Background Patients with lung cancer face a heightened risk of atherosclerosis-related cardiovascular events. Despite the strong scientific rationale, there is currently a lack of clinical evidence examining the impact of immune checkpoint inhibitors (ICIs) on the advancement of atherosclerosis in patients with lung cancer. The objective of our study was to investigate whether there is a correlation between ICIs and the accelerated progression of atherosclerosis among individuals with lung cancer.
Methods In this case–control (2:1 matched by age and gender) study, total, non-calcified, and calcified plaque volumes were measured in the thoracic aorta using sequential contrast-enhanced chest CT scans. Univariate and multivariate rank-based estimation regression models were developed to estimate the effect of ICI therapy on plaque progression in 40 cases (ICI) and 20 controls (non-ICI).
Results The patients had a median age of 66 years (IQR: 58–69), with 50% of them being women. At baseline, there were no significant differences in plaque volumes between the groups, and their cardiovascular risk profiles were similar. However, the annual progression rate for non-calcified plaque volume was 7 times higher in the ICI group compared with the controls (11.2% vs 1.6% per year, p=0.001). Conversely, the controls showed a greater progression in calcified plaque volume compared with the ICI group (25% vs 2% per year, p=0.017). In a multivariate model that considered cardiovascular risk factors, the use of an ICI was associated with a more substantial progression of non-calcified plaque volume. Additionally, individuals treated with combination ICI therapy exhibited greater plaque progression.
Conclusions ICI therapy was associated with more non-calcified plaque progression. These findings underscore the importance of conducting studies aimed at identifying the underlying mechanisms responsible for plaque advancement in patients undergoing ICI treatment.
Trial registration number NCT04430712.
- Immune Checkpoint Inhibitors
- Non-Small Cell Lung Cancer
Data availability statement
Data are available upon reasonable request. The data, analytic methods, and study materials will be available upon reasonable request after the institutional approval and following the institutional process.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Patients with lung cancer face a heightened risk of atherosclerosis-related cardiovascular events.
Despite robust scientific plausibility, limited clinical data are testing the effect of immune checkpoint inhibitor (ICI) therapy on atherosclerotic plaque progression among patients with cancer. Importantly, there are limited data on the effects of ICI therapy on the different atherosclerotic plaque components.
WHAT THIS STUDY ADDS
ICIs are associated with a higher rate of aortic plaque progression in patients with lung cancer.
Patients with lung cancer who receive ICIs show a higher rate of non-calcified plaque progression, whereas patients with lung cancer who do not receive ICIs show a higher rate of calcified plaque progression.
The combination use of ICIs is associated with a higher rate of aortic plaque progression.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY
Patients with lung cancer have a high risk for plaque progression and cardiovascular events.
Optimization of risk factors and medical therapy is of utmost importance in this population.
Atherosclerotic plaque volumes, plaque characteristics, and changes in plaque volumes, assessed by CT angiography, are associated with future cardiovascular events and an established outcome measure for randomized clinical trials.1–4 Total plaque volume usually consists of calcified plaque (CP) and non-calcified plaque (NCP) portions and the risk for coronary events seems principally related to NCP and qualitative high-risk plaque features.5
Immune checkpoint inhibitors (ICI) represent a paradigm shift in cancer care by leveraging the immune system to identify and target cancer cells.6 It is estimated that one in every three patients with cancer is eligible for an ICI, and this proportion continues to increase.7 There are now four different ICI targets approved with over 80 different cancer indications.8 9 Consistent animal and cellular studies have demonstrated that these immune checkpoints targeted by approved cancer therapies are also critical negative regulators of atherosclerosis.10–12 ICIs have demonstrated distinctly durable responses and represent the advent of a relatively new treatment approach for patients with lung cancer.13 Despite robust scientific plausibility, there are limited clinical data testing the effect of ICI therapy on atherosclerotic plaque progression among patients with cancer and, importantly, there are limited data on the effects of ICI therapy on the different atherosclerotic plaque components.10 14 Therefore, the primary goal of this study was to test the impact of ICI therapy on the progression of NCP, and CP volume. The cohort selected for the study were patients with lung cancer. This patient group was selected as lung cancer is one of the most common indications for ICI therapy. There are no prior data on atherosclerosis progression with ICI in patients with lung cancer, and patients with lung cancer, at baseline, face a heightened risk of atherosclerosis-related cardiovascular events.15
The data, analytic methods, and study materials will be available on reasonable request after the institutional approval and following the institutional process.
Study design, setting, and population
Cases were selected from all individuals treated with an ICI through the end of March 2019 at a single academic institution (Massachusetts General Hospital, Boston, Massachusetts, USA) using the following criteria: (1) they had undergone two thoracic contrast-enhanced CT studies as part of their routine clinical care for cancer staging; (2) the baseline CT was before ICI therapy start (in cases), and the follow-up scan was at least 1 year after starting therapy; (3) subjects had aortic atherosclerosis in the first CT study, and (4) images were of adequate quality for the quantification of plaque. Controls (2:1 ratio case:controls) were selected from all patients treated for lung cancer at our center with at least two CT scans. For the control group, using an ICI at any time point was an exclusion criterion. Controls were matched to cases based on age, gender, and timing of the two CT scans. The study entry date for the cases and controls was defined as the date of the baseline CT examination.
Covariates were derived from the Research Patient Data Registry. Funding for the study was provided through an Investigator-Initiated Study from AstraZeneca. The funder had a role in the design of the project but had no role in the collection, analysis, and interpretation of the data or the development of the manuscript. The funder had no role in the decision to submit this manuscript for review and publication. The authors vouch for the completeness and accuracy of the data and all analyses.
Covariates of interest included patient demographics, medications, and cardiovascular risk factors (eg, diabetes mellitus, hypertension, history of smoking). Data relevant to cancer included the cancer type, stage, prior radiation therapy and cancer therapy during the study period. Data specific to the ICI cohort included the type of ICI, the use of combined ICI therapy, the occurrence of immune-related adverse events (irAEs), and steroid use during the study period.
CT image acquisition and analysis
CT images were acquired per standard departmental protocol for cancer staging. Only images with sufficient image quality were included. The complete analysis protocol, accuracy, and reproducibility of these methods have been reported by our group previously.14 16–18 This volumetric plaque assessment technique has demonstrated excellent intra-observer and inter-observer and interscan reproducibility.1 19 20 Briefly, aortic plaque measurements were performed on contrast-enhanced chest CT in the descending thoracic aorta in a standardized fashion in a core laboratory. The reader was blinded to all other study variables, including group status and sequence of imaging studies.14 Image analysis was performed using a dedicated and validated analysis software (QAngio CT, V.188.8.131.52, Medis Medical Imaging Systems, Leiden, the Netherlands)21 by a cardiovascular radiologist with >10 years of experience. The ascending aorta and the aortic arch were spared due to motion artifacts on non-gated images. Aortic segments for evaluation were established manually. Segment length and level were kept identical for the different time points to minimize variability. Segmentation of inner and outer vessel boundaries was performed semi-automatedly with manual adjustments. Plaque volume was calculated automatically, voxels with an attenuation of ≥130 Hounsfield Units (HU) were assigned to the CP volume, and plaque volume with attenuation less than 130 HU was considered NCP. Total plaque volume is the sum of CP and NCP volumes. Plaque change was calculated as the difference in plaque volume between the baseline and follow-up CT scans. Annualized relative change in plaque volumes was calculated as the percentage difference between baseline and follow-up scans, adjusted for the time difference between the two scans (%/year).
Descriptive statistics were used to assess the distribution of variables; continuous variables were summarized as mean with (SD) or medians with IQRs, and categorical variables were summarized as counts and percentages. Distribution was checked with the Shapiro-Wilk test. Categorical data were compared with Pearson’s χ2 test or Fisher’s exact test. Non-normally distributed data were analyzed with the Wilcoxon signed-rank test. The primary outcome of interest was the annualized relative change in CP and NCP volumes over time. The secondary imaging outcomes were the annualized absolute changes in CP and NCP volumes over time. The annualized rates of changes in plaque volumes were compared between the two groups using the Wilcoxon signed-rank test. Univariate and multivariate rank-based estimation regression models were built to estimate the effect of ICI therapy on plaque progression. This approach was chosen due to the non-normally distributed data with low sample size. The multivariate rank-based estimation regression model included ICI use, age, gender, diabetes, hyperlipidemia, hypertension, statin use, history of smoking, and prior radiation therapy. As a sensitivity analysis, a 1:1 propensity score matching was performed in a subset of patients using the MatchIt package, with a generalized linear model and caliper of 0.1 without replacement. The following variables were used to create propensity scores: gender, history of smoking, and cancer stage. All statistical tests were two-tailed, and p values of less than 0.05 were considered statistically significant. Analyses were performed with R software using the gtsummary, dplyr, MatchIt and Rfit packages.22
Patient demographics, comorbidities, and cancer data
Baseline demographics and clinical characteristics are summarized in table 1.
Among the entire cohort, the median age of patients was 66 (IQR: 58–69) years, 50% were women, and 63% had a history of smoking. Overall, cases and controls were similar in age, gender, and cardiovascular risk factors were numerically, but not significantly higher among the cases. For example, 65% in the ICI-treated group had a history of hypertension compared with a rate of hypertension of 65% in non-ICI controls. However, the proportions with smoking history were higher in the ICI cohort (72 vs 45%, p=0.037). The use of cardiovascular medicines was similar between cases and controls. For example, statin use was not different between cases and controls (42 vs 50%, p=0.2). Among the cases, programmed death-protein 1 (PD-1) inhibitor therapy was most prescribed (50%), followed by programmed death-ligand-1 (PD-L1) (35%) targeted therapy and combination therapy of cytotoxic-T-lymphocyte associated protein 4 (CTLA-4), and PD-L1 (15%) inhibition. The most common treatments administered among the controls included surgery (3 (15%)), radiation (6 (30%)), and chemotherapy (9 (45%)). During the study period, ICI-treated patients received other therapies in similar proportions to controls: 2 (5.0%) were treated with surgery, 7 (18%) were treated with radiation, and 18 (45%) were treated with chemotherapy. The baseline characteristics of the sensitivity analysis cohort were similar to the full cohort (online supplemental table S6). Among the cases during the study period, 47.5% (19/40) had irAEs (table 1), and out of these patients, 94.7% (18/19) received corticosteroid therapy.
Atherosclerotic plaque characteristics
The median time difference between baseline and follow-up CTs was similar among the groups (median (IQR), 1.40 (1.19–2.41) and 1.52 years (1.15–2.36), p=0.7). Comparing cases and controls, we found no differences regarding total plaque volume, NCP, and CP volume at baseline (prior to the ICI for cases, table 2).
There was an increase in total, NCP, and CP volume over time in patients treated with an ICI and in non-ICI controls. However, the progression rates of total plaque volume, NCP, and CP volume differed between the groups (table 3, online supplemental tables S1,S6,).figure 1
The yearly progression rate for total plaque volume was almost twofold greater among the ICI cohort as compared with the non-ICI cohort (10.1% vs 5.95% per year, p=0.025). This increase was mainly driven by NCP progression which was sevenfold higher in the ICI cohort as compared with non-ICI-treated patients (11.2% vs 1.6% per year, p=0.001, table 3). In contrast, the yearly progression rate of CP volume was greater among the controls. Specifically, the rate of CP volume progression was 1.6% per year among those on an ICI therapy compared with a rate of 25% per year among those not on ICI therapy (p=0.017). Similar results were found for the absolute changes in plaque volumes (online supplemental table S1).
In the sensitivity analysis cohort, similar results were found, specifically NCP progression was fourfold higher in the ICI cohort as compared with non-ICI-treated patients (11.2% vs 2.6% per year, p=0.045, online supplemental table S6). In contrast, the yearly progression rate of CP volume was 1.3% per year among those on an ICI therapy compared with a rate of 40.7% per year among those not on ICI therapy (p=0.015). Similar results were found for the absolute changes in plaque volumes (online supplemental table S6).
Demographic, clinical, and cancer-related variables were included in a univariable rank-based estimation regression model (online supplemental table S2). In univariate rank-based estimation regression, the use of an ICI was associated with a significant difference in relative plaque volume change per year, for NCP (β=7.8, p=0.002), and CP (β=−19.5, p=0.01) (online supplemental table S2). Among the ICI-treated patients only, in univariate rank-based estimation regression, the use of combination ICI therapy was associated with greater plaque progression for both NCP (β=18.2, p<0.001), and CP (β=34.0, p<0.01) volumes (online supplemental table S3). The occurrence of irAEs was not associated with plaque progression (online supplemental table S3). Prior radiation therapy had a borderline significant effect on absolute and relative NCP progression in the full cohort (β=−70.9, p=0.06 and β=−4.5, p=0.29, online supplemental table S2) and among the cases (β=−101.5, p=0.06 and β=−7.8, p=0.08, online supplemental table S3).
Among the controls, in univariate rank-based estimation regression, neither age >66 years, gender, prior radiation, radiation during the study period nor chemotherapy during the study period had a significant effect on plaque progression (online supplemental table S4).
In a multivariate model, which included known cardiovascular risk factors (age, sex, hypertension, diabetes mellitus, hyperlipidemia, history of smoking, history of radiation therapy, and statin use), the use of an ICI was associated with a difference in relative change in plaque volume per year, NCP (β=7.9, p=0.015) and CP (β=−20.7, p=0.022) (table 4).
Hyperlipidemia was also associated with a difference in relative plaque volume change per year, NCP (β=8.5, p=0.043), and CP (β=19.1, p=0.10) (table 4). Similar results were found for the absolute changes per year (online supplemental table S5). Our results showed a similar tendency when repeated for the sensitivity analysis cohort with a lower sample size (online supplemental table S7).
In this case–control imaging study of patients with lung cancer, ICIs were associated with a higher rate of aortic plaque progression. Specifically, ICI therapy was associated with a higher rate of non-calcified plaque progression. In contrast, patients with lung cancer who did not receive ICI therapy had a higher rate of calcified plaque progression. Moreover, cases that received combination ICI therapy had higher progression rates than those who received single-agent ICI therapy.
Until recently, data on the cardiovascular toxicities of ICIs have been principally related to the development of myocarditis.23–25 In a previous study, we found that patients with melanoma had a greater than threefold increase in the rate of atherosclerotic plaque progression after starting ICI therapy.14 The rate of plaque progression in patients with melanoma (6.7% per year) and with lung cancer (10.2% per year) treated with an ICI is significantly higher than reported in patients with subclinical (2.4% per year),24 and clinical cardiovascular disease (0.5–1.3% per year).26 It is also worth highlighting that patients with lung cancer who did not receive ICI therapy also had an increased rate of plaque progression (6.0% per year) as compared with patients with melanoma not treated with an ICI. These results align with the knowledge that, among all cancer types, patients with lung cancer have the highest rates of cardiovascular comorbidities and highest mortality when admitted with different cardiovascular causes.15 Atherosclerotic plaque quantification on CT angiography images has very good intra-reader and inter-reader variability,27 and interscan reproducibility.20 Taking together, these imaging studies support an association between ICI use and with accelerated progression of atherosclerosis among patients with lung cancer.
ICI therapy principally increased the rate of NCP progression, whereas patients who did not receive ICI therapy had a higher rate of calcified plaque progression. Highlighting the effect of ICI on NCP may be of particular importance. Non-calcified plaque is considered a more inflammatory plaque and is defined as a plaque that may be at a higher risk of rupture and of causing atherosclerotic cardiovascular events.5 These findings of a particular increase in vulnerable plaque may align with the known basic mechanisms of the ICI effect on atherosclerosis. Macrophages and T cells are pivotal in driving plaque formation, progression, and vulnerability within atherosclerotic lesions. This process is characterized by persistent inflammation and immune activation. The delicate balance between proinflammatory and anti-inflammatory factors greatly influences the development and rupture of atherosclerotic plaques. It is noteworthy that ICIs have the potential to impact this intricate process.28
ICIs, much like HIV, can hasten the progression of atherosclerosis by triggering inflammation and immune activation. In patients who are positive for HIV with undetectable viral loads, there is an elevated risk of cardiovascular complications attributed to continuous immune activation and inflammation, leading to the advancement of atherosclerosis. Moreover, arterial inflammation in patients who are positive for HIV is associated with a higher prevalence of non-calcified and high-risk plaques, which is intriguing considering that the same immune checkpoints, CTLA-4 and PD-1, are known to play a significant role in this context.29
Atherosclerosis is mainly driven by T cells, particularly T helper Type 1 (Th1) cells, associated with proatherogenic cytokines like interferon(IFN)-γ and tumor necrosis factor-α. Inhibiting Th1 cells reduces IFN-γ levels and protects against atherosclerosis.30 In patients treated with ICIs, plaques exhibit T-cell subsets with signs of exhaustion and macrophages with activated phenotypes linked to plaque vulnerability. The presence of exhausted T cells expressing PD-1 in atherosclerotic plaques suggests that PD-1 inhibitors may activate T cells in plaques and worsen atherosclerosis.10
Specifically, consistent animal and cellular studies have confirmed that these immune checkpoints are critical negative regulators of atherosclerosis with a marked increase in inflammatory T cells.10–12 31 32 For example, the PD-1/PD-L1 pathway downregulates the proatherogenic T-cell response, and administration of a blocking anti-PD-1 antibody increases atherosclerotic inflammation.12 31 Furthermore, mice lacking PD-L1 have a threefold increase in atherosclerotic plaque with an associated increase in T cells and macrophages.12 31
The combination use of two types of ICI was associated with an even higher rate of plaque progression. These results could be in line with a recent publication on the heritability of coronary artery disease, where shared environmental factors mainly influenced NCP, in contrast, calcified volume was more determined by genetics.27 We could speculate that ICI therapy, as an environmental factor, may affect NCP and have a lesser impact on CP. In patients with melanoma undergoing ICI therapy, those who were concomitantly taking a statin had a lower rate of atherosclerotic plaque progression (annual progression rate of total plaque volume: 5.2% on statin vs 8.3% not on statin; p=0.04).14 In this current study, similar to the prior, after adjusting for statin use, there remained a significant increase in plaque progression, suggesting that statin optimization alone may be insufficient to prevent plaque progression among patients on ICI. Another concern with statins is that the concomitant use of statins and ICI may increase the risk for skeletal myopathies, a known adverse event with both statins and ICI.33 It remains unclear whether patients with cancer receiving ICI therapy with a higher prevalence of positive cardiovascular history face an increased risk of plaque progression and cardiovascular events. Overall, ICI therapy is considered the first-line treatment for specific patients with lung cancer; however, it is important to emphasize the significance of baseline risk assessment and awareness.13
The primary limitation of our study is the retrospective nature of the study at a single center and the smaller sample size. This study was not designed to test the association between ICI use and cardiac events. However, in a matched cohort and a case-crossover study of over 5600 patients with cancer, ICI therapy was associated with a threefold higher risk for atherosclerotic cardiovascular events as compared with patients with cancer who did not have ICI.12 14 There remain several unmeasured residual confounders that may have influenced plaque progression. These include cancer stage, physical activity, family history, and other active inflammatory diseases. The time between the baseline and follow-up CT scans minimally differed in each subject. However, we adjusted for this by calculating annualized progression rates, and the median time difference between baseline and follow-up CTs was similar among the groups. From baseline to follow-up CTs, the median time was 1.40 and 1.52 years among the cases and controls. Further studies are required to assess whether the observed increase in atherosclerotic plaque progression is temporary or permanent and to evaluate the effect of ICI therapy in those patients with cancer who have a shorter overall survival time. However, patients with cancer must survive long enough to have a clinical impact on plaque progression and experience a cardiovascular event. Since the pool of candidates for ICI therapy is expanding, these drugs are also combined with other cancer therapies; therefore, these patients will have more prolonged overall survival, where the significance of atherosclerotic plaque progression would increase. Moreover, we were not able to quantify and include aortic root exposure by radiation. This study does not show any data on de-novo plaque formation in patients who otherwise have no plaques since we enrolled only patients with pre-existing atherosclerosis. Finally, due to the small sample size, we were not able to adjust for differences in cancer stage among the cases and controls. However, we performed a sensitivity analysis, 1:1 propensity score matched on gender, history of smoking, and cancer and our results showed similar results or similar tendencies as compared with the results from the full cohort.
In conclusion, in this case–control study of patients with lung cancer, there was a higher rate of aortic atherosclerotic plaque progression in patients who received ICI therapy. ICI therapy was associated with a higher rate of total and NCP progression. The progression noted principally in NCP suggests that these patients may be at a higher risk of plaque rupture as NCP is a more vulnerable plaque. Among cases, those who received combination ICI therapy had higher progression rates than those who received single-agent ICI therapy. Taken together, these results provide additional data to consider ICI therapy as a modifier of atherosclerosis and cardiovascular risk. Patients with lung cancer who receive ICI therapy should undergo a comprehensive cardiovascular risk evaluation and maximization of optimal medical therapy with close monitoring after that. Further, larger cohort studies demonstrating the role of ICI therapy in atherosclerotic plaque progression in patients with lung cancer are warranted.
Data availability statement
Data are available upon reasonable request. The data, analytic methods, and study materials will be available upon reasonable request after the institutional approval and following the institutional process.
Patient consent for publication
The Partners Human Research Committee approved the study, and no informed consent was required due to its retrospective nature (2021A007515). The Partners Human Research Committee approved the study, and no informed consent was required due to its retrospective nature.
We gratefully acknowledge the Cardiovascular Imaging Research Center (CIRC) research team for providing feedback on the study design and interpretation. The CIRC is a combined effort of the Division of Cardiology and the Department of Radiology at Massachusetts General Hospital.
Contributors TGN had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis and for the overall content as a guarantor. ZDD, BF, JT, and JK drafted the study protocol and analysis plan. ZDD, JT, JK, BF, PM-H, BM, and TGN helped with the data acquisition, analysis, and interpretation. All authors contributed to the data collection and the design, analysis, interpretation, and drafting of the manuscript.
Funding Funding for the study (NCT04430712) was provided through an Investigator-Initiated Study from AstraZeneca. ZDD was supported by the ÚNKP-22-4-II12 SE new national excellence program of the ministry for innovation and technology from the national research, development, and innovation fund source. TGN is supported by a gift from A. Curt Greer and Pamela Kohlberg, the Michael and Kathryn Park Endowed Chair in Cardiology, and a Hassenfeld Scholar Award. TGN is also supported by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute grants (R01HL130539, R01HL137562, R01HL159187, K24HL150238). Project supports BM no. NVKP_16-1– 2016-0017 (‘National Heart Program’). NVKP_16-1–2016-0017 has been implemented with support from the National Research, Development, and Innovation Fund of Hungary, financed under the NVKP_16 funding scheme. BM is also supported by the Thematic Excellence Programme (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary, within the framework of the Therapeutic Development and Bioimaging thematic programs of the Semmelweis University. JT reports funding by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – TA 1438/1-2.T.
Competing interests TGN has been a consultant to and received fees from Parexel Imaging, Intrinsic Imaging, Amgen, Sanofi, Genentech, Roche, and AbbVie, outside of the current work. TGN also reports consultant fees from Bristol Myers Squibb for a Scientific Advisory Board focused on myocarditis related to immune checkpoint inhibitors. The study was funded directly by an unrestricted grant from AstraZeneca. TGN also reports research grant funding from Bristol Myers Squibb for work related to immune checkpoint inhibitors. BF reports unrelated grant support from MedImmune/AstraZeneca and MedTrace, as well as grants from NIH/NHLBI outside the submitted work. JT reports speaker’s bureau Siemens Healthcare GmbH and speakers bureau Bayer AG, reviewer Universimed Cross Media Content GmbH, and consultant Core Lab Black Forrest GmbH, all unrelated to this work.
Provenance and peer review Not commissioned; externally peer reviewed.
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