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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 2  |  Page : 73-77

Gender differences in cardiotoxicities associated with immune checkpoint inhibitor therapy in cancer patients


1 Department of Medicine, Nazareth Hospital, Pennsylvania, PA; Department of Public Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
2 Department of Internal Medicine, East Tennessee State University, Johnson City, TN, USA

Date of Submission12-May-2020
Date of Decision20-Jun-2020
Date of Acceptance21-Jun-2020
Date of Web Publication01-Aug-2020

Correspondence Address:
Dr. Sheharyar Minhas
260 Holme Avenue, Philadelphia 19152, PA
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCPC.JCPC_29_20

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  Abstract 


Background: Immune checkpoint inhibitors (ICIs) are increasingly being used for cancer therapy. Cardiotoxicity from ICIs has largely been underestimated since cardiovascular monitoring is not routinely performed after initiating immunotherapy. Cardiotoxic side effects are uncommon but are serious complications of ICIs with a high morbidity and mortality. Aims and Objectives: To determine gender differences in the risk of CVEs in cancer patients that receive immunotherapy. To determine the risk of CVEs in males and females who received different number of ICI injections. To study other possible risk factors for adverse CVEs in patients who received immunotherapy with ICIs. Materials and Methods: In this observational, retrospective, pharmacovigilance study, we used MarketScan Databases to compare cardiovascular adverse events reported in patients who received ICIs. The data used in this study was fully integrated and de-identified data. The study included 16,574 patients who had cancer and underwent ICI therapy between January 1, 2011, and December 31, 2018. ICI drugs in this study included nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and ipilimumab. The time to an event and the end of follow-up was counted from the time of first ICI injection. Our primary exposure variable was gender. Results: This study demonstrated that time to adverse CVE in cancer patients that receive ICI therapy is affected by the gender. The hazard time to CVEs between the male and female gender varied by age. There was no difference in CVEs between males and females at a younger age. The hazard time to CVEs increased with age above 60 years in males when compared to females. The hazard of time to CVE in males was 1.18 times the hazard in females at the mean study age of 60.5 years. Adjusted Kaplan–Meier survival curves for males and females stratified by ICI injection categories showed that those with fewer number of ICI injections had a shorter time to CVE. Conclusions: The number of ICI injections and the gender both impact adverse cardiovascular events in cancer patients. Managing and reducing cardiotoxicity is vital for safe delivery of this effective therapy. Future studies should assess whether late onset chronic cardiotoxicity can occur with ICI therapy.

Keywords: Cancer, cardiotoxicity, cardiovascular events, immune checkpoint inhibitors, immunotherapy


How to cite this article:
Minhas S, Minhas A, Malik M. Gender differences in cardiotoxicities associated with immune checkpoint inhibitor therapy in cancer patients. J Clin Prev Cardiol 2020;9:73-7

How to cite this URL:
Minhas S, Minhas A, Malik M. Gender differences in cardiotoxicities associated with immune checkpoint inhibitor therapy in cancer patients. J Clin Prev Cardiol [serial online] 2020 [cited 2020 Aug 10];9:73-7. Available from: http://www.jcpconline.org/text.asp?2020/9/2/73/291225




  Introduction Top


One of the most promising developments in cancer treatment is immunotherapy. Indications for immune checkpoint inhibitors (ICIs) are growing, and currently include various malignancies such as renal cell carcinoma, melanoma, breast cancer, colorectal cancer, Hodgkin's lymphoma, and several other cancers. Tumor cells evade the host-immune system by overexpressing the ligands of ICIs, resulting in a state of T-cell nonresponsiveness.[1] Effective T-cell-mediated antitumor response is amplified by ICIs by blocking the T-cell activation inhibitory pathway. The use of ICIs as a first-line therapy is rapidly expanding for an increasing number of cancers.[2] ICIs are monoclonal antibiotics that target the host-regulatory receptors such as program cell death receptor-1 (PD-1), programmed cell death ligand 1, and cytotoxic T-lymphocyte protein 4 (CTLA-4). Currently approved ICIs by the Food and Drug Administration in the United States are atezolizumab, avelumab, cemiplimab, durvalumab, ipilimumab, nivolumab, and pembrolizumab.[3] The remarkable effect of ICIs as anti-neoplastic agents is shadowed by their potential for inducing inflammatory and autoimmune side effects known as immune-related adverse events (IRAEs). These side effects can include colitis, dermatitis, hepatitis, pleuritis, pneumonitis, pruritis, and nephritis.[4]

Cardiotoxicity from ICIs has largely been underestimated since cardiovascular monitoring is not routinely performed after initiating immunotherapy. Cardiotoxic side effects are uncommon but are serious complications of ICIs with a high morbidity and mortality. Most cardiotoxic side effects appear to be inflammatory in nature. Cardiotoxicity can be assessed with assistance of electrocardiography, cardiac biomarkers, cardiac imaging such as echocardiography or cardiac magnetic resonance imaging, and endomyocardial biopsy. Cardiac IRAEs appear to be more common in patients treated with CTLA-4 antagonists compared to PD-1 inhibitors, and the risk of cardiotoxicity increases with combination therapy.[5],[6] Myocarditis is the most common cardiac IRAE. The prevalence of myocarditis has been reported in 0.06%–2.4% of patients on ICIs.[7],[8] Johnson et al. reported that patients who received combination therapy with nivolumab plus ipilimubab versus nivoumab alone had more frequent and severe myocarditis (0.275 vs. 0.06%).[9] The findings from this study showed there were 18 drug-related cases of myocarditis (0.09%) reported among 20,594 patients who were treated with these ICIs. Other cardiac adverse events from ICIs include conduction system abnormalities, acceleration of atherosclerotic coronary lesions, heart failure, pericardial disease, and Takotsubo syndrome.[10],[11]

To further evaluate ICI-related cardiotoxicity, we performed a retrospective cohort study of cancer patients who received different number of ICI injections to determine the relative risk of cardiovascular events (CVEs) in males and females. We also studied other possible risk factors for adverse CVEs in patients who received immunotherapy with ICIs.

The objectives of this study were to evaluate the gender differences in the risk of CVEs in cancer patients receiving ICIs and to identify the possible risk factors.


  Methods Top


In this observational, retrospective, pharmacovigilance study, we used MarketScan Databases to compare the cardiovascular adverse events reported in patients who received ICIs. MarketScan Databases track millions of patients throughout the health-care system. The information is contributed by hospitals, electronic medical record providers, Medicare, and Medicaid. The data used in this study were a subset of fully integrated and de-identified data obtained from centers all over the North America. The data were retrospectively collected from the electronic health records. The study included 16,574 patients who had cancer and underwent ICI therapy between January 1, 2011, and December 31, 2018. ICI drugs in this study included nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and ipilimumab.

Primary was the time to CVEs. Gender was the primary exposure. The CVEs included in this study were acute coronary syndrome, acute congestive heart failure, cardiomyopathy, cardiogenic shock, and stroke. International Classification of Diseases codes were used to obtain the information on these CVEs. For individuals who experienced multiple CVEs, the first event was used for data analysis purposes. Participants were censored at the end of the study if they did not experience any CVE. The time to an event and the end of follow-up was counted from the time of first ICI injection. Our primary exposure variable was gender. Other variables included in the study were the number of ICI injections administered (1, 2–5, >5), age at enrollment, history of smoking, history of diabetes, type of cancer, history of chemotherapy, history of radiation therapy, and history of cancer surgery in the patient.

Statistical analysis

Basic demographic information on all the variables was compared across the male and female gender. The Chi-square test was used to obtain the means of all the variables. Cox-proportional hazards (PH) assumption was tested for each of the variables using the goodness of fit test and by plotting the log-log plots. Multivariable Cox PH model was used with the primary exposure of gender using a stepwise forward selection method (entry criteria α = 0.25, stay criteria α = 0.05). Hazard ratio for each of the retained covariates with a significant interaction was estimated using the PROC PHREG statement. The final model was stratified for any variable that did not meet the PH assumption. α = 0.05 value was used to determine the statistical significance. This study was performed using the SAS® 9.4 software.


  Results Top


Sixteen thousand and five hundred seventy-four patients with cancer receiving ICI therapy were included in this study. At least one cardiovascular IRAE was reported in 3804 (23%) of the patients. Baseline clinical characteristics by gender group are shown in [Table 1]. Age, primary cancer type, history of cancer surgery, history of chemotherapy, and history of diabetes were significantly different between the male and female gender. ICI number of injections, history of radiation exposure, and history of smoking were not significantly different between the two genders. Primary cancer type was significantly different between the genders. Breast and cervical cancers were found predominately in the female patients. Bladder, esophageal, head and neck squamous cell, hepatocellular, Hodgkin's lymphoma, lung, malignant melanoma, mediastinal large B-cell lymphoma, Merkel, renal cell, and stomach cancers were predominately diagnosed in the male patients. Colorectal cancer was equally found in the male and female patients. There was a significant interaction between gender and both age and history of smoking [Table 2]. There was no significant interaction between gender and history of diabetes, history of radiation, and history of chemotherapy [Table 2]. A multivariable Cox PH model with the primary exposure of gender was derived using the stepwise forward selection method with entry criteria at 0.25 and slay criteria at 0.05. Forward selection begins with no variables selected (null model) and adds the most significant variable. At each subsequent step, it adds the most significant variable of those not in the model, until there are no variables that meet the criteria. [Table 3] addresses the strength of association for all the independent variables. The hazard time to CVEs between the male and female gender varied by age [Table 4]. There was no difference in CVEs between males and females at a younger age. The hazard time to CVEs increased with age above 60 years in males when compared to females. The hazard of time to CVE in males was 1.18 times the hazard in females at the mean study age of 60.5 years. Adjusted Kaplan–Meier survival curves for males and females stratified by ICI injection categories showed that those with fewer number of ICI injections had a shorter time to CVE [Figure 1].
Table 1: Descriptive statistics*

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Table 2: Likelihood ratio test for interaction

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Table 3: Strength of association between the variables

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Table 4: Hazard ratios for variables with significant interaction, strata=Immune checkpoint inhibitor

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Figure 1: Survival curves by number of immune checkpoint inhibitor injections (adjusted for age, history of diabetes, radiation, smoking, chemotherapy, and gender)

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  Discussion Top


Gender-related differences of the immune response may translate into differences in the efficacy of ICI therapy in men and women. We found that males who treated with ICI therapy had a poor outcome compared to their female counterparts. Our study demonstrated that the time to adverse CVE in cancer patients that receive ICI therapy is affected by the gender. Time to CVE in male patients who were treated with ICI therapy was shorter than the female patients who were treated with ICI therapy. These differences in the immune system between men and women could be relevant in cancer, as well as their reaction to therapies. Men have a higher mortality from cancer, which is not only because of the differences in biological and environmental factors, but also in the immune system. Therapeutic agents are increasingly targeting cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed death receptor-1 (PD-1) proteins which plan an important role in tumor-induced immunosuppression. Sex hormones regulate the expression and function of CTLA-4 and PD-1 and can result in different response to ICI therapy in men and women.

Aging is associated with a decrease in the effectiveness of the immune system. In our study, the hazard time to CVEs between the male and female patients varied with age. Our study found no statistical significance in CVEs between male and female participants at a younger age. The hazard time to CVEs increased with age above 60 years in the male participants compared to the female participants. This reflects that there are differences in immune response in the older population in addition to the gender differences. Elderly male patients are more prone to CVEs and the risks associated with ICI therapy need to be taken into consideration in this patient population.

The duration of ICI therapy also affects the time to CVEs. The results of our study revealed that fewer number of ICI injections were associated with a shorter time to a CVE compared to a higher number of ICI injections, in both male and female gender, stratified by ICI injection categories. Past studies have shown all cases reported so far of cardiotoxicity have occurred during the 1st year of immunotherapy or immediately after the ICI infusion.[12],[13] The duration of ICI therapy raises some pertinent questions. It was not clear whether the shorter duration of ICI therapy impacted the time to CVE or whether it acted as a surrogate for a more advanced illness, and therefore, a higher risk for CVE. There were other limitations in our study. Our study did not capture deaths which could have potentially affect the data analysis. Out study also did not have a control group of patients who did not receive ICI therapy. Future studies should assess whether late-onset chronic cardiotoxicity can occur with ICI therapy.


  Conclusion Top


ICI immunotherapy has revolutionized cancer treatment. Patients are now increasingly treated with ICIs, leading to a new and exciting era of oncology care. ICI-mediated cardiotoxicity is currently considered to be relatively rare, but potentially serious with significant adverse events including cardiotoxicity. The gender affects the time to CVE in cancer patients that receive ICI therapy, but the effect varies with age. Male gender and advanced age >60 years old increases the risk of ICI-mediated cardiotoxicity. ICI immunotherapy is also associated with earlier tome to CVE. Managing and reducing cardiotoxicity is vital for safe delivery of this effective therapy. There needs to be multidisciplinary approach between primary care physicians, cardiologists, oncologists, and immunologists for better understanding and management of ICI associated cardiotoxicity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 2015;15:486-99.  Back to cited text no. 1
    
2.
Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol 2015;33:1974-82.  Back to cited text no. 2
    
3.
Gill J, Prasad V. A reality check of the accelerated approval of immune-checkpoint inhibitors. Nat Rev Clin Oncol 2019;16:656-8.  Back to cited text no. 3
    
4.
Guha, A, Al-Kindi S, Jain P, Tashtish N, ElAmm C, Oliveira, G. Association between Myocarditis and other immune-related adverse events secondary to immune checkpoint inhibitor use. Int J Cancer 2020. [doi: 10.1002/ijc. 32960].  Back to cited text no. 4
    
5.
Tajiri K, Ieda M. Cardiac complications in immune checkpoint inhibition therapy. Front Cardiovasc Med 2019;6:3.  Back to cited text no. 5
    
6.
Tawbi HA, Forsyth PA, Algazi A, Hamid O, Hodi FS, Moschos SJ, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med 2018;379:722-30.  Back to cited text no. 6
    
7.
Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375:1749-55.  Back to cited text no. 7
    
8.
Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol 2018;71:1755-64.  Back to cited text no. 8
    
9.
Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375:1749-55.  Back to cited text no. 9
    
10.
Tomita Y, Sueta D, Kakiuchi Y, Saeki S, Saruwatari K, Sakata S, et al. Acute coronary syndrome as a possible immune-related adverse event in a lung cancer patient achieving a complete response to anti-PD-1 immune checkpoint antibody. Ann Oncol 2017;28:2893-5.  Back to cited text no. 10
    
11.
Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterina JM, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018;36:1714-68.  Back to cited text no. 11
    
12.
Menzies AM, Johnson DB, Ramanujam S, Atkinson VG, Wong ANM, Park JJ, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol 2017;28:368-76.  Back to cited text no. 12
    
13.
Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375:1749-55.  Back to cited text no. 13
    


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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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