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Background: The efficacy of HLX02, a trastuzumab biosimilar, in combination with chemotherapy for treating metastatic breast cancer (BC) has been established as equivalent to the reference Herceptin. This study aimed to assess the treatment response of HLX02-based neoadjuvant therapy in HER2-positive BC, with a focus on HR-positive versus HR-negative subgroups. Additionally, we investigated the potential role of a CDK4/6 inhibitor in combination with anti-HER2 therapy. Methods: This retrospective study included HER2-positive BC patients who received HLX02-based neoadjuvant therapy followed by curative surgery at Anhui Provincial Cancer Hospital between March 2021 and August 2023. Pathological complete response (pCR) rates were analyzed, and subgroup analyses evaluated predictors of pCR. In vitro experiments using BT-474 and MCF-7 cell lines assessed the effects of combining CDK4/6 inhibitors with anti-HER2 therapy on cell viability and apoptosis. Results: The study included 67 patients with a median age of 53 years. The overall pCR rate was 53.73%, with higher pCR rates observed in HR-negative patients compared to HR-positive patients (63.89% vs. 41.94%). Dual HER2 blockade with HLX02 and pertuzumab was associated with a numerically improved pCR rate (62.16%). ER expression significantly increased post-treatment, potentially indicating treatment resistance mechanisms. In vitro, the combination of CDK4/6 inhibitors with anti-HER2 therapy significantly reduced cell viability and promoted apoptosis in HR-positive, HER2-positive cell lines. Conclusion: HLX02 demonstrates real-world efficacy as part of neoadjuvant therapy for HER2-positive BC, especially in HR-negative patients. The lower pCR rate in HR-positive patients highlights the need for additional strategies. Combining CDK4/6 inhibitors with anti-HER2 therapy presents a promising approach for HR-positive HER2-positive patients, warranting further clinical validation.