Neoadjuvant dual HER2 blockade with trastuzumab and pertuzumab plus chemotherapy represents the current standard-of-care for HER2-positive breast cancer. Importantly, Xenium in situ profiling further revealed biological correlates underlying model predictions, including HER2-enriched tumor cell aggregation and neutrophil-helper T-cell interactions, thereby highlighting the mechanistic interpretability of the model. Collectively, HER2-LADDER unites digital pathology and high-resolution spatial profiling into a clinically accessible AI framework, offering a robust, transparent, and biologically grounded tool to tailor individualized HER2-targeted therapy optimization.

P2, N=63, Completed, City of Hope Medical Center | Active, not recruiting --> Completed

Multimodal HER2 testing is needed to accurately identify candidates for HER2-targeted treatment, as NGS alone misses a significant proportion of cases. Patients who develop resistance to one anti-HER2 agent may still achieve benefit from subsequent HER2-directed regimens. Early and serial treatment with HER2-directed agents should be considered for patients with HER2 + GI cancers.

P2, N=702, Recruiting, West German Study Group | Active, not recruiting --> Recruiting | N=402 --> 702 | Trial completion date: Jun 2029 --> Sep 2030 | Trial primary completion date: Jun 2025 --> Jun 2030

Given the clinical severity, inpatient treatment was promptly initiated with trastuzumab and pertuzumab every three weeks, combined with weekly paclitaxel at a 50% dose reduction. In carefully selected patients, early and sustained HER2-directed therapy can lead to meaningful clinical recovery when options appear limited. Such cases help bridge the evidence gap for this high-risk group and may inform future therapeutic considerations.

Patient characteristics reflect current Chinese practice. Increasing adoption of diarrhoea prophylaxis in real-world practice reflects growing clinical experience with neratinib and its recognised benefit in preventing diarrhoea.

In a real-world setting, anthracycline-free neoadjuvant chemotherapy with dual HER2 blockade achieved pCR rates comparable to anthracycline-containing regimens with acceptable toxicity and preserved cardiac safety, suggesting that it may be a reasonable treatment option for selected patients.

Existing studies are generally limited by small sample sizes and a lack of long-term survival data, and high-level evidence directly comparing pyrotinib-based strategies with trastuzumab plus pertuzumab is scarce. Future research should prioritize biomarker-driven patient selection, response-adaptive trial designs, and standardized toxicity management to optimize clinical decision-making.

Prior anti-EGFR therapy and resistance alterations detected by baseline ctDNA profiling are associated with reduced efficacy of PER + TRA in HER2-amplified mCRC. Integrating treatment history with baseline ctDNA profiling might enable improved patient selection for dual HER2-targeted therapy.

P1/2, N=33, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting | Trial completion date: Aug 2026 --> May 2027 | Trial primary completion date: Aug 2026 --> Apr 2027

P2, N=16, Active, not recruiting, Fox Chase Cancer Center | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2026

P1, N=258, Not yet recruiting, Shanghai Henlius Biotech