Editor's Note: Breast cancer is one of the most common malignancies among women globally, and continuous advancements in treatment modalities have brought new hope to many patients. At the 2024 SIBCS conference during the "Fourth 3C Summit Forum – Frontline Notes on the 2025 Breast Cancer Guideline Revision," Dr. Lei Fan from Fudan University Shanghai Cancer Center presented a report on the "Advances and Controversies in Adjuvant Therapy for Breast Cancer," discussing the latest research findings and controversies in adjuvant therapy for different breast cancer subtypes. This article provides a summary of Dr. Fan’s lecture for our readers.

Dr. Fan analyzed adjuvant therapy progress and controversies based on the three primary molecular subtypes of breast cancer: Luminal, triple-negative breast cancer (TNBC), and HER2-positive breast cancer.

PART 1: Advances and Controversies in Adjuvant Therapy for Luminal Breast Cancer

Luminal breast cancer comprises 60-70% of all breast cancer cases, with endocrine therapy as the mainstay treatment. In clinical practice, risk stratification is used to determine patient treatment plans, with de-escalation of chemotherapy and the introduction of various drugs (e.g., CDK4/6 inhibitors, PARP inhibitors) facilitating more precise, individualized treatment for this subtype.

Dr. Fan highlighted the monarchE and NATALEE studies as key research efforts evaluating the efficacy of CDK4/6 inhibitors in adjuvant therapy for Luminal breast cancer, though there are notable differences in study design and outcomes. The monarchE study focused on early-stage high-risk HR+/HER2- breast cancer patients with ≥4 positive axillary lymph nodes or 1-3 positive nodes combined with high-risk factors (e.g., grade 3 histology, tumor size ≥5 cm, or Ki-67 ≥20%). The study reported an absolute improvement in 3-year invasive disease-free survival (iDFS) of 4.8%, increasing to 7.6% at 5 years.

The NATALEE study included a broader patient population, such as stage IIA N0 patients with high-risk factors (e.g., Ki-67 ≥20%, high-risk genetic profile), as well as IIB and all stage III patients. The study showed that ribociclib provided a 4.9% absolute benefit in iDFS for the entire cohort, with an even greater benefit (5.1%) among N0 patients after 4 years of follow-up.

Despite the notable efficacy of CDK4/6 inhibitors in adjuvant therapy for Luminal breast cancer, Dr. Fan noted some ongoing controversies:

1. Treatment Choice for N0 Patients: In the NATALEE study, only about 15% of the cohort were N0 patients, while in real-world settings, N0 patients make up 60-70% of Luminal breast cancer cases. This raises the question of how to precisely select N0 patients for CDK4/6 inhibitor therapy.
2. Duration of Endocrine Therapy: The addition of CDK4/6 inhibitors prompts discussion on whether the duration of endocrine therapy should be adjusted, especially for low-risk N1 patients.
3. Post-CDK4/6 Inhibitor Therapy Options: Defining CDK4/6 inhibitor resistance and selecting follow-up treatment for resistant patients remains a challenge.
4. Chemotherapy De-escalation: For premenopausal, intermediate-risk patients with a 21-gene score of 16-25, the benefit of chemotherapy is still a topic of debate.

PART 2: Progress and Controversies in Immunotherapy for Triple-Negative Breast Cancer (TNBC)

TNBC is a challenging subtype with unique clinical and immunogenic characteristics, making it a hot topic in clinical research. In recent years, immunotherapy has achieved significant advances in TNBC. The publication of overall survival (OS) data from the KEYNOTE-522 study has established the role of neoadjuvant and adjuvant immunotherapy, but discrepancies remain between clinical benefit and survival outcomes across studies, warranting further analysis.

The KEYNOTE-522 study, a phase III trial, evaluated neoadjuvant pembrolizumab combined with chemotherapy, followed by pembrolizumab monotherapy in early-stage TNBC. The study’s 5-year median OS data, presented at the 2024 ESMO conference, demonstrated improved event-free survival (EFS) and OS, with notable benefits for patients who did not achieve pathological complete response (non-pCR).

Dr. Fan emphasized that immunotherapy offers sustained survival benefits, likened to a “gentle rain” of continuous improvement rather than an immediate surge. Moving forward, the exploration of immunotherapy in TNBC should focus on:

1. Optimal Timing of Immunotherapy: Neoadjuvant immunotherapy has shown superior efficacy compared to adjuvant or late-stage treatment.
2. Combination Therapy: For pCR patients, combining other novel drugs may offer further benefits.
3. Patient Selection: High tumor burden patients may experience better immunotherapy outcomes.

Fudan University Shanghai Cancer Center is currently conducting the COSMOS study, enrolling stage II-III TNBC patients to explore the efficacy of immunotherapy combined with anti-angiogenic agents. This research aims to offer new treatment options for early high-risk TNBC patients, and we look forward to the data outcomes.

PART 3: Advances in HER2-Positive Breast Cancer Treatment

While advances in HER2-positive breast cancer treatment have been relatively limited, 2024 saw two notable studies offering new insights for this subtype.

The WSG-TP-II study, a phase II trial, investigated de-escalation therapy for HR+/HER2+ breast cancer. Results showed that both endocrine therapy combined with dual HER2-targeted agents and chemotherapy combined with dual HER2-targeted agents achieved excellent 5-year survival outcomes after 4 cycles (12 weeks) of treatment. This suggests that de-escalation therapy remains valuable even in the era of intensified adjuvant therapy.

The HERA study analyzed ovarian function suppression (OFS) in premenopausal HR+/HER2+ triple-positive breast cancer patients. The study included 965 patients, with 501 receiving tamoxifen monotherapy and 464 receiving OFS with either tamoxifen (269 patients) or exemestane (195 patients). The findings demonstrated that OFS combined with endocrine therapy was superior to endocrine therapy alone, and OFS with an aromatase inhibitor (AI) outperformed OFS with tamoxifen. This underscores the importance of endocrine therapy in HR+/HER2+ breast cancer.

Dr. Fan pointed out that there are still some controversies in the treatment of HER2-positive breast cancer, such as de-escalation therapy for triple-positive breast cancer and the choice of endocrine therapy. As antibody-drug conjugates (ADCs) are gradually introduced into breast cancer treatment, there is hope that they may reshape treatment approaches for early-stage patients.

PART 4: Controversies and Future Directions

Despite significant progress in adjuvant therapy for breast cancer, some controversies and unresolved issues remain. For Luminal breast cancer, questions persist on the precise selection of N0 patients for CDK4/6 inhibitors, adjustments to endocrine therapy duration, and post-CDK4/6 resistance strategies. In TNBC, optimizing immunotherapy timing, patient selection, and treatment combinations are pressing concerns. In HER2-positive breast cancer, de-escalation therapy for triple-positive patients, endocrine therapy choices, and ADC applications are worth further exploration.

Looking to the future, the continuous emergence of new drugs and clinical research is expected to offer more precise and effective personalized treatment options for breast cancer patients. Additionally, deeper exploration of the mechanisms and biology of breast cancer will be essential to developing more targeted and effective treatment strategies.

Expert Profile

Dr. Lei Fan

• Deputy Chief Physician, Breast Surgery Department, Fudan University Shanghai Cancer Center
• PhD in Oncology, Fudan University
• Master’s Supervisor
• Member of the Youth Committee, Breast Cancer Professional Committee, Chinese Anti-Cancer Association
• Member of the Youth Committee, Breast Group, Chinese Medical Association Oncology Division
• Vice Chair of the Breast Specialty Committee, Shanghai Female Physicians Association
• Vice Chair of the Youth Committee, Molecular Targeted Oncology Section, Shanghai Medical Association
• Member, International Medical Exchange Committee, Chinese Anti-Cancer Association
• Member, Breast Cancer Committee, Shanghai Anti-Cancer Association
• Committee Member, Psychosomatic Medicine, Shanghai Medical Association
• Member, Science Popularization Committee, Shanghai Female Physicians Association
• Fellow, Massachusetts General Hospital Cancer Center, Harvard Medical School
• Principal Investigator on national and Shanghai grants, author of over 30 SCI-indexed publications, with first-author and corresponding-author publications in The Lancet Oncology, JAMA Oncology, and others.