Editor’s Note: HER2-positive breast cancer was once associated with aggressive behavior and poor prognosis. However, with the rapid advancement of targeted therapies—particularly antibody–drug conjugates (ADCs)—this subtype has evolved into a highly treatable and potentially curable disease. In 2025, landmark studies across neoadjuvant, adjuvant, and metastatic settings have reshaped treatment paradigms toward greater precision and individualization. During the 2025 Yixian Breast Cancer Conference and CSCO BC South Forum, Oncology Frontier interviewed Professor Chang Gong from Sun Yat-sen Memorial Hospital, Sun Yat-sen University, who summarized the most impactful annual advances in HER2-positive breast cancer treatment.Q1: Key Advances in Neoadjuvant and Adjuvant Treatment in 2025
Oncology Frontier: For patients who fail to achieve pCR after neoadjuvant therapy, treatment escalation has become standard. What were the most important 2025 advances in neoadjuvant and adjuvant therapy for HER2-positive breast cancer?
Professor Chang Gong: In 2025, HER2-positive breast cancer achieved major breakthroughs in both early-stage and advanced disease, with one defining trend: ADCs are moving from late-line therapy into early-stage neoadjuvant and adjuvant intensification.
The overarching strategy has become risk-adapted precision:
- For low-risk or highly treatment-sensitive patients, we pursue de-escalation to minimize toxicity
- For high-risk or pCR-unlikely patients, we pursue escalation, using more potent but tolerable regimens
HER2-positive disease accounts for 20–25% of breast cancer cases. Once associated with poor outcomes, it now represents one of the most favorable prognostic subtypes due to sustained HER2-targeted innovation. In early-stage disease, the primary goal is cure.
De-Escalation Strategy: The neoCARHP Trial (ASCO 2025)
The neoCARHP study, led by Professor Kun Wang’s team at Guangdong Provincial People’s Hospital, explored carboplatin-free neoadjuvant therapy versus standard TCbHP.
Key findings:
- pCR rates remained ~65% overall, comparable to platinum-containing regimens
- HR-negative patients achieved pCR rates of 77–78%
- Significant reductions in hematologic toxicity and marrow suppression
This study directly impacts clinical practice, supporting THP (taxane + dual HER2 blockade) as a de-escalated option for early-stage, node-negative, low-tumor-burden patients.
Escalation Strategy: The DB-11 Trial (ESMO 2025)
High-risk patients—especially those with large tumor burden or node-positive disease—continue to show lower pCR rates with conventional dual-target chemotherapy.
The DB-11 trial addressed this unmet need by evaluating T-DXd-based neoadjuvant intensification in higher-risk HER2-positive patients (≥cT3 or cN+).
Key results:
- T-DXd + THP increased pCR by ~11.2% overall
- Triple-positive tumors saw a 9.1% absolute pCR improvement
- Lower rates of ≥Grade 3 toxicities compared with anthracycline-based regimens
- Reduced treatment discontinuation
This breaks the previous pCR ceiling and confirms that ADC escalation in high-risk neoadjuvant settings yields meaningful benefit.
Strategic Summary (Early-Stage HER2+)
- Early-stage / low-risk patients: THP de-escalation may be sufficient
- High-risk patients: ADC-based escalation (e.g., T-DXd) is likely superior
- Formulation innovation (e.g., subcutaneous HER2 dual antibodies) may further improve convenience, adherence, and quality of life
Q2: Practice-Changing Advances in Advanced HER2-Positive Breast Cancer
Oncology Frontier: What was the most practice-changing development in 2025 for metastatic HER2-positive breast cancer, and could it influence 2026 guidelines?
Professor Chang Gong: The most transformative advance in 2025 is unquestionably the DESTINY-Breast09 trial.
This study compared:
- T-DXd ± pertuzumab vs.
- Standard first-line THP (trastuzumab + pertuzumab + taxane)
Unlike earlier trials, DB-09 enrolled a higher-risk, real-world population, including patients with:
- Prior therapy progression
- Brain metastases
- PIK3CA mutations
- HR+/HER2+ tumors (allowed endocrine maintenance)
Key Results (ASCO 2025)
- Median PFS reached 40.7 months in the T-DXd + pertuzumab arm
- Consistent benefit across all high-risk subgroups
- Rapid, deep, and durable responses
This represents a major leap beyond CLEOPATRA-era benchmarks, positioning ADC-based regimens as potential first-line standards.
Safety Considerations
While efficacy is remarkable, ILD (interstitial lung disease) remains a critical safety concern:
- Overall ILD incidence: ~12.1%
- Grade ≥3 ILD remains low in Chinese populations, but requires vigilant monitoring
Clinical and Guideline Impact
Although formal approvals and guideline updates are pending, DB-09 is a landmark trial that:
- Redefines first-line HER2+ metastatic therapy
- Supports ADC-based regimens as new frontline contenders
- Will likely influence 2026 international guidelines
Emerging Challenges
As ADCs move to earlier lines, key unanswered questions arise:
- Optimal sequencing after first-line T-DXd
- Switching target vs switching payload
- Cross-resistance patterns
- Best salvage strategies
These questions will shape future clinical research and treatment algorithms.
Expert Profile
Professor Chang Gong
Sun Yat-sen Memorial Hospital, Sun Yat-sen University Yixian Breast Cancer Center
A leading expert in HER2-positive breast cancer, focusing on precision therapy optimization, ADC-based treatment strategies, and personalized escalation/de-escalation approaches in early and metastatic disease.
