How a New Monoclonal Antibody is Redefining Breast Cancer Treatment
In January 2025, the U.S. FDA greenlit a breakthrough that shattered decades-old breast cancer classifications: fam-trastuzumab deruxtecan-nxki (Enhertu) became the first HER2-targeted therapy approved for HER2-low and HER2-ultralow metastatic breast cancer. This approval marks a paradigm shift—60-70% of previously "HER2-negative" patients now qualify for targeted treatment, turning hopeless cases into manageable chronic conditions 1 5 .
First FDA-approved therapy for HER2-low and HER2-ultralow breast cancer, expanding treatment options for 60-70% of previously classified "HER2-negative" patients.
Initial FDA approval for HER2-positive breast cancer
Approval expanded to HER2-low metastatic breast cancer
Breakthrough approval for HER2-ultralow classification
Traditionally, breast cancer was split into:
| Classification | IHC/ISH Status | Patient Population |
|---|---|---|
| HER2-positive | IHC 3+ or IHC 2+/ISH+ | 15-20% |
| HER2-low | IHC 1+ or IHC 2+/ISH- | 50-60% |
| HER2-ultralow | IHC 0 (membrane staining) | 20-25% |
HER2 (Human Epidermal Growth Factor Receptor 2) is a protein that drives cancer growth. Enhertu—an antibody-drug conjugate (ADC)—combines:
Monoclonal antibody targeting HER2
Potent chemotherapy payload
Releases drug inside cancer cells
This "smart missile" delivers 8x more chemotherapy to tumors than normal cells, minimizing systemic toxicity 5 8 .
The phase III trial enrolled 866 patients with HR-positive, HER2-low or HER2-ultralow metastatic breast cancer who progressed after endocrine therapy. Key design elements:
| Endpoint | Enhertu | Chemotherapy | Improvement |
|---|---|---|---|
| Median PFS (overall) | 13.2 months | 8.1 months | 63% risk reduction (HR 0.64) |
| Confirmed ORR | 62.6% | 34.4% | Near doubling of response |
| HER2-ultralow PFS | 15.1 months | 8.3 months | HR 0.76 |
Exploratory Analysis: HER2-ultralow patients—previously deemed "untargetable"—saw tumor shrinkage rates of 65.7% vs. 30.8% with chemo 1 .
| Adverse Event | Enhertu (%) | Chemotherapy (%) |
|---|---|---|
| Decreased white blood cells | 43.1 | 59.2 |
| Nausea | 20.1 | 10.3 |
| Alopecia | 18.7 | 28.9 |
| Interstitial lung disease | 12.0* | 0.0 |
| Tool | Function | Impact |
|---|---|---|
| Ventana PATHWAY HER2 (4B5) | Standardized IHC staining for HER2-low/ultralow | FDA-approved companion diagnostic; minimizes lab variability |
| RECIST v1.1 guidelines | Tumor response assessment via CT/MRI | Enabled blinded independent central review of trial outcomes 1 |
| Trastuzumab deruxtecan | HER2-directed ADC payload delivery | Delivers cytotoxic payload only to HER2-expressing cells 5 |
| Circulating tumor DNA (ctDNA) | Mutation tracking in blood | Monitored resistance mechanisms in translational sub-studies 5 |
DESTINY-Breast09 shows Enhertu + pertuzumab extends 1st-line PFS to 40.7 months—surpassing traditional chemo/anti-HER2 combos 8 .
Trials exploring ADCs + immunotherapy (e.g., KEYNOTE-D19) may overcome resistance 8 .
"With PFS exceeding one year and response rates over 60%, Enhertu offers a new standard for HR-positive, HER2-low/ultralow metastatic breast cancer post-endocrine therapy."
Enhertu's approval signifies more than a new drug—it redefines cancer classification itself. By leveraging ultra-sensitive diagnostics to identify "hidden" HER2 expression, we've unlocked targeted therapy for thousands left behind by traditional paradigms. As ADC technology evolves, one truth emerges: In the war against cancer, the smallest molecular fingerprints may hold the biggest keys to victory.