In a 52-year-old woman with newly diagnosed high‑risk HER2‑positive (estrogen‑receptor‑negative) stage III breast cancer, which neoadjuvant regimen demonstrated the highest pathologic complete response rate in the DESTINY‑Breast11 phase III trial?

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T-DXd followed by THP achieved the highest pCR rate in DESTINY-Breast11

Based on the DESTINY-Breast11 phase III trial, the regimen of T-DXd (trastuzumab deruxtecan) for 4 cycles followed by THP (paclitaxel, trastuzumab, pertuzumab) for 4 cycles achieved the highest pathologic complete response (pCR) rate at 67.3%, significantly superior to the current standard ddAC-THP regimen (56.3%, p=0.003). 1

Evidence from DESTINY-Breast11

The DESTINY-Breast11 trial directly compared three neoadjuvant regimens in high-risk HER2-positive early breast cancer (≥cT3cN0 or cT0-4cN1-3):

  • T-DXd monotherapy (8 cycles): 43.0% pCR
  • T-DXd followed by THP (4+4 cycles): 67.3% pCR
  • ddAC-THP (current standard, 4+4 cycles): 56.3% pCR

The T-DXd-THP regimen demonstrated an absolute pCR rate difference of 11.2% (95% CI: 4.0-18.3%, p=0.003) compared to the standard anthracycline-containing regimen 1. This benefit was consistent across hormone receptor subgroups:

  • HR-positive: 61.4% vs 52.3% (ΔpCR 9.1%)
  • HR-negative: 83.1% vs 67.1% (ΔpCR 16.1%)

Safety Profile Advantage

Beyond superior efficacy, the T-DXd-THP regimen showed markedly improved tolerability compared to anthracycline-based therapy:

  • Grade ≥3 adverse events: 37.5% (T-DXd-THP) vs 55.8% (ddAC-THP)
  • Serious adverse events: 10.6% vs 20.2%
  • Left ventricular dysfunction (all grades): 1.3% vs 6.1%

Importantly, adjudicated drug-related interstitial lung disease/pneumonitis rates remained low and comparable across all arms (4.4-5.1%) 1.

Clinical Context and Guideline Alignment

While current NCCN guidelines 2 list dose-dense AC followed by THP as a preferred regimen for HER2-positive disease, these guidelines predate the DESTINY-Breast11 results. The trial's findings represent a paradigm shift, offering an anthracycline-free option that achieves superior pCR rates with reduced toxicity—addressing long-standing concerns about anthracycline-associated cardiotoxicity and secondary malignancies 3.

The T-DXd monotherapy arm (Answer B) was closed early by the Independent Data Monitoring Committee due to inferior efficacy (43.0% pCR), demonstrating that T-DXd alone is insufficient for high-risk disease 1.

Answer: C - T-DXd followed by THP

For your 52-year-old patient with high-risk, HER2-positive, ER-negative stage III breast cancer, the T-DXd-THP regimen (Answer C) achieved the highest pCR rate in DESTINY-Breast11 and represents the most effective neoadjuvant approach based on the most recent phase III evidence. This regimen combines the potent antibody-drug conjugate T-DXd with dual HER2 blockade (trastuzumab-pertuzumab) and chemotherapy, while avoiding anthracycline-related toxicities that are particularly relevant given the need for optimal cardiac safety in HER2-targeted therapy.

The early EFS data, though immature (4.5% events), showed a favorable trend (HR 0.56,95% CI 0.26-1.17) supporting the pCR findings as a meaningful surrogate for long-term outcomes 1.

References

2
Guideline

breast cancer version 3.2014.

Journal of the National Comprehensive Cancer Network : JNCCN, 2014

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