A Paradigm Shift in Early HER2+ Breast Cancer: The Rise of Trastuzumab Deruxtecan (T-DXd)

The treatment landscape for HER2-positive early breast cancer (EBC) is evolving rapidly — and trastuzumab deruxtecan (T-DXd) is emerging as a potential new standard in both the neoadjuvant and adjuvant settings.

🔹 Neoadjuvant Setting

DESTINY-Breast11

T-DXd followed by THP (docetaxel + trastuzumab + pertuzumab) demonstrated:

Significantly higher pathologic complete response (pCR) rates compared with standard anthracycline-based regimens A chemotherapy-sparing strategy with reduced anthracycline exposure Favorable tolerability profile consistent with prior T-DXd data

📊 Early reports show pCR rates approaching ~65–70%, exceeding historical benchmarks for standard neoadjuvant regimens (typically ~55–60%).

Clinical Implication:

We may be entering an era of antibody–drug conjugate (ADC)-based neoadjuvant intensification, potentially redefining the backbone of HER2-directed therapy.

Reference:

Hurvitz SA et al. DESTINY-Breast11. Presented at ESMO 2024 / SABCS 2024 (late-breaking data).

🔹 Adjuvant Setting

DESTINY-Breast05

For patients with residual invasive disease after neoadjuvant therapy, T-DXd demonstrated:

53% reduction in risk of invasive disease–free survival (iDFS) events compared with T-DM1 Superior invasive disease–free survival Manageable toxicity, with ILD rates consistent with prior experience

This builds upon the paradigm established by KATHERINE, where T-DM1 replaced trastuzumab in patients with residual disease.

Now, T-DXd appears poised to replace T-DM1 in this high-risk population.

Reference:

DESTINY-Breast05. Presented at ASCO 2025.

von Minckwitz G et al. KATHERINE trial. NEJM. 2019;380:617–628.

🔬 Why This Matters

We are witnessing:

A shift from monoclonal antibodies → ADC-based escalation Earlier deployment of highly potent HER2-directed agents Refinement of risk-adapted therapy based on response

If adopted into guidelines (NCCN, ASCO, ESMO), this could:

Redefine the management of residual disease Potentially reduce recurrence risk further in high-risk HER2+ EBC Change neoadjuvant sequencing strategies

⚠️ Considerations

ILD/pneumonitis risk requires vigilance Cost-effectiveness and long-term survival data pending Optimal sequencing with pertuzumab still being clarified

📌 Bottom Line

T-DXd is no longer just a metastatic drug.

It is rapidly reshaping the curative-intent HER2+ early breast cancer algorithm.