The Changing Landscape of HER2-Positive Breast Cancer
For decades, a diagnosis of HER2-positive breast cancer was met with significant concern. This subtype, characterized by the over-expression of the Human Epidermal Growth Factor Receptor 2 (HER2) protein, was historically known for being aggressive and having a poor prognosis. The advent of HER2-targeted therapies, starting with trastuzumab, revolutionized treatment, turning a once-deadly diagnosis into a highly manageable one. However, the cornerstone of this success has traditionally been a combination of targeted therapy and intensive chemotherapy.
While chemotherapy is effective, it is also toxic. Patients often endure hair loss, severe nausea, neuropathy, and long-term risks to heart and bone marrow health. As our understanding of tumor biology deepens, a pivotal question has emerged: Do all HER2-positive patients truly need chemotherapy? Or can we identify a subset of patients who can achieve a cure using only targeted biological agents and immunotherapy?
The WSG-KEYRICHED-1 Trial: A Bold Step Toward De-escalation
The West German Study Group (WSG) recently conducted the KEYRICHED-1 trial to explore this very possibility. This phase 2, multicenter trial focused specifically on a biological subset known as HER2-enriched (HER2-E) breast cancer. Unlike the general HER2-positive population, the HER2-enriched subtype, identified through PAM50 genomic testing, is particularly sensitive to HER2-targeted agents.
In this study, researchers investigated a neoadjuvant (pre-surgery) regimen that completely omitted traditional chemotherapy. Instead, patients received a triplet of biological agents:
1. Pembrolizumab: An immune checkpoint inhibitor (anti-PD-1) that helps the immune system recognize and attack cancer cells.
2. Trastuzumab: A monoclonal antibody that targets the HER2 receptor.
3. Pertuzumab: Another monoclonal antibody that prevents the HER2 receptor from pairing with other receptors, providing a dual blockade.
A Case in Point: Sarah’s Journey
Consider Sarah, a 46-year-old marketing executive and mother of two. When Sarah was diagnosed with Stage II HER2-positive breast cancer, her first thought was of the grueling chemotherapy sessions she had seen others endure. She was terrified of the fatigue and the physical changes that would hinder her ability to work and care for her family.
Sarah’s tumor was tested using a genomic assay, confirming it was the HER2-enriched subtype. Under the framework of a clinical trial similar to KEYRICHED-1, she was offered a chance to start treatment with only immunotherapy and HER2-blockers. For twelve weeks, Sarah received her infusions. She experienced some mild skin irritation and fatigue, but she never lost her hair, and she continued to lead her team at work. When Sarah eventually went to surgery, the pathology report showed a Pathological Complete Response (pCR)—meaning no invasive cancer cells remained in the breast or lymph nodes. For Sarah, the biological approach worked without the need for toxic chemicals.
What the Data Tell Us: Results of the KEYRICHED-1 Trial
The trial enrolled 48 women with early-stage, HER2-enriched breast cancer. The primary goal was to see if at least 52.2% of patients would achieve a pCR. While the final results showed that 47% (20 out of 43 evaluable patients) reached pCR, falling just short of the strict statistical target, the findings remain highly significant.
In the world of oncology, achieving nearly a 50% complete response rate in just 12 weeks without a single drop of chemotherapy is a remarkable feat. It suggests that for nearly half of these patients, the biological triplet was sufficient to eradicate the tumor before the surgeon even picked up a scalpel.
Safety and Quality of Life
One of the most compelling aspects of the trial was the safety profile. Only 8% of patients experienced grade 3-4 adverse events related to the treatment. These included issues like elevated liver enzymes, drug hypersensitivity, and one instance of a panic attack. Compare this to traditional chemotherapy regimens, where the rate of severe side effects is often much higher. No deaths occurred, and the vast majority of patients completed the 12-week course successfully. This high level of tolerability is a major win for patient quality of life.
Decoding the Response: The Multiomic Breakthrough
If 47% of patients responded perfectly, what happened to the other 53%? To answer this, the researchers performed a sophisticated multiomic factor analysis, looking at genes, immune cells, and protein markers within the tumor microenvironment.
They discovered that certain biological “fingerprints” could predict who would respond best to this chemo-free approach. Patients with high scores in factors related to immune response and tumor-infiltrating lymphocytes (TILs) had a much higher pCR rate. Specifically, the study identified four key genes—FNBP1, CD36, MYCN, and SIX1—that were strongly associated with a positive response.
| Group Category | Pathological Complete Response (pCR) Rate | Clinical Significance |
|---|---|---|
| High Multiomic Factor Score | 66.7% | Highly likely to benefit from chemo-free regimens |
| Low Multiomic Factor Score | 28.6% | May require traditional chemotherapy to achieve pCR |
This data shows that we are moving toward a future of precision medicine where a patient’s unique genetic signature determines whether they can safely skip chemotherapy.
Expert Insights and Commentary
Dr. Michael Thompson, a lead investigator in the field (fictional name for illustrative commentary), notes: The KEYRICHED-1 trial is a hypothesis-generating milestone. While we aren’t yet at the point where we can routinely skip chemotherapy in the clinic for all HER2-positive patients, this trial proves that for the HER2-enriched population, the immune system and targeted antibodies are a powerhouse duo. The next step is to use the biomarkers we identified to select the right patients for larger, randomized trials.
Experts emphasize that the combination of pembrolizumab with dual HER2 blockade leverages the synergy between the immune system and monoclonal antibodies. Trastuzumab and pertuzumab don’t just block growth signals; they also flag cancer cells for the immune system to destroy. Pembrolizumab then takes the brakes off the immune cells, allowing for a more aggressive attack on the tumor.
Practical Considerations for Patients
If you or a loved one are facing a HER2-positive breast cancer diagnosis, it is important to understand that the current standard of care still involves chemotherapy for most patients. However, these findings open up important conversations with oncology teams:
1. Genomic Subtyping: Ask your doctor if your tumor is HER2-enriched. This goes beyond the standard HER2-positive/negative test and can provide more insight into the tumor’s biology.
2. Clinical Trials: Inquire about neoadjuvant trials that explore de-escalated treatments. These trials offer access to cutting-edge combinations like the one used in KEYRICHED-1.
3. Biomarker Testing: As precision medicine advances, testing for markers like Tumor Infiltrating Lymphocytes (TILs) may become more common in guiding treatment intensity.
Conclusion
The WSG-KEYRICHED-1 trial brings us one step closer to a world where breast cancer treatment is no longer a “one-size-fits-all” sledgehammer approach. By identifying the HER2-enriched subtype and utilizing the power of immunotherapy, we can successfully treat a significant portion of patients while sparing them the long-term consequences of chemotherapy. The roadmap for the future is clear: more research, better biomarkers, and a continued focus on treating the person, not just the pathology.
Funding and clinicaltrials.gov
The WSG-KEYRICHED-1 trial was funded by Merck Sharp & Dohme and NanoString Technologies. The study is registered with ClinicalTrials.gov under the identifier NCT03988036.
References
Kuemmel S, Graeser M, Schmid P, et al. Chemotherapy-free neoadjuvant pembrolizumab combined with trastuzumab and pertuzumab in HER2-enriched early breast cancer (WSG-KEYRICHED-1): a single-arm, phase 2 trial. Lancet Oncol. 2025 May;26(5):629-640. doi: 10.1016/S1470-2045(25)00097-X.
Graeser M, Gluz O, Schmid P, et al. Multiomic Factor Analysis for Pathologic Complete Response after Pembrolizumab + Trastuzumab + Pertuzumab in HER2-Enriched Early Breast Cancer: WSG-Keyriched-1 Trial. Clin Cancer Res. 2026 Jan 6;32(1):214-223. doi: 10.1158/1078-0432.CCR-25-1923.