Mortality In Cancer Survivors Research Articles

Associations Between Fasting Glucose and Cardiovascular Disease Mortality in Cancer Survivors: A Population-based Cohort Study

Associations Between Fasting Glucose and Cardiovascular Disease Mortality in Cancer Survivors: A Population-based Cohort Study

Analysis of dietary inflammatory potential and mortality in cancer survivors using NHANES data.

In the United States, cancer is a leading cause of mortality, with inflammation playing a crucial role in cancer progression and prognosis. Diet, with its capacity to modulate inflammatory responses, represents a potentially modifiable risk factor in cancer outcomes. This study utilized data from the National Health and Nutrition Examination Survey (NHANES, 1999-2018) to investigate the association between the Dietary Inflammatory Index (DII), which reflects dietary-induced inflammation, and mortality among cancer survivors. A total of 3,011 participants diagnosed with cancer were included, with DII scores derived from dietary recall data. All-cause and cancer-related mortalities served as primary endpoints. The study identified a significant linear positive correlation between higher DII scores and all-cause mortality among cancer survivors. Each unit increase in DII was associated with a 10% higher risk of all-cause mortality (hazard ratio [HR] per 1-unit increase, 1.10; 95% confidence interval [CI], 1.04-1.15). Similarly, a unit increase in DII was associated with a 13% higher risk of cancer-related mortality (HR per 1-unit increase, 1.13; 95% CI, 1.02-1.25). Kaplan-Meier analyses demonstrated higher all-cause mortality rates in individuals with elevated DII scores. Sensitivity analyses confirmed the robustness of these findings. Adoption of an anti-inflammatory diet, characterized by lower DII scores, may improve survival outcomes in cancer survivors. These results emphasize the critical role of dietary interventions in post-cancer care.

Multivitamin use and all-cause and cause-specific mortality in cancer survivors.

Despite no sufficient evidence on benefits and harms of multivitamin use, cancer survivors use multivitamins as a self-care strategy to improve or maintain health. We examined if multivitamin use was associated with mortality in cancer survivors. 15,936 male and 7026 female cancer survivors in the NIH-AARP Diet and Health Study were included in the analysis. Types and frequency of multivitamin use at on average 4.6 years after cancer diagnosis were assessed. Multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression models. Multivitamin use was not associated with lower all-cause mortality risk in all female (RR = 0.94, 95% CI:0.87-1.01 daily vs. no use) or male cancer survivors (RR = 0.96, 95% CI:0.91-1.00); however, a modest inverse association for CVD mortality was observed in female survivors of reproductive cancers (RR = 0.75, 95% CI:0.61-0.92) and male survivors of non-reproductive cancers (RR = 0.81, 95% CI:0.70-0.94). Multivitamin use was also associated with a lower risk of cancer-specific mortality in survivors of skin (RR = 0.65, 95% CI:0.48-0.88) and breast (RR = 0.79, 95% CI:0.65-0.95) cancer. Multivitamin use may provide a modest survival benefit to some cancer survivors. Cancer care providers should talk with cancer survivors about potential benefits and harms of multivitamin use.

Heart Disease Mortality in Cancer Survivors: A Population-Based Study in Japan.

Data on the risk of cardiovascular-related mortality in patients with cancer are limited. This retrospective cohort study used data from the Osaka Cancer Registry and vital statistics in Japan between 1985 and 2013. The causes of death were investigated, and the risk of fatal heart disease was analyzed. Standardized mortality ratios were calculated to compare the risk of fatal heart disease between patients with cancer and the general population. Fine and Gray competing risk regression models were used to assess the risk of fatal heart disease among patients with cancer. In total, 682 886 patients with cancer were included in the analysis, and 335 635 patients died during the study period. Heart disease was the leading cause of noncancer deaths, with 10 686 deaths. Among the patients who died of heart disease, 5017 had ischemic heart disease, 3598 had heart failure, 356 had hypertensive disease, and 1715 had other heart diseases. The standardized mortality ratio for heart disease was 2.80 (95% CI, 2.74-2.85). The standardized mortality ratio for ischemic heart disease, heart failure, and hypertensive disease were 3.26 (95% CI, 3.17-3.35), 2.69 (95% CI, 2.60-2.78), and 5.97 (95% CI, 5.38-6.63), respectively. The risk of fatal heart disease increased over time after cancer diagnosis. Men were more likely to die of heart disease than women (subdistribution hazard ratio, 1.08 [95% CI, 1.02-1.16]). The risk of fatal heart disease among cancer survivors has decreased in recent years. Cancer survivors have a higher risk of fatal heart disease than the general population.

Association between fasting glucose and cardiovascular disease mortality in cancer survivors: a population-based study

Abstract Background Prevention of subsequent cardiovascular disease (CVD) is an essential part of care among cancer survivors. Purpose We investigated the association of fasting blood sugar (FBS) with the risk of CVD mortality in cancer survivors. Methods Using nationwide cohort data, we included cancer patients who underwent health examination during 2009-2010 and survived more than 5 years as of Dec 31, 2010. We excluded those with known CVD. Participants were categorized into 5 groups by FBS levels. Clinical endpoint was mortality due to CVD (ischemic heart disease, stroke, heart failure, or sudden cardiac death). Results Among 177,774 cancer survivors (mean age 59.9 ± 23.0 years, female 59.1%), a reverse L-shaped association was observed between FBS and overall CVD mortality (Figure 1). Adjusted hazard ratios (95% confidence intervals) were 1.14 (0.72-1.81), 1.00 (reference), 1.02 (0.94-1.11), 1.40 (1.24-1.58), and 2.28 (1.88-2.77) for FBS <70, 70-99, 100-125, 126-179, and 180mg/dL, respectively. When we stratified by age, the risk of hypoglycemia (FBS < 70mg/dL) for CVD mortality was evident in middle aged adults (<65 years), but not in older adults (≥65 years) (Figure 2). Among middle aged cancer survivors, the adjusted hazard ratio (95% confidence intervals) were 2.97 (1.32-6.69), 1.00 (reference), 0.95 (0.74-1.21), 1.58 (1.13-2.21), and 1.97 (1.19-3.26) for FBS <70, 70-99, 100-125, 126-179, and 180mg/dL, respectively. Conclusion The strict control of elevated FBS is essential to prevent CVD mortality even in cancer survivors. Meanwhile, the risk of hypoglycemia in middle-aged cancer survivors should not be overlooked either.Figure 1Figure 2

Abstract 15108: Systematic Review to Explore Differential Frequencies of Coronary Artery Disease in Survivors of Different Cancers

Introduction: The leading non-neoplastic cause of morbidity and mortality in cancer survivors is cardiovascular disease, of which coronary artery disease (CAD) is emerging as a significant burden. Inherent in screening is an understanding of pre-test risk, and the association of CAD with particular cancers is not well-defined. Hypothesis: To develop a systematic review to explore differential frequencies of CAD in survivors of different cancers. Methods: We searched MEDLINE and EMBASE (2006-2021) for studies of CAD in survivors. For studies without a control population, we utilized a community prevalence for CAD from the 2021 US. National Centre of Health Statistics; 0.5% for 18-44 years, 4.7% for 45-64 years, 11% for 65-74 years and 19.5% for >75 years. A random-effects model was used to compare CAD prevalence in survivors and controls. Results: Twenty studies (736,956 survivors) involved 17 types of cancer (bladder, breast, colorectal, hematologic, head and neck, kidney, liver, lung, melanoma, ovarian, pancreatic, prostate, renal, stomach, testicular, thyroid, uterus). Survivors overall were associated with an increased risk of CAD compared to controls (risk difference = 0.11, 95% CI: 0.07-0.15, p=0.0, I2=99.93%). Eight cancer types (breast, hematologic, head and neck, kidney, liver, pancreatic, stomach, and testicular) resulted in a significantly higher CAD compared to other cancer types (Figure). Conclusions: Cancer survivors are at an increased risk of CAD compared to general population, but certain cancer types associate with a significantly higher CAD risk.

Joint association of sedentary behavior and vitamin D status with mortality among cancer survivors

BackgroundSedentary behavior and vitamin D deficiency are independent risk factors for mortality in cancer survivors, but their joint association with mortality has not been investigated.MethodsWe analyzed data from 2914 cancer survivors who participated in the National Health and Nutrition Examination Survey (2007–2018) and followed up with them until December 31, 2019. Sedentary behavior was assessed by self-reported daily hours of sitting, and vitamin D status was measured by serum total 25-hydroxyvitamin D (25(OH)D) levels.ResultsAmong 2914 cancer survivors, vitamin D deficiency was more prevalent in those with prolonged daily sitting time. During up to 13.2 years (median, 5.6 years) of follow-up, there were 676 deaths (cancer, 226; cardiovascular disease, 142; other causes, 308). The prolonged sitting time was associated with a higher risk of all-cause and noncancer mortality, and vitamin D deficiency was associated with a higher risk of all-cause and cancer mortality. Furthermore, cancer survivors with both prolonged sitting time (≥ 6 h/day) and vitamin D deficiency had a significantly higher risk of all-cause (HR, 2.05; 95% CI: 1.54–2.72), cancer (HR, 2.33; 95% CI, 1.47–3.70), and noncancer mortality (HR, 1.91; 95% CI, 1.33–2.74) than those with neither risk factor after adjustment for potential confounders.ConclusionsIn a nationally representative sample of U.S. cancer survivors, the joint presence of sedentary behavior and vitamin D deficiency was significantly associated with an increased risk of all-cause and cancer-specific mortality.

Codiotoxicity of anthraciclines and the possibilities of its correction

Due to the increased effectiveness of oncology treatments, cardiovascular disease, including chronic heart failure, is a major cause of morbidity and mortality in cancer survivors, limiting their life expectancy. Screening of 4700 literary sources from the databases "Scopus", "Web of Science", "PubMed / MedLine", "The CochraneLibrary" was carried out for the keywords "anthracycline-induced cardiotoxicity", "cardiooncology", "cancer therapy-related cardiac dysfunction", "sacubitril/valsartan" for the last 10 years. The review, based on the analysis of highly cited articles, outlines the current understanding of the cardiotoxicity of anthracyclines, its mechanisms and possibilities for correction, including the use of sacubitril/valsartan.

Pan-Cancer Analysis of Postdiagnosis Exercise and Mortality.

The impact of postdiagnosis exercise on cause-specific mortality in cancer survivors and whether this differs on the basis of cancer site is unclear. We performed an analysis of 11,480 patients with cancer enrolled in the Prostate, Lung, Colorectal, and Ovarian cancer screening trial. Patients with a confirmed diagnosis of cancer completing a standardized survey quantifying exercise after diagnosis were included. The primary outcome was all-cause mortality (ACM); secondary end points were cancer mortality and mortality from other causes. Cox models were used to estimate the cause-specific hazard ratios (HRs) for ACM, cancer, and noncancer mortality as a function of meeting exercise guidelines versus not meeting guidelines with adjustment for important clinical covariates. After a median follow-up of 16 years from diagnosis, 4,665 deaths were documented (1,940 due to cancer and 2,725 due to other causes). In multivariable analyses, exercise consistent with guidelines was associated with a 25% reduced risk of ACM compared with nonexercise (HR, 0.75; 95% CI, 0.70 to 0.80). Compared with nonexercise, exercise consistent with guidelines was associated with a significant reduction in cancer mortality (HR, 0.79; 95% CI, 0.72 to 0.88) and mortality from other causes (HR, 0.72; 95% CI, 0.66 to 0.78). The inverse relationship between exercise and cause-specific mortality varied by exercise dose. Exercise consistent with guidelines was associated with a reduced hazard of ACM for multiple cancer sites. Reduction in cancer mortality for exercisers was only observed in head and neck and renal cancer. In this pan-cancer sample of long-term cancer survivors, exercise consistent with guidelines was associated with substantial ACM benefit driven by both reductions in cancer and noncancer mortality. The cause-specific impact of exercise differed as a function of cancer site.

Abstract P2179: Endothelial-derived Extracellular Vesicles Communicate With Cardiomyocytes To Elicit Cancer Therapy-related Cardiac Dysfunction

Background: Treatment with the anthracycline, epirubicin, can result in cancer-therapy related cardiac dysfunction (CTRCD), a leading cause of non-malignant mortality in cancer survivors. Endothelial cells (ECs) lining the blood vessels are the first point of contact of epirubicin and secrete factors that are pivotal in regulating cardiac function. Of these factors, extracellular vesicles (EVs) are known to mediate intercellular communication. It remains unknown whether and how EC-EVs affect cardiomyocyte function in the context of CTRCD. Hypothesis: We hypothesize that epirubicin exposure leads to altered EC-EV cargo which mediates cardiomyocyte dysfunction. Methods: Human umbilical vein endothelial cells (HUVEC) were exposed to the peak and trough concentrations of epirubicin and endothelial function was assessed. EC-EVs were isolated via ultracentrifugation and EV size and concentration were measured through nanoparticle tracking analysis. The protein content of EC-EVs was determined using liquid chromatography with tandem mass spectrometry. Pluripotent stem cell-derived cardiomyocytes (iPSC-CM) were exposed to physiological concentrations of EVs (1x1010 particles/mL) and contractility was assessed in real-time. Results: Epirubicin exposure increased endothelial leak, apoptosis, and adhesion molecule expression. We observed an increase in size and concentration of EC-EVs and proteomic analysis revealed altered EV cargo including reduced cardiomyocyte protective factors, CNP and eNOS in EVs from epirubicin treated HUVEC in comparison to control. Treatment of iPSC-cardiomyocytes with EVs from epirubicin treated HUVECs resulted in reduced contractility compared to EVs from healthy ECs. Cleavage of EC-EV surface proteins via proteinase K abrogated the effects of EC-EVs on iPSC-cardiomyocytes. Cardiomyocyte-specific pathways targeted by EC-EVs from epirubicin- compared to control-treated cells are currently on-going. Conclusion: We demonstrate that epirubicin treatment leads to endothelial dysfunction and altered release of EVs capable of mediating cardiomyocyte dysfunction. Our results show the potential role of EC-EVs in CTRCD pathogenesis and highlight their influence on cardiomyocyte function.

Associations of Fat Mass and Sarcopenia With All-Cause and Cancer-Specific Mortality in Cancer Survivors

Purpose of the study: The role of body composition in cancer outcomes is of great clinical interest. We investigated whether the risks of all-cause and cancer-specific mortality differ by levels of total fat mass and sarcopenia status in cancer survivors. Methods: Participants included 1682 adult cancer survivors who had undergone dual-energy x-ray absorptiometry (DXA) examination to measure body composition, gathered from the 1999–2006 and 2011–2018 National Health and Nutrition Examination Survey (NHANES). Total fat mass was categorized into tertiles (we assessed high vs. low tertiles), and sarcopenia was defined by appendicular skeletal muscle mass index (females < 5.45 kg/m2 and males < 7.26 kg/m2). Multivariable Cox proportional hazards models were performed to estimate adjusted hazard ratio (aHR) and 95% confidence interval (CI); we also stratified by race. In addition, we performed a restricted cubic spline analysis to assess the potential non-linear association between fat mass and all-cause mortality. Results: The mean age of study participants was 61.9 years, and they were followed up for an average of 9.67 years. Overall, sarcopenia was present in 304 (25.0%), and 561 (33.4%) of the participants had high total fat mass. Participants with higher fat mass had 30% increased risk of all-cause mortality (aHR = 1.30, 95% CI = 1.06–1.61) compared to participants with low fat mass, while participants with sarcopenia had a 51% higher risk (aHR = 1.51, 95% CI = 1.22–1.88) than participants with no sarcopenia. A restricted cubic spline analysis revealed a J-shaped association between fat mass and all-cause mortality. Further, sarcopenia was also associated with a higher risk of cancer-specific mortality (aHR = 1.74, 95% CI = 1.23–2.29) compared to non-sarcopenia. The association between sarcopenia and all-cause mortality was twice as strong in Non-Hispanic Blacks (aHR = 2.99, 95% CI = 1.39–6.06) compared to Non-Hispanic Whites (aHR = 1.53, 95% CI = 1.19–1.95). Conclusion: Our findings show opposing relations of fat mass and appendicular skeletal muscle mass index with mortality in a national sample of cancer survivors, and the relationships may differ by race. These results emphasize the importance of maintaining a healthy body composition among cancer survivors.

Abstract 3036: Associations of total body fat mass and skeletal muscle index with all-cause and cancer-specific mortality in cancer survivors

Abstract Purpose of the Study: The purpose of the study was to investigate whether the risks of all-cause and cancer-specific mortality differ by levels of total fat mass and sarcopenia status in cancer survivors. Additionally, we conducted subgroup analysis to assess potential effect modification by race/ethnicity. The role of body composition in cancer outcomes is of great clinical interest, and measures of body composition that differentiate fat mass from skeletal muscle mass can help redefine our understanding of body composition for cancer survival. Methods: Participants included 1682 adult cancer survivors who had undergone dual-energy x-ray absorptiometry (DXA) examination to measure body composition, gathered from the 1999-2006 and 2011-2018 National Health and Nutrition Examination Survey (NHANES). Total fat mass (weight of fat in the body) was categorized into tertiles (we assessed high vs. low tertiles), and sarcopenia was defined by appendicular skeletal muscle mass index (females < 5.45kg/m2 and males < 7.26kg/m2). Multivariable Cox proportional hazards models were performed to estimate adjusted hazard ratio (aHR) and 95% confidence interval (CI); we also stratified by race. In addition, we performed a restricted cubic spline analysis to assess the potential non-linear association between fat mass and all-cause mortality. Results: The mean age of study participants was 61.9 years, and they were followed up for an average of 9.67 years. Overall, sarcopenia was present in 304 (25.0%), and 561 (33.4%) of the participants had high total fat mass. Participants with higher fat mass had 30% increased risk of all-cause mortality (aHR=1.30, 95% CI=1.06-1.61) compared to participants with low-fat mass, while participants with sarcopenia had a 51% higher risk (aHR=1.51, 95% CI=1.22-1.88) than participants with no sarcopenia. A restricted cubic spline analysis revealed a J-shaped association between fat mass and all-cause mortality. Further, sarcopenia was also associated with a higher risk of cancer-specific mortality (aHR=1.74, 95% CI=1.23-2.29) compared to non-sarcopenia. The association between sarcopenia and all-cause mortality was twice as strong in Non-Hispanic Blacks (aHR=2.99, 95% CI=1.39-6.06) compared to Non-Hispanic Whites (aHR=1.53, 95% CI=1.19-1.95). Conclusion: Our findings show opposing relations of fat mass and appendicular skeletal muscle mass index with mortality in a national sample of cancer survivors, and the relationships may differ by race. These results emphasize the importance of maintaining a healthy body composition among cancer survivors. Citation Format: Livingstone Aduse-Poku, Shama D. Karanth, Meghann Wheeler, Danting Yang, Caretia Washington, Jesus Fabregas, Ting-Yuan David Cheng, Dejana Braithwaite. Associations of total body fat mass and skeletal muscle index with all-cause and cancer-specific mortality in cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3036.

Abstract 3209: Metabolic characterization of radiation-induced cardiotoxicity

Abstract Background: Approximately 50% of all cancer patients receive radiation therapy as a component of their cancer care. While radiation therapy has demonstrable benefit in improving survival in patients, radiation-induced heart disease (RIHD) is a major contributor to morbidity and mortality in cancer survivors with history of thoracic radiation. Understanding metabolic changes underlying RIHD may enable development of novel diagnostic and therapeutic approaches for early detection and treatment of RIHD. The high energetic demands of the heart require properly functioning mitochondria to meet the ATP production needs. Fatty acids are the primary metabolic substrates for energy production in a healthy heart. However, under conditions of stress, the cardiac metabolism shifts towards increased glucose utilization. In this study, we characterize the impact of radiation of cardiac substrate utilization and energy production. Methods: Pre-clinical RIHD models were established by administering whole heart radiation (8Gy x 5) in mice and rats followed by structural and biochemical characterization. Transmission electron microscopy and western blot analyses were used to characterize structural and biochemical changes in the heart in response to radiation. Spectrophotometric assays and Western blot analyses were used to characterize changes in pyruvate dehydrogenase (PDH) activity and function in the heart in response to radiation. Results: Our studies identified myocardial mitochondrial dysfunction as an early event following exposure of heart to radiation. Cardiac irradiation resulted in increased mitochondrial fusion and higher expression of MFN1, a key protein that mediates mitochondrial fusion. The pathological structural and biochemical changes in the myocardial mitochondria are associated with reduced glucose metabolism due to impaired PDH activity. This decline was mediated by increased phosphorylation of PDH in irradiated hearts, which inhibits its activity. Conclusion: Cardiac irradiation results in early metabolic dysregulation, especially in glucose metabolism, which may be exploited for early detection and mitigation of radiation-induced cardiotoxicity. Citation Format: Sarah C. Elliott, Jayesh Sharma, Elizabeth R. Zhang-Velten, Abdallah Elnwasany, Chantal Vidal, Luke Szweda, Prasanna Alluri. Metabolic characterization of radiation-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3209.

Associations of Total Body Fat Mass and Skeletal Muscle Index with All-Cause and Cancer-Specific Mortality in Cancer Survivors.

Purpose: The importance of body composition on cancer outcomes is of great clinical interest. Measures of body composition that differentiate fat mass from skeletal muscle mass can help redefine our understanding of body composition for cancer survival. We investigated whether the risk of all-cause and cancer-specific mortality differ by levels of total fat mass and sarcopenia status in cancer survivors. Our secondary aim was a subgroup analysis assessing the role of race within these associations. Methods: Participants included 1682 adult cancer survivors who had undergone a dual-energy X-ray absorptiometry (DXA) examination to measure body composition, from the 1999-2006 and 2011-2018 National Health and Nutrition Examination Survey (NHANES). Total fat mass was categorized into tertiles (we assessed high vs. low tertiles), and sarcopenia was considered as having an appendicular skeletal muscle mass index less than 7.26 kg/m2 for males and less than 5.45 kg/m2 for females. Multivariable Cox proportional hazard models estimated the adjusted hazard ratio (aHR) and 95% confidence interval (CI). Results: The mean age of study participants was 61.9 years, and they were followed up for an average of 9.67 years. The prevalence of sarcopenia was 25.0% (N = 304), and 33.4% (N = 561) had a high total fat mass. Participants with a higher fat mass (aHR = 1.30, 95% CI = 1.06-1.61) and with sarcopenia (aHR = 1.51, 95% CI = 1.22-1.88) had a 30% and 51% increased risk of all-cause mortality compared to participants with a low fat mass and with no sarcopenia, respectively. Further, sarcopenia (aHR = 1.74, 95% CI = 1.23-2.29) was associated with a higher risk of cancer-specific mortality in cancer survivors. The association between sarcopenia and all-cause mortality was twice as strong in Black people (aHR = 2.99, 95% CI = 1.39-6.06) compared to White people (aHR = 1.53, 95% CI = 1.19-1.95). Conclusions: Our findings show the opposing relations of fat mass and appendicular skeletal muscle mass index with mortality in a national sample of cancer survivors, and that the relationships may differ by race. These results emphasize the importance of maintaining a healthy body composition among cancer survivors.

Abstract A022: Proteomic age acceleration associated with all-cause mortality in cancer survivors in the Atherosclerosis Risk in Communities (ARIC) Study. [R

Abstract Background: Longer lifespan and improved cancer treatment led to a rapid rise in the number of cancer survivors. However, many cancer survivors have physiological dysregulations at earlier chronological ages than those without cancer, suggesting that cancer survivors’ biological age is higher than their chronological age, i.e., they have accelerated aging. Cancer survivors’ biological age may be estimated by a novel proteomic aging clock (PAC). The deviation of PAC from chronological age is called proteomic age acceleration (PAA). To our knowledge, no studies examined whether PAA in cancer survivors is associated with increased all-cause mortality. We studied PAAs of two PACs – a newly created clock in ARIC (so called, “new” PAC) and the published 491-protein clock by Lehallier [2020] in relation to all-cause mortality in cancer survivors. Methods: ARIC is a prospective cohort of White and Black women and men, followed in 1987-2019. In 2011-13 (Visit 5), 5000 plasma proteins were measured using SomaScan, an aptamer-based assay. Using elastic net regression (alpha=0.5), we constructed a new PAC in a training set of two-thirds randomly selected cancer-free participants (N = 2466). This clock included 619 proteins and was internally validated in the remaining 1233 cancer-free participants (test set). We also computed Lehallier’s PAC using weights estimated in ARIC. We calculated PAA as residuals after regressing PAC on chronological age. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality per 1 standard deviation (SD, ~2.6 yrs for PAAs for both PACs) increase in PAA in 806 survivors of all cancer at Visit 5, and survivors of breast, prostate, and colorectal cancer. HRs were adjusted for chronological age, sex, race, center, education, BMI, smoking status, alcohol intake, eGFR, physical activity, time since cancer diagnosis, diabetes, and aspirin use. Results: 272 deaths were identified in 4963 person-yrs (median follow-up=6.98 yrs). In the test set, both PACs were correlated with chronological age [Pearson correlation coefficient (r): new PAC=0.75; Lehallier’s PAC=0.70] and with each other [r=0.89]. For both PACs, those with higher PAA tended to be White and have lower physical activity and a lower eGFR. Both PAAs were significantly associated with all-cause mortality in cancer survivors [per 1 SD: HR (95% CI): new PAC=1.42 (1.24-1.62); Lehallier’s PAC=1.40 (1.22-1.61)]. The HRs were not modified by sex or race. Both PAAs were significantly associated with all-cause mortality in 169 breast cancer survivors [HR: new PAC=1.54 (1.05-2.25); Lehallier’s PAC=1.72 (1.13-2.64)]. PAA of the new PAC was also associated with all-cause mortality in 78 colorectal cancer survivors [HR=1.96 (1.19-3.22)]. PAA for each PAC was not associated with all-cause mortality in 255 prostate cancer survivors. Conclusion: Proteomic aging clocks hold the promise as a potential biomarker for premature mortality in cancer survivors. Funding: NHLBI, NCI, NPCR Citation Format: Shuo Wang, Anne H. Blaes, Josef Coresh, Corinne E. Joshu, James S. Pankow, Bharat Thyagarajan, Elizabeth A. Platz, Weihua Guan, Anna Prizment. Proteomic age acceleration associated with all-cause mortality in cancer survivors in the Atherosclerosis Risk in Communities (ARIC) Study. [R] [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A022.

Abstract B001: Elevated all-cause and cardiovascular mortality in cancer survivors with sarcopenia

Abstract Abstract: Sarcopenia, a condition characterized by the loss of muscle mass, strength and function with age, is highly prevalent in cancer survivors. The relationship between sarcopenia and prognosis among cancer survivors is not well understood. Methods: From the Third National Health and Nutrition Examination Survey (NHANES III), we identified 946 participants who were diagnosed with cancer (mean age 60.6 years); the most common disease sites were breast, prostate, colon and melanoma. We assembled an age, sex and race-matched cohort of 1,857 participants without cancer (mean age, 60.2 years). Sarcopenia was defined by appendicular lean mass and body height (men <7.26 kg/m2, women <5.45 kg/m2). Proportional-hazard models were used to assess whether sarcopenia was associated with all cause and CVD-specific time to death after taking into account baseline age, sex, race/ethnicity, smoking status, and energy intake for each cohort. In the cancer survivor cohort, models were additionally adjusted for a history of having more than one cancer and time since diagnosis. Mortality was ascertained from the National Center for Health Statistics Linked Mortality Files. Results: There were 321 deaths among cancer survivors (33.9% of the cohort) during a median follow-up of 10.5 years versus 495 deaths among participants without cancer (26.7% of the cohort) during a median follow-up of 10.9 years. Deaths from cardiovascular disease (CVD) were observed in 58 (6.1%) cancer survivors versus 122 (6.6%) participants without cancer. Overall, sarcopenia was more prevalent among cancer survivors versus the matched cohort (22.2% versus 19.7% respectively). Rates of CVD death were more than twice higher among cancer survivors with versus without sarcopenia (adjusted hazard ratio, 2.17, 95% confidence interval [CI], 1.16 to 4.05). All-cause mortality was 79% higher (adjusted hazard ratio, 1.79; 95% CI, 1.36 to 2.36) among cancer survivors with versus without sarcopenia. No significant associations were seen between sarcopenia and rates of death from all causes and CVD specifically among participants without cancer. Conclusion: Cancer survivors with sarcopenia have an increased risk of all-cause and CVD-specific mortality. In contrast, sarcopenia was not a major predictor of these outcomes in the matched cohort without cancer. Citation Format: Dejana Braithwaite, Shama Karanth, Christiaan Leeuwenburgh, Todd M. Manini, Meghann Wheeler, Danting Yang, Livingstone Aduse-Poke, Stephen Anton, Frank Penedo, Erin M. Siegel, Jonathan D. Licht, Dongyu Zhang. Elevated all-cause and cardiovascular mortality in cancer survivors with sarcopenia [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B001.

Left atrial appendage volume as a prognostic Indicator of long-term mortality in Cancer survivors treated with thoracic radiation

BackgroundCancer survivors with prior chest radiation therapy (CXRT) frequently present with atrial fibrillation, heart failure, and have higher overall long-term mortality. There are no data examining the utility of left atrial (LA) and LA appendage (LAA) volume-indices to predict clinical outcomes in these patients.ObjectivesWe examined the prognostic value of cardiac phase-dependent 3-D volume-rendered cardiac computerized tomography (CT)-derived LA and LAA volume-indices to predict mortality and major adverse cardiac events (MACE) in cancer survivors treated with thoracic irradiation.MethodWe screened 625 consecutive patients with severe aortic stenosis who had undergone transcatheter aortic valve replacement from 2012 to 2017. Based on the gated cardiac CT image quality, we included 184 patients (CXRT:43, non-CXRT:141) for further analysis. We utilized multiplane-3D-reconstructed cardiac CT images to calculate LA and LAA volume-indices, and examined the prognostic role of CCT-derived LA and LAA volume-indices in predicting the all-cause mortality, cardiovascular (CV) mortality, and MACE. We used multivariate cox-proportional hazard analysis to identify the clinical predictors of survival.ResultsOverall, the CXRT group had significantly elevated LAA volume-index compared to non-CXRT group (CXRT:11.2 ± 8.9 ml/m2; non-CXRT:8.6 ± 4.5 ml/m2, p = 0.03). On multivariate cox-proportional hazard analysis, the elevated LAA volume and LAA volume-index were the strongest predictors of reduced survival in CXRT group compared to non-CXRT group (LAA volume: RR = 1.03,95% CI 1.0–1.01, p = 0.01; and LAA volume index: RR = 1.05, 95% CI 1.0–1.01, p = 0.03). LAA volume > 21.9 ml was associated with increased mortality. In contrast, LA volume was not a significant predictor of mortality.ConclusionWe describe a novel technique to assess LA and LAA volume using 3-D volume-rendered cardiac CT. This study shows enlarged LAA volume rather than LA volume carries a poor prognosis in cancer-survivors treated with prior CXRT. Compared to conventionally reported markers, LAA volume of > 21.9 ml was incremental to that of other risk factors.

Stroke mortality in cancer survivors: A population-based study in Japan

IntroductionThe association between cancer survivors and stroke deaths remains unclear. We aimed to evaluate the risk of fatal stroke in patients with cancer. Materials and methodsThis study was conducted using data from the Osaka Cancer Registry and vital statistics in Japan, collected from 1985 to 2013. We extracted patient data and investigated the causes of death. Standardized mortality ratios were calculated to compare the risk of stroke in patients with cancer to that in the general population. Poisson regression models were used to estimate the risk of stroke in patients with cancer and other cancer subgroups. Stroke types were used for risk stratification. ResultsWe identified 688,473 eligible patients with cancer. The cohort contributed 2,668,126 person-years at risk. During the study period, 337,117 patients died; stroke was the cause of death in 5496 patients. Stroke types included cerebral infarction (3259), intracerebral hemorrhage (1539), subarachnoid hemorrhage (364), and other cerebrovascular diseases (334). The crude mortality rate from fatal stroke was 205.99 per 100,000 person-years. The standardized mortality ratio (95 % confidence interval) for fatal stroke was 1.75 (1.71–1.80). When stratified by stroke types, the ratios for cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage were 1.83 (1.76–1.89), 2.38 (2.26–2.50), and 2.28 (2.03–2.56), respectively. The risk of fatal stroke increased with time after cancer diagnosis. The multivariate Poisson regression model indicated that men were more likely to die of stroke than women. ConclusionsCancer survivors have a higher risk of fatal stroke than the general population across all stroke types.

Cancer Therapy-Related Hypertension: A Scientific Statement From the American Heart Association.

Contemporary anticancer drugs have significantly improved cancer survival at the expense of cardiovascular toxicities, including heart disease, thromboembolic disease, and hypertension. One of the most common side effects of these drugs is hypertension, especially in patients treated with vascular endothelial growth factor inhibitors, as well as tyrosine kinase inhibitors and proteasome inhibitors. Adjunctive therapy, including corticosteroids, calcineurin inhibitors, and nonsteroidal anti-inflammatories, as well as anti-androgen hormone therapy for prostate cancer, may further increase blood pressure in these patients. Cancer therapy-induced hypertension is often dose limiting, increases cardiovascular mortality in cancer survivors, and is usually reversible after interruption or discontinuation of treatment. The exact molecular mechanisms underlying hypertension are unclear, but recent discoveries indicate an important role for reduced nitric oxide generation, oxidative stress, endothelin-1, prostaglandins, endothelial dysfunction, increased sympathetic outflow, and microvascular rarefaction. In addition, genetic polymorphisms in vascular endothelial growth factor receptors are implicated in vascular endothelial growth factor inhibitor-induced hypertension. Diagnosis, management, and follow-up of cancer therapy-induced hypertension follow national hypertension guidelines because evidence-based clinical trials specifically addressing patients who develop hypertension as a result of cancer therapy are currently lacking. Rigorous baseline assessment of patients before therapy is started requires particular emphasis on assessing and treating cardiovascular risk factors. Hypertension management follows guidelines for the general population, although special attention should be given to rebound hypotension after termination of cancer therapy. Management of these complex patients requires collaborative care involving oncologists, cardiologists, hypertension specialists, primary care professionals, and pharmacists to ensure the optimal therapeutic effect from cancer treatment while minimizing competing cardiovascular toxicities.

Dietary inflammatory index, and depression and mortality risk associations in U.S. adults, with a special focus on cancer survivors.

A higher risk for depression and mortality is associated with the inflammatory potential of diet measured through the Dietary Inflammatory Index (DII). The roles of DII in the risk of depression and death in cancer survivors were unclear. We aimed to examine the association between energy-adjusted DII (E-DII) score and risk of depression, and mortality using data from the 2007-2018 National Health and Nutrition Examination Survey (NHANES), with a special focus on cancer survivors. The 24-h dietary recall interview was used as a basis to calculate the E-DII score and the Patient Health Questionnaire-9 (PHQ-9) was used to measure the depressive outcomes. Logistic regression analyses were performed to determine the association between quartiles of E-DII score and depression. Cox proportional hazard regression and competing risk analyses were used to estimate the risks of quartiles of E-DII score or depression on mortality. A total of 27,447 participants were included; including 24,694 subjects without cancer and 2,753 cancer survivors. The E-DII score and depression were not distributed differently between the two groups. However, the E-DII scores were positively associated with within each group's depression (all P trend < 0.001) and participants with higher E-DII scores had a higher risk of depression (subjects without cancer: ORQ4 vs Q1: 2.17, 95% CI: 1.75-2.70; cancer survivors: ORQ4 vsQ1: 1.78, 95% CI: 1.09-2.92). The median follow-up time were 87 person-months, a total of 1,701 (4.8%) and 570 (15.2%) all-cause deaths in subjects without cancer and cancer survivors were identified by the end of 2019. The highest E-DII scores quartile was associated with the highest risk of all-cause (HRQ4 vsQ1: 1.90, 95% CI: 1.54-2.35) and cardiovascular disease (CVD) cause death (HRQ4 vsQ1: 2.50, 95% CI: 1.69-2.3.7) in the subjects without cancer. Moreover, participants with depressive symptoms had higher all-cause mortality (HR: 1.29, 95% CI: 1.04-1.59). No significant correlation was found for E-DII scores or depression with all-cause, cancer-cause or CVD-cause mortality in cancer survivors. Our findings demonstrate that E-DII score was positively associated with depression risk. A higher E-DII score or depressive symptom may increase the risks of all-cause and CVD-cause mortality only among general subjects.