A Comprehensive Analysis of Adverse Events Associated with HER2 Inhibitors Approved for Breast Cancer Using the FDA Adverse Event Report System (FAERS)
Abstract
1. Introduction
2. Results
2.1. Baseline Characteristics of the Analytic Dataset
2.2. Construction of the Analytical Data Table
2.3. Number of Reports
2.4. Frequently Reported AEs
2.5. Hierarchical Cluster Analysis
2.6. PCA
3. Discussion
3.1. Baseline Characteristics and Number of AE Reports Related to HER2 Inhibitors
3.2. Classification of HER2 Inhibitors Based on Hierarchical Clustering Analysis
3.3. Classification of AEs Based on Clustering Analysis
- Cluster 1: abdominal pain, alopecia, cardiac failure, chills, cough, death, dyspnea, general physical health deterioration, malaise, pneumonia, pyrexia, and urinary tract infection.
- Cluster 2: anxiety, arthralgia, back pain, dizziness, drug ineffective, erythema, headache, hypoesthesia, myalgia, pain, pain in extremity, paresthesia, pruritus, and rash.
- Cluster 3: anemia, febrile neutropenia, neutropenia, decreased platelet count, pleural effusion, thrombocytopenia, decreased white blood cell count.
- Cluster 4: asthenia, constipation, decreased appetite, dehydration, diarrhea, epistaxis, fatigue, malignant neoplasm progression, nausea, stomatitis, vomiting, and decreased weight.
- Cluster 5: hair color changes, hair disorders, abnormal hair texture, and madarosis.
- Cluster 6: infusion-related reactions and ILD.
- Cluster 7: myelosuppression.
- Cluster 8: breast cancer metastatic, cardiotoxicity, disease progression, decreased ejection fraction, hypokalemia, metastases to the central nervous system, mucosal inflammation, peripheral neuropathy, and palmar–plantar erythrodysesthesia syndrome
3.4. PCA
3.5. Limitations and Strengths
4. Materials and Methods
4.1. Data Table Construction
4.2. Terminology for AEs and Targeted Drugs
4.3. Selection and Exclusion Criteria
- Selection Criteria
- Drugs with HER2-inhibitory activity approved for breast cancer treatment.
- AEs reported in association with the above drugs in the FAERS database.
- AEs with the number of reports exceeding approximately 10% of the maximum count observed (i.e., >1500 reports).
- PTs coded using MedDRA version 27.1.
- Drugs designated as primary or suspect in the FAERS DRUG table.
- Primary IDs corresponding to HER2 inhibitors were fully retained after merging.
- Exclusion Criteria
- Drugs not classified as HER2-targeted agents or not approved for breast cancer treatment.
- AEs with 1500 or fewer total reports.
- AE terms deemed nonclinical or nonspecific, such as “no adverse event” or “off-label use.”
- Concomitant and interaction drugs listed in the FAERS DRUG table.
- Records with missing values in the DRUG or REAC tables after merging.
4.4. Outcomes
4.5. Disproportionality Analysis of AEs Associated with HER2 Inhibitors
4.6. Construction of the Data Matrix for Clustering and PCA
4.7. Hierarchical Clustering Analysis
4.8. PCA
4.9. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AE | Adverse event |
FDA | Food and Drug Administration |
ILD | Interstitial lung disease |
JSPS | Japan Society for the Promotion of Science |
lnROR | Natural logarithm of the reporting odds ratio |
PCA | Principal component analysis |
QoL | Quality of life |
RORs | Reporting odds ratios |
SRSs | Spontaneous reporting systems |
mAbs | Monoclonal antibodies |
ADCs | Antibody–drug conjugates |
TKIs | Tyrosine kinase inhibitors |
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Characteristics | No. | (%) | |
---|---|---|---|
Number of Reports | 96,222 | ||
Sex | |||
Data available | 82,416 | ||
Female | 76,736 | 93.11% | |
Male | 5108 | 6.20% | |
Unknown | 572 | 0.69% | |
Age (years) | |||
Data available | 57,608 | ||
<30 | 675 | 1.17% | |
30–39 | 4618 | 8.02% | |
40–49 | 11,135 | 19.33% | |
50–59 | 17,031 | 29.56% | |
60–69 | 14,645 | 25.42% | |
70–79 | 7626 | 13.24% | |
80 or older | 1878 | 3.26% | |
Median (IQR) | 57 (48–66) | ||
Body weight (kg) | |||
Data available | 27,265 | ||
<40 | 379 | 1.39% | |
40–49 | 2382 | 8.74% | |
50–59 | 6365 | 23.35% | |
60–69 | 7140 | 26.19% | |
70–79 | 4705 | 17.26% | |
80–89 | 3067 | 11.25% | |
90 or more | 3227 | 11.84% | |
Median (IQR) | 65 (56–78) | ||
Reporting countries (Top 5) | |||
Data available | 95,625 | ||
United States | 37,984 | 39.72% | |
China | 6111 | 6.39% | |
Japan | 5945 | 6.22% | |
United Kingdom | 5646 | 5.90% | |
Canada | 5516 | 5.77% |
Drug | Number of Reports | (%) | First Report Date |
---|---|---|---|
Monoclonal antibodies (mAbs) | 141,878 | (69.14) | |
Trastuzumab | 101,528 | (49.48) | 7 January 2004 |
Pertuzumab | 40,264 | (19.62) | 29 October 2004 |
Margetuximab | 86 | (0.04) | 9 March 2021 |
Antibody–drug conjugates (ADCs) | 20,711 | (10.09) | |
Trastuzumab emtansine (T-DM1) | 13,613 | (6.63) | 23 September 2011 |
Trastuzumab deruxtecan (T-DXd) | 7098 | (3.46) | 22 January 2020 |
Tyrosine kinase inhibitors (TKIs) | 42,607 | (20.76) | |
Lapatinib | 27,103 | (13.21) | 24 August 2004 |
Tucatinib | 9259 | (4.51) | 4 November 2004 |
Neratinib | 5535 | (2.70) | 31 July 2009 |
Pyrotinib | 710 | (0.35) | 20 December 2018 |
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Yajima, A.; Uesawa, Y. A Comprehensive Analysis of Adverse Events Associated with HER2 Inhibitors Approved for Breast Cancer Using the FDA Adverse Event Report System (FAERS). Pharmaceuticals 2025, 18, 1510. https://doi.org/10.3390/ph18101510
Yajima A, Uesawa Y. A Comprehensive Analysis of Adverse Events Associated with HER2 Inhibitors Approved for Breast Cancer Using the FDA Adverse Event Report System (FAERS). Pharmaceuticals. 2025; 18(10):1510. https://doi.org/10.3390/ph18101510
Chicago/Turabian StyleYajima, Airi, and Yoshihiro Uesawa. 2025. "A Comprehensive Analysis of Adverse Events Associated with HER2 Inhibitors Approved for Breast Cancer Using the FDA Adverse Event Report System (FAERS)" Pharmaceuticals 18, no. 10: 1510. https://doi.org/10.3390/ph18101510
APA StyleYajima, A., & Uesawa, Y. (2025). A Comprehensive Analysis of Adverse Events Associated with HER2 Inhibitors Approved for Breast Cancer Using the FDA Adverse Event Report System (FAERS). Pharmaceuticals, 18(10), 1510. https://doi.org/10.3390/ph18101510