Association of N-terminal pro–brain natriuretic peptide with survival among US cancer survivors

Abstract

Background

N-terminal pro–brain natriuretic peptide (NT-proBNP) is a cardiac biomarker associated with the risk of heart failure and death in the general population, but it has not been explored in cancer survivors.

Methods

Using a US nationally representative sample of adults 20 years of age and older from the National Health and Nutrition Examination Survey from 1999 to 2004, this study compared NT-proBNP levels between adults without cancer (n = 12 574) and adult cancer survivors (n = 787). It examined the association of NT-proBNP with all-cause and cause-specific mortality among cancer survivors.

Results

Cancer survivors had higher NT-proBNP levels than adults without cancer (median [interquartile range] = 125.4 pg/mL [52.4-286.0] vs 43.2 pg/mL [20.3-95.0]). In particular, survivors of breast, prostate, and colorectal cancers had higher NT-proBNP levels than adults without cancer (multivariable-adjusted P < .05). In total, 471 survivors died (141 from cancer; 95 from cardiac disease) during a median follow-up period of 13.4 years (9393 person-years). Among cancer survivors, higher NT-proBNP levels were statistically associated with increased risks of all-cause death (hazard ratio [HR] = 1.31, 95% confidence interval [CI] = 1.18 to 1.46) and cardiac death (HR = 1.55, 95% CI = 1.21 to 2.00) but not with death from cancer (HR = 1.10, 95% CI = 0.92 to 1.32]). Higher NT-proBNP levels were associated with elevated overall mortality in survivors of prostate cancer (HR = 1.49, 95% CI = 1.22 to 1.81) and colorectal cancer (HR = 1.78, 95% CI = 1.00 to 3.16) (P = .169 for interaction). Nonlinear dose-response relationships were observed between NT-proBNP and mortality, with statistically significant relationships emerging above 125 pg/mL.

Conclusions

Cancer survivors had higher NT-proBNP levels than adults without cancer, and elevated NT-proBNP levels were associated with higher risks of all-cause and cardiac mortality in cancer survivors.

The population of cancer survivors has grown considerably over the past few decades, and it is projected to rise to 26 million by 2040 in the United States (1). Due to advances in early detection, diagnosis, and treatment, the cancer survival rate has improved substantially, with approximately 69% of survivors living 5 or more years after diagnosis (2). As cancer survival rates increase, competing causes of mortality and morbidity become more important in cancer survivors (3). Cardiovascular disease (CVD) is prevalent; in fact, it is becoming the leading cause of death in some cancer survivors (4,5). Cancer and CVD share several common risk factors (eg, smoking, obesity, and physical inactivity) and pathophysiologic mechanisms (6,7), thereby predisposing cancer survivors to elevated risks of CVD. Additionally, cancer treatments can lead to cardiotoxicity, further increasing the risk of CVD mortality and morbidity (8,9). Despite the fact that CVD is common in cancer survivors, there is currently a lack of consensus regarding the utility and methodology of monitoring cardiovascular health during cancer survivorship, given the lack of a standardized measure linked to long-term outcomes among cancer survivors.

N-terminal pro–brain natriuretic peptide (NT-proBNP), synthesized in response to cardiac myocyte stretch, is a diagnostic biomarker of heart failure (HF) and has been recognized as a sensitive marker of myocarditis and long-term cardiotoxicity (9,10). Recent studies also revealed that NT-proBNP secretion is strongly influenced by inflammatory cytokines, broadening its indicative capacity beyond cardiac conditions to encompass a variety of inflammatory processes (11,12). In the general population, elevated levels of circulating NT-proBNP are associated with risks of incident HF, CVD, and all-cause mortality (13-15). Emerging evidence suggests that NT-proBNP measured during cancer treatment can be a biomarker for monitoring cardiovascular health (16) and was associated with left ventricular dysfunction, symptomatic HF, arrhythmia, and sudden cardiac death at 1 year (17). The relationship between NT-proBNP and long-term outcomes, however—specifically, mortality—in posttreatment cancer survivors has not been fully examined. Given distinct therapeutic regimens and patient characteristics, cardiovascular risks and their impacts on survival outcomes may vary across malignancies. More work evaluating the relationship between NT-proBNP and cause-specific mortality across different malignancies is needed to identify individuals at risk, to elucidate the biological mechanisms underlying cardiotoxic effects of cancer itself and cancer treatment, and to inform the development of monitoring and interventional strategies to mitigate cardiovascular risks in cancer survivors.

The goals of the current study were to evaluate NT-proBNP levels in adults without cancer and adult cancer survivors in a nationally representative sample of the US population and to examine the association of NT-proBNP with all-cause and cause-specific mortality among cancer survivors, both overall and by cancer type. This evidence has the potential to inform risk-stratification strategies and the development of CVD screening, preventive, and management strategies in cancer survivorship.

Methods

Study population

The National Health and Nutrition Examination Survey (NHANES) is a research program conducted by the National Center for Health Statistics (NCHS) to monitor the health and nutritional status of the US population. In brief, the NHANES has continuously surveyed a nationally representative sample of the US population in 2-year cycles since 1999. Each NHANES participant completed an in-person interview, a set of physical examinations, and laboratory tests in a mobile examination center (MEC). All NHANES protocols were approved by the NCHS ethics review board, and written informed consent was obtained from all participants. For this analysis, we analyzed data on sociodemographic characteristics, lifestyle factors, medical history, and NT-proBNP levels from all adults without cancer and cancer survivors aged 20 years or older recruited during the 3 cycles of NHANES from 1999 to 2004, which was combined to create a nationally representative sample of the US population aged 20 years or older. This modeling investigation was exempt from human subjects review because it was based on published data and nationally representative, deidentified data sets that included no personally identifiable information.

Diagnosis of cancer

Data on cancer diagnosis, including type of cancer and patient age at diagnosis, were collected during the in-person interview. Up to 3 separate cancer diagnoses could be included for each individual (Supplementary Table 1, available online) (6). Participants were asked, “Have you ever been told by a doctor or other health professional that you had cancer or a malignancy of any kind?” Individuals who responded “Yes” were defined as cancer survivors, and then were asked, “What kind of cancer was it?” and “How old were you when this cancer was first diagnosed?” Years since the first diagnosis of cancer were calculated as the difference between current age and age at first diagnosis. Individuals with only nonmelanoma cancer and unknown-type skin cancers were excluded from analyses.

Ascertainment of mortality

The NCHS provided mortality data that were linked to the National Death Index through December 31, 2019. The International Statistical Classification of Diseases, Tenth Revision (ICD-10) was used to record the underlying cause of death (6,18). Cardiac disease mortality was classified as death caused by heart disease (ICD-10 codes I00-I09, I11, I13, and I20-I51) and cancer mortality as death caused by malignant neoplasms (ICD-10 codes C00-C97). The duration of follow-up was defined as the interval in months from the interview date to the date of death or through December 31, 2019, for those participants who did not experience an event.

NT-proBNP measurement

Serum from stored surplus specimens from the NHANES 1999-2004 participants was tested for NT-proBNP during 2018 to 2020 at the University of Maryland School of Medicine, Baltimore (19). NT-proBNP was measured in serum on the cobas e 611 autoanalyzer (Roche Diagnostics, Indianapolis, IN). The lower and upper limits of detection were 5 pg/mL and 35 000 pg/mL, respectively. For analytic results below the limit of detection, an imputed fill value (the limit of detection divided by square root of 2 [3.54 pg/mL]) was used. NT-ProBNP was analyzed as a log-transformed variable and categorized using empiric cut points based on the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America Guideline for the Management of Heart Failure into less than 125, 125 to less than 450, 450 to less than 900, and 900 pg/mL or more (20-23). Elevated NT-proBNP was defined as 125 pg/mL or higher (22).

Sociodemographic characteristics, lifestyle behaviors, and chronic conditions

Self-reported sociodemographic characteristics included sex (male vs female), race and ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, and other [American Indian/Native Alaskan/Pacific Islander, Asian, multiracial]), and educational attainment (less than high school, high school, and beyond high school), family income-to-poverty ratio (<1.3 [lowest income], 1.3 to <3.5, ≥3.5 [highest income]) (6,18). Participants’ weight and height were measured during the physical examination at the mobile examination center. Body mass index was calculated as weight in kilograms divided by height in meters squared and categorized into 3 groups (<25 kg/m², 25.0-29.9 kg/m², ≥30 kg/m²). Lifestyle factors included smoking status (never, former, and current), alcohol use (never, former, current, unknown), leisure-time physical activity (inactive vs active) (17) and the Healthy Eating Index-2015 (continuous) (24).

Hypertension was defined by self-report as having received a diagnosis of hypertension from a health professional or by having an NHANES-measured systolic blood pressure of 130 mm Hg or a diastolic blood pressure of 80 mm Hg or higher. Hypercholesterolemia was defined by self-report as having a diagnosis of hypercholesterolemia from a health professional or by an NHANES-measured total cholesterol level of 6.21 mmol/L or higher. History of CVD (congestive HF, coronary heart disease, myocardial infarction, stroke) was defined by self-report of having a diagnosis of CVD from a health professional (6,18). Diabetes was defined by self-report as having a diagnosis of diabetes from a health care professional, by having a prescription for insulin, or by having an NHANES-measured hemoglobin A_1c of 6.5% or more or fasting plasma glucose of 7.0 mmol/L or higher. Chronic kidney disease (CKD) was defined as an NHANES-measured estimated glomerular filtration rate less than 60 mL/min/1.73 m² or urine albumin to creatinine ratio greater than 30 mg/g (25).

Statistical analysis

All analyses were conducted following the NHANES analytic guidelines to calculate nationally representative estimates. To ensure adequate sample sizes for obtaining precise estimates at the population level, NHANES oversampled certain underrepresented subgroups. Each participant was assigned a weighting parameter for adjustments to account for the unequal probability of selection, subgroup oversampling, and nonresponse. After applying the weighting parameters, 12 574 adults without cancer and 787 cancer survivors included in this analysis were representative of 189 234 316 adults without cancer and 11 660 121 cancer survivors in the United States. All analyses were performed using Stata, version 17.0, software (StataCorp LLC, College Station, TX). Statistical tests were 2-sided, and statistical significance was set at a P value less than .05. The restricted cubic splines were plotted using R, version 4.2.2 (R Project for Statistical Computing, Vienna, Austria).

Sample sizes (weighted percentage), median (interquartile range [IQR]) of NT-proBNP concentrations, and the prevalence of elevated NT-proBNP levels (≥125 pg/mL, 95% confidence intervals [CIs]) were estimated according to participants’ sociodemographic and lifestyle factors, health conditions, and cancer type and history (cancer survivor only). In cancer survivors, multivariable Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) and 95% confidence intervals for the associations of NT-proBNP with overall and cause-specific mortality, respectively. Final-stage multivariable models were adjusted for age, sex, race and ethnicity, education level, family poverty ratio, body mass index, smoking status, alcohol use, leisure-time physical activity and Healthy Eating Index-2015, hypertension, hypercholesterolemia, diabetes, and history of CVD, CKD, years since the first diagnosis of cancer, type of first cancer diagnosis, and number of cancer types. Restricted cubic splines in the Cox regression models were used to examine the dose-response associations between NT-proBNP and mortality outcomes for potential nonlinearity. All analyses were conducted overall and by sociodemographic and lifestyle factors, health conditions, and cancer type and history, respectively. Participants who died during the first year of follow-up were excluded to reduce the probability of reverse causation (26).

Results

A total of 12 574 adults without cancer (representing 189 234 316 US adults without cancer) and 787 cancer survivors (representing 11 660 121 US cancer survivors) were included in the current analysis (Table 1). Cancer survivors tended to be older, female, non-Hispanic White, and physically inactive and were more likely to have diabetes, CVD, and CKD than adults without cancer (all P < .05). The median (IQR) age at the time of cancer diagnosis was 59 (42-69) years, and median (IQR) age at the time of NT-proBNP assessment was 69 (55-78) years for cancer survivors. The median (IQR) time between cancer diagnosis and NT-proBNP assessment was 8 (4-14) years since their first cancer diagnosis.

Table 1.

Sample size and NT-proBNP levels according to characteristics among US adults without cancer and cancer survivors 20 years of age and older, NHANES 1999-2004^a

Characteristics	No. of participants (weighted %)			NT-proBNP, pg/mL median (IQR)		Elevated NT-proBNPb, % (95% CI)
	Adults without cancer	Cancer survivor	P	Adults without cancer	Cancer survivor	Adults without cancer	Cancer survivor
All	12 574 (100)	787 (100)	—	43.2 (20.3-95.0)	124.5 (52.4-286)	15.8 (15.0 to 16.5)	43.8 (39.6 to 47.9)
Age at NT-proBNP assessment, y
Median (IQR)	43 (27-62)	69 (55-78)	—	—	—	—	—
<65	8558 (82.5)	308 (53.0)	<.001	36 (18.3-69.1)	55.2 (30.1-111.2)	9.4 (8.7 to 10.2)	22.4 (17.0 to 27.7)
≥65	2593 (13.3)	479 (47.0)		158.3 (75.9-356.4)	192.3 (96.3-452.1)	59.4 (57.1 to 61.8)	67.9 (63.0 to 72.8)
Sex
Male	6027 (48.4)	346 (34.3)	<.001	29.2 (13.6-69.2)	145.7 (55.7-312.7)	9.7 (8.9 to 10.5)	45.3 (39.1 to 51.5)
Female	6547 (51.6)	441 (65.7)		57.0 (30.3-112.3)	113.0 (50.2-264.3)	21.5 (20.2 to 22.7)	43.0 (37.5 to 48.4)
Race and ethnicity
Non-Hispanic White	5863 (69.7)	567 (85.9)	<.001	55.9 (27.1-122.8)	141.8 (64.5-313.8)	18.0 (17.0 to 19.1)	45.0 (40.4 to 49.7)
Non-Hispanic Black	2462 (11.4)	105 (7.1)		30.3 (14.1-66.4)	81.5 (29.1-217.1)	12.4 (11.0 to 13.8)	29.8 (20.4 to 39.2)
Hispanic	3783 (14.1)	98 (4.8)		37.4 (18.1-78.5)	65.2 (38.7-182.1)	9.4 (8.0 to 10.7)	34.7 (18.6 to 50.9)
Non-Hispanic other	466 (4.8)	17 (2.2)		33.9 (16.4-67.4)	158 (41.7-290.9)	9.3 (6.3 to 12.3)	58.2 (29.3 to 87.1)
Educational attainment
<High school	3620 (19.5)	228 (22.3)	.273	52.9 (24.5-138.6)	135 (56-319.8)	23.7 (21.9 to 25.5)	51.8 (43.4 to 60.2)
High school or General Educational Development	4086 (29.3)	204 (28.0)		35.5 (16.4-75.9)	105 (49.1-261.8)	15.2 (13.8 to 16.6)	40.5 (32.5 to 48.4)
>High school	4868 (51.2)	355 (49.7)		43.9 (21.6-88.1)	130.5 (52.5-277.4)	13.1 (12.0 to 14.1)	42.0 (36.1 to 48.0)
Family poverty income ratio
<1.3	3658 (21.1)	172 (19.7)	.378	41.3 (19.3-97.1)	95.5 (45.9-264.5)	18.3 (16.7 to 20.0)	38.7 (29.3 to 48.1)
1.3 to <3.5	5362 (40.4)	372 (43.4)		45.4 (21.2-103.7)	159.3 (64.7-346.4)	18.1 (16.8 to 19.3)	54.2 (48.1 to 60.4)
≥3.5	3554 (38.5)	243 (36.8)		41.7 (20.2-82.5)	99.6 (50.2-211.9)	11.9 (10.7 to 13.1)	34.2 (27.5 to 40.9)
Body mass index, kg/m2
<25	4527 (36.4)	287 (39.3)	.191	44.4 (21.0-96.8)	151.7 (64.4-370.9)	16.2 (14.9 to 17.5)	46.1 (39.1 to 53.1)
25 to <30	4258 (33.8)	264 (29.7)		41.6 (19.9-94.6)	135.1 (55.5-298.6)	15.2 (14.0 to 16.5)	49.9 (42.7 to 57.1)
≥30	3789 (29.8)	236 (31.0)		43.1 (20.1-93.4)	89.4 (43.0-199.7)	15.8 (14.4 to 17.2)	34.9 (27.8 to 42.1)
Smoking status
Never smoker	7239 (53.0)	305 (37.3)	<.001	39.1 (18.4-82.5)	122.7 (51.5-269.8)	14.6 (13.6 to 15.6)	46.3 (39.5 to 53.1)
Former smoker	2835 (22.9)	348 (40.7)		61.3 (27.8-148.9)	155.4 (62.0-322.9)	22.3 (20.5 to 24.0)	49.0 (42.7 to 55.4)
Current smoker	2500 (24.1)	134 (21.9)		39.5 (19.6-85.2)	86.7 (42.7-203.6)	12.1 (10.7 to 13.6)	29.7 (20.9 to 38.5)
Leisure-time physical activity
Inactive	5299 (35.6)	392 (43.7)	<.001	51.3 (23.6-129.3)	170.1 (64.5-404.7)	22.8 (21.4 to 24.2)	53.2 (47.0 to 59.4)
Active	7275 (64.4)	395 (56.3)		38.6 (18.3-77.8)	93.9 (46.3-208.4)	11.9 (11.0 to 12.7)	36.4 (31.0 to 41.9)
Diabetes
No	11 264 (92.1)	649 (85.5)	<.001	41 (19.5-87.2)	120.9 (51.6-283.8)	14.6 (13.8 to 15.4)	41.8 (37.4 to 46.3)
Yes	1304 (7.8)	138 (14.5)		72.6 (31.7-201.1)	141.9 (63.3-300.9)	29.3 (26.1 to 32.4)	55.1 (44.8 to 65.3)
Cardiovascular disease
No	11 464 (92.8)	596 (78.8)	<.001	39.3 (19.0-81.1)	99.0 (47.7-215.8)	12.6 (11.8 to 13.3)	38.5 (33.9 to 43.1)
Yes	1110 (7.2)	191 (21.2)		180.3 (69.8-490.3)	259.5 (91.5-597.5)	56.9 (53.1 to 60.6)	63.4 (55.0 to 71.7)
Chronic kidney disease
No	10 918 (89.6)	606 (79.6)	<.001	39.6 (19.2-81.3)	97.3 (47.3-217.4)	12.9 (12.2 to 13.7)	37.4 (32.9 to 41.9)
Yes	1656 (10.4)	181 (20.4)		104 (37.2-376.6)	268.9 (124.1-585.4)	40.3 (37.2 to 43.3)	68.7 (59.3 to 78.0)
Cancer type
Breast	—	138 (19.7)	—	—	165.2 (86.4-376.2)	—	55.5 (45.7 to 65.3)
Prostate	—	160 (13.2)	—	—	147.3 (64.0-298.8)	—	50.0 (40.9 to 59.2)
Colorectal	—	85 (7.5)	—	—	173.6 (77.2-452.1)	—	60.5 (47.9 to 73.1)
Gynecologic	—	161 (23.6)	—	—	64.9 (39.6-148.7)	—	25.4 (17.7 to 33.1)
Melanoma	—	65 (10.7)	—	—	102.4 (49.9-211.9)	—	34.8 (22.1 to 47.4)
Other	—	202 (28.1)	—	—	136.6 (48.9-295.1)	—	46.3 (38.1 to 54.4)
Time since cancer diagnosis, yc
Median (IQR)		8 (4-14)	—	—	—	—	—
0-1	—	85 (10.4)	—	—	108.8 (53.2-348.3)	—	42.7 (29.5 to 56.0)
2-5	—	193 (23.1)	—	—	118.9 (52.3-250.6)	—	42.3 (33.7 to 50.9)
≥6	—	509 (66.6)	—	—	129.4 (53.8-283.8)	—	44.4 (39.3 to 49.5)
Age at cancer diagnosis, y
Median (IQR)	—	59 (42-69)	—	—	—	—	—
0-39	—	245 (41.7)	—	—	64.3 (29.1-157.3)	—	25.8 (19.8 to 31.9)
≥40	—	542 (58.3)	—	—	166.1 (74.0-365.8)	—	56.6 (51.5 to 61.7)
No. of cancer types
1	—	684 (88.0)	—	—	121.9 (52.3-280.4)	—	43.2 (38.7 to 47.6)
≥2	—	103 (12.0)	—	—	151.9 (56.6-313.8)	—	48.1 (36.6 to 59.5)

a

Weighted to be nationally representative. CI = confidence interval; NHANES = National Health and Nutrition Examination Survey; NT-proBNP = N-terminal pro–brain natriuretic peptide.

b

Defined as NT-proBNP ≥125 pg/mL.

c

Time between NT-proBNP measurement and cancer diagnosis.

Distribution of NT-proBNP in adults without cancer and cancer survivors

The median (IQR) level of NT-proBNP was higher in cancer survivors (125.4 [52.4-286.0] pg/mL) than in adults without cancer (43.2 [20.3-95.0] pg/mL) at the population level (Figure 1, A). After adjusting for sociodemographic and lifestyle factors as well as health conditions, cancer survivors (β = 0.12, 95% CI = 0.04 to 0.21) had a statistically higher NT-proBNP level than adults without cancer. In particular, survivors of breast cancer (female patients only; β = 0.24, 95% CI = 0.08 to 0.40), prostate cancer (male patients only; β = 0.20, 95% CI = 0.02 to 0.38), and colorectal cancer (CRC; β = 0.27, 95% CI = 0.03 to 0.52) had higher NT-proBNP levels than adults without cancer (Figure 1, B).

Figure 1.

Comparing NT-proBNP levels between adults without cancer and cancer survivors 20 years of age or older, NHANES 1999-2004. All estimates were weighted to be nationally representative. A) Distribution of NT-proBNP among adults without cancer and Cancer Survivors. B) Stratified β-coefficients and 95% confidence intervals for NT-proBNP for cancer survivors vs adults without cancer. β-coefficients were estimated using log-transformed NT-proBNP values and adjusted for age (in years), sex (male or female), race and ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, and other), educational attainment (less than high school, high school graduate, above high school), family poverty ratio (<1.30, 1.30-3.49, or ≥3.5), body mass index (kg/m²; <25, 25-29.9, and ≥30), leisure-time physical activity (inactive or active), smoking status (never, former, and current), alcohol use (never, former, and current), Healthy Eating Index-2015, hypertension (yes or no), hypercholesterolemia (yes or no), diabetes (yes or no), history of cardiovascular disease (yes or no), and chronic kidney disease (yes or no). CI = confidence interval; NHANES = National Health and Nutrition Examination Survey; NT-proBNP = N-terminal pro–brain natriuretic peptide.

Among cancer survivors, NT-proBNP levels were higher in those 65 years of age and older (median = 192.3 [IQR = 96.3-452.1] pg/mL) than in those younger than 65 years of age (median = 55.2 [IQR = 30.1-111.2] pg/mL) (Table 1). Male survivors had a higher NT-proBNP level (median = 145.7 [IQR = 55.7-312.7] pg/mL) than did female survivors (median = 113.0 [IQR = 50.2-264.3] pg/mL). Physically inactive individuals had higher NT-proBNP levels (median = 170.1 [IQR = 64.5-404.7] pg/mL) than did those who were physically active (median = 93.9 [IQR = 46.3-208.4] pg/mL). NT-proBNP levels were also substantially higher in cancer survivors with CVD (median = 259.5 [IQR = 91.5-597.5] pg/mL) vs those without CVD (median = 99.0 [IQR = 47.7-215.8] pg/mL) and higher in survivors with CKD (median = 268.9 [IQR = 124.1-585.4] pg/mL) vs without CKD (median = 97.3 [IQR = 47.3-217.4] pg/mL) (Supplementary Table 2, available online).

NT-proBNP and mortality in cancer survivors

During a median follow up of 13.4 years (or 9393 person-years) after assessment of NT-proBNP levels, 471 deaths occurred; 141 survivors died of cancer, and 95 died of cardiac disease. Cancer survivors with higher NT-proBNP levels were at increased risks of all-cause and cardiac mortality (Supplementary Figure 1, available online). After adjusting for covariates, each 1-unit increase in log NT-proBNP was associated with a 31% increased risk of all-cause mortality and a 55% increased risk of cardiac mortality (Figure 2). Compared with those with NT-proBNP levels below 125 pg/mL, the hazard ratios for all-cause mortality among survivors with NT-proBNP levels of 125 to less than 450 pg/mL, 450 to less than 900 pg/mL, and 900 pg/mL and higher were 1.42 (95% CI = 1.08 to 1.86), 1.82 (95% CI = 1.17 to 2.84), and 3.36 (95% CI = 2.19 to 5.14), respectively (Table 2). A similar pattern was noted for mortality related to cardiac disease and other noncancer causes. Cancer mortality, however, did not rise proportionally with increases in NT-proBNP levels (P = .297 for trend). Similar results were seen in a cohort encompassing all cancers, including nonmelanoma and unknown-type skin cancers (Supplementary Figure 2, available online).

Figure 2.

Association of NT-proBNP with all-cause and cause-specific mortality among us cancer survivors 20 years of age or older, NHANES 1999-2019. Hazard ratios were estimated using log-transformed NT-proBNP values and adjusted for age (in years), sex (male or female), race and ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, and other), educational attainment (less than high school, high school graduate, above high school), family poverty ratio (<1.30, 1.30-3.49, or ≥3.5), body mass index (kg/m²; <25, 25-29.9, and ≥30), leisure-time physical activity (inactive or active), smoking status (never, former, and current), alcohol use (never, former, and current), Healthy Eating Index-2015, hypertension (yes or no), hypercholesterolemia (yes or no), diabetes (yes or no), history of cardiovascular disease (yes or no), chronic kidney disease (yes or no), years since first diagnosis of cancer, type of first cancer diagnosis, and number of cancer types. CI = confidence interval; NHANES = National Health and Nutrition Examination Survey; NT-proBNP = N-terminal pro–brain natriuretic peptide.

Table 2.

Association of NT-proBNP with all-cause and cause-specific mortality among US cancer survivors 20 years of age and older, NHANES 1999-2019

Mortality outcome	Death, n/N	Weighted death, No. (%)	Hazard ratio (95% CI)
			Age adjusteda	Multivariable model 1a,b	Multivariable model 2a,b,c
All cause
NT-proBNP, pg/mL
<125	154/395	490 423 (29.9)	1 (Referent)	1 (Referent)	1 (Referent)
125 to <450	190/260	595 386 (65.5)	1.58 (1.22 to 2.06)	1.51 (1.15 to 1.97)	1.42 (1.08 to 1.86)
450 to <900	60/63	178 684 (91.5)	2.29 (1.53 to 3.43)	2.09 (1.34 to 3.25)	1.82 (1.17 to 2.84)
≥900	67/69	164 980 (96.1)	3.82 (2.43 to 6.00)	3.65 (2.40 to 5.58)	3.36 (2.19 to 5.14)
P for trendd	N/A	N/A	<.001	<.001	<.001
Cardiac disease
NT-proBNP, pg/mL
<125	26/395	76 991 (4.7)	1 (Referent)	1 (Referent)	1 (Referent)
125 to <450	35/260	118 533 (13.0)	1.54 (0.82 to 2.87)	1.49 (0.79 to 2.81)	1.37 (0.71 to 2.66)
450 to <900	15/63	40 483 (20.7)	2.20 (0.89 to 5.43)	2.65 (1.13 to 6.24)	1.26 (0.36 to 4.40)
≥900	19/69	44 830 (26.1)	5.13 (2.25 to 11.7)	6.16 (2.79 to 13.6)	4.80 (2.06 to 11.2)
P for trend	N/A	N/A	<.001	<.001	<.001
Cancer
NT-proBNP, pg/mL
<125	55/395	180 148 (11.0)	1 (Referent)	1 (Referent)	1 (Referent)
125 to <450	59/260	198 834 (21.9)	1.64 (1.00 to 2.71)	1.57 (0.96 to 2.55)	1.44 (0.90 to 2.32)
450 to <900	12/63	33 304 (17.1)	1.16 (0.49 to 2.75)	0.90 (0.36 to 2.26)	0.86 (0.35 to 2.15)
≥900	15/69	31 677 (18.4)	1.89 (0.91 to 3.91)	1.61 (0.8 to 3.23)	1.51 (0.72 to 3.18)
P for trend	N/A	N/A	.033	.204	.297
All other causes
NT-proBNP, pg/mL
<125	73/395	233 284 (14.2)	1 (Referent)	1 (Referent)	1 (Referent)
125 to <450	96/260	278 019 (30.6)	1.58 (1.08 to 2.31)	1.45 (0.97 to 2.17)	1.37 (0.91 to 2.04)
450 to <900	33/63	104 897 (53.7)	3.37 (1.88 to 6.04)	3.08 (1.65 to 5.75)	2.99 (1.65 to 5.41)
≥900	33/69	88 473 (51.5)	4.98 (2.65 to 9.34)	4.78 (2.54 to 8.99)	4.29 (2.25 to 8.21)
P for trend	N/A	N/A	<.001	<.001	<.001

a

Adjusted for age (in years). CI = confidence interval; N/A = not applicable; NHANES = National Health and Nutrition Examination Survey; NT-proBNP = N-terminal pro–brain natriuretic peptide.

b Multivariable model additionally adjusted for sex (male or female), race and ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, and other), educational attainment (less than high school, high school graduate, above high school), family poverty ratio (<1.30, 1.30-3.49, or ≥3.5), body mass index (kg/m²; <25, 25-29.9, and ≥30), smoking status (never, former, and current), alcohol use (never, former, and current), and Healthy Eating Index-2015.

c

Additionally adjusted for hypertension (yes or no), hypercholesterolemia (yes or no), history of diabetes (yes or no), history of cardiovascular disease (yes or no), years since first diagnosis of cancer, type of first cancer diagnosis, and number of cancer types.

d

Tested using log-transformed NT-proBNP values.

Higher levels of NT-proBNP were statistically associated with higher all-cause mortality among survivors with prostate cancer (HR = 1.49, 95% CI = 1.22 to 1.81) and CRC (HR = 1.78, 95% CI = 1.00 to 3.16) but not breast cancer (HR = 1.36, 95% CI = 0.88 to 2.09) or gynecologic cancers (HR = 1.10, 95% CI = 0.73 to 1.68). Despite these differences, no statistically significant interaction was noted by cancer type (P = .169 for interaction). Additionally, there was no statistically significant difference in the relationship between NT-proBNP and time since cancer diagnosis (P = .266 for interaction) or age at cancer diagnosis (P = .459 for interaction). The association between NT-proBNP level and all-cause mortality remained consistent by most subgroups, including age, sex, race and ethnicity, body mass index, smoking status, leisure-time physical activity, diabetes, CVD, and CKD (all P > .5 for interaction). Higher levels of NT-proBNP were associated with elevated all-cause mortality in subgroups defined by education and family income levels, but this relationship was more pronounced in survivors with an educational attainment greater than high school and in those with higher family income levels (all P < .005 for interaction) (Figure 3).

Figure 3.

Stratified hazard ratios and 95% confidence intervals for association of NT-proBNP with all-cause mortality according to (A) cancer type and (B) sociodemographic and lifestyle factors and health conditions. Hazard ratios were estimated using log-transformed NT-proBNP values and adjusted for age (in years), sex (male or female), race and ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, and other), educational attainment (less than high school, high school graduate, above high school), family poverty ratio (<1.30, 1.30-3.49, or ≥3.5), body mass index (calculated as weight in kilograms divided by height in meters squared) (<25, 25-29.9, and ≥30), leisure-time physical activity (inactive or active), smoking status (never, former, and current), alcohol use (never, former, and current), Healthy Eating Index-2015, hypertension (yes or no), hypercholesterolemia (yes or no), diabetes (yes or no), history of cardiovascular disease (yes or no), chronic kidney disease (yes or no), years since first diagnosis of cancer, type of first cancer diagnosis, and number of cancer types. CI = confidence interval; GED = General Educational Development test; NT-proBNP = N-terminal pro–brain natriuretic peptide.

The shape of the relationships between NT-proBNP level and all-cause, cardiac, and cancer-specific mortality differed (Figure 4). The associations between NT-proBNP level and both all-cause and cardiac mortality exhibited nearly linear trends, with hazard ratios becoming statistically significant at NT-proBNP levels of 125 pg/mL and higher for all-cause mortality and 600 pg/mL and higher for cardiac mortality. In contrast, there was an inverse, U-shaped association with cancer mortality, although it was not statistically significant.

Figure 4.

Dose-response association of NT-proBNP with all-cause, cardiac, and cancer mortality among US cancer survivors 20 years of age or older, NHANES 1999-2019. Hazard ratios were adjusted for age (in years), sex (male or female), race and ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, and other), educational attainment (less than high school, high school graduate, above high school), family poverty ratio (<1.30, 1.30-3.49, or ≥3.5), body mass index (calculated as weight in kilograms divided by height in meters squared) (<25, 25-29.9, and ≥30), leisure-time physical activity (inactive or active), smoking status (never, former, and current), alcohol use (never, former, and current), Healthy Eating Index-2015, hypertension (yes or no), hypercholesterolemia (yes or no), diabetes (yes or no), history of cardiovascular disease (yes or no), chronic kidney disease (yes or no), years since first diagnosis of cancer, type of first cancer diagnosis, and number of cancer types. CI = confidence interval; NHANES = National Health and Nutrition Examination Survey; NT-proBNP = N-terminal pro–brain natriuretic peptide.

Discussion

In this US nationally representative cohort, NT-proBNP levels were higher in cancer survivors, particularly survivors of breast cancer, prostate cancer, and CRC, than in adults without cancer. Overall, 40% of cancer survivors had an NT-proBNP level of 125 pg/mL or higher, a threshold for pre-HF (22). Over a median follow-up of 13.3 years, elevated NT-proBNP levels were associated with increased all-cause and cardiac but not cancer-specific mortality. There was a nonlinear relationship between NT-proBNP level and all-cause mortality, with a 3-fold increased risk of death in survivors with NT-proBNP levels of 900 pg/mL and higher compared with those with NT-proBNP levels below 125 pg/mL. The observed relationship between NT-proBNP level and mortality was similar across different cancer types, age at cancer diagnosis, lifestyle factors, and health conditions. Notably, more than one-third of cancer survivors in this cohort received a cancer diagnosis before they were 40 years of age, and the majority were younger than 65 years of age at the time of analysis, highlighting the importance of cardiac outcomes, even in younger cancer survivors.

The association of NT-proBNP level with mortality has previously been explored in noncancer populations (13). A report from the Framingham Offspring Study of 3346 adults free of HF, with a mean follow-up of 5.2 years, found that 1 SD of log NT-proBNP was associated with a 27% increase in all-cause mortality (14). Other studies have shown that NT-proBNP, independent of other CVD biomarkers, can predict mortality in high-risk patients, such as in individuals with diabetes (27), CVD (15), and kidney disease (28). Recent studies have also begun to explore the relationship between NT-proBNP level and mortality in patients with cancer and survivors. In a prospective cohort of 555 patients with mixed types of cancer who had not received prior cardiotoxic treatment, NT-proBNP level was a significant predictor of all-cause mortality at a median follow-up of 25 months (29). Another single-center cohort study linked elevated NT-proBNP level with decreased 5-year survival in patients with cancer at high risk for CVD (30). Many cancer survivors, especially those diagnosed with cancers of the breast and prostate (31,32), do not die from cancer but from other comorbidities, such as CVD (33). Increased NT-proBNP levels may predict increased cardiovascular mortality in cancer survivors, but the relationship between NT-proBNP level and long-term mortality among survivors with diverse cancers, particularly at the population level, has been understudied.

To our knowledge, our study is the first to investigate prospective associations of NT-proBNP level with long-term survival among cancer survivors at the population level. Our results demonstrate that NT-proBNP was elevated in cancer survivors, with 40% having elevated NT-proBNP. Particularly, survivors of breast cancer, prostate cancer, and CRC had higher levels of NT-proBNP than did adults without cancer, with more than 50% having elevated NT-proBNP levels. Our findings also illustrated distinct dose-response relationships between NT-proBNP and the respective risks of cardiac and cancer mortality. The risk of cardiac mortality increased exponentially with rising NT-proBNP levels, while an inverse U-shaped association with cancer mortality appeared to be nonsignificant. Although these results warrant replication in other datasets, they do suggest a complex interplay between competing causes of mortality in cancer survivors and a potential mediating role of cardiovascular risks.

Our findings suggested that NT-proBNP could be a potential tool to monitor cardiovascular health in cancer survivors across malignancies (34). Previous studies have demonstrated that higher NT-proBNP levels were observed in long-term survivors of childhood cancers (35) and breast cancer (36) treated with anthracyclines or radiation therapy (17). Current guidelines for managing cardiovascular toxicity related to cancer treatment primarily focus on monitoring patients during their treatment (37). Guidelines on cardiac monitoring after cancer treatment vary among organizations (38-41). In noncancer populations, monitoring NT-proBNP has been shown to improve cardiac outcomes. For example, the STOP-HF (the St Vincent’s Screening to Prevent Heart Failure) trial demonstrated that NT-proBNP-based screening reduced risk of HF and hospitalization for cardiac events in individuals with cardiac risk factors (42), prompting the American Heart Association/American College of Cardiology/Heart Failure Society of America to incorporate NT-proBNP as a key monitoring biomarker for HF (20). Our findings that NT-proBNP levels above 125 pg/mL were associated with an increased risk of all-cause and cardiac mortality align with the threshold defining pre-HF in noncancer populations according to the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America Guideline for the Management of Heart Failure (22,42). Although future research is needed to evaluate whether early identification of cardiovascular risk in cancer survivors leads to improvements in long-term outcomes, our data suggest a potential role for NT-proBNP as a monitoring biomarker in cancer survivorship (43-45).

Several limitations of this work should be considered. First, NHANES did not collect data on cancer treatment, including the use of cardiotoxic drugs, making it difficult to determine the effects of cardiotoxic treatment on NT-proBNP and subsequent cardiac events. Further studies are needed to examine whether cancer treatments affect the observed relationship between NT-proBNP and cancer survival outcomes. Additionally, it is important to note that the association between NT-proBNP and mortality outcomes among cancer survivors could be explained by the shared risk factors for cancers and heart disease. NT-proBNP could be a marker of prefrailty and frailty, which are the result of diseases that are common risks for both heart disease and cancer. Our study also evaluated a single measure of NT-proBNP after cancer diagnosis. Future studies should use repeated NT-proBNP measurements over time (ie, before, during, and after cancer diagnosis and treatments), particularly in survivors of cancer types affected by treatment-induced cardiotoxicity, to establish its validity and utility in clinical prediction beyond routine geriatric assessments and cardiac symptom monitoring and physical examination. In addition, our exploratory analysis evaluating the relationship between NT-proBNP level and mortality across different racial and ethnic groups may be limited by the small sample sizes from minority populations. Future work is needed to determine whether NT-proBNP levels predict increased cardiovascular mortality in diverse populations of cancer survivors. Finally, the number of individuals with cancer in this cohort was relatively modest and included oversampling of some cancers, such as gynecologic cancers, leading to limited power in the analyses of the relationship between NT-proBNP level and mortality outcomes in some malignancies.

In this nationally representative sample of US adults, cancer survivors had higher NT-proBNP levels than did individuals without cancer. Elevated NT-proBNP levels was associated with higher risks of all-cause and cardiac mortality. Future studies evaluating the frequency of NT-proBNP elevations in cancer survivors, the relationship between NT-proBNP level and cancer outcomes, and the development of intervention strategies to reduce cardiac events and mortality in cancer survivors are needed.

Data availability

The data that support the findings of this study are publicly available at the NCHS site (https://www.cdc.gov/nchs/nhanes/index.htm).

Author contributions

Chao Cao, PhD, MPH (Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Software; Supervision; Validation; Visualization; Writing—original draft; Writing—review & editing), Lin Yang, PhD (Data curation; Formal analysis; Methodology), Anju Nohria, MD, MSc (Investigation; Writing—review & editing), Erica L. Mayer, MD, MPH (Investigation; Writing—review & editing), Ann H. Partridge, MD, MPH (Investigation; Writing—review & editing), Jennifer A. Ligibel, MD (Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Resources; Software; Supervision; Validation; Visualization; Writing—original draft; Writing—review & editing).

Funding

C. Cao is supported by the US National Cancer Institute grant No. 5T32CA092203.

Conflicts of interest

A.N. receives research support from Bristol Myers Squibb and consulting fees from Altathera Pharmaceuticals, AstraZeneca, Bantam Pharmaceuticals, Regeneron Pharmaceuticals, and Takeda Oncology.

Acknowledgements

The funders had no role in the study design; data collection, analysis, or interpretation; or writing of the manuscript or decision to submit it for publication.