Immune Checkpoint Inhibitors, Atherosclerotic Cardiovascular Events, and Plaque Progression Among Women With Cancer

Abstract

Background

Immune checkpoint inhibitors (ICIs) are associated with a 3‐fold risk of atherosclerotic cardiovascular disease (ASCVD). However, the biology of atherosclerosis is different among women and men, and ASCVD risk factors among women treated with an ICI are incompletely understood. This study aimed to identify factors associated with ASCVD in women following ICIs and to characterize plaque progression.

Methods

In a single‐center retrospective study, clinical and cancer‐related factors were compared among women treated with ICIs who did and did not experience ASCVD. Competing risk analysis estimated the effect of ICIs on cardiovascular risk. In an imaging substudy, the rate of atherosclerotic plaque progression post‐treatment was compared between women and men.

Results

Among 1188 female patients treated with an ICI, 54 (5%) experienced an ASCVD with a median time to event of 174 days. Patients with ASCVD had a higher prevalence of prior myocardial infarction and coronary revascularization (15% versus 6%, P=0.007) and prior stroke (7% versus 2%, P=0.039). Competing risk analyses, adjusting for cardiovascular risk factors, revealed an almost 3‐fold increased risk of post‐ICI ASCVD in women with prior cardiovascular events (hazard ratio, 2.71 [95% CI, 1.24–5.95]; P=0.013). In an imaging study, the annual rate of plaque progression post‐ICI was 6% for total and 7% for non‐calcified plaque, with similar rates of progression observed in women and men.

Conclusions

In female patients treated with ICIs, 5% developed an ASCVD, and a history of cardiovascular events was a risk factor. In an imaging study, plaque progressed in a short time frame after ICI therapy.

Nonstandard Abbreviations and Acronyms

ICI

immune checkpoint inhibitor

MCP‐1

monocyte chemoattractant protein‐1

NCP

noncalcified plaque

PD‐1

programmed cell death protein 1

PD‐L1

programmed cell death ligand 1

VCAM

vascular cell adhesion molecule

Clinical Perspective.

What Is New?

• In female patients with cancer receiving immune checkpoint inhibitor (ICI) therapy, a history of cardiovascular events was associated with a nearly 3‐fold increased risk of incident atherosclerotic cardiovascular disease (ASCVD), including myocardial infarction, revascularization, and ischemic stroke following ICI treatment.

• Despite this elevated risk, no significant sex‐based difference in coronary plaque progression was observed after receiving ICI therapy.

• These findings suggest that in women, factors beyond plaque burden, such as inflammation and plaque vulnerability, may play a more significant role in ICI‐associated ASCVD risk.

What Are the Clinical Implications?

• Female patients with cancer and pre‐existing ASCVD should be considered at heightened cardiovascular risk when treated with ICIs and may benefit from tailored risk stratification and monitoring.

• Preventive strategies, including optimization of atherosclerotic risk factors before, during, and after ICI therapy, as well as consideration of advanced imaging or biomarkers, may be important in these patients, particularly women with prior ASCVD.

• Further research on sex‐specific ASCVD risks after ICI therapy is needed to inform risk stratification, targeted surveillance, and preventive strategies in female patients with cancer.

Recent preclinical and clinical evidence has linked immune checkpoint inhibitor (ICI) therapy to an increased risk of atherosclerotic cardiovascular disease (ASCVD). ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ For example, in a matched‐cohort study of 5864 patients, there was a >3‐fold increased risk in major ASCVD events, including acute myocardial infarction, coronary revascularization, and ischemic stroke following ICI therapy in both men and women. ⁵ A subgroup analysis showed a trend toward higher ASCVD event rates in women on an ICI compared with men on an ICI (hazard ratio [HR], 6.0 versus 3.93; P=0.087). ⁵ However, the factors that might drive a higher risk of ASCVD among women on an ICI are unknown. Sexual dimorphism in ASCVD events, subclinical atherosclerosis, and cardiovascular biomarkers is well‐documented in cardiovascular disease (CVD), autoimmune, and various chronic diseases marked by immune dysregulation and inflammation. ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² Furthermore, although distinctions in the onset, outcomes, and risk of cardiotoxicity associated with several cancer therapies are known, our understanding of sex‐specific differences in ICI‐associated immune‐related adverse events remains limited. ¹³ , ¹⁴ , ¹⁵ Therefore, our study's first aim was to understand the factors associated with an increased risk for ASCVD among women treated with an ICI. The study's second aim was to characterize plaque progression among women treated with an ICI. The assessment of changes in atherosclerotic plaque volume and morphological features indicating plaque vulnerability using computed tomography (CT) has become a valuable and well‐established surrogate biomarker for cardiovascular risk assessment in many clinical studies, ⁵ , ⁶ , ⁸ , ¹⁰ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ and in two recent studies, predominantely among male patients, the rate of atherosclerotic plaque progression was higher after an ICI. ⁵ , ⁶ However, there are limited data on atherosclerotic plaque progression after exposure to ICI therapy among women.

METHODS

The authors vouch for the completeness and accuracy of the data and all analyses. The study was approved by the Partners Human Research Committee (institutional review board), and no informed consent was required. The data, analytic methods, and study materials will be available upon reasonable request after institutional approval and following the institutional process.

Clinical Study Population, Procedures, Outcomes

We conducted a retrospective study to identify clinical and cancer‐related factors associated with ASCVD and to assess plaque progression in women following ICI therapy. We used a previously published clinical cohort, ⁵ focusing on female patients with complete data who received ICI therapy at a single academic institution (Massachusetts General Hospital, Boston, MA) through the end of follow‐up, defined as the date of final chart review in March 2019. The study variables included patient demographics, prescribed medications, cardiovascular risk factors, cancer type, stage, and therapy during the study period. Information on the use of an ICI (type and use of combination therapy) was obtained from a pharmacy database, and the covariates of interest were derived from the RPDR (Research Patient Data Registry). The study entry date was defined as the date of the first ICI administration, and the at‐risk period was defined as 2 years after ICI initiation, ending at final chart review. ASCVD was defined as a composite of myocardial infarction, coronary revascularization, and ischemic stroke occurring after initial ICI exposure. Events were initially identified from the individual review of all patient records using a broad keyword search, and then all potential clinical events were independently adjudicated by a study team blinded to all other data and using standard definitions (Data S1; keywords and definitions used for each of the adjudicated clinical events). ²⁰ , ²¹ , ²² The date of death was obtained from the RPDR. When the date of death was unavailable, patients were censored at the last date of follow‐up.

CT Substudy Imaging Acquisition and Analysis

For the sex‐stratified CT imaging substudy, patients from 2 published imaging cohorts by our group ⁵ , ⁶ were used to assess atherosclerotic plaque progression in female and male patients with cancer after receiving ICI therapy. This imaging substudy included patients with melanoma from the initial study cohort ⁵ and patients with lung cancer from a subsequent cohort, ⁶ all treated with an ICI and with available serial CT scans suitable for thoracic plaque quantification. Our inclusion criteria included patients with at least 2 thoracic contrast‐enhanced CT scans as part of their standard clinical cancer staging. The subimaging study entry was the date of the baseline CT scan, which was done shortly before initiating ICI therapy, and the subsequent scan was at least 1 year after initial exposure to an ICI. Additionally, we selected patients who had evidence of aortic atherosclerosis in their initial CT scans and had high‐quality images that would allow plaque quantification. We measured the thoracic atherosclerotic plaque burden over time in baseline scans conducted before ICI therapy and follow‐up scans taken after ICI had started.

Thoracic aortic plaque volume was measured in a standardized fashion in a core laboratory by trained experts who were blinded to all other study variables, including treatment status and timing of imaging studies. The complete analysis protocol, accuracy, and reproducibility of these methods have been reported by our group previously. ⁵ , ⁶ , ²³ In brief, aortic segments for evaluation were established manually, and segmentation of inner and outer vessel boundary segmentation was performed semiautomatedly with manual adjustments. Plaque volume was calculated automatically, and plaque volume with attenuation <130 HU was considered as non‐calcified plaque volume (QAngioCT, version 3.1.4.2; Medis Medical Imaging Systems, Leiden, the Netherlands). ²⁴ Plaque progression was determined by measuring the difference in plaque volume between baseline and subsequent CT scans. The annualized plaque progression rate was then calculated as plaque change per year, presented in relative rates (percent per year).

Statistical Analysis

Descriptive statistics were used to assess the distribution of variables. Continuous variables were summarized as mean±SD or median with interquartile range (IQR), and categorical variables were summarized as count and percentage. Categorical data were compared with the Pearson χ² test or Fisher exact test. Non‐normally distributed data were analyzed with the Wilcoxon signed rank test. Cox proportional hazard regression analysis was performed to calculate HRs with 95% CIs, counting only the first cardiovascular event. We used a competing risks framework to estimate the time‐dependent cumulative incidence of cardiovascular events and all‐cause death following ICI therapy. Specifically, we applied the cuminc() function from the cmprsk R package, treating all‐cause death as competing events for cardiovascular events outcomes. Analyses were stratified by prior cardiovascular event status. Cumulative incidence curves for cardiovascular events and all‐cause death, stratified by prior cardiovascular event status, were generated through 2 years of follow‐up, with numbers at risk reported at each time point. Incidence rates per 100 person‐years were calculated to account for differential follow‐up time. Univariate and multivariate models were used to establish an association between baseline risk factors (including variables such as age, body mass index, hypertension, diabetes, renal disease, smoking, prior cardiovascular event, aspirin use, statin use, and dyslipidemia) and ASCVD risk in female patients with cancer who received ICI therapy, and cause‐specific hazard models were built to estimate subject‐specific probabilities of the occurrence of an ASCVD event over time in the presence of competing risks. ²⁵ , ²⁶ Individuals were right‐censored if they did not experience a cardiovascular event by the end of follow‐up or were lost to follow‐up. Two approaches were applied. In the first approach, a parsimonious multivariable Cox proportional hazard model was performed, including known cardiovascular risk factors (model 1). In a second approach, a forward stepwise selection was used; clinically relevant unique predictor variables with a value of P<0.10 in univariable analysis were entered into the final multivariable model (model 2). The incremental value between steps was measured by the likelihood‐ratio test. The proportional hazard assumption was tested using log–log plots and examining Schoenfeld residuals. Risk factors that were statistically significant in the univariate model were included in a multivariate analysis.

The primary imaging outcome was the annualized relative change in total plaque volume, whereas the secondary outcomes were the changes in total and noncalcified plaque (NCP) volume. All statistical tests were 2‐tailed, and P values <0.05 were considered statistically significant. R software using the packages gtsummary, dplyr, and Rfit was used for analysis. Competing risk survival analysis was performed using the R packages survival and cmprsk. ²⁶

RESULTS

Patient Demographics, Comorbidities, and Cancer Data

In this retrospective study, we used a previously published cohort, ⁵ focusing on female patients who received ICI therapy. Of the original 1211 patients, 23 were excluded due to incomplete clinical or follow‐up data relevant for this analysis, resulting in a final sample of 1188 patients. The baseline demographics and clinical characteristics of the clinical study cohort are summarized in Table 1. Among the female cohort (n=1188), the median age was 64 years (IQR, 54–72), and history of cigarette smoking was noted among 34%. During a median follow‐up of 197 days (IQR, 71–421), 54 patients had an ASCVD event following ICI therapy (4.6%), with a time to event of 174 days (IQR, 95–446). The events included were myocardial infarction (n=20, 37%), myocardial infarction with a percutaneous intervention (n=11, 21%), percutaneous intervention alone (n=5, 9%), and ischemic stroke (n=18, 33%). Overall, female patients without and with cardiovascular events were similar on age, body mass index, cancer type, and several baseline cardiovascular risk factors such as hyperlipidemia, history of smoking, diabetes, hypertension, and congestive heart failure. In contrast, the proportions of women with a history of prior myocardial infarction and coronary revascularization (7% versus 2%, P=0.043), any prior cardiovascular event (6% versus 17%, P=0.007), and prior stroke (7% versus 2%, P=0.039) were higher in the cohort that developed an ASCVD event after exposure to ICIs. Female patients with an ASCVD event following ICI exposure had a higher rate of β‐blocker use (44% versus 31%, P=0.037), whereas the use of other cardiovascular medications, including statins and aspirin, was similar between the cohorts.

Table 1.

Baseline Demographics of the Female Cohort (n=1188).

Demographic	Full cohort (n=1188)		No cardiovascular events on an ICI (n=1134)		Cardiovascular events on an ICI (n=54)		P value
Baseline characteristics
Age, y, median (IQR)	64	54–72	64	57–71	66	56–73	0.2
Body mass index, kg/m2, median (IQR)	25	22–29	25	22–29	24	21–28	0.6
Race, n (%)
White	1053	(91)	1006	(91)	47	(87)	0.3
Black	23	(2)	21	(1.9)	2	(3.7)
Hispanic	13	(1.1)	12	(1.1)	1	(1.9)
Asian	47	(4.1)	45	(4.1)	2	(3.7)
Other†	19	(1.6)	17	(1.5)	2	(3.7)
Baseline risk factors, n (%)
Congestive heart failure	108	(9.1)	102	(9.0)	6	(11)	0.6
Hypertension	613	(52)	585	(52)	28	(52)	0.9
Diabetes	61	(5.1)	59	(5.2)	2	(3.7)	0.9
Renal disease	139	(12)	134	(12)	5	(9.3)	0.6
Dyslipidemia	313	(26)	295	(26)	18	(33)	0.2
History of smoking	404	(34)	381	(34)	23	(43)	0.2
Prior cardiovascular events	78	(6.6)	69	(6.1)	9	(17)	0.007*
Prior stroke	29	(2.4)	25	(2.2)	4	(7.4)	0.039*
Cholesterol levels, median (IQR)
Total cholesterol	186	159–218	186	160–219	171	150–194	0.082
Low‐density lipoprotein	102	79–132	104	80–132	85	64–103	0.081
High‐density lipoprotein	55	44–68	56	44–69	46	44–53	0.100
Baseline medications, n (%)
Angiotensin‐converting enzyme inhibitors	285	(24)	270	(24)	15	(28)	0.5
Angiotensin II receptor blockers	117	(9.9)	108	(9.6)	9	(17)	0.091
β‐Blockers	371	(32)	347	(31)	24	(44)	0.037*
Calcium channel blockers	255	(22)	240	(21)	15	(28)	0.3
Diuretics	353	(30)	335	(30)	18	(33)	0.6
Statins	373	(32)	350	(31)	23	(43)	0.079
Aspirin	354	(30)	333	(30)	21	(39)	0.15
Cancer types, n (%)
Thoracic	398	(34)	378	(33)	20	(37)	0.68
Melanoma	285	(24)	271	(24)	14	(26)
Gynecological	119	(10)	111	(9.8)	8	(15)
Gastrointestinal	111	(9.3)	109	(9.6)	2	(3.7)
Head and neck	73	(6.1)	69	(6.1)	4	(7.4)
Neurological	52	(4.4)	52	(4.6)	0	(0)
Genitourinary	49	(4.1)	47	(4.1)	2	(3.7)
Hematological	47	(4)	45	(4)	2	(3.7)
Breast	46	(3.9)	44	(3.9)	2	(3.7)
Sarcoma	8	(0.7)	8	(0.7)	0	(0)
Prior cancer therapy, n (%)
Anthracyclines	102	(8.7)	98	(8.7)	4	(7.4)	>0.9
5‐Fluorouracil	107	(9.1)	104	(9.2)	3	(5.6)	0.5
Platinum‐based chemotherapy	513	(44)	494	(44)	19	(35)	0.2
Tyrosine kinase inhibitors	45	(3.8)	42	(3.7)	3	(5.6)	0.5
Anaplastic lymphoma kinase inhibitors	8	(0.7)	8	(0.7)	0	(0)	>0.9
Prior radiation therapy	955	(81)	915	(81)	40	(74)	0.4
Class of immune checkpoint inhibitor therapy, n (%)
Programmed cell death protein 1	852	(72)	810	(71)	42	(78)	0.7
Programmed cell death‐ligand1	135	(11)	129	(11)	6	(11)
Cytotoxic‐T‐lymphocyte associated protein 4	98	(8.2)	94	(8.3)	4	(7.4)
Cytotoxic‐T‐lymphocyte associated protein 4 and programmed cell death‐protein 1/programmed cell death ligand 1	103	(8.7)	101	(8.9)	2	(3.7)
Immune checkpoint inhibitor drug, n (%)
Atezolizumab	76	(6.4)	73	(6.4)	3	(5.6)	>0.9
Avelumab	26	(2.2)	23	(2)	3	(5.6)
Durvalumab	35	(2.9)	35	(3.1)	0	(0)
Ipilimumab	86	(7.2)	82	(7.2)	4	(7.4)
Nivolumab	382	(32)	366	(32)	16	(30)
Pembrolizumab	502	(42)	476	(42)	26	(48)
Ipilimumab and nivolumab	81	(6.8)	79	(7)	2	(3.7)

ICI indicates immune checkpoint inhibitor; and IQR, interquartile range.

^*Statistically significant if P < 0.05.

^†American Indian/Alaska Native, Native Hawaiian/Other Pacific Islander, multiracial, and other self‐identified groups were combined into a single “Other” category.

Prior exposure to potentially cardiotoxic therapies and radiation treatment among female patients is summarized in Table 1. There were no statistically significant differences in prior treatment regimens between female patients who developed ASCVD events post‐ICI and those who did not. ICI treatment history is also shown in Table 1, with monotherapy with PD‐1 (programmed cell death protein 1) being the most common regimen (72%), followed by PD‐L1 (programmed cell death ligand 1) (11%). There was no difference on the type of ICI therapy received between female patients who developed an ASCVD event and those who did not (P=0.7). Using a competing risks analysis stratified by prior cardiovascular event status, we observed that female patients with cancer treated with ICI therapy had a higher cumulative incidence of ASCVD events if they had a prior cardiovascular event. At 1 and 2 years, cumulative incidence of an ASCVD event was 8.0% and 16.2%, respectively, in patients with prior cardiovascular events, compared with 3.2% and 5.2%, respectively, in those without (Figure S1). In an univariate competing risk analysis among all female patients with cancer who received ICI therapy, which included known cardiovascular risk factors (age, body mass index, hypertension, diabetes, history of cigarette smoking, dyslipidemia, renal disease, prior cardiovascular event, statin use, and aspirin use), having a prior cardiovascular event was associated with a >3 times higher rate for the composite cardiovascular outcome in a cause‐specific hazard model (HR, 3.53 [95% CI, 1.72–7.23]; (P<0.001) (Table 2). Similarly, in a multivariate competing risk analysis including age, history of cigarette smoking, a prior cardiovascular event, statin, and aspirin use, having a prior cardiovascular event was also associated with >2.5‐fold increase in the risk for the composite cardiovascular outcome (HR, 2.71 [95% CI, 1.24–5.95]; P<0.013), as shown in Table 3.

Table 2.

Univariate Competing Risk Analysis in Female Patients With Cancer Who Received Immune Checkpoint Inhibitor Therapy (n=1188^*)

Outcome	Cause‐specific hazard model
	Composite cardiovascular outcome			All‐cause death
Variable	HR	95% CI	P value	HR	95% CI	P value
Age	1.02	1.00–1.04	0.06	1.01	1.00–1.02	0.03
Body mass index, kg/m2	0.98	0.93–1.03	0.40	0.98	0.96–1.00	0.01
Body mass index >30 kg/m2	1.02	0.52–1.99	0.96	0.88	0.70–1.10	0.26
Hypertension	1.09	0.64–1.85	0.76	1.24	1.04–1.49	0.02
Diabetes	0.82	0.30–2.28	0.71	1.40	1.07–1.85	0.02
Renal disease	0.96	0.38–2.42	0.94	1.64	1.28–2.11	0.00
Smoking	1.62	0.94–2.77	0.08	1.23	1.02–1.48	0.03
Prior cardiovascular event	3.53	1.72–7.23	<0.001†	1.33	0.94–1.89	0.11
Statin	1.71	0.99–2.93	0.05	1.27	1.05–1.54	0.01
Aspirin	1.62	0.94–2.80	0.08	1.21	0.99–1.46	0.06
Dyslipidemia	1.50	0.85–2.64	0.16	1.34	1.10–1.63	0.00
Low‐density lipoprotein >100 mg/dL	0.36	0.11–1.13	0.08	1.03	0.75–1.41	0.87
Cholesterol >200 mg/dL	0.55	0.17–1.71	0.30	0.94	0.69–1.28	0.70

HR indicates hazard ratio.

^*Statistically significant if P < 0.05.

^† Statistically significant if P < 0.05.

Table 3.

Multivariate Competing Risk Analysis in Female Patients With Cancer Who Received Immune Checkpoint Inhibitor Therapy (n=1188)

Outcome	Cause‐specific hazard model
	Composite cardiovascular outcome			All‐cause death
Variable	HR	95% CI	P value	HR	95% CI	P value
Age	1.02	0.99–1.04	0.30	1.01	1.00–1.01	0.21
Smoking	1.39	0.80–2.41	0.25	1.19	0.98–1.44	0.077
Prior cardiovascular event	2.71	1.24–5.95	0.013†	1.15	0.79–1.65	0.47
Statin	1.12	0.57–2.21	0.75	1.13	0.90–1.42	0.29
Aspirin	1.09	0.57–2.12	0.79	1.04	0.83–1.30	0.74

HR indicates hazard ratio.

^† Statistically significant if P < 0.05.

Atherosclerotic Plaque Characteristics

For the imaging substudy, we identified 80 patients (38 women and 42 men), including 40 patients with melanoma from an initial study cohort ⁵ and 40 patients with lung cancer from a subsequent cohort, ⁶ and baseline characteristics are summarized in Table 4. The median age of female patients was 63 years (IQR, 57–68), whereas that of male patients was 69 years (IQR, 65–73; P=0.006). Hyperlipidemia was less prevalent in the female cohort (37% versus 67%, P=0.008), but the use of statins was similar between women and men (50% versus 42%, P=0.2). No other baseline differences were observed between female and male patients on baseline hypertension, diabetes, history of smoking, use of other cardiac medications, cancer type, and cancer treatment.

Table 4.

Baseline Demographics of the Substudy Imaging Cohort With Aortic Plaque Measurements

Demographic	Women (n=38)		Men (n=42)		P value
Baseline characteristics
Age, y, median (IQR)	63	57–68	69	65–73	0.006
Race, n (%)
White	38	(100)	42	(100)	NA
Baseline risk factors, n (%)
Hypertension	22	(58)	23	(55)	0.8
Diabetes	7	(18)	8	(19)	>0.9
Hyperlipidemia	14	(37)	28	(67)	0.008
History of smoking	20	(53)	28	(67)	0.2
History of myocardial infarction	3	(7.9)	5	(12)	0.7
History of coronary revascularization	3	(7.9)	5	(12)	0.7
History of stroke	1	(2.6)	3	(7.1)	0.6
Baseline medications, n (%)
Angiotensin‐converting enzyme inhibitors or angiotensin II receptor blockers	9	(24)	13	(31)	0.5
β‐Blockers	13	(34)	17	(40)	0.6
Calcium channel blockers	4	(11)	7	(17)	0.4
Diuretics	11	(29)	12	(29)	>0.9
Statins	13	(34)	21	(50)	0.2
Aspirin	12	(32)	19	(45)	0.2
Cancer types, n (%)
Melanoma	18	(47)	22	(52)	0.7
Thoracic	20	(53)	20	(48)
Immune checkpoint inhibitor therapy, n (%)
Programmed cell death protein 1	22	(58)	21	(50)	0.8
Programmed cell death ligand 1	5	(13)	9	(21)
Cytotoxic‐T‐lymphocyte associated protein 4	6	(16)	6	(14)
Cytotoxic‐T‐lymphocyte associated protein 4 and programmed cell death protein 1/programmed cell death ligand 1	5	(13)	6	(14)

IQR indicates interquartile range; and NA, not applicable.

After a median interval of 2.2 years after initial exposure to ICI therapy, female patients had an increase in the median total plaque and NCP volumes between baseline and follow‐up scans (Table 5). Specifically, in female patients, the median rate of progression after initial ICI therapy was 6% per year for total plaque volume (IQR, 1–12) and 7% per year for NCP (IQR, 1–14), as shown in Table 6. Similarly, male patients had an increase in the median total and NCP volumes after initial ICI therapy compared with baseline (Table 5), and the yearly relative rate of progression did not significantly differ between women and men for total plaque (P=0.13) or NCP (P=0.4) volumes (Table 6).

Table 5.

Atherosclerotic Plaque Volumes at Baseline and at Follow‐Up (Wilcoxon Signed Rank Test)

	Women (n=38)		Men (n=42)		P value
Plaque volumes at baseline, mm3/y, median (IQR)
Total plaque volume	1390	(406–2140)	1559	(548–2586)	0.9
Noncalcified plaque	1129	(356–1996)	957	(400–1834)	0.7
Plaque volumes at follow‐up, mm3/y, median (IQR)
Total plaque volume	1759	(401–2815)	2183	(765–3442)	0.3
Noncalcified plaque	1643	(326‐2288)	1539	(579–2684)	0.6

IQR indicates interquartile range.

Table 6.

Relative Change in Thoracic Atherosclerotic Plaque Volume From Baseline to Follow‐Up (Wilcoxon Signed Rank Test)

	Women (n=38)		Men (n=42)		P value
Relative change per year, %/y, median (IQR)
Total plaque volume	6	(1–12)	11	(5–23)	0.13
Noncalcified plaque	7	(1–14)	11	(3–25)	0.4

DISCUSSION

In our study of female patients with cancer, we found a 5% incidence of ASCVD events (including myocardial infarction, coronary revascularization, and ischemic stroke) following initial exposure to ICI therapy, with a median time to event at 174 days. Notably, prior exposure to potentially cardiotoxic cancer therapies, radiation treatment, and the type of ICI therapy received did not significantly differ between female patients who developed ASCVD events and those who did not. The risk of an ASCVD event was approximately 2.5‐ to 3‐fold higher among women who received ICI treatment and had a history of a prior cardiovascular events. This was reflected in a higher cumulative incidence of ASCVD events among female patients with a history of prior cardiovascular events at 1 year and 2 years (8.0% and 16.2%) compared with those without prior cardiovascular events (3.2% and 5.2%), respectively. Similarly, after receiving ICI therapy, women with prior cardiovascular events had a significantly increased risk for the composite cardiovascular outcome seen in both univariate (HR, 3.53 [95% CI, 1.72–7.23]; P<0.001) and multivariate (HR, 2.71 [95% CI, 1.24–5.95]; P=0.013) competing risk models. These findings highlight that, in female patients with cancer treated with an ICI, underlying ASCVD may increase susceptibility to further ICI‐related atherosclerotic events. Additionally, our sex‐stratified imaging study showed that ICI therapy was linked to an increase in median total plaque and NCP volumes, with an annual progression rate of 6% for total plaque and 7% for NCP or high‐risk plaque among women (central illustration). Male patients also showed increased median total plaque and NCP volumes after initial ICI therapy exposure compared with baseline, with no significant sex difference in plaque volume or annual relative rate of plaque progression.

The relationship between cancer and CVD is complex and bidirectional. Some patients develop cancer and later experience cardiovascular complications, often driven by the cardiotoxic effects of cancer therapies, whereas others have preexisting CVD or risk factors such as hypertension, diabetes, obesity, physical inactivity, and smoking that may contribute to cancer development and outcomes. ²⁷ , ²⁸ Data show that patients with CVD may have an elevated risk of cancer, potentially due to mechanisms involving inflammation, oxidative stress, and immune and metabolic dysregulation. ²⁸ , ²⁹ In our study, the ASCVD event rate among women exposed to an ICI, when adjusted for length of follow‐up, is higher than the 4% cumulative incidence of ASCVD in a recent 10‐year follow‐up study of >125 000 women without cancer. ³⁰ However, data on ASCVD risk in women with cancer, particularly those exposed to ICI therapy, remain limited due to the exclusion of patients with concurrent CVD or cancer in most clinical trials, the underrepresentation of women, and the different combinations of adverse events in the composite outcome across many studies. ¹² , ³¹ , ³²

Nevertheless, evidence suggests an increased ASCVD risk among patients with cancer and cancer survivors, even after adjusting for preexisting traditional cardiovascular risk factors, influenced by specific cancer treatments and their cardiotoxicity. ³³ , ³⁴ , ³⁵ , ³⁶ For example, in a prospective analysis of the community‐based ARIC (Atherosclerosis Risk in Communities) study of 12 414 participants (55% women), cancer survivors had a 37% higher risk of CVD, independent of traditional cardiovascular risk factors. ³⁴ Another population‐based cohort of approximately 4.5 million adults, including 224 016 participants with a new cancer diagnosis (57% women), with a median follow‐up of nearly 12 years, found that those with cancer had a significantly higher risk for cardiovascular death (HR, 1.33), acute myocardial infarction (HR, 1.01), and stroke (HR, 1.44), particularly in the first year after cancer diagnosis. ³⁶ Specifically among women with cancer, a 10‐year study of 78 556 female veteran patients with cancer aged 30 to 80 years showed a faster rate of increase in ASCVD risk scores postdiagnosis of the 10 most common cancers compared with women without cancer. ³³ Similarly, a retrospective study based on the Surveillance, Epidemiology, and End Results database of >1 million patients with breast cancer reported a 4.6% incidence of heart disease‐related mortality over 22 years. ³⁵ Among patients exposed to ICI therapy, our findings of an increased risk of ASCVD are consistent with those reported by others. For instance, a smaller study in a predominantly male population reported an incidence of 2.2% for acute coronary syndrome and 1.6% for stroke. ³² A pharmacovigilance study found a lower incidence of myocardial infarction (0.5%) and cerebral ischemia (0.6%). ³¹ Overall, these findings suggests that ICI treatment affects ASCVD risk beyond the underlying cardiovascular risk profile of patients and highlights the importance of sex‐specific risk assessment in this population.

The results of our sex‐stratified CT imaging substudy align with prior findings showing an increase in the rate of total atherosclerotic plaque progression from 2.1% per year pre‐ICI to 6.7% per year post‐ICI in patients with cancer ⁵ These rates of plaque progression are 3‐fold higher than those observed in patients with subclinical (2.4% per year) ³⁷ and clinical (0.5%–1.3% per year) CVD. ³⁸ Atherosclerotic plaque progression after exposure to ICI therapy appears to be primarily driven by NCP. For example, there was a 7‐fold higher NCP progression in ICI‐treated compared with non‐ICI treated patients with lung cancer. ⁶ Similarly, a recent study in patients with melanoma after exposure to ICI therapy showed a reduced growth rate of calcified aortic plaque volume, suggesting a shift in plaque composition toward an NCP phenotype. ³⁹ NCP is considered a more inflammatory and potentially unstable plaque and prone to rupture, ⁴⁰ which may contribute to the increased incidence of ASCVD events following ICI therapy. Thus, the increase in NCP volume after exposure to ICI therapy aligns with the role of immune checkpoints as critical negative regulators of atherosclerosis, modulating inflammatory T‐cell activation and influencing atherosclerotic plaque changes. ⁴¹ T cells are one of the dominant immune cell types in human atherosclerotic lesions. ⁴² cluster of differentiation 4 (CD4+) and cluster of differentiation 8 (CD8+) T cells are among the primary immune cell types in atherosclerotic plaques, and they are known to express PD‐1. Therefore, inhibition of the PD‐1/PD‐L1 pathway with ICI therapy may drive progression toward a high‐risk plaque phenotype. ⁴² , ⁴³ In addition, several biological factors modified by ICIs, which relate to monocyte and endothelial activation (sCD163 [soluble cluster of differentiation 163], sCD14 [soluble cluster of differentiation 14], MCP‐1 [monocyte chemoattractant protein‐1], VCAM [vascular cell adhesion molecule]) and inflammation (IL‐6 [interleukin‐6], CRP [C‐reactive protein]) have been linked to NCP progression and plaque vulnerability, potentially increasing the risk of ASCVD events. ² , ⁴² , ⁴⁴ Taken together with our results, these findings suggest that the systemic inflammatory milieu induced by ICIs may promote plaque progression and alter plaque stability, leading to increased ASCVD risk after exposure to ICI therapy. Thus, the evidence indicates that the adverse cardiovascular effects of ICIs are multifactorial and underscore the importance of closely monitoring ASCVD risk in patients undergoing ICI therapy.

In our study, absolute plaque volumes or relative percentage change over time were not significantly different between women compared with men following ICI therapy. Notably, in our prior study, subgroup analysis showed a trend toward higher ASCVD event rates in women on an ICI compared with men on an ICI. ⁵ These findings suggest that sex‐based differences in ASCVD risk after ICI therapy may extend beyond plaque burden and involve complex biological factors. In the general population, women tend to have a lower coronary plaque burden and fewer high‐risk plaque features compared with men of similar age, regardless of their cardiometabolic risk profile. ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ However, sex differences in plaque progression, vulnerability, and rupture increase with age, likely due to changes in vascular pathophysiology and inflammation. ⁴⁹ In patients with acute coronary syndrome, women are more likely to present with noncalcified plaques and plaque erosion, whereas men more often demonstrate calcified plaques and plaque rupture. ⁴⁹ , ⁵⁰ , ⁵¹ Features of plaque vulnerability, such as lipid‐rich cores and thin‐cap fibroatheromas, also increase with age in women but not in men. ⁴⁹ Hormonal influences, particularly the protective effects of estrogen in premenopausal women, may further modulate plaque composition and progression toward acute coronary syndrome. ⁵² Consequently, immune response, inflammation, fibrosis, hormonal changes, and genetic factors may contribute to sex‐specific effects of ICI therapy on atherosclerotic plaque progression and ASCVD risk. ⁹ , ¹¹ , ⁴⁸ Additional evidence shows that women with chronic immune activation conditions, such as HIV or autoimmune diseases, have distinct plaque characteristics compared with men. ⁸ , ¹⁰ , ⁵³ , ⁵⁴ , ⁵⁵ For instance, Zanni et al found that among individuals with HIV, women had a lower prevalence of subclinical coronary plaque, including noncalcified and vulnerable plaques, compared with men, even after adjusting for ASCVD risk factors. However, women had key differences in systemic immune and inflammatory biomarkers such as higher levels of IL‐6, high‐sensitivity CRP, and D‐dimer. ¹⁰ These observations emphasize the need for further research to understand sex‐specific factors influencing ASCVD risk and plaque biology, particularly in patients with cancer treated with ICI therapy. Improved understanding could help guide specific preventive pharmacotherapies, such as lipid‐lowering management or antiplatelet therapies, in this patient population.

Study Limitations

The study needs to be interpreted within the context of the study design. Although this is the largest study by several fold of women exposed to an ICI, this was a retrospective single‐center academic study. The sample size for our CT substudy was relatively modest; however, for comparison, this is the largest imaging study among women treated with ICI therapy where plaque was measured. Given the retrospective design, a limitation of this study is the age range in our cohort (54–72 years), with a median age of 64 years, which reflects real‐world treatment at our institution during the study period, but limits representation of younger and older patients who may also receive ICI therapy. Importantly, the age distribution in our current cohort is consistent with that of our 2 previously published studies, where the median age across a larger combined ICI‐treated population of 5744 patients was ≈66 years, ⁵ , ⁶ further supporting that this range reflects a typical oncology practice at the time these studies were conducted. This cohort also reflects earlier patterns of ICI use in women, because more recent approvals have expanded indications to include triple‐negative breast cancer and endometrial and cervical cancers. These evolving indications highlight the importance of future prospective studies to evaluate cardiovascular outcomes in more recent and diverse patient populations, particularly among women receiving ICI therapy. This observational study was not designed to assess the association between ICI use and ASCVD events, but builds on a previously published matched‐cohort study from our group, linking ICI therapy to increased ASCVD risk and accelerated plaque progression in patients with cancer. ⁵ Given the evidence of distinct pathophysiological profiles in ASCVD risk between men and women, and the limited data on sex‐based differences in plaque morphology and progression following ICI therapy, the primary focus of this study was to characterize the incidence and clinical predictors of ASCVD events, as well as plaque progression, specifically among women treated with ICI therapy. Several potential factors could have contributed to plaque progression in this female cohort such as cancer stage, family history of CVD, racial and ethnic variations in cardiovascular risk profiles, sex‐specific risk factors (eg, lifetime estrogen exposure, pregnancy‐related factors, prior hormonal treatments), physical activity levels, metabolic or endocrine disorders, and the presence of inflammatory or autoimmune diseases. Therefore, additional studies are necessary to evaluate sex‐specific drivers of coronary atherosclerosis after exposure to ICI therapy beyond traditional cardiovascular risk factors.

CONCLUSIONS

In this observational study involving female patients exposed to an ICI, we observed a 5% rate of ASCVD over a short follow‐up period of 197 days. A prior history of cardiovascular events was a risk factor for major ASCVD events, including myocardial infarction, coronary revascularization, and ischemic stroke, in women following ICI treatment. In parallel, the CT imaging substudy showed high annual plaque progression rates, especially for high‐risk NCP. Given the increasing use of ICIs in cancer treatment, it is crucial to consider sex as a significant variable and investigate its impact on cardiovascular risk and atherosclerotic plaque progression during and after ICI therapy. Without mechanistic research in this area and given the underrepresentation of women in clinical studies, there is a risk of misapplying insights gained from studies that primarily involve male patients to female patients. Therefore, further research is needed to understand sex‐specific factors influencing ASCVD risk after ICI therapy, which may provide insights into sex‐specific ASCVD mechanisms in other conditions with persistent immune activation and heightened inflammation.

Sources of Funding

Dr Neilan is supported by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute (grants R01HL130539, R01HL137562, R01HL159187, K24HL150238). Dr Zanni reports support from K24AI157882. Dr Merkely was supported by project number RRF‐2.3.1‐21‐2022‐00003, which was implemented with support from the European Union. TKP2021‐EGA‐23 was implemented with support from the Ministry of Culture and Innovation of Hungary from the National Research, Development and Innovation Fund, financed under the TKP2021‐EGA funding scheme. Dr Vágó was supported by TKP2021‐NKTA‐46, which was implemented with support provided by the Ministry of Culture and Innovation of Hungary from the National Research, Development, and Innovation Fund, financed under the TKP2021‐NKTA funding scheme. Dr Drobni and this article were supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. Dr Varga is supported by a Momentum Research Grant from the Hungarian Academy of Sciences (LP‐2021‐14). Dr Taron reports funding by Deutsche Forschungsgemeinschaft (German Research Foundation) (TA 1438/1–2).

Disclosures

Dr Neilan has been a consultant to and received fees from Bristol Myers Squibb, Amgen, Sanofi, Genentech, Roche, and AbbVie. The study was funded, in part, by an unrestricted grant from AstraZeneca. Dr Neilan also reports research grant funding from Bristol Myers Squibb, Abbott, and AstraZeneca. Dr Zanni is Principal Investigator on a research grant from Gilead to her institution (Massachusetts General Hospital), unrelated to this article. Dr Foldyna reports unrelated grant support from MedImmune/AstraZeneca and MedTrace, as well as grants from the National Institutes of Health/National Heart, Lung, and Blood Institute outside the submitted work. Dr Taron reports speaker's bureau fees from Siemens Healthcare GmbH and speaker's bureau fees from Bayer AG, being a reviewer for Universimed Cross Media Content GmbH, and consultant to Core Laboratory Black Forrest GmbH, all unrelated to this work. The remaining authors of this work have no relevant disclosures.

Supporting information

Data S1

Figure S1