Breast cancer has been one of the largest global threats to women’s health for decades, with the American Cancer Society estimating nearly 297,790 new cases in U.S. women during 2023 alone.  


Recent developments in clinical research have highlighted the possibility of targeting HER2 receptors, which cause malignant growth when overexpressed and are not only the root of 15-20% of breast cancers, but also 10-30% of gastroesophageal cancers.  


HER2 is often targeted in oncology due to its role in:  

  • Signaling cell proliferation  
  • Tumor angiogenesis  
  • Prevention of apoptosis  


While the discovery and use of anti-HER2 therapies has been a source of hope for many, a common humanized monoclonal antibody used in these therapies named ‘Trastuzumab’ has been found to cause cardiotoxicity, or heart failure, within patients.  


Though no study has directly connected the risk of heart failure and its correlation to undergoing these combination and monotherapies, experts have used pharmacovigilance databases to draw some associations between the use of these therapies and heart failure.  


Follow along as we dive into recent findings concerning treatments related to:  

  • Anti-HER2 therapies 
  • Early stage & metastatic breast cancer therapies  
  • Other combination therapies  


Anti-HER2 Therapies 


HER2, or ‘human epidermal growth factor receptor-2’, is a major therapeutic target for patients with HER2-positive breast cancers.  


These therapies include:  

  • Monoclonal antibodies  
  • Tyrosine kinase inhibitors  
  • Antibody-drug conjugates 


Monoclonal Antibodies  


Treatment names: Trastuzumab, Pertuzumab  


As stated above, while the discovery of anti-HER2 therapies was and still continues to be a fount of hope for health care professionals and patients alike, the correlation between trastuzumab and heart failure must be observed.  


After sifting through 18,756 reports of adverse drug reaction within pharmacovigilance databases, it was found that 11.04% of these reports were filed due to heart failure.  


Additionally, a higher risk for heart failure while undergoing monoclonal antibody therapies was reported in both the full cohort of adverse drug reaction cases as well as the subgroup of breast cancer cases.  


Tyrosine Kinase Inhibitors  


Treatment names: Tucatinib, Neratinib, Lapatinib, Afatinib  


While there were fewer adverse drug reactions reported for these therapies, only 655 cases, 0.31% of these reports were made because of heart failure.  


Though this is a smaller amount of reports and heart failure cases, it still must be taken into consideration when evaluating the pharmacovigilance efforts made toward these types of therapies.  


Antibody Drug Conjugates (ADCs) 


Treatment names: Trastuzumab Deruxtecan (T-DXd), Trastuzumab Emtansine (T-DM1) 


These therapies were the most moderate in terms of adverse drug reactions reports when compared to the previous two types of anti-HER2 therapies.  


Among 4,930 adverse drug reaction reports, 1.56% of them were made due to heart failure.  


Early Stage & Metastatic Breast Cancer Therapies 


There were two types of early stage & metastatic cancer therapies that were included within this correlative research:  

  • ACTH  
  • AC-THP  


While undergoing these therapies, 22% of patients treated were reported to have an adverse drug reaction of heart failure.  




Treatment sequence: Doxorubicin/Cyclophosphamide followed by Trastuzumab/Paclitaxel 




Treatment sequence: Doxorubicin/Cyclophosphamide followed by Paclitaxel/ Trastuzumab/Pertuzumab 


Researchers found that patients using either ACTH or AC-THP had a heart failure risk 4-6 times greater than patients using other combination regimens.  


Other Combinations  


Professionals also observed the correlation between heart failure and other common combination therapies, such as:  

  • Trastuzumab combined with other monotherapies 
  • Lapatinib combined with other monotherapies  


Trastuzumab and Other Monotherapies  


Treatment combinations: 

  • Trastuzumab, Pertuzumab and Paclitaxel  
  • Trastuzumab, Pertuzumab and Docetaxel 
  • Trastuzumab and Pertuzumab  
  • Trastuzumab and HER2 Tyrosine Kinase Inhibitor 


When comparing these treatment combinations with platinum-based chemotherapy, researchers found the therapies above to be associated with a heart failure risk 2-3 times as high.  


Lapatinib and Other Monotherapies 


Lapatinib as a monotherapy showed great promise, as only 0.63% of adverse drug reaction reports were filed because of heart failure.  


The drug was then tried as a combination therapy within the following treatment sequences:  

  • Lapatinib and Trastuzumab  
  • Lapatinib and Taxane-based Chemotherapy  
  • Lapatinib and Platinum-based Chemotherapy  
  • Lapatinib, Carboplatin and Paclitaxel 


Unfortunately, these treatments showed the risk of heart failure as an adverse reaction being up to 11x higher when being used as combination therapies.  



Altogether, future clinical studies should be conducted to confirm the associations found within our databases. Furthermore, pharmacovigilance needs to be at the forefront of monitoring all adverse drug reactions in cancer indications.


JACC: CardioOncology, Written By Sarah Waliany MD, MS et al.