The WSG-KEYRICHED-1 trial represents a significant step toward personalized, less toxic cancer therapies by identifying which HER2-positive patients can achieve complete response with targeted therapies alone.
Imagine a future where certain breast cancer patients could undergo effective treatment without losing their hair or experiencing the debilitating fatigue of chemotherapy. This vision is steadily moving from possibility to reality, thanks to groundbreaking research in cancer biomarkers.
The WSG-KEYRICHED-1 trial represents a significant step toward this future, exploring whether we can use specific molecular signatures to identify which patients with HER2-positive breast cancer might achieve complete cancer eradication through targeted therapies alone—bypassing chemotherapy entirely 4 .
This research frontier matters profoundly because while chemotherapy saves lives, it often comes with substantial physical and emotional costs. The Keyriched-1 trial doesn't just test new drug combinations; it challenges fundamental cancer treatment paradigms and pushes us toward more personalized, less toxic approaches. By analyzing multiple biomarkers, researchers hope to create a "predictive blueprint" that can tell us in advance which patients are most likely to benefit from chemotherapy-free treatment 4 6 .
of breast cancers are HER2-positive
of patients may not need chemotherapy
achieved pCR without chemotherapy in Keyriched-1
HER2-positive breast cancer accounts for approximately 15-20% of all breast cancer cases and was historically considered one of the most aggressive forms of the disease 2 . The "HER2" name refers to a protein called Human Epidermal Growth Factor Receptor 2 that sits on the surface of breast cells. In HER2-positive cancer, these receptors are overproduced—a condition known as "HER2 amplification"—causing cells to divide and multiply uncontrollably 6 .
The discovery of HER2's role led to a revolutionary class of medicines known as targeted therapies, specifically designed to block HER2 receptors. Trastuzumab (Herceptin) was the pioneering drug in this category, dramatically improving outcomes for HER2-positive patients. Later, pertuzumab (Perjeta) was developed to target a different part of the HER2 receptor, creating a powerful "dual blockade" when combined with trastuzumab 1 2 .
HER2 gene amplification leads to overexpression of HER2 receptors on cell surfaces, driving uncontrolled cell growth.
For years, the standard approach for HER2-positive breast cancer involved combining these targeted drugs with chemotherapy. However, researchers noticed that a significant subset of patients—approximately 30-40%—achieved excellent outcomes with less intensive treatments 4 7 . This observation sparked the "de-escalation" movement: the strategic reduction of treatment intensity for patients who can maintain excellent outcomes while avoiding unnecessary side effects.
| Treatment Era | Therapeutic Approach | Key Limitations |
|---|---|---|
| Pre-Targeted Therapy | Chemotherapy alone | High recurrence rates, poor prognosis |
| Initial Targeted Therapy | Chemotherapy + trastuzumab | Significant chemotherapy side effects |
| Dual Blockade | Chemotherapy + trastuzumab + pertuzumab | Improved efficacy but continued chemotherapy toxicity |
| Current De-escalation | Chemotherapy-free regimens (investigational) | Identifying appropriate patients remains challenging |
The WSG-KEYRICHED-1 trial was a multicenter, single-arm, phase 2 study conducted at 15 breast cancer centers across Germany 4 . The trial addressed a compelling question: Could patients with the "HER2-enriched" molecular subtype achieve pathological complete response with a short, chemotherapy-free regimen of pembrolizumab (an immunotherapy drug) combined with the dual HER2-blockade of trastuzumab and pertuzumab? 5
The scientific premise was intriguing—the HER2-enriched subtype is characterized by high immune cell infiltration within tumors, suggesting these cancers might be particularly susceptible to immunotherapy approaches 4 . Previous research had also demonstrated that patients with this specific molecular subtype tend to respond better to anti-HER2 therapies overall 6 .
The trial employed strict molecular criteria for participation, enrolling 48 women with previously untreated, early-stage HER2-positive breast cancer of the HER2-enriched subtype, as determined by the PAM50 gene expression assay 4 5 . This meticulous patient selection represents the core principle of precision medicine: matching the right treatment to the right patient based on their cancer's specific biological characteristics.
Participants received four cycles of intravenous pembrolizumab, trastuzumab, and pertuzumab over 12 weeks before undergoing surgery. The primary endpoint was pathological complete response (pCR), defined as the absence of invasive cancer in the breast and lymph nodes at the time of surgery 4 .
Patients Enrolled
Centers in Germany
Weeks of Treatment
Treatment Cycles
Potential participants underwent comprehensive biomarker testing using the PAM50 assay to confirm HER2-enriched subtype 4 5 .
Tumor imaging (breast ultrasound, CT scans), cardiac function tests, and laboratory studies were performed 5 .
Patients underwent surgery within 3 weeks after treatment completion, with pathological assessment of response 4 .
The "combined biomarker analysis" referenced in the abstract likely involved multiple sophisticated techniques to identify predictors of treatment response:
After a median follow-up of 8.6 months, the results offered promising evidence for the chemotherapy-free approach 4 :
While this did not meet the pre-specified statistical threshold for significance (52.2%), it demonstrates that a clinically meaningful proportion of HER2-enriched patients can achieve complete response without chemotherapy 4 . The response rate is particularly notable given the short treatment duration of only 12 weeks 7 .
The triplet regimen demonstrated a manageable safety profile with only 4 patients (8%) experiencing grade 3-4 treatment-related adverse events 4 7 . The most common side effects included:
Serious adverse events occurred in four patients, but no treatment-related deaths were reported 4 . This safety data is particularly important when considering that the regimen completely omitted conventional chemotherapy, which typically causes more frequent and severe side effects like hair loss, low blood counts, and nerve damage.
| Outcome Measure | Result | Significance |
|---|---|---|
| Pathological Complete Response (pCR) | 47% (20/43) | Did not meet primary endpoint (p=0.22) |
| Treatment Duration | 12 weeks | Shorter than conventional chemotherapy regimens |
| Most Common Grade 3-4 Adverse Events | Increased ALT, drug hypersensitivity, nephritis, panic attack | Only 4 patients (8%) experienced grade 3-4 treatment-related events |
| Treatment Discontinuation Due to Adverse Events | 3 patients (6%) | All related to pembrolizumab component |
The trial's design presupposed that the HER2-enriched molecular subtype would predict better response to the chemotherapy-free regimen. Previous research supports this hypothesis—one study found that MammaTyper-defined HER2-enriched patients showed significantly better response to anti-HER2 therapy compared to those defined by immunohistochemistry alone 6 .
The HER2-enriched subtype is characterized by:
While the complete combined biomarker analysis from Keyriched-1 is not fully detailed in the available sources, other studies provide clues about promising predictive biomarkers:
Dynamics during treatment may predict response; patients achieving rapid ctDNA clearance tend to have better outcomes 1 .
Predictive strength: High
Higher levels of immune cells within tumors may enhance response to immunotherapy combinations 2 .
Predictive strength: Moderate to High
While not consistently predictive across all cancers, this immune checkpoint marker might help identify patients most likely to benefit from pembrolizumab .
Predictive strength: Moderate
| Tool/Reagent | Primary Function | Application in Keyriched-1 |
|---|---|---|
| PAM50 Gene Expression Assay | Molecular subtyping of breast cancer | Identification of HER2-enriched patients for trial enrollment |
| Immunohistochemistry (IHC) | Protein-level detection of HER2, ER, PR | Standard pathology confirmation of HER2 status |
| Pembrolizumab | Anti-PD-1 immunotherapy | Blockade of immune checkpoint pathways to enhance anti-tumor immunity |
| Trastuzumab | HER2-targeted monoclonal antibody | Primary blockade of HER2 signaling pathways |
| Pertuzumab | HER2-targeted monoclonal antibody | Complementary HER2 blockade at different receptor domains |
| ctDNA Analysis | Liquid biopsy via blood sample | Potential monitoring of treatment response and minimal residual disease |
The Keyriched-1 trial represents a compelling step toward personalized, chemotherapy-free treatment for a biologically distinct subset of HER2-positive breast cancer. While the study did not meet its primary statistical endpoint, it provides compelling evidence that nearly half of carefully selected patients can achieve complete pathological response without chemotherapy 4 7 .
The broader implication of this research extends beyond the specific drug combination tested. It demonstrates a fundamental shift in oncology: from categorizing cancers solely by organ of origin and traditional markers to understanding their molecular wiring and immune microenvironment. This approach allows us to ask not just "what type of cancer is this?" but "what treatment approach best matches this cancer's specific vulnerabilities?"
Researchers emphasize that randomized trials are needed to definitively establish the efficacy of this chemotherapy-free approach 4 .
Future studies will likely integrate multimodal biomarker panels combining intrinsic subtyping, immune profiling, and circulating tumor DNA analysis.
As Dr. Sherko Kuemmel, the study's lead author, and colleagues concluded: "The WSG-KEYRICHED-1 trial highlights the potential of a short chemotherapy-free combination of pembrolizumab with dual anti-HER2 therapy, warranting the initiation of randomised trials investigating the immunotherapy without chemotherapy in patients with HER2-enriched breast cancer" 4 . For patients facing HER2-positive breast cancer, this research direction offers hope for effective treatments that preserve quality of life—a crucial dimension of cancer care that extends beyond survival statistics alone.