A New Era in HER2-Positive Breast Cancer: Pathological Complete Response May Allow Less Chemotherapy

Is Less Enough—and More Too Much?

Is the CompassHER2 pCR Study Changing Chemotherapy for HER2-Positive Breast Cancer?

📌 Introduction: Why Does This Study Matter?

Accounting for approximately 20% of breast cancers, HER2-positive breast cancer was once considered a subtype with an unfavorable course. Over the past 20 years, anti-HER2 therapies have turned it into a success story. However, that success often came with a heavy burden of chemotherapy . Until now, the standard was a combination of an anthracycline + a taxane + anti-HER2 antibodies .

But is it possible to reduce chemotherapy while maintaining efficacy? The CompassHER2 pCR study, which seeks to answer this question, attracted considerable attention at ASCO 2025.

🧪 Key Features of the Study

• Name: CompassHER2 pCR (EA1181)
• Design: Phase 2, single-arm (nonrandomized)
• Patient population: Patients with early-stage (stage II-IIIa) HER2-positive breast cancer, including both ER-negative and ER-positive disease
• Treatment:
  • A taxane (paclitaxel or docetaxel) for 12 weeks
  • Trastuzumab + pertuzumab (THP regimen)
  • No anthracycline!
• Postoperative approach:
  • pCR (pathological Complete Response, meaning a complete pathological response) achieved: Continue with HER2-targeted therapy alone (trastuzumab ± pertuzumab)
  • Patients who do not achieve pCR receive T-DM1 or similar intensified adjuvant therapies.

🎯 Key Findings: Who Benefits More?

✅ Overall pCR Rate:

• All patients: 44%
• Patients with HER2+/ER− disease: 64%
• Patients with HER2+/ER+ disease: 32%

🔍 The Level of ER Positivity Matters!

• ER 1-10%: pCR 62.5%
• ER 11-69%: pCR 51.6%
• ER ≥70%: pCR 22.5% ➡️ In other words, pCR increases as ER expression decreases.

🧬 The HER2DX pCR Score Emerges as an Effective Biomarker

The HER2DX pCR scoreis based on the gene-expression profile of a patient's tumor tissue and certain clinical characteristics, providing a genomic risk score. It is used to predict pathological complete response (pCR) to neoadjuvant treatment, such as the THP regimen in an individual patient.

In this study, the HER2DX score was calculated using tumor samples from biopsies of 569 patients enrolled in CompassHER2 pCR.

• The pCR rate reached 68% in patients with a high HER2DX pCR score.

  • This means that approximately two-thirds of these patients became tumor-free before surgery with THP alone.

• In patients with a low score, the pCR rate was only 19%.

  • This group therefore appears more resistant to treatment.

If incorporated into clinical practice, HER2DX could:

• Both prevent unnecessary chemotherapy,

• And identify high-risk patients earlier to support differentiated treatment decisions.

📉 The Progression Rate Was Very Low

• Proportion of patients whose disease progressed during THP: 0.7%

⚖️ Comparison With the Traditional Approach

The strongest message from this study is:

In patients who achieve pCR after 12 weeks of taxane-containing THP, anthracyclines or additional chemotherapy are not needed. This could represent a groundbreaking change in patient comfort and long-term adverse effects.

🧭 What Will Change in Clinical Practice?

If the patient:

• Has HER2+/ER- disease and
• achieves pCR, 👉 postoperative treatment may continue without additional chemotherapy, using HER2-targeted antibody therapy alone .

If the patient:

• Is ER-positive and
• has a high HER2DX score / low ER expression, 👉 a good response may again be expected with less chemotherapy.

➡️ This approach shows that personalized treatment can also be applied to the intensity of chemotherapy .

🔮 What Could Happen in the Future?

Data on the primary endpoint of CompassHER2, 3-year recurrence-free survival (RFS) , have not yet been released. However, the high pCR rates and low progression rate are encouraging.

If these results are confirmed:

• ✅ Chemotherapy intensity could be substantially reduced in patients with early-stage HER2-positive disease.
• ✅ Biomarkers such as HER2DX could help predict who will recover with less treatment.

📣 Final Thoughts

In HER2-positive breast cancer, it may now be possible to achieve more with less. CompassHER2 pCR is more than a proposal for a regimen: it is a call to rethink chemotherapy .

👉 These findings also have the potential to reduce the healthcare system's chemotherapy burden while improving patient comfort and quality of life.

📌 This study suggests that patients whose tumors disappear completely (pCR) may achieve successful outcomes with less chemotherapy.

❗ However, not all patients achieve this response. More information is therefore needed about the long-term outcomes of other patients treated with fewer drugs.