Editor’s Note: Targeted therapy has always been a critical component of systemic treatment for HER2-positive breast cancer patients. Currently, small-molecule tyrosine kinase inhibitors (TKIs) are commonly used HER2-targeted therapies. What role do TKIs play in the neoadjuvant treatment of HER2-positive breast cancer, and what drug combinations yield the best treatment outcomes? At the 2024 South-North Forum, Prof. Junjie Li from Fudan University Cancer Hospital presented a report titled “What’s Next for Neoadjuvant Therapy in HER2-Positive Breast Cancer?” This article compiles the key points from his lecture.

Prof. Junjie Li began by addressing the somewhat hesitant tone of the topic “What’s Next for Neoadjuvant Therapy in HER2-Positive Breast Cancer?” which might suggest that TKIs have had their moment but might be phased out. However, a review of relevant literature reveals that in the field of neoadjuvant therapy for HER2-positive breast cancer, TKIs have a consistent role: “I came, I am here, and I will always be here!”

Era 1: TKI Monotherapy + Chemotherapy

Over 20 years ago, the emergence of trastuzumab (H) revolutionized the survival and treatment pathway for HER2-positive breast cancer patients. Clinical studies like NOAH demonstrated that for neoadjuvant treatment of HER2-positive patients, combining trastuzumab with chemotherapy significantly increased the pCR rate compared to chemotherapy alone. Subsequently, small-molecule TKIs were introduced, and various studies explored the efficacy of TKI monotherapy combined with chemotherapy in neoadjuvant treatment. However, the conclusions indicated that TKI + chemotherapy was seemingly less effective than H + chemotherapy.

Era 2: TKI + H + Chemotherapy

The introduction of pertuzumab ushered in a new era for HER2-positive breast cancer treatment, marking the beginning of dual-target therapy with trastuzumab and pertuzumab. Results from studies like NeoSphere and PEONY showed that dual-target therapy (trastuzumab + pertuzumab) was far more effective than monotherapy. Both studies indicated that the 4-cycle THP regimen (docetaxel combined with dual targets) achieved a much higher pCR rate compared to the TH (monotherapy combined with docetaxel) regimen. Additionally, the NSABP B41 and NeoALTTO studies found that the TL (trastuzumab combined with lapatinib) regimen had a higher short-term pCR rate compared to monotherapy with trastuzumab or lapatinib. The PHEDRA study further revealed that the tpCR rate in the pyrotinib combined with trastuzumab and docetaxel group was 41.0%, 19% higher than the placebo combined with trastuzumab and docetaxel group, with good overall safety, providing a new treatment option for neoadjuvant therapy in early-stage HER2-positive breast cancer. Overall, the pCR rates for H + TKI and H + P neoadjuvant therapy are similar, maintaining between 40% and 60% as treatment cycles increase.

Prof. Li noted that despite the similar pCR rates between H + TKI (large and small molecules combined) and H + P (dual-target) neoadjuvant therapy, the clinical application of combined large and small molecules is relatively low, and guideline recommendations are not very high. The reasons include that dual-target therapy with trastuzumab and pertuzumab combined with chemotherapy has long been the standard neoadjuvant treatment for HER2-positive breast cancer according to multiple authoritative guidelines. Additionally, neoadjuvant therapy is just one step in the entire treatment process for breast cancer patients, followed by a series of guideline-approved and clinically recognized mature treatment strategies. Therefore, unless better treatment outcomes (equivalence is meaningless) are achieved and recommended by international guidelines, it is difficult to challenge the established position of dual-target therapy in neoadjuvant treatment.

Era 3.1: New Populations

Prof. Li mentioned that in the new era, we need to identify optimal populations for combined large and small molecule neoadjuvant therapy. Studies like PHEDRA and NeoALTTO suggest that in HR+/HER2+ (triple-positive breast cancer; TPBC) patients, combined large and small molecule therapy yields better results. This indicates that future research could explore the overall strategy of combined large and small molecule therapy in these populations.

Era 3.2: New Strategies

Prof. Li emphasized that “brain metastasis” is the most challenging issue in HER2-positive breast cancer. Currently, the strongest treatment strategy for this population involves ADC drugs, followed by TKIs. Could combining these two drug types improve patient survival? Would bringing this combined strategy forward to neoadjuvant therapy achieve better outcomes? Fudan University Cancer Hospital has already initiated related research, verifying the potential of ADC + TKI combined therapy for brain metastasis and proving its promising treatment prospects.

In conclusion, Prof. Li stated that any treatment regimen must consider both efficacy and the accessibility and safety of the drugs. Studies like the PHILA research have demonstrated the safety of combined large and small molecule therapy, and clinicians have experience managing common side effects like diarrhea associated with TKI treatment. He expressed confidence that combined large and small molecule therapy would perform well in the 6-month neoadjuvant setting. In summary, in the field of neoadjuvant therapy for HER2-positive breast cancer, TKIs play a consistent role: “I came, I am here, and I will always be here!”

Prof. Junjie Li

– Associate Chief Physician, MD, Master’s Supervisor at Breast Surgery, Fudan University Cancer Hospital

– Administrative Deputy Director of Breast Surgery, Director of the Pudong Ward, and Department Teaching Secretary

– Graduated from Fudan University’s seven-year clinical medicine program in 2008 and completed specialized training in breast cancer at Massachusetts General Hospital Cancer Center, USA

– Focuses on clinical and basic research in breast cancer, participating in and designing multiple international and domestic multicenter clinical trials, with nearly 20 SCI papers published in authoritative journals like JCO

– Principal investigator of a National Natural Science Foundation project

– Holds positions as a young expert in the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association, a young expert in the Breast Cancer Group of the Chinese Medical Association, a standing member and secretary of the Breast Cancer Professional Committee of the Shanghai Anti-Cancer Association, a standing member of the International Medical Exchange Committee of the Chinese Anti-Cancer Association, deputy director of the Youth Committee of the Beijing Cancer Prevention and Treatment Society, and an editorial board member of the Chinese Journal of Breast Disease.