Breast cancer remains one of the most common cancers worldwide, with a growing understanding of its molecular subtypes shaping treatment options1. Enhertu (fam-trastuzumab deruxtecan-nxki) has emerged as a groundbreaking targeted therapy for HER2-low breast cancer, a subgroup previously lacking effective targeted treatments2. Recent clinical trials have demonstrated significant improvements in progression-free survival and overall survival with Enhertu compared to chemotherapy in this patient population23.
HER2-Low Breast Cancer Explained
HER2-low breast cancer deaths is a distinct subset characterized by low levels of HER2 protein expression, defined by immunohistochemistry (IHC) scores of 1+ or 2+ without HER2 gene amplification2. This differentiates it from HER2-negative breast cancer (IHC 0) and HER2-positive disease (IHC 3+ or gene amplified)2. HER2 (human epidermal growth factor receptor 2) is a receptor tyrosine kinase that regulates cell growth and survival, and its overexpression leads to increased tumor aggressiveness4. HER2-low tumors represent a significant proportion of breast cancers previously classified as HER2-negative2.
Before the advent of Enhertu, treatment options for HER2-low breast cancer were limited primarily to endocrine therapy for hormone receptor-positive disease or chemotherapy, with no approved targeted therapies specifically for this group25. The recognition of HER2-low as a biologically relevant category has opened new avenues for personalized treatment2.
Enhertu Mechanism of Action
Enhertu is a next-generation antibody-drug conjugate (ADC) composed of a humanized anti-HER2 monoclonal antibody (trastuzumab) linked to a potent topoisomerase I inhibitor payload (deruxtecan)4. The trastuzumab component specifically binds to HER2 receptors on cancer cells, allowing targeted delivery of the cytotoxic payload directly into tumor cells4. The drug-to-antibody ratio is high, approximately 8:1, enhancing the amount of chemotherapy delivered per antibody molecule4.
Upon binding to HER2, Enhertu is internalized by the cancer cell, where the linker is cleaved to release deruxtecan intracellularly, causing DNA damage and cell death4. Importantly, Enhertu exhibits a "bystander effect," where the released payload can diffuse into neighboring tumor cells with low or heterogeneous HER2 expression, broadening its antitumor activity4. This mechanism underlies its efficacy in HER2-low breast cancer, a population that previously lacked effective HER2-targeted therapies2.
“Endocrine therapy is typically used in the initial treatment of HR-positive metastatic breast cancer, and following progression, subsequent chemotherapy is associated with poor outcomes. Trastuzumab deruxtecan offers a potential new standard of care for patients with HR-positive, HER2-low or HER2-ultralow metastatic breast cancer following endocrine therapy, with a median progression-free survival exceeding one year and a response rate of more than 60 percent.”
— Aditya Bardia, MD, MPH, UCLA Health Jonsson Comprehensive Cancer Center6
Eligibility for Enhertu Treatment
Enhertu is approved for adult patients with unresectable or metastatic HER2-low breast cancer, defined as IHC 1+ or IHC 2+ without gene amplification, who have progressed on one or more endocrine therapies in the metastatic setting3. It is also indicated for patients with HER2-ultralow breast cancer (IHC 0 with membrane staining) under similar conditions3. Additionally, patients with HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence within six months of completing adjuvant chemotherapy are eligible3.
The drug is also approved for HER2-positive breast cancer patients who have received prior anti-HER2 regimens and for HER2-mutant non-small cell lung cancer after prior systemic therapy27. Ongoing clinical trials are evaluating Enhertu’s role in other HER2-expressing solid tumors8.
Enhertu Administration and Dosage
Enhertu is administered as an intravenous infusion at a dose of 5.4 mg/kg every three weeks (21-day cycle) until disease progression or unacceptable toxicity occurs39. The infusion typically lasts between 30 to 90 minutes and is given under the supervision of a healthcare professional9. Premedication to prevent nausea and vomiting may be provided as needed9.
Treatment should be guided by regular monitoring of patient response and tolerability, with dose modifications applied for adverse effects9. The dosing regimen is consistent across HER2-low and HER2-positive breast cancer indications3.
Enhertu Efficacy and Clinical Results
The efficacy of Enhertu in HER2-low breast cancer was established primarily through the DESTINY-Breast04 and DESTINY-Breast06 Phase III trials23. In DESTINY-Breast06, 866 patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer were randomized to receive Enhertu or physician’s choice chemotherapy3. The trial demonstrated a significant improvement in progression-free survival (PFS), with a median PFS of 13.2 months for Enhertu versus 8.1 months for chemotherapy in the HER2-low population (hazard ratio [HR] 0.62; p < 0.0001)3. Overall survival (OS) data were immature at the time of analysis but showed a favorable trend3.
In patients with measurable disease, the confirmed objective response rate (ORR) was 65.7% with Enhertu compared to 30.8% with chemotherapy3. These results mark Enhertu as the first HER2-directed therapy to show a survival benefit in HER2-low breast cancer2.
“In a trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician’s choice of chemotherapy.”
— Shanu Modi, M.D.10
Common and Serious Side Effects
Enhertu’s safety profile includes both common and serious adverse events. The most frequent side effects reported in clinical trials include gastrointestinal symptoms such as nausea and vomiting, as well as hematologic toxicities like neutropenia and anemia113. Other common adverse reactions include fatigue, alopecia, decreased appetite, diarrhea, and elevated liver enzymes39.
A serious and potentially fatal risk associated with Enhertu is interstitial lung disease (ILD) or pneumonitis, which requires vigilant monitoring and prompt management113. Patients should be regularly assessed for respiratory symptoms such as cough, dyspnea, and fever, and treatment should be discontinued if ILD of grade 2 or higher develops3.
| Common Side Effects | Serious Risks |
|---|---|
| Nausea and vomiting113 | Interstitial lung disease (ILD)113 |
| Neutropenia and anemia11 | Embryo-fetal toxicity3 |
| Fatigue113 | Cardiac dysfunction (LVEF decrease)3 |
| Alopecia113 | Myelosuppression11 |
| Elevated liver enzymes3 |
Important Treatment Considerations
Before initiating Enhertu, patients should be evaluated for pre-existing lung conditions, cardiac function, and pregnancy status due to risks of ILD, heart failure, and embryo-fetal toxicity39. Effective contraception is advised for females during treatment and for 7 months after the last dose, and for males with female partners of reproductive potential during treatment and for 4 months afterward39.
Regular monitoring of left ventricular ejection fraction (LVEF) is recommended, with treatment interruption or discontinuation based on severity of cardiac dysfunction3. Hematologic parameters should be closely observed to manage neutropenia and anemia11.
Patients with moderate renal impairment require more frequent monitoring, and safety in severe renal impairment has not been established3. Enhertu is not approved for pediatric use, and elderly patients may experience higher rates of severe adverse reactions3.
💡 Did You Know? Enhertu demonstrated a highly statistically significant and clinically meaningful improvement in invasive disease-free survival compared to T-DM1 in early breast cancer settings, highlighting its expanding role in HER2-targeted therapy12.
When to Contact Your Healthcare Team
Patients receiving Enhertu should promptly report any new or worsening symptoms, especially:
- Respiratory symptoms such as cough, shortness of breath, or fever, which may indicate ILD or pneumonitis113.
- Signs of infection, including fever or chills, due to neutropenia-related immunosuppression11.
- Unusual bleeding or bruising, which could signal thrombocytopenia9.
- Symptoms of heart failure, including chest pain, swelling of legs, or rapid weight gain3.
- Pregnancy or suspected pregnancy, given the risk of fetal harm3.
Early communication with the healthcare team allows timely intervention to manage side effects and optimize treatment outcomes.
Enhertu’s approval marks a paradigm shift in breast cancer treatment by extending HER2-targeted therapy benefits to patients with low HER2 expression, a group that previously had limited options. Its unique mechanism and clinical efficacy offer hope for improved outcomes in this large patient population.10236
Summary and Key Takeaways
- HER2-low breast cancer is defined by low HER2 protein expression (IHC 1+ or 2+ without gene amplification) and represents a significant subgroup previously lacking targeted therapies2.
- Enhertu is a HER2-directed antibody-drug conjugate that delivers a potent chemotherapy payload directly to HER2-expressing tumor cells, including those with low HER2 levels, through a bystander effect4.
- It is approved for unresectable or metastatic HER2-low breast cancer after progression on endocrine therapy or chemotherapy, offering a new standard of care3.
- Clinical trials demonstrated significant improvements in progression-free survival and objective response rates compared to chemotherapy, with a manageable safety profile23.
- Serious risks include interstitial lung disease and cardiac toxicity, necessitating close monitoring and prompt management113.
