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 …
Summary data for Figure 1.
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 …
Characteristics | Overall (N = 8015) |
---|---|
Year of diagnosis % (N) | |
2001–2002 | 25.6 (2072) |
2003–2004 | 24.4 (1952) |
2005–2006 | 25.8 (2064) |
2007–2008 | 24.0 (1927) |
Age at diagnosis % (N) | |
<50 years | 23.0 (1842) |
50–65 years | 51.3 (4111) |
>65 years | 25.7 (2062) |
Menopausal status % (N) | |
Premenopausal | 30.4 (2289) |
Postmenopausal | 69.6 (5251) |
Missing (N) | 475 |
Stage % (N) | |
Stage I | 48.2 (3690) |
Stage II | 39.4 (3014) |
Stage III | 12.4 (948) |
Missing (N) | 363 |
Tumor size % (N) | |
≤2 cm | 25.7 (2000) |
2–5 cm | 44.0 (3418) |
> 5 cm | 30.3 (2351) |
Missing (N) | 246 |
Comorbidity % (N) | |
None | 90.1 (7222) |
1 | 5.5 (439) |
≥2 | 4.4 (354) |
History of hypertension | |
No | 94.6 (7579) |
Yes | 5.4 (436) |
History of chronic pulmonary disease or tobacco abuse | |
No | 96.6 (7746) |
Yes | 3.4 (269) |
Surgery % (N) | |
No | 1.0 (79) |
Yes, breast-conserving | 60.7 (4852) |
Yes, mastectomy | 38.3 (3058) |
Missing (N) | 26 |
Radiotherapy % (N) | |
No | 22.5 (1774) |
Yes, left-sided | 37.5 (2962) |
Yes, right-sided | 39.1 (3088) |
Yes, both-sided | 0.85 (67) |
Missing (N) | 124 |
Chemotherapy % (N) | |
No | 58.5 (4604) |
Yes | 41.5 (3262) |
Missing (N) | 149 |
Hormone therapy % (N) | |
No | 18.10 (1424) |
Yes, tamoxifen | 53.0 (4247) |
Yes, aromatase inhibitors | 19.3 (1550) |
Yes, type unknown | 8.1 (645) |
Missing (N) | 149 |
Trastuzumab therapy % (N) * | |
No | 87.3 (2180) |
Yes | 12.7 (316) |
Missing (N) | 1497 |
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).
Arrhythmia | Heart failure | Ischemic heart disease | ||||
---|---|---|---|---|---|---|
No. | HR (95% CI) | No. | HR (95% CI) | No. | HR (95% CI) | |
Time since diagnosis | ||||||
<1 year | 64 | 2.14 (1.63–2.81) | 22 | 2.71 (1.70–4.33) | 38 | 1.45 (1.03–2.04) |
1–2 years | 34 | 1.08 (0.76–1.53) | 19 | 2.07 (1.27–3.37) | 34 | 1.12 (0.79–1.61) |
2–5 years | 107 | 1.07 (0.88–1.30) | 38 | 1.14 (0.82–1.59) | 72 | 0.84 (0.66–1.07) |
5–10 years | 204 | 1.13 (0.98–1.30) | 78 | 1.02 (0.81–1.29) | 104 | 0.82 (0.67–1.00) |
10–17 years | 161 | 1.42 (1.21–1.67) | 86 | 1.28 (1.03–1.59) | 59 | 0.79 (0.61–1.03) |
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.
Total No. | HR (95% CI) for arrhythmia | HR (95% CI) for heart failure | HR (95% CI) for ischemic heart disease | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Treatment variables | N | Model 1 | Model 2 | N | Model 1 | Model 2 | N | Model 1 | Model 2 | |
Radiotherapy | ||||||||||
Right-sided | 2948 | 216 | REF (1.00) | REF (1.00) | 80 | REF (1.00) | REF (1.00) | 99 | REF (1.00) | REF (1.00) |
Left-sided | 3075 | 213 | 0.93 (0.77–1.13) | 0.93 (0.77–1.13) | 87 | 1.03 (0.76–1.40) | 1.07 (0.79–1.45) | 119 | 1.14 (0.87–1.49) | 1.16 (0.89–1.51) |
Both-sided | 67 | 4 | 0.65 (0.24–1.76) | 0.63 (0.23–1.70) | 4 | 1.81 (0.66–4.95) | 1.75 (0.63–4.85) | 3 | 1.08 (0.34–3.40) | 0.98 (0.31–3.11) |
Chemotherapy | ||||||||||
No. | 4604 | 376 | REF (1.00) | REF (1.00) | 133 | REF (1.00) | REF (1.00) | 207 | REF (1.00) | REF (1.00) |
Anthracyclines-based | 1426 | 83 | 1.18 (0.97–1.45) | 1.08 (0.84–1.39) | 51 | 2.30 (1.70–3.10) | 1.74 (1.20–2.52) | 44 | 1.31 (0.99–1.72) | 1.29 (0.92–1.81) |
Anthracyclines + taxanes | 286 | 10 | 1.15 (0.63–2.10) | 1.01 (0.53–1.92) | 13 | 4.71 (2.57–8.63) | 3.09 (1.55–6.14) | 6 | 1.36 (0.63–2.93) | 1.29 (0.57–2.95) |
CMF | 96 | 6 | 1.08 (0.55–2.14) | 1.04 (0.51–2.12) | 3 | 1.21 (0.36–4.00) | 0.90 (0.27–3.04) | 2 | 1.11 (0.49–2.51) | 1.04 (0.46–2.36) |
Hormone therapy | ||||||||||
No. | 1424 | 89 | REF (1.00) | REF (1.00) | 49 | REF (1.00) | REF (1.00) | 43 | REF (1.00) | REF (1.00) |
Tamoxifen | 4247 | 298 | 0.91 (0.72–1.15) | 0.95 (0.74–1.23) | 99 | 0.57 (0.41–0.79) | 0.84 (0.58–1.20) | 142 | 0.91 (0.65–1.27) | 1.03 (0.71–1.48) |
Aromatase inhibitors | 1550 | 119 | 1.02 (0.77–1.35) | 0.99 (0.74–1.32) | 61 | 1.05 (0.71–1.56) | 1.08 (0.72–1.61) | 85 | 1.53 (1.05–2.24) | 1.52 (1.03–2.26) |
Trastuzumab* | ||||||||||
No. | 2137 | 126 | REF (1.00) | REF (1.00) | 38 | REF (1.00) | REF (1.00) | 60 | REF (1.00) | REF (1.00) |
Yes | 304 | 17 | 1.15 (0.70–1.92) | 1.50 (0.79–2.83) | 13 | 3.05 (1.62–5.76) | 2.34 (1.05–5.22) | 12 | 1.75 (0.94–3.27) | 1.83 (0.85–3.96) |
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.
Treatment-specific analysis of trastuzumab was restricted to patients diagnosed between 2005 and 2008.
Disease codes | ICD-10 | ICD-9 |
---|---|---|
Arrhythmia | I47, I48, I49 | 427 |
Atrial fibrillation | I48 | 427D |
Tachycardia and other cardiac arrhythmias | I47, I49 | 427A–C, 427E–J |
Heart failure | I50 | 428A, 428B, 428X |
Ischemic heart disease | I20–I25 | 410–414 |
Myocardial infarction | I21, I22 | 410 |
Angina pectoris | I20 | 411B, 413, 414A |
Hypertension | I10–I15 | 401–405 |
Tobacco abuse and Chronic Pulmonary Disease | J40–J47, J60–J67, F17, I278, I279, J684, J701, J703 | 490–496,500–505, 416W, 416X, 506E, 508B, 508W, 305B |
ICD = International Classification of Diseases.
Cumulative incidence, % (95% CI) | ||||||
---|---|---|---|---|---|---|
6 months | 1 year | 2 years | 5 years | 10 years | 15 years | |
Arrhythmia | ||||||
Breast cancer | 0.49 (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 control | 0.20 (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 cancer | 0.09 (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 control | 0.05 (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 cancer | 0.26 (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 control | 0.13 (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) |
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.
HR (95% CI) for arrhythmia | HR (95% CI) for heart failure | HR (95% CI) for ischemic heart disease | ||||
---|---|---|---|---|---|---|
Treatment variables | <10 years | >10 years | <10 years | >10 years | <10 years | >10 years |
Radiotherapy | ||||||
Right-sided | REF (1.00) | REF (1.00) | REF (1.00) | REF (1.00) | REF (1.00) | REF (1.00) |
Left-sided | 0.99 (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-sided | 0.26 (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 | ||||||
No | REF (1.00) | REF (1.00) | REF (1.00) | REF (1.00) | REF (1.00) | REF (1.00) |
Anthracyclines-based | 1.08 (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 + taxanes | 1.02 (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) |
CMF | 1.24 (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 | ||||||
No | REF (1.00) | REF (1.00) | REF (1.00) | REF (1.00) | REF (1.00) | REF (1.00) |
Tamoxifen | 0.91 (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 inhibitors | 0.97 (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 * | ||||||
No | REF (1.00) | REF (1.00) | REF (1.00) | REF (1.00) | REF (1.00) | REF (1.00) |
Yes | 1.56 (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) |
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.
STATA script for the analyses.