1. Epidemiology and Global Health
  2. Medicine

Risk of heart disease following treatment for breast cancer – results from a population-based cohort study

  1. Haomin Yang  Is a corresponding author
  2. Nirmala Bhoo-Pathy
  3. Judith S Brand
  4. Elham Hedayati
  5. Felix Grassmann
  6. Erwei Zeng
  7. Jonas Bergh
  8. Weiwei Bian
  9. Jonas F Ludvigsson
  10. Per Hall
  11. Kamila Czene
  1. Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, China
  2. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden
  3. Centre for Epidemiology and Evidence-Based Practice, Faculty of Medicine, University of Malaya, Malaysia
  4. Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Sweden
  5. Department of Oncology-Pathology, Karolinska Institutet, Sweden
  6. Health and Medical University, Germany
  7. Breast Cancer Center, Karolinska University Hospital, Sweden
  8. Karolinska Comprehensive Cancer Center, Sweden
  9. Department of Pediatrics, Örebro University Hospital, Sweden
  10. Department of Oncology, Södersjukhuset, Sweden
https://doi.org/10.7554/eLife.71562
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Cite this article
  1. Haomin Yang
  2. Nirmala Bhoo-Pathy
  3. Judith S Brand
  4. Elham Hedayati
  5. Felix Grassmann
  6. Erwei Zeng
  7. Jonas Bergh
  8. Weiwei Bian
  9. Jonas F Ludvigsson
  10. Per Hall
  11. Kamila Czene
(2022)
Risk of heart disease following treatment for breast cancer – results from a population-based cohort study
eLife 11:e71562.
https://doi.org/10.7554/eLife.71562
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3 figures, 6 tables and 2 additional files

Figures

Figure 1
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Time-dependent hazard ratio of heart diseases in breast cancer patients compared to age-matched women.

In all models, time since index date was the underlying time scale and a restricted cubic spline with four internal and two boundary knots (five degrees of freedom) placed at quintiles of the event times was used for the baseline hazard. Time-dependent effects were modelled by adding interaction terms with time using a second spline with three degrees of freedom.

Figure 1—source data 1

Summary data for Figure 1.

https://cdn.elifesciences.org/articles/71562/elife-71562-fig1-data1-v2.xlsx
Appendix 1—figure 1
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Flowchart of the data.
Appendix 3—figure 1
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Cumulative incidence of heart disease in breast cancer patients and matched women.

Aalen-Johansen estimates of the cumulative risk of heart disease by time since index date, in breast cancer patients and matched women from the general population. BC: breast cancer; REF: reference women in the matched controls from the general population; No.: number.

Tables

Table 1
Descriptive characteristics of the study population.
CharacteristicsOverall (N = 8015)
Year of diagnosis % (N)
2001–200225.6 (2072)
2003–200424.4 (1952)
2005–200625.8 (2064)
2007–200824.0 (1927)
Age at diagnosis % (N)
<50 years23.0 (1842)
50–65 years51.3 (4111)
>65 years25.7 (2062)
Menopausal status % (N)
Premenopausal30.4 (2289)
Postmenopausal69.6 (5251)
Missing (N)475
Stage % (N)
Stage I48.2 (3690)
Stage II39.4 (3014)
Stage III12.4 (948)
Missing (N)363
Tumor size % (N)
≤2 cm25.7 (2000)
2–5 cm44.0 (3418)
> 5 cm30.3 (2351)
Missing (N)246
Comorbidity % (N)
None90.1 (7222)
15.5 (439)
≥24.4 (354)
History of hypertension
No94.6 (7579)
Yes5.4 (436)
History of chronic pulmonary disease or tobacco abuse
No96.6 (7746)
Yes3.4 (269)
Surgery % (N)
No1.0 (79)
Yes, breast-conserving60.7 (4852)
Yes, mastectomy38.3 (3058)
Missing (N)26
Radiotherapy % (N)
No22.5 (1774)
Yes, left-sided37.5 (2962)
Yes, right-sided39.1 (3088)
Yes, both-sided0.85 (67)
Missing (N)124
Chemotherapy % (N)
No58.5 (4604)
Yes41.5 (3262)
Missing (N)149
Hormone therapy % (N)
No18.10 (1424)
Yes, tamoxifen53.0 (4247)
Yes, aromatase inhibitors19.3 (1550)
Yes, type unknown8.1 (645)
Missing (N)149
Trastuzumab therapy % (N) *
No87.3 (2180)
Yes12.7 (316)
Missing (N)1497
  1. *

    Missingness on individual variables is less than 5%, except for menopausal status (5.9%, N = 488). Treatment-specific analysis of trastuzumab was restricted to patients diagnosed between 2005 and 2008 (missingness = 37.5%, N = 1497).

Table 2
Hazard ratios for heart diseases in breast cancer patients compared to the matched cohort.
ArrhythmiaHeart failureIschemic heart disease
No.HR (95% CI)No.HR (95% CI)No.HR (95% CI)
Time since diagnosis
<1 year642.14 (1.63–2.81)222.71 (1.70–4.33)381.45 (1.03–2.04)
1–2 years341.08 (0.76–1.53)192.07 (1.27–3.37)341.12 (0.79–1.61)
2–5 years1071.07 (0.88–1.30)381.14 (0.82–1.59)720.84 (0.66–1.07)
5–10 years2041.13 (0.98–1.30)781.02 (0.81–1.29)1040.82 (0.67–1.00)
10–17 years1611.42 (1.21–1.67)861.28 (1.03–1.59)590.79 (0.61–1.03)

  1. Abbreviations: No. = number of cases. HR = hazard ratio. CI = confidence interval. The HRs are estimated using flexible parametric model and conditioned on matching criteria (year of birth). In all models, time since index date was the underlying time scale and a restricted cubic spline with four internal and two boundary knots (five degrees of freedom) placed at quintiles of the event times was used for the baseline hazard. All analyses were stratified by time since index date. Statistically significant results with p-value<0.05 are bolded.

Table 3
Hazard ratios for heart diseases in breast cancer patients by different adjuvant therapies.
Total No.HR (95% CI) for arrhythmiaHR (95% CI) for heart failureHR (95% CI) for ischemic heart disease
Treatment variablesNModel 1Model 2NModel 1Model 2NModel 1Model 2
Radiotherapy
Right-sided2948216REF (1.00)REF (1.00)80REF (1.00)REF (1.00)99REF (1.00)REF (1.00)
Left-sided30752130.93 (0.77–1.13)0.93 (0.77–1.13)871.03 (0.76–1.40)1.07 (0.79–1.45)1191.14 (0.87–1.49)1.16 (0.89–1.51)
Both-sided6740.65 (0.24–1.76)0.63 (0.23–1.70)41.81 (0.66–4.95)1.75 (0.63–4.85)31.08 (0.34–3.40)0.98 (0.31–3.11)
Chemotherapy
No.4604376REF (1.00)REF (1.00)133REF (1.00)REF (1.00)207REF (1.00)REF (1.00)
Anthracyclines-based1426831.18 (0.97–1.45)1.08 (0.84–1.39)512.30 (1.70–3.10)1.74 (1.20–2.52)441.31 (0.99–1.72)1.29 (0.92–1.81)
Anthracyclines + taxanes286101.15 (0.63–2.10)1.01 (0.53–1.92)134.71 (2.57–8.63)3.09 (1.55–6.14)61.36 (0.63–2.93)1.29 (0.57–2.95)
CMF9661.08 (0.55–2.14)1.04 (0.51–2.12)31.21 (0.36–4.00)0.90 (0.27–3.04)21.11 (0.49–2.51)1.04 (0.46–2.36)
Hormone therapy
No.142489REF (1.00)REF (1.00)49REF (1.00)REF (1.00)43REF (1.00)REF (1.00)
Tamoxifen42472980.91 (0.72–1.15)0.95 (0.74–1.23)990.57 (0.41–0.79)0.84 (0.58–1.20)1420.91 (0.65–1.27)1.03 (0.71–1.48)
Aromatase inhibitors15501191.02 (0.77–1.35)0.99 (0.74–1.32)611.05 (0.71–1.56)1.08 (0.72–1.61)851.53 (1.05–2.24)1.52 (1.03–2.26)
Trastuzumab*
No.2137126REF (1.00)REF (1.00)38REF (1.00)REF (1.00)60REF (1.00)REF (1.00)
Yes304171.15 (0.70–1.92)1.50 (0.79–2.83)133.05 (1.62–5.76)2.34 (1.05–5.22)121.75 (0.94–3.27)1.83 (0.85–3.96)

  1. Total No. refers to the total number of patients. N events refers to the number of observed cases. HR = hazard ratio; CI = confidence interval; CMF = cyclophosphamide, methotrexate, and fluorouracil; REF: reference women in the matched controls from the general population. Hazard ratios are estimated from Cox proportional hazards models with time since diagnosis as underlying time scale. Hazard ratios for model 1 are adjusted for age and calendar period. Hazard ratios for model 2 are multivariable adjusted including age at diagnosis, year of diagnosis, menopausal status, Charlson comorbidity index, clinical stage, tumor size, type of surgery, history of hypertension, chronic pulmonary disease and tobacco abuse, and all treatment variables listed in the table.

  2. *

    Treatment-specific analysis of trastuzumab was restricted to patients diagnosed between 2005 and 2008.

Appendix 2—table 1
ICD codes used in the analyses.
Disease codesICD-10ICD-9
ArrhythmiaI47, I48, I49427
 Atrial fibrillationI48427D
 Tachycardia and other cardiac arrhythmiasI47, I49427A–C, 427E–J
Heart failureI50428A, 428B, 428X
Ischemic heart diseaseI20–I25410–414
 Myocardial infarctionI21, I22410
 Angina pectorisI20411B, 413, 414A
HypertensionI10–I15401–405
Tobacco abuse and Chronic Pulmonary DiseaseJ40–J47, J60–J67, F17, I278, I279, J684, J701, J703490–496,500–505, 416W, 416X, 506E, 508B, 508W, 305B

  1. ICD = International Classification of Diseases.

Appendix 2—table 2
Cumulative incidence estimates of heart diseases in breast cancer patients and age matched controls.
Cumulative incidence, % (95% CI)
6 months1 year2 years5 years10 years15 years
Arrhythmia
Breast cancer0.49 (0.35–0.66)0.81 (0.63–1.02)1.25 (1.02–1.52)2.77 (2.41–3.16)6.04 (5.49–6.63)11.03 (10.04–12.08)
Matched control0.20 (0.17–0.23)0.38 (0.34–0.42)0.79 (0.73–0.85)2.18 (2.08–2.29)4.98 (4.83–5.13)8.21 (7.99–8.45)
Heart failure
Breast cancer0.09 (0.04–0.18)0.28 (0.18–0.42)0.53 (0.38–0.71)1.06 (0.85–1.32)2.32 (1.98–2.70)4.80 (4.13–5.54)
Matched control0.05 (0.03–0.06)0.10 (0.08–0.13)0.22 (0.19–0.26)0.68 (0.63–0.74)1.87 (1.77–1.96)3.78 (3.62–3.95)
Ischemic heart disease
Breast cancer0.26 (0.17–0.40)0.48 (0.35–0.65)0.92 (0.73–1.16)1.93 (1.64–2.27)3.59 (3.17–4.05)5.68 (4.98–6.44)
Matched control0.13 (0.11–0.16)0.33 (0.29–0.37)0.72 (0.67–0.78)1.91 (1.81–2.00)3.85 (3.72–3.99)5.90 (5.71–6.09)

  1. Abbreviations: CI = confidence interval. Cumulative incidence estimates of heart diseases in all breast cancer patients (N = 8015) at different time-points following the index date ( = date of diagnosis in breast cancer patients). Cumulative incidence estimates are obtained from Aalen-Johansen estimation.

Appendix 2—table 3
Hazard ratios for heart diseases by different adjuvant therapies and time since diagnosis.
HR (95% CI) for arrhythmiaHR (95% CI) for heart failureHR (95% CI) for ischemic heart disease
Treatment variables<10 years>10 years<10 years>10 years<10 years>10 years
Radiotherapy
 Right-sidedREF (1.00)REF (1.00)REF (1.00)REF (1.00)REF (1.00)REF (1.00)
 Left-sided0.99 (0.79–1.24)0.80 (0.57–1.14)1.13 (0.77–1.66)0.94 (0.56–1.56)1.13 (0.84–1.53)1.29 (0.70–2.37)
 Both-sided0.26 (0.04–1.90)1.01 (0.30–3.36)1.49 (0.36–6.24)2.37 (0.54–10.41)0.84 (0.20–3.43)1.64 (0.21–12.89)
Chemotherapy
 NoREF (1.00)REF (1.00)REF (1.00)REF (1.00)REF (1.00)REF (1.00)
 Anthracyclines-based1.08 (0.81–1.46)1.07 (0.65–1.76)1.75 (1.11–2.76)1.66 (0.86–3.19)1.27 (0.87–1.85)1.36 (0.60–3.09)
 Anthracyclines + taxanes1.02 (0.51–2.01)0.87 (0.13–5.77)3.72 (1.72–8.03)0.00 (0.00–0.00)1.38 (0.60–3.18)0.00 (0.00–0.00)
 CMF1.24 (0.59–2.61)0.74 (0.18–3.15)1.16 (0.33–4.05)0.00 (0.00–0.00)0.97 (0.33–2.84)1.17 (0.16–8.41)
Hormone therapy
 NoREF (1.00)REF (1.00)REF (1.00)REF (1.00)REF (1.00)REF (1.00)
 Tamoxifen0.91 (0.67–1.23)1.08 (0.67–1.73)0.76 (0.49–1.20)0.98 (0.52–1.84)0.93 (0.62–1.39)1.50 (0.64–3.53)
 Aromatase inhibitors0.97 (0.70–1.36)1.05 (0.56–1.95)0.93 (0.58–1.49)1.47 (0.66–3.27)1.47 (0.96–2.24)1.31 (0.43–4.01)
Trastuzumab *
 NoREF (1.00)REF (1.00)REF (1.00)REF (1.00)REF (1.00)REF (1.00)
 Yes1.56 (0.82–2.97)0.00 (0.00–0.00)2.60 (1.14–5.89)0.00 (0.00–0.00)1.71 (0.76–3.87)6.95 (0.56–85.58)

  1. HR = hazard ratio; CI = confidence interval. Hazard ratios are estimated from Cox proportional hazards models with time since diagnosis as underlying time scale. Hazard ratios are multivariable adjusted including age at diagnosis, year of diagnosis, menopausal status, Charlson comorbidity index, clinical stage, type of surgery, hypertension, chronic pulmonary disease and tobacco abuse, and all treatment variables listed in the table. * Treatment-specific analysis of trastuzumab was restricted to patients diagnosed between 2005 and 2008.

Additional files

Transparent reporting form
https://cdn.elifesciences.org/articles/71562/elife-71562-transrepform1-v2.docx
Source code 1

STATA script for the analyses.

https://cdn.elifesciences.org/articles/71562/elife-71562-code1-v2.zip

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  1. Haomin Yang
  2. Nirmala Bhoo-Pathy
  3. Judith S Brand
  4. Elham Hedayati
  5. Felix Grassmann
  6. Erwei Zeng
  7. Jonas Bergh
  8. Weiwei Bian
  9. Jonas F Ludvigsson
  10. Per Hall
  11. Kamila Czene
(2022)
Risk of heart disease following treatment for breast cancer – results from a population-based cohort study
eLife 11:e71562.
https://doi.org/10.7554/eLife.71562