drugs, Chinese Medical Education Association
• Chair, Cancer Prevention and Clinical Research Committee, China Association of Gerontology and Geriatrics
• Chair, Breast Cancer Alliance, Yangtze River Academic Belt
• Chair-Elect, Clinical Research Committee on Antitumor Drugs, Shanghai Anti-Cancer Association
• Standing Member, Breast Cancer Professional Committee, Chinese Anti-Cancer Association
• Deputy Convener, Youth Committee, Breast Cancer Professional Committee, Chinese Anti-Cancer Association
• Member, Breast Cancer Expert Committee, Chinese Society of Clinical Oncology (CSCO)
• Member, Cancer Clinical Research Management Committee, Chinese Anti-Cancer Association
• Recipient of Shanghai “Rising Star in Medicine” and served as a part-time clinical reviewer for the National Medical Products Administration (NMPA) Center for Drug Evaluation
• Recognized as one of the Top 10 Medical Pioneer Experts in 2023 and awarded the Outstanding Contribution Award of “People’s Good Doctor” in 2023
• Published over 80 SCI-indexed papers as first author, co-first author, or corresponding author in leading journals such as Lancet Oncology, Annals of Oncology, Nature Communications, Clinical Cancer Research, Journal of Hematology & Oncology, and Signal Transduction and Targeted Therapy.