Trastuzumab Deruxtecan: A Potential First Choice Also in Early-Stage HER2-Positive Breast Cancer

📊 Quick Summary – The Most Important Results

In HER2-positive breast cancer, T-DXd (trastuzumab deruxtecan) reduced recurrence risk and completely eliminated more tumors before treatment in two major trials compared with the current standard, T-DM1.

• DESTINY-Breast05: In women receiving T-DXd, the risk of recurrence or death fell by 53%. Compared with T-DM1, this means that of every 100 patients, approximately 9 additional women lived cancer-free .
• 3-year cancer-free survival: T-DXd 92% versus T-DM1 84%. In other words, 92 of every 100 women receiving T-DXd remained disease-free after three years.
• Development of brain metastases: Less common in the T-DXd group (HR 0.64), a promising finding particularly for high-risk patients.
• DESTINY-Breast11: In high-risk patients who had not yet undergone surgery, T-DXd-containing treatment led to complete tumor disappearance more often than standard treatment; pathological complete response (pCR) was 67% versus 56%.
• Difference by hormone receptor status: In hormone receptor-positive patients, %61versus 52%; in hormone receptor-negative patients, %83versus 67% success was observed.

DESTINY-Breast05: Fewer Recurrences After Surgery (Adjuvant Setting)

This trial enrolled women who had received chemotherapy before surgery but whose tumor had not completely disappeared (residual disease). A total of 1,635 women were divided into two groups: one received T-DXd , the other the then-standard drug T-DM1. The aim was to measure the time without disease recurrence (disease-return-free survival – IDFS).

The results are clear: T-DXd halved the risk of recurrence or death (53% risk reduction). After three years, 92% remained cancer-free, representing approximately a 9-point difference compared with T-DM1 .

Comment: In women whose tumors did not completely disappear despite neoadjuvant treatment, these results show T-DXd is more effective than T-DM1 at keeping disease away . In real-world terms, the difference means 1 in every 10 patients lives without recurrence.

DESTINY-Breast11: Greater Success Before Surgery (Neoadjuvant Setting)

This second trial enrolled women who had not yet undergone surgery and had high-risk HER2-positive breast cancer, totaling 927 participants. The aim was to compare the drugs' rates of completely eliminating the tumor before surgery (medically termed “complete response” or pCR).

T-DXd-containing treatment (T-DXd-THP), compared with conventional chemotherapy, produced a complete tumor response in many more women: 67% versus 56%, an additional improvement in one of every 10 patients. The difference was similar in both hormone receptor-positive and hormone receptor-negative subgroups.

• Hormone receptor-positive: 61% (T-DXd) vs 52% (conventional treatment)
• Hormone receptor-negative: 83% (T-DXd) vs 67% (conventional treatment)

Early data also suggest T-DXd reduces the likelihood of disease returning after treatment . Although follow-up remains short, this combination is expected eventually to become standard preoperative treatment .

🛡️ Safety: Careful Monitoring, Safe Use

In both trials, rates of serious side effects (such as nausea, weakness, and low blood counts) were similar: Around 50% with T-DXd and 52% with T-DM1. Overall, the side-effect profiles of the two drugs were therefore quite similar.

However, T-DXd treatment carries a specific concern: Lung inflammation or an inflammatory-like condition (medically termed “interstitial lung disease – ILD”). It can present with symptoms such as cough, shortness of breath, or chest tightness .

In the trial, this occurred in approximately 10% of T-DXd patients, with very few severe cases. With T-DM1, the rate was below 2%. Because of this difference, physicians now ask about respiratory symptoms at every follow-up visit and, if needed, request early chest computed tomography (CT) .

In cases recognized early, stopping the drug and starting cortisone (steroid) treatment reportedly led to complete ILD resolution. It is therefore very important that patients promptly report new symptoms such as cough or shortness of breath to their doctor .

Overall, although T-DXd is a potent and effective drug , regular assessment and careful monitoring allow safe use. In experienced centers, with attentive monitoring, its benefits far outweigh its risks.

🔎 DROZDOGAN Academy Commentary

These trials mark a new era in breast cancer treatment. It is becoming possible not only to control disease but also to increase the chance of complete recovery .

• After surgery (in patients whose tumors persist despite neoadjuvant treatment), T-DXdis a strong enough candidate to replace the previous standard, T-DM1. Fewer patients experience recurrence, with longer cancer-free survival.
• Before surgery, T-DXd-containing treatments significantly increase the likelihood of complete tumor disappearance. This may eventually mean fewer operations, less additional treatment, and longer disease-free lives.
• Like any powerful drug, T-DXd has aspects requiring caution. Lung inflammation (ILD) risk is low, but careful monitoring and treatment at experienced centers matter. Prompt symptom reporting improves safety.
• Brain metastasis risk was another setting in which T-DXd showed promising results, suggesting less brain involvement may occur with this drug in the future.
• In conclusion: These data show the beginning of the “ADC era” in early breast cancer. The aim is now not just treatment but complete recovery for more patients. Treatment selection should balance risk level, side-effect profile, and quality of life more carefully than ever.

A Quick Roadmap for Clinical Practice

1. Residual invasive disease after neoadjuvant treatment: Adjuvant T-DXd should be considered.
2. Neoadjuvant selection: For high-risk cases, the T-DXd-THP regimen is rational; proceed in line with local boards and updated guidelines.
3. ILD monitoring: Baseline lung assessment, early symptom education, a low threshold for CT; if suspected, stop promptly/start steroids.
4. Patient education: Nausea management, cardiac monitoring (low risk but important), and emphasis on long-term follow-up.

📚 References

1. Geyer C, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with high-risk HER2-positive primary breast cancer with residual invasive disease after neoadjuvant therapy: Interim analysis of DESTINY-Breast05. ESMO Congress 2025 – LBA1.
2. Harbeck N, et al. DESTINY-Breast11: Neoadjuvant trastuzumab deruxtecan alone (T-DXd) or followed by paclitaxel + trastuzumab + pertuzumab (T-DXd-THP) vs SOC for high-risk HER2-positive early breast cancer. ESMO Congress 2025 – Abstract 291O.

Note: Summaries are based on congress presentations; final peer-reviewed publications may differ.