Cardiovascular mortality among cancer survivors who developed breast cancer as a second primary malignancy

Chengshi Wang; Kejia Hu; Chuanxu Luo; Lei Deng; Katja Fall; Rulla M Tamimi; Unnur A Valdimarsdóttir; Fang Fang; Donghao Lu

doi:10.1038/s41416-021-01549-w

. 2021 Sep 27;125(10):1450–1458. doi: 10.1038/s41416-021-01549-w

Cardiovascular mortality among cancer survivors who developed breast cancer as a second primary malignancy

Chengshi Wang ^1,², Kejia Hu ³, Chuanxu Luo ¹, Lei Deng ⁴, Katja Fall ⁵, Rulla M Tamimi ^6,⁷, Unnur A Valdimarsdóttir ^6,^8,⁹, Fang Fang ³, Donghao Lu ^3,^6,^10,^✉

PMCID: PMC8575780 PMID: 34580431

Abstract

Background

To assess the risk of cardiovascular mortality among cancer survivors who developed breast cancer as a second malignancy (BCa-2) compared with patients with first primary breast cancer (BCa-1) and the general population.

Methods

Using the Surveillance, Epidemiology, and End Results database, we conducted a population-based cohort study including 1,024,047 BCa-1 and 41,744 BCa-2 patients diagnosed from the age 30 between 1975 and 2016, and the corresponding US female population (994,415,911 person-years; 5,403,551 cardiovascular deaths). Compared with the general population and BCa-1 patients, we calculated incidence rate ratios (IRRs) of cardiovascular deaths among BCa-2 patients using Poisson regression. To adjust for unmeasured confounders, we performed a nested, case-crossover analysis among BCa-2 patients who died from cardiovascular disease.

Results

Although BCa-2 patients had a mildly increased risk of cardiovascular mortality compared with the population (IRR 1.08) and BCa-1 patients (IRR 1.15), the association was pronounced among individuals aged 30–49 years (BCa-2 vs. population: IRR 6.61; BCa-2 vs. BCa-1: IRR 3.03). The risk elevation was greatest within the first month after diagnosis, compared with the population, but comparable with BCa-1 patients. The case-crossover analysis confirmed these results.

Conclusion

Our findings suggest that patients with BCa-2 are at increased risk of cardiovascular mortality.

Subject terms: Outcomes research, Cancer epidemiology, Cardiovascular diseases, Epidemiology

Introduction

Over the past few decades, breast cancer-specific survival has substantially improved with the development of better cancer treatment and medical care [1]. However, non-cancer causes account for about 40% of deaths among breast cancer survivors and cardiovascular disease is one of the leading causes [2]. Patients with primary breast cancer as the first malignancy (BCa-1) are at risk for cardiovascular diseases, potentially because of shared risk factors between breast cancer and cardiovascular disease, including (e.g., age, smoking, obesity and a sedentary lifestyle) [3], adverse effects of cancer treatment [4] and psychological distress [5]. Some [2, 6, 7], but not all [8–10], studies suggest that patients with breast cancer are at increased risk of cardiovascular deaths, compared with the general population. Although the absolute risk of cardiovascular mortality is high among elderly patients with breast cancers [11], the relative risk is not increased [9]. The risk is however less studied for younger patients, although an increased mortality risk of cardiovascular diseases has been shown for BCa-1 patients before age 45 [12]. Our previous work, [13] supported by the work of others [14], revealed that elevated cardiovascular mortality in a relatively short time after the diagnosis of BCa-1.

Given the improved cancer survivorship, second primary cancers have become increasingly common [15]. As the most common type, breast cancer as a second primary malignancy (BCa-2) accounts for 45% of second cancers developed among female cancer survivors [16, 17] and 8–10% of newly diagnosed breast cancers [16, 18]. Previous studies have illustrated radiotherapy and chemotherapy could impact on the risk of cardiovascular diseases among cancer patients [19]. Lifetime dose limitation is recommended for certain cancer treatments (e.g., radiotherapy and anthracycline chemotherapy) [20, 21]. Although it is unlikely for patients to receive an over-limit dose for the same regimen due to the second malignancy, patients with BCa-2 may have received radiotherapy for the first malignancy and anthracycline for BCa-2 or vice versa. In addition, trastuzumab is reported to show cardiotoxic effects, especially in concurrent use with anthracyclines [22]. It is therefore plausible that the second-round treatment for BCa-2 may impose additional cardiotoxicity. Moreover, it is well-documented that patients who had recently received a BCa-1 diagnosis as a major stressor had an increased risk of cardiovascular mortality [13]. However, little is known about the risk of cardiovascular mortality among cancer survivors who developed BCa-2 and the risks in different age groups.

Leveraging a large-scale population-based cancer cohort and aggregated population data in the US, by different attained age groups, we assessed the risk of cardiovascular mortality among BCa-2 patients compared with BCa-1 patients and the general female population. To address risk factors shared between breast cancer and cardiovascular disease (e.g., smoking, obesity, alcohol consumption and physical activity) [3, 5], we further performed a nested, self-matched case-crossover analysis among BCa-2 patients who died from cardiovascular disease to confirm our findings.

Methods

Study design

Based on the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, we conducted a population-based cohort study of female patients age ≥30 years with primary breast cancer diagnosed between January 1, 1975 and December 31, 2016 in 13 states. The SEER contains information on demographic, tumour, clinical characteristics and follow-up covering about 30% of the US population by 2000. We identified 1,302,817 patients with primary invasive breast cancer confirmed by pathological diagnosis. We further excluded patients who were male (N = 9715), without information of birth year (N = 79), younger than 30 years at diagnosis for whom the risk of cardiovascular death is very low (N = 6715), or patients whose race was unknown (N = 5008). Patients were followed from breast cancer diagnosis until death, the occurrence of a subsequent malignancy, or December 31, 2016, whichever occurred first. Patients without accurate follow-up dates were excluded (N = 158,831; baseline characteristics and cardiovascular mortality rate are described in Supplementary Table 1).

Using the U.S. Census Bureau’s Population Estimates Program, we also included 994,415,911 person-years from the female population in the corresponding 13 states from 1975 to 2016.

Ascertainment of second primary breast cancer

Among the remaining 1,122,469 patients with breast cancer, 98,052 were recorded as not having cancer as their first malignancy. By linking to the previous diagnoses of malignancy in SEER, we excluded patients with breast cancer as the third or above primary malignancy (N = 2645), and patients with no information on previous malignancies (N = 52,817; the baseline characteristics and cardiovascular mortality rate are described in Supplementary Table 1). BCa-2 patients with a prior history of breast cancer (i.e., likely contralateral breast cancer) were excluded (N = 846) because of the difficulty to determine whether the underlying cause of death was the first or second breast cancer. Thus, BCa-2 in this study represents primary breast cancer as a second malignancy subsequent to a non-mammary malignancy. Finally, we included 1,066,161 patients with primary breast cancer (41,744 BCa-2 and 1,024,417 BCa-1). The exclusions are illustrated in Supplementary Fig. 1.

Fig. 1 — IRR incidence rate ratio, m month, y years. BCa-2 vs. population: The general population served as a constant reference to be compared with different periods after cancer diagnosis in patients with BCa-2. IRRs were adjusted for attained age (30–64, 65–69, 70–74, 75–79, 80–84 or ≥85 years), race (white, black or other), region of residence (Northeast, Midwest, South or West) and calendar year at follow-up (1975–1989, 1990–1993, 1994–1997, 1998–2001, 2002–1006, 2007–2011 or 2012–2016). Patients who were not white/black were grouped at the national level when comparing BCa-2 with the population. BCa-2 vs. BCa-1: IRRs were additionally adjusted for time since diagnosis (0 to <1 month, 1 to <6 months, 6 to <12 months, 1 to <2 years, 2 to <5 years, 5 to <10 years and ≥10 years), tumour stage (localised, regional, distant or unknown), histology (duct, lobular, mixed or other), grade (well differentiation, moderate differentiation, poor differentiation, undifferentiation or unknown), oestrogen receptor status (positive, negative or unknown), progesterone receptor status (positive, negative or unknown), human epidermal growth factor receptor 2 status (positive, negative or unknown), surgery (no surgery, yes surgery or unknown), radiotherapy (yes or no/unknown) and chemotherapy(yes or no/unknown).

Ascertainment of cardiovascular deaths and follow-up

Cardiovascular death was defined as the primary outcome. Patient follow-up was performed periodically by different hospital-based and population-based registries. To ensure the maximal follow-up, personal contacts were also periodically implemented for those who were considered lost to follow-up.

The cause of death was derived from death certificates with algorithms to identify a single, disease-specific cause after considering tumour sequence, site of the cancer diagnosis, and comorbidities. We used the International Classification of Diseases codes (Supplementary Table 2) to identify deaths from cardiovascular disease [23]. We also studied subgroups of cardiovascular deaths, classified as due to disease of the heart, cerebrovascular disease or other cardiovascular diseases.

Covariates

Baseline information was obtained from the U.S. Census Bureau’s Population Estimates Program for the general female population and from SEER for breast cancer patients, including age and calendar year at census or cancer diagnosis, race, and region of residence. We then derived attained age groups, namely age at follow-up and calendar year at follow-up for all groups, and time since diagnosis for breast cancer patients. Because CVD risk is highly correlated with age which increases along with follow-up [24], we used attained age rather than age at diagnosis to better control for the confounding effect of age.

We extracted information on clinical characteristics from SEER for breast cancer patients, including tumour stage, tumour size, histology, tumour grade, the status of oestrogen receptor (ER, available from 1990 onward), progesterone receptor (PR, available from 1990 onward) and human epidermal growth factor receptor 2 (HER2, available from 2010 onward). Molecular subtype (available from 2010 onward) was classified as hormone receptor-positive (HR + )/HER2−, HR + /HER2 + , hormone receptor-negative (HR−)/HER2 + , triple-negative or unknown. We also extracted information on treatment, including surgery, radiotherapy and chemotherapy, for breast cancer (both BCa-1 and BCa-2) and for the first primary malignancy of BCa-2 patients, respectively. All missing values of the covariates including molecular subtypes and treatment were coded to the “unknown” category.

Statistical analysis

We considered the general population and BCa-1 patients as the first and second reference groups, respectively. Using Poisson regression, we estimated the incidence rate ratios (IRRs) and 95% confidence intervals (95% CIs) of cardiovascular deaths among patients with BCa-2, compared with patients with BCa-1 and the general population. To alleviate the concern of the different risks of developing a subsequent malignancy between BCa-1 and BCa-2, We performed an additional analysis without censoring follow-up at the occurrence of a subsequent malignancy. Because age at cancer diagnosis is important for clinical interpretation, we conducted an additional analysis by grouping BCa-1 and BCa-2 patients based on age at breast cancer diagnosis (attained age was also adjusted for).

We also plotted the cumulative mortality rate for BCa-2 and BCa-1 patients using a competing risk model which addresses the influence of dying from cancers and other none cancer causes preventing cancer patients dying from cardiovascular disease [25]. Such analysis was not conducted by using the general population as the reference group because the data at the individual level were not available.

Given that the increased risk was limited to attained age before 80 years, we performed subsequent associations by attained age of 30–79 and ≥80. We estimated the risk of type-specific cardiovascular deaths and, to shed light on the temporal pattern, calculated period-specific IRRs by time since cancer diagnosis. To explore the potential influence of first malignancy on cardiovascular deaths, we calculated IRRs by classifying BCa-2 patients according to characteristics of their first malignancies, including top ten common sites, tumour stage, chemotherapy, radiotherapy, and surgery of first malignancy. We also performed subgroup analyses by tumour characteristics and treatment modes of breast cancer. To illustrate the influence of different radiation strategies in the different eras, we performed a subgroup analysis to assess the risks during 1975–1989 and 1990–2016, separately. Since the increased risk was primarily detected in BCa-2 patients at attained age of 30–79 years, we only performed subgroup analyses in this age group.

In these analyses, we firstly adjusted for demographic characteristics (Model A) when comparing BCa-2 patients with the general population and BCa-1 patients. When comparing BCa-2 patients with BCa-1 patients, we additionally controlled for tumour characteristics (Model B) and treatment modes (Model C). Covariates are categorised as shown in Supplementary Table 3. We only applied Model C (full model) in secondary analyses when comparing BCa-2 patients with BCa-1 patients.

To address common risk factors (e.g., smoking, obesity, alcohol consumption, and menopausal status) between breast cancer and cardiovascular diseases, we conducted a nested, self-matched, case-crossover analysis [26] among BCa-2 patients who died from cardiovascular diseases. Using a similar approach implemented in previous work [13], we compared the occurrence of BCa-2 diagnosis during the first month preceding cardiovascular death (hazard period) with that of 17 1-month periods before the hazard period (control periods). Briefly, the hazard period was chosen for comparability according to the results of the primary analysis; the control period was chosen to account for potentially varying baseline risk over time and to minimise autocorrelation in exposure in both periods while limiting carryover effects. In the case-crossover analysis, patients served as their own controls, i.e., self-matching, which directly eliminated confounding by risk factors that were constant within patients during the sampling period but often differed between individuals. Conditional logistic regression was performed to estimate the odds ratios (OR) in the hazard period, as compared with the control periods.

All statistical analyses were conducted using STATA (version 14.1; Stata Corporation). P < 0.05 indicates the statistical significance. This study was approved by the Biomedical Research Ethics Committee at West China Hospital, Sichuan University (reference number 2018-230).

Results

Demographic and clinical characteristics

Compared with the general population and BCa-1 patients, BCa-2 patients were older, more likely to be white and residents in the Northeast (Supplementary Table 3). Compared with BCa-1, BCa-2 tumours were better differentiated, of smaller size and of less advanced stage, and more likely to be HR + /HER2− and treated by surgery only. Fewer BCa-2 patients were followed for ≥10 years after cancer diagnosis.

Cardiovascular mortality risk by attained age

During a median follow-up of 5.9 years (interquartile range, 2.4–11.3 years), we observed 3,550 (mortality rate 1.6 per 100 person-years) and 71,298 (mortality rate 0.9 per 100 person-years) cardiovascular deaths among BCa-2 and BCa-1 patients, respectively, during a median follow-up of 3.7 years (interquartile range, 1.4–7.6 years) and 6 years (interquartile range, 2.5–11.4 years). The cumulative mortality rate of cardiovascular disease was higher among BCa-2 patients than that in BCa-1 patients by 20 years after the diagnosis (19.44% vs. 13.60%; Supplementary Fig. 2). There were 5,403,551 cardiovascular deaths (mortality rate 0.5 per 100 person-years) in the general population.

Fig. 2 — CI confidence interval, IRR incidence rate ratio, MR mortality rate per 100 person-years, N number of deaths. ^aIRRs were adjusted for attained age (30–64, 65–69, 70–74 or 75–79 years), race (white, black or other), region of residence (Northeast, Midwest, South or West), and calendar year at follow-up (1975–1989, 1990–1993, 1994–1997, 1998–2001, 2002–1006, 2007–2011 or 2012–2016). Patients who were not white/black were grouped at the national level when comparing BCa-2 with the population. ^bIRRs were additionally adjusted for time since diagnosis (0 to <1 month, 1 to <6 months, 6 to <12 months, 1 to <2 years, 2 to <5 years, 5 to <10 years and ≥10 years), tumour stage (localised, regional, distant or unknown), histology (duct, lobular, mixed, or other), grade (well differentiation, moderate differentiation, poor differentiation, undifferentiation or unknown), oestrogen receptor status (positive, negative or unknown), progesterone receptor status (positive, negative or unknown), human epidermal growth factor receptor 2 status (positive, negative or unknown), surgery (no surgery, yes surgery or unknown), radiotherapy (yes or no/unknown) and chemotherapy (yes or no/unknown).

Compared with the general population, BCa-2 patients had a mildly increased risk of cardiovascular mortality (IRR 1.08, 95% CI 1.05–1.12; Table 1) when controlling for demographic factors. A higher magnitude association was observed for younger patients (P for interaction <0.001): IRR was greatest among patients at attained age of 30–49 years (IRR 6.61, 95% CI 3.99–10.97; Table 1), whereas no risk elevation was noted beyond attained age 80 (IRR 0.98, 95% CI 0.94–1.02; Table 2). A similar pattern was noted when comparing BCa-2 patients with BCa-1 patients, which was independent of tumour characteristics and treatment modes (Table 1). The additional analysis without censoring follow-up at the occurrence of a subsequent malignancy yielded very similar results (Supplementary Table 4). Moreover, the additional analysis by grouping BCa-1 and BCa-2 patients based on age at breast cancer diagnosis (Supplementary Table 5) showed largely comparable trends to our original analyses based on attained age.

Table 1.

Incidence rate ratios (IRRs) of cardiovascular deaths among patients with the primary breast cancer (BCa-2) developed from non-mammary malignancy, compared with the female population and patients with primary breast cancer (BCa-1): a population-based study in the U.S., 1975–2016.

	References		BCa-2, N (MR)	BCa-2 vs. population	BCa-2 vs. BCa-1
	Population, N (MR)	BCa-1, N (MR)	BCa-2, N (MR)	IRR (95% CI)^a	IRR (95% CI)^b	IRR (95% CI)^c	IRR (95% CI)^d
Overall	5,403,551 (0.5)	76,221 (0.9)	3784 (1.7)	1.08 (1.05–1.12)	1.14 (1.10–1.18)	1.16 (1.12–1.20)	1.15 (1.12–1.19)
By attained age, year
30–49	127,513 (0.03)	575 (0.1)	15 (0.2)	6.61 (3.99–10.97)	3.03 (1.81–5.07)	3.17 (1.90–5.31)	3.03 (1.81–5.07)
50–64	464,183 (0.2)	4232 (0.1)	111 (0.2)	1.82 (1.51–2.20)	1.62 (1.34–1.95)	1.65 (1.37–2.00)	1.60 (1.32–1.93)
65–69	330,584 (0.5)	3608 (0.3)	143 (0.5)	1.42 (1.21–1.68)	1.40 (1.19–1.66)	1.45 (1.22–1.71)	1.41 (1.19–1.67)
70–74	487,637 (0.9)	5646 (0.6)	261 (0.8)	1.30 (1.15–1.47)	1.34 (1.18–1.52)	1.37 (1.21–1.56)	1.35 (1.19–1.53)
75–79	705,186 (1.6)	8893 (1.1)	439 (1.3)	1.15 (1.04–1.26)	1.19 (1.08–1.31)	1.21 (1.10–1.34)	1.20 (1.09–1.32)
80–84	954,840 (2.9)	13,299 (2.2)	692 (2.3)	1.06 (0.99–1.14)	1.13 (1.04–1.22)	1.15 (1.06–1.24)	1.14 (1.05–1.23)
≥85	2333608 (7.4)	35,045 (5.9)	1889 (5.8)	0.95 (0.91–0.99)	1.04 (1.00–1.09)	1.06 (1.01–1.11)	1.06 (1.02–1.12)
P for interaction^e				<0.001	<0.001	<0.001	<0.001

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CI confidence interval, IRR incidence rate ratio, MR mortality rate per 100 person-years, N number of deaths.

^aIRRs were adjusted for attained age (30–49, 50–64, 65–69, 70–74, 75–79, 80–84 or ≥ 85 years), race (white, black or other), region of residence (Northeast, Midwest, South or West), and calendar year at follow-up (1975–1989, 1990–1993, 1994–1997, 1998–2001, 2002–1006, 2007–2011 or 2012–2016). Patients who were not white/black were grouped at the national level when comparing BCa-2 with the population.

^bIRRs were additionally adjusted for time since diagnosis (0 to <1 month, 1 to <6 months, 6 to <12 months, 1 to <2 years, 2 to <5 years, 5 to <10 years or ≥10 years).

^cIRRs were additionally adjusted for tumour stage (localised, regional, distant or unknown), histology (duct, lobular, mixed or other), grade (well differentiation, moderate differentiation, poor differentiation, undifferentiation or unknown), oestrogen receptor status (positive, negative or unknown), progesterone receptor status (positive, negative or unknown), and human epidermal growth factor receptor 2 status (positive, negative or unknown).

^dIRRs were additionally adjusted for surgery (no surgery, yes surgery or unknown), radiotherapy (yes or no/unknown), and chemotherapy (yes or no/unknown).

^eWe added an interaction term between BCa-2 and attained age (30–49, 50–64 years, every 5 years afterwards, or ≥85 years) and reported the significance level of the term as P for interaction.

Table 2.

Incidence rate ratios (IRRs) of type-specific cardiovascular deaths among patients with the primary breast cancer (BCa-2) developed from non-mammary malignancy, compared with the female population and patients with primary breast cancer (BCa-1): a population-based study in the U.S., 1975–2016.

	Population, N (MR)	BCa-1, N (MR)	BCa-2, N (MR)	BCa-2 vs. population IRR (95% CI)^a	BCa-2 vs. BCa-1 IRR (95% CI)^b
Overall cardiovascular deaths
By attained age
30–79 years	2,115,103 (0.2)	22,954 (0.3)	969 (0.6)	1.31 (1.23–1.40)	1.34 (1.25–1.43)
≥80 years	3,288,448 (5.1)	48,344 (4.0)	2581 (4.1)	0.98 (0.94–1.02)	1.08 (1.04–1.13)
Due to disease of heart
By attained age
30–79 years	1,581,858 (0.2)	17,441 (0.3)	730 (0.5)	1.34 (1.25–1.44)	1.34 (1.24–1.44)
≥80 years	2,367,637 (3.7)	35,354 (2.9)	1912 (3.1)	1.00 (0.95–1.04)	1.10 (1.05–1.15)
Due to cerebrovascular disease
By attained age
30–79 years	406,367 (0.0)	4054 (0.1)	169 (0.1)	1.20 (1.03–1.40)	1.29 (1.10–1.50)
≥80 years	683,665 (1.1)	9513 (0.8)	482 (0.8)	0.92 (0.84–1.01)	1.04 (0.95–1.14)
Due to other cardiovascular diseases
By attained age
30–79 years	126,878 (0.0)	1459 (0.0)	70 (0.0)	1.32 (1.04–1.66)	1.46 (1.15–1.86)
≥80 years	237,146 (0.4)	3477 (0.3)	187 (0.3)	0.93 (0.81–1.08)	1.09 (0.94–1.26)

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CI confidence interval, IRR incidence rate ratio, MR mortality rate per 100 person-years, N number of deaths.

^aIRRs were adjusted for attained age (30–64, 65–69, 70–74, 75–79, 80–84 or ≥85 years), race (white, black or other), region of residence (Northeast, Midwest, South or West) and calendar year at follow-up (1975–1989, 1990–1993, 1994–1997, 1998–2001, 2002–1006, 2007–2011 or 2012–2016). Patients who were not white/black were grouped at the national level when comparing BCa-2 with the population.

^bIRRs were additionally adjusted for time since diagnosis (0 to <1 month, 1 to <6 months, 6 to <12 months, 1 to <2 years, 2 to <5 years, 5 to <10 years and ≥10 years), tumour stage (localised, regional, distant or unknown), histology (duct, lobular, mixed or other), grade (well differentiation, moderate differentiation, poor differentiation, undifferentiation or unknown), oestrogen receptor status (positive, negative or unknown), progesterone receptor status (positive, negative or unknown) and human epidermal growth factor receptor 2 status (positive, negative, or unknown), surgery (no surgery, yes surgery or unknown), radiotherapy (yes or no/unknown) and chemotherapy (yes or no/unknown).

Given the pronounced interaction with attained age, we performed subsequent analyses by attained age 30–79 and ≥80 years. The stronger associations among patients at attained age 30–79 years were observed for deaths from heart, cerebrovascular, and other cardiovascular diseases, when comparing BCa-2 patients with the general population and BCa-1 patients (Table 2).

Cardiovascular mortality risk by time since diagnosis

When compared with the general population, the cardiovascular mortality in BCa-2 patients with attained age 30–79 years was particularly high within the first month after cancer diagnosis (IRR 3.20, 95% CI 2.34–4.38; Fig. 1 and estimates in Supplementary Table 6). The risk was however similar between BCa-2 and BCa-1 patients during this period. The risk among BCa-2 patients was elevated through and beyond 10 years after cancer diagnosis when compared with either the general population or BCa-1 patients. Among patients with attained age ≥80 years, BCa-2 was only associated with increased risk of cardiovascular mortality within the first month (IRR 2.39, 95% CI 1.89–3.02) and ≥10 years (IRR 1.21, 95% CI 1.13–1.31) after diagnosis, compared with the general population. A similar pattern was found when comparing BCa-2 patients with BCa-1 patients.

In the case-crossover analysis, the risk of cardiovascular mortality was significantly higher during the first month after BCa-2 diagnosis (OR 1.95, 95% CI 1.51–2.51), both before and after attained age of 80 years, than those at reference times (Table 3).

Table 3.

Odds ratios of cardiovascular deaths after the diagnosis of primary breast cancer (BCa-2) developed in survivors of non-mammary malignancy in case-crossover analysis^a: a population-based study in the U.S., 1975–2016.

	Cardiovascular deaths, N		OR (95% CI)
	Control period	Hazard period
Overall	577	66	1.95 (1.51–2.51)
By attained age
30–79 years	240	28	1.98 (1.34–2.93)
≥80 years	337	38	1.92 (1.37–2.68)

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CI confidence interval, OR odds ratio, N number of deaths.

^aThis analysis included all breast cancer patients who died of cardiovascular diseases. The hazard period was defined as the 1 month (30 days) preceding cardiovascular death and the control periods as the 17 1-month periods preceding the hazard period.

Factors that modify cardiovascular mortality risk

Considering the non-increased risk among patients at attained age of ≥80 years, subgroup analyses were restricted to those at attained age of 30–79 years. In the analyses by first malignancy’s characteristics (Fig. 2), BCa-2 patients with a prior cancer in the lung, kidney, uterine cervix, urinary bladder, or uterine corpus were at a higher risk of cardiovascular mortality, compared with the general population. Moreover, the association was strongest in BCa-2 patients whose first malignancy was at a disseminated stage, diagnosed within one year before BCa-2, or treated by chemo-/radiotherapy. Similar patterns were found when comparing BCa-2 patients with BCa-1 patients.

In the analyses by breast cancer characteristics, IRRs were greater in BCa-2 patients with the distant stage (IRR 2.83, 95% CI 2.08–3.84) or not treated by radiotherapy for breast cancer (IRR 1.59, 95% CI 1.47–1.71) when comparing with the general population (P for difference <0.05; Supplementary Table 7). Comparable IRRs were noted when comparing BCa-2 patients with BCa-1 patients. Interestingly, for those who were treated with radiotherapy for breast cancer, BCa-2 patients diagnosed during 1975–1989 had an elevated, though non-significant, risk of cardiovascular mortality compared to the general population, whereas no risk increase among those diagnosed afterwards (Supplementary Table 8).

Discussion

To the best of our knowledge, this is the first study to comprehensively examine the risk of cardiovascular mortality among cancer survivors who developed primary breast cancer. We found that BCa-2 patients, particularly between attained age of 30 and 79 years, were at higher risk of cardiovascular mortality than the general population and BCa-1 patients. The risk was most pronounced within the first month after a cancer diagnosis than that in the general population. Most importantly, this finding was confirmed by case-crossover analysis which controls for confounders, particularly risk factors shared between breast cancer and cardiovascular disease.

A recent study reported that childhood cancer survivors (age at first malignancy <21 years) who developed BCa-2 were at increased risk of mortality due to causes other than breast cancer compared with those with BCa-1, and 33% of the deaths were attributable to cardiovascular causes [27]. Our findings further suggest an increased risk of cardiovascular mortality among adult cancer survivors who developed BCa-2. An earlier study showed that the risk of cardiac mortality was two times higher among patients with localised BCa-2 and four times higher among patients with regional or distant BCa-2 subsequent to Hodgkin’s lymphoma, compared with patients with BCa-1 [28]. In line with that, our data also suggest that BCa-2 patients with a prior blood malignancy were at, albeit non-significant, increased risk of cardiovascular deaths compared with BCa-1 patients. Moreover, our data extended the knowledge to the increased risk of cardiovascular mortality among BCa-2 patients overall and patients with other cancer types as the first malignancy. Most importantly, no studies have compared the risk of cardiovascular mortality among BCa-2 patients with that of the general population, which should have more impactful implications for public health interests.

Age is positively correlated with cardiovascular mortality in the general population [29] as well as in breast cancer patients [9]. A study of postmenopausal breast cancer patients suggested that, although the absolute risk was high, older patients at diagnosis of localised breast cancer were not at increased risk of cardiovascular disease compared to their cancer-free peers [9]. Interestingly, our data showed that the relative risk of cardiovascular mortality was particularly high among young patients with BCa-2 compared with the general population, whereas no risk elevation was observed beyond attained age of 80 years. This is in line with a recent study showing that cancer patients (all sites) diagnosed before age 85 have an increased mortality of heart disease compared to the general population; and that the younger a cancer survivor is diagnosed, the higher the relative risk is [6].

Cancer treatment may introduce cardiotoxicity and predispose patients to cardiovascular disease. For example, radiation-related cell damage may activate acute inflammatory cascades and develop myocardial fibrosis and subsequently cardiac damage [30]. It is known that radiotherapy is associated with increased risks of cardiovascular disease [30] and deaths [31–34] in cancer survivors including breast cancer. This is supported by our findings on the greater risk increase of cardiovascular mortality in BCa-2 patients who received radiotherapy for their first malignancy. In addition, some chemotherapy may take a toll on the circulatory system with resulting increased risk of cardiovascular mortality [11]. For instance, anthracycline imposes cardiotoxicity through reactive oxygen species and oxidative stress [35]. Our findings of a greater risk of cardiovascular mortality in BCa-2 patients who underwent chemotherapy for their first malignancy lend further support to this mechanism. Although we lack data on site of radiotherapy and type of chemotherapy, the treatment for breast cancer is mainly based on molecular subtypes and tumour stage which have been adequately adjusted for in our analysis. Moreover, our previous study found that BCa-2 patients received less intensive treatment (e.g., both surgery and chemo-/radiotherapy) for breast cancer than BCa-1 patients [36]. The increased risk of cardiovascular mortality in BCa-2 patients is, therefore, less likely attributable to the cancer treatment for breast cancer. Nevertheless, the risk is also increased among BCa-2 patients who did not receive radiotherapy or chemotherapy for their first malignancy. This suggests that our findings cannot be completely explained by the “extra” cancer treatment due to the first malignancy.

Certain lifestyle factors (e.g., smoking) might predispose patients for both BCa-2 and cardiovascular disease [3]. Indeed, we observed the greatest risk of cardiovascular mortality among BCa-2 patients with a prior lung cancer—a group predominated by smokers. Other potential confounders include obesity [3], menopausal status [37] and alcohol consumption [5]. Thus, one might argue that a BCa-2 is an incidental event in a patient who has risk factors for both malignancies and cardiovascular disease. Reassuringly, the case-crossover analysis which confirmed the associations strongly argues against such explanation. This analysis also alleviates concerns of unmeasured risk factors for cardiovascular disease (e.g., diabetes and lipids) which are presumably stable during a short period.

It is not implausible that psychological stress may contribute to cardiovascular mortality [38], particularly in this vulnerable group. Stress is associated with an increased risk of alterations in cardiac regulation [39], potentially via activation of the sympathetic nervous system and haemostasis [40, 41]. Diagnosis and living with cancer are highly stressful. Ample evidence including ours have illustrated the immediately increased risks of cardiovascular diseases or mortality [42], suicide [43, 44] and mental disorders [45] after receiving a diagnosis of first malignancy. For example, the risk of cardiovascular mortality within the first month after receiving a BCa-1 diagnosis was almost doubled compared to cancer-free individuals [13], highlighting the acute and substantial effect of stress on the circulating system induced by cancer diagnosis. However, it is poorly documented how patients would respond to a second malignancy. In line with the studies on first malignancies, we found the risk of cardiovascular mortality was most pronounced within the first month after BCa-2 diagnosis compared with the general population. By contrast, the risk within the first month after breast cancer diagnosis was similar between BCa-2 and BCa-1 patients, supporting the equivalently high stress induced by a cancer diagnosis. Moreover, we noted a greater risk of cardiovascular mortality among BCa-2 patients diagnosed within one year after the diagnosis of first malignancy. This may be explained by the cancer-induced coagulation dysregulation via inducing arterial thrombosis due to the tumour cell capacity to interact with and activate the host haemostatic system [46, 47]. For instance, Navi et al. showed that the incidence of myocardial infarction among patients with a new primary cancer increased 6 months after cancer diagnosis compared to cancer-free individuals [47]. Gross et al. showed that the risk of in-stent thrombosis was higher in patients with coronary artery disease if cancer was present [46].

The major merit of our study is the population-based prospective cohort design which assures minimal selection and recall biases. The large sample size allows us to illustrate the interactions with attained age, time since diagnosis, and other factors. Our study however has several limitations. The major concern is the misclassification of some causes of death. However, it is less likely that the misclassification would differ substantially between the general population and patients with breast cancer. Second, the aggregated population data included individuals with cancer, resulting in an underestimation of the true associations. Third, metastasis from the first malignancy may be misclassified as BCa-2. However, as the pathological diagnosis was required for inclusion and any uncertain case was considered as a metastasis in SEER, such misclassification should be minimal [48]. Moreover, we have observed increased risk among BCa-2 patients with a localised malignancy as the first. In addition, competing risk (e.g., cancer) may prevent individuals from dying from cardiovascular disease. Reassuringly, in this case, we would have observed a decreased risk of cardiovascular mortality among BCa-2 patients. Furthermore, BCa-2 patients differed from BCa-1 patients in terms of age and follow-up time (due to different overall survival). However, we have always performed analyses by attained age groups (e.g., Table 1) and time since cancer diagnosis (e.g., Fig. 1) in which individuals between groups were highly comparable. In addition, we lacked information on sites of radiotherapy. The association we showed for patients who received radiotherapy for their first malignancy is mixed with radiotherapy on body sites other than chest; the latter is less likely to confer an increased risk of cardiovascular mortality. That said, the increased risk would likely have been underestimated. Last, individuals without accurate follow-up dates were excluded. Although the clinical characteristics of these patients were largely similar to those of the patients included in the study, the cardiovascular mortality rate was higher among the excluded BCa-2 patients than that of the patients included in the analysis (2.3 vs. 1.5 per 100 person-years). We therefore might have underestimated the association after excluding these patients.

Conclusions

Our findings suggest that BCa-2 patients are at increased risk of cardiovascular mortality, compared with the general population and BCa-1 patients. Although BCa-2 may be considered as a non-modifiable risk factor for cardiovascular mortality, our results may highlight the potential need for monitoring cardiovascular disease among BCa-2 patients. The pronounced risk within the first month after receiving a diagnosis of BCa-2 may lend support to the integration of stress management in cancer care.

Supplementary information

Checklist^{(1.7MB, pdf)}

Supplement^{(203.2KB, docx)}

Author contributions

CW and DL had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: CW and DL. Acquisition, analysis or interpretation of the data: CW, KH and DL. Drafting of the manuscript: CW, KH, CL and DL. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: CW. Obtained funding: CW and DL. Administrative, technical or material support: DL. Study supervision: DL.

Funding information

This study was supported by the National Natural Science Foundation of China (grant number: 81872307; to Dr. Lu) and Swedish Research Council (grant number: 2018-00648; to Dr. Lu) and Full-time Postdoc Research and Development Foundation of West China Hospital (grant number: 2019HXBH098; to Dr. Wang).

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study was reviewed by the Biomedical Research Ethics Committee at West China Hospital, Sichuan University (reference number 2018-230).

Consent to publish

Not applicable.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

The online version contains supplementary material available at 10.1038/s41416-021-01549-w.

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Checklist^{(1.7MB, pdf)}

Supplement^{(203.2KB, docx)}

[CR1] 1.Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, et al. SEER Cancer Statistics Review, 1975-2016, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2016/, based on November 2018 SEER data submission, posted to the SEER web site, April 2019 (2019). Accessed 19 September 2019.

[CR2] 2.Riihimaki M, Thomsen H, Brandt A, Sundquist J, Hemminki K. Death causes in breast cancer patients. Ann Oncol. 2012;23:604–10. doi: 10.1093/annonc/mdr160. [DOI] [PubMed] [Google Scholar]

[CR3] 3.Mehta LS, Watson KE, Barac A, Beckie TM, Bittner V, Cruz-Flores S, et al. Cardiovascular disease and breast cancer: where these entities intersect: a scientific statement from the American Heart Association. Circulation. 2018;137:e30–e66. doi: 10.1161/CIR.0000000000000556. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR4] 4.Curigliano G, Cardinale D, Dent S, Criscitiello C, Aseyev O, Lenihan D, et al. Cardiotoxicity of anticancer treatments: epidemiology, detection, and management. CA: A Cancer J Clin. 2016;66:309–25. doi: 10.3322/caac.21341. [DOI] [PubMed] [Google Scholar]

[CR5] 5.Muirhead L. Cancer risk factors among adults with serious mental illness. Am J preventive Med. 2014;46:S98–103. doi: 10.1016/j.amepre.2013.10.028. [DOI] [PubMed] [Google Scholar]

[CR6] 6.Sturgeon KM, Deng L, Bluethmann SM, Zhou S, Trifiletti DM, Jiang C, et al. A population-based study of cardiovascular disease mortality risk in US cancer patients. Eur Heart J. 2019;40:3889–97. doi: 10.1093/eurheartj/ehz766. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR7] 7.Bradshaw PT, Stevens J, Khankari N, Teitelbaum SL, Neugut AI, Gammon MD. Cardiovascular disease mortality among breast cancer survivors. Epidemiology. 2016;27:6–13. doi: 10.1097/EDE.0000000000000394. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR8] 8.Weberpals J, Jansen L, Muller OJ, Brenner H. Long-term heart-specific mortality among 347 476 breast cancer patients treated with radiotherapy or chemotherapy: a registry-based cohort study. Eur Heart J. 2018;39:3896–903. doi: 10.1093/eurheartj/ehy167. [DOI] [PubMed] [Google Scholar]

[CR9] 9.Park NJ, Chang Y, Bender C, Conley Y, Chlebowski RT, van Londen GJ, et al. Cardiovascular disease and mortality after breast cancer in postmenopausal women: results from the Women’s Health Initiative. PLoS ONE. 2017;12:e0184174. doi: 10.1371/journal.pone.0184174. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR10] 10.Hedayati E, Papakonstantinou A, Gernaat SAM, Altena R, Brand JS, Alfredsson J, et al. Outcome and presentation of heart failure in breast cancer patients: findings from a Swedish register-based study. Eur Heart J Qual Care Clin Outcomes. 2020;6:147–55. doi: 10.1093/ehjqcco/qcz039. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR11] 11.Gernaat SAM, Ho PJ, Rijnberg N, Emaus MJ, Baak LM, Hartman M, et al. Risk of death from cardiovascular disease following breast cancer: a systematic review. Breast cancer Res Treat. 2017;164:537–55. doi: 10.1007/s10549-017-4282-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR12] 12.Hooning MJ, Aleman BM, van Rosmalen AJ, Kuenen MA, Klijn JG, van Leeuwen FE. Cause-specific mortality in long-term survivors of breast cancer: a 25-year follow-up study. Int J Radiat Oncol Biol Phys. 2006;64:1081–91. doi: 10.1016/j.ijrobp.2005.10.022. [DOI] [PubMed] [Google Scholar]

[CR13] 13.Fang F, Fall K, Mittleman MA, Sparén P, Ye W, Adami HO, et al. Suicide and cardiovascular death after a cancer diagnosis. N. Engl J Med. 2012;366:1310–8. doi: 10.1056/NEJMoa1110307. [DOI] [PubMed] [Google Scholar]

[CR14] 14.Ye Y, Otahal P, Marwick TH, Wills K E, Neil AL, Venn AJ. Cardiovascular and other competing causes of death among patients with cancer from 2006 to 2015: an Australian population-based study. Cancer. 2019;125:442–52. [DOI] [PubMed]

[CR15] 15.Travis LB. The epidemiology of second primary cancers. Cancer Epidemiol, Biomark Prev. 2006;15:2020–6. doi: 10.1158/1055-9965.EPI-06-0414. [DOI] [PubMed] [Google Scholar]

[CR16] 16.Donin N, Filson C, Drakaki A, Tan HJ, Castillo A, Kwan L, et al. Risk of second primary malignancies among cancer survivors in the United States, 1992 through 2008. Cancer. 2016;122:3075–86. doi: 10.1002/cncr.30164. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR17] 17.Chao C, Bhatia S, Xu L, Cannavale KL, Wong FL, Huang PS, et al. Incidence, risk factors, and mortality associated with second malignant neoplasms among survivors of adolescent and young adult cancer. JAMA Netw Open. 2019;2:e195536. doi: 10.1001/jamanetworkopen.2019.5536. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR18] 18.Ye Y, Otahal P, Wills KE, Neil AL, Venn AJ. Temporal trends in the risk of second primary cancers among survivors of adult-onset cancers, 1980 through 2013: an Australian population-based study. Cancer. 2018;124:1808–18. doi: 10.1002/cncr.31247. [DOI] [PubMed] [Google Scholar]

[CR19] 19.Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for practice guidelines: the task force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC) Eur Heart J. 2016;37:2768–801. doi: 10.1093/eurheartj/ehw211. [DOI] [PubMed] [Google Scholar]

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PERMALINK

Cardiovascular mortality among cancer survivors who developed breast cancer as a second primary malignancy

Chengshi Wang

Kejia Hu

Chuanxu Luo

Lei Deng

Katja Fall

Rulla M Tamimi

Unnur A Valdimarsdóttir

Fang Fang

Donghao Lu

Abstract

Background

Methods

Results

Conclusion

Introduction

Methods

Study design

Ascertainment of second primary breast cancer

Ascertainment of cardiovascular deaths and follow-up

Covariates

Statistical analysis

Results

Demographic and clinical characteristics

Cardiovascular mortality risk by attained age

Table 1.

Table 2.

Cardiovascular mortality risk by time since diagnosis

Table 3.

Factors that modify cardiovascular mortality risk

Discussion

Conclusions

Supplementary information

Author contributions

Funding information

Competing interests

Ethics approval and consent to participate

Consent to publish

Footnotes

Supplementary information

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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