Editor’s Note: In the first-line treatment of advanced HER2-positive breast cancer, the combination of pyrotinib and trastuzumab has introduced a new therapeutic model. The complementary mechanisms of large and small molecules have achieved a median progression-free survival (mPFS) of 24.3 months, setting a new standard for first-line treatment of advanced HER2-positive breast cancer. This combination therapy is now recommended by three major domestic guidelines: CSCO BC, CBCS, and ABCC. While the success of this dual-target regimen in advanced stages is clear, its effectiveness in early-stage treatment remains to be seen. Can it provide a new dual-target option for neoadjuvant therapy in HER2-positive breast cancer? In this issue, “Oncology Frontier” invites Prof. Xiaowei Qi to share insights from his report at the South-North Forum titled “Clinical and Translational Research on Pyrotinib Combined with Trastuzumab as Neoadjuvant Therapy for HER2-Positive Breast Cancer,” offering an in-depth exploration of this new dual-target regimen in early anti-HER2 therapy.
Introduction to Anti-HER2 Therapeutic Drugs and Mechanisms
Currently, three main categories of drugs dominate the clinical anti-HER2 therapy: large-molecule monoclonal antibodies, small-molecule tyrosine kinase inhibitors (TKIs), and antibody-drug conjugates (ADCs). For neoadjuvant therapy of HER2-positive breast cancer, the treatment approach has shifted from single-agent chemotherapy to multi-drug regimens combining chemotherapy and targeted therapy. The dual-target regimen of trastuzumab combined with pertuzumab is the current standard for neoadjuvant therapy of HER2-positive breast cancer.
Large-molecule monoclonal antibodies primarily act extracellularly, inhibiting the formation of homodimers and heterodimers, thereby blocking the HER2 signaling pathway and preventing downstream signal transduction, which stops tumor cell proliferation. TKIs, on the other hand, act directly on the intracellular kinase activity region, binding covalently to the ATP binding sites of the HER2 and EGFR kinase regions inside the cell, preventing the formation of homodimers and heterodimers of HER2 and EGFR, inhibiting their autophosphorylation, blocking downstream signaling pathways, and thereby inhibiting tumor cell growth.
1. Oncology Frontier: Thank you, Prof. Qi, for sharing your insights at the South-North Forum. You and your team have conducted extensive research on the application value of the pyrotinib-trastuzumab dual-target regimen in the neoadjuvant setting. This includes launching multicenter clinical studies and conducting translational research on biomarkers predicting the efficacy of pyrotinib combined with trastuzumab as neoadjuvant therapy. What drives your confidence in the pyrotinib-trastuzumab combination and motivates your team to invest valuable time and effort in this research?
Prof. Xiaowei Qi: A meta-analysis including four large randomized controlled trials (NeoALTTO, CALGB 40601, NSABP B41, CHER-LOB) suggested that combining lapatinib with trastuzumab in neoadjuvant therapy significantly improves the pCR rate compared to trastuzumab alone, reducing the risk of recurrence and death by 38% and 35%, respectively. The PHOEBE study, which established the standard of pyrotinib plus capecitabine for second-line treatment in advanced stages, confirmed that pyrotinib outperformed lapatinib in combination with capecitabine. Although both pyrotinib and lapatinib are small-molecule TKIs, they differ: pyrotinib is an irreversible, pan-HER TKI that blocks HER1, HER2, and HER4, while lapatinib reversibly blocks HER1 and HER2. When we initiated our research, there were no studies on pyrotinib combined with trastuzumab as neoadjuvant therapy for early HER2-positive breast cancer. However, based on the mechanism of pyrotinib and its significant efficacy in advanced stages, our team, under the guidance of Professors Jun Jiang and Yi Zhang, embarked on this series of explorations.
2. Oncology Frontier: Could you share with our readers the key findings from your clinical and translational research?
Prof. Xiaowei Qi: Based on pyrotinib’s potent and rapid tumor shrinkage and its excellent efficacy in advanced clinical stages, our center initiated studies on pyrotinib as neoadjuvant therapy for HER2-positive breast cancer early on. We added pyrotinib to the traditional EC-TH regimen (epirubicin + cyclophosphamide followed by docetaxel + trastuzumab), creating the EC-TH+Pyro regimen. Patients receiving this regimen achieved a pathological complete response (pCR) rate of 73.7%, roughly double the pCR rate reported in other studies using the EC-TH regimen. Encouraged by these impressive results, we expanded the sample size to 175 cases in a multicenter study, achieving a tpCR rate of 68.6%. These results indicate that the pyrotinib-trastuzumab dual-target regimen offers new hope for early HER2-positive breast cancer patients and could be a viable neoadjuvant treatment option.
Despite the promising high pCR rate with the dual-target regimen, some patients respond poorly or develop resistance. Therefore, it is essential to explore the characteristics of patients sensitive or resistant to this regimen. To this end, our center launched a translational study to identify biomarkers predicting the efficacy of pyrotinib combined with trastuzumab as neoadjuvant therapy. We found that PIK3CA mutations were associated with the pCR rate of the dual-target regimen, with PIK3CA wild-type patients showing significantly higher pCR rates than those with PIK3CA activating mutations (80.8% vs. 26.3%). Recent follow-up data also suggest poorer prognosis in patients with mutations compared to wild-type patients. This indicates that patients with PIK3CA mutations benefit less from pyrotinib-trastuzumab neoadjuvant therapy, and combining PI3K inhibitors with anti-HER2 therapy might be a viable strategy for these patients.
3. Oncology Frontier: What impact do you believe the emergence of the pyrotinib-trastuzumab dual-target regimen will have on the neoadjuvant treatment landscape for HER2-positive breast cancer?
Prof. Xiaowei Qi: Various domestic experts have explored different approaches to pyrotinib in the neoadjuvant setting. The PHEDRA study, initiated by Prof. Jing Wu from Fudan University Cancer Hospital, showed a tpCR rate of 41% with the 4-cycle TH+Pyro regimen. Prof. Zhenzhen Liu’s team from Henan Cancer Hospital reported a tpCR rate of 55.1% with the 6-cycle TCbH+Pyro regimen in the Panphila study. Prof. Xiaowen Ding from the Affiliated Cancer Hospital of the Chinese Academy of Sciences achieved a tpCR rate of 71% with the 6-cycle TCbH+Pyro regimen. The NeoATP study led by Prof. Jinsong Lu from Renji Hospital, Shanghai Jiao Tong University School of Medicine, indicated a tpCR rate of 73.6% with the 4-cycle (16-week) TPH (weekly) + Pyro regimen. These findings underscore that the pyrotinib-trastuzumab dual-target regimen is a viable neoadjuvant treatment option for early HER2-positive breast cancer patients.
Moreover, small-molecule TKIs have the advantage of potent and rapid tumor shrinkage. Particularly for patients who do not respond or tolerate the 2-cycle or 4-cycle trastuzumab-pertuzumab dual-target therapy and are not eligible for surgery, switching to or adding pyrotinib could provide a surgical opportunity and achieve pCR.
Currently, pyrotinib is covered by insurance for neoadjuvant therapy and has received level II recommendations from the CSCO BC and CBCS guidelines. Clinically, we can choose the combination of subcutaneous trastuzumab and oral pyrotinib, balancing efficacy and convenience. This enhanced accessibility and convenience will further benefit early-stage patients with the pyrotinib-trastuzumab dual-target regimen.
– Deputy Director/Assistant Director, Breast and Thyroid Surgery, Southwest Hospital, Army Medical University
– Associate Chief Physician, Associate Professor, Doctoral Supervisor
– Recipient of the Chongqing Outstanding Youth Fund
– High-level Young Medical Talent in Chongqing
– Member of the Breast Cancer Professional Committee of the Chinese Society of Clinical Oncology (CSCO-BC)
– Youth Member of the Breast Cancer Group of the Oncology Branch of the Chinese Medical Association
– Young Expert of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association (CBCS)
– Vice Chairman of the Young Breast Cancer Scholars Group (YBCSG)
– Standing Member of the Breast Disease Branch of the Chongqing Medical Association
– Standing Member of the Breast Cancer Professional Committee of the Chongqing Anti-Cancer Association
– Editorial Board Member of the Chinese Journal of Breast Disease, Chinese Journal of General Surgery, Journal of Clinical Oncology (Chinese Edition), and Cancer Innovation
