Table 3.
Within-cohort comparison of cardiovascular disease rates after breast cancer by treatment
| Any cardiovascular event | Ischaemic heart disease ≥10 years after breast cancer treatmenta | Valvular heart disease | Heart failureb | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n/Nd | HR | (95% CI) | n/Nd | HR | (95% CI) | n/Nd | HR | (95% CI) | n/Nd | HR | (95% CI) | |
| Multivariable model c | ||||||||||||
| Radiation field f | ||||||||||||
| Breast, right-sided (no IMC) | 230/2562 | 1.00 | Ref. | 48/1684 | 1.00 | Ref. | 51/2519 | 1.00 | Ref. | 40/2520 | 1.00 | Ref. |
| Chest wall, right-sided (no IMCe) | 61/315 | 1.24 | 0.93–1.65 | 24/244 | 1.73 | 1.05–2.85 | 10/349 | 0.51 | 0.25–1.03 | 23/350 | 1.68 | 0.98–2.88 |
| IMC, right-sided (+/− breast/chest wall) | 344/1804 | 1.50 | 1.26–1.78 | 180/1478 | 2.54 | 1.84–3.52 | 97/1824 | 1.26 | 0.88–1.79 | 90/1824 | 1.78 | 1.21–2.61 |
| Breast, left-sided (no IMC) | 272/2761 | 1.11 | 0.93–1.32 | 70/1821 | 1.37 | 0.95–1.98 | 56/2797 | 1.00 | 0.69–1.47 | 41/2798 | 0.87 | 0.56–1.35 |
| Chest wall, left-sided (no IMCe) | 71/302 | 1.83 | 1.39–2.40 | 96/226 | 2.57 | 1.61–4.11 | 16/352 | 0.91 | 0.50–1.62 | 20/352 | 1.42 | 0.80–2.50 |
| IMC, left-sided (+/− breast/chest wall) | 413/1963 | 1.66 | 1.41–1.97 | 190/1621 | 2.20 | 1.59–3.04 | 162/2002 | 2.00 | 1.44–2.78 | 118/2002 | 1.94 | 1.33–2.82 |
| No radiation therapy | 221/1825 | 1.21 | 1.00–1.46 | 72/1222 | 1.50 | 1.04–2.17 | 44/1738 | 0.78 | 0.52–1.18 | 44/1741 | 1.22 | 0.79–1.89 |
| Chemotherapy f | ||||||||||||
| No chemotherapy | 1258/8238 | 1.00 | Ref. | 506/6112 | 1.00 | Ref. | 336/8296 | 1.00 | Ref. | 274/8301 | 1.00 | Ref. |
| CMF-like regimen | 240/1727 | 1.00 | 0.87–1.16 | 105/1363 | 1.07 | 0.85–1.33 | 72/1751 | 1.15 | 0.88–1.50 | 44/1749 | 0.89 | 0.64–1.24 |
| Anthracycline-based regimen | 193/2252 | 1.51 | 1.25–1.82 | 21/1107 | 1.00 | 0.61–1.64 | 43/2262 | 1.75 | 1.16–2.65 | 84/2263 | 4.32 | 3.07–6.07 |
| Endocrine therapy | ||||||||||||
| No endocrine therapy | 1518/10201 | 1.00 | Ref. | 605/7614 | 1.00 | Ref. | 406/10283 | 1.00 | Ref. | 345/10286 | 1.00 | Ref. |
| Endocrine therapy | 173/2016 | 0.97 | 0.80–1.17 | 27/968 | 0.85 | 0.55–1.29 | 45/2026 | 1.22 | 0.83–1.79 | 57/2027 | 0.93 | 0.65–1.31 |
| Summary model h | ||||||||||||
| Breast, right-sided (no IMC) | 230/2562 | 1.00 | Ref. | 48/1684 | 1.00 | Ref. | 51/2519 | 1.00 | Ref. | 40/2520 | 1.00 | Ref. |
| IMC (left- or right-sided, +/− breast/chest wall) | 757/3629 | 1.56 | 1.35–1.84 | 370/3099 | 2.36 | 1.74–3.22 | 259/3826 | 1.63 | 1.18–2.24 | 208/3826 | 1.82 | 1.27–2.63 |
| Joint effects of treatments f,g | ||||||||||||
| Breast RT (no IMC), no anthracyclines | 441/4475 | 1.00 | Ref. | 111/3102 | 1.00 | Ref. | 97/4423 | 1.00 | Ref. | 59/4312 | 1.00 | Ref. |
| IMC RT, no anthracyclines | 690/3113 | 1.54 | 1.35–1.75 | 361/2697 | 2.00 | 1.50–2.66 | 242/3159 | 1.74 | 1.35–2.25 | 165/2993 | 2.14 | 1.55–2.96 |
| Breast RT (no IMC), anthracyclines | 61/848 | 1.52 | 1.16–1.99 | 7/402 | 1.88 | 0.90–3.93 | 10/893 | 1.24 | 0.64–2.40 | 20/941 | 5.10 | 3.12–8.34 |
| IMC RT, anthracyclines | 67/654 | 2.09 | 1.62–2.69 | 9/402 | 2.32 | 1.19–4.55 | 17/667 | 2.86 | 1.76–4.65 | 31/683 | 9.23 | 6.01–14.18 |
| Test for departure from additivity/multiplicativity | p = 0.70/0.74 | p = 0.57/0.27 | p = 0.51/0.96 | p = 0.06/0.68 | ||||||||
n/N number of events/number at risk, HR hazard ratio, CI confidence interval, IMC internal mammary chain, Ref. reference category.
The analyses shown in this table include all diagnoses of cardiovascular disease, e.g. if a patient was diagnosed with ischaemic heart disease and then later with valvular heart disease, then both are listed. Analyses considering just the first diagnosis of cardiovascular disease are in Supplementary Table 4.
aBecause the proportional hazard assumption did not hold for the ischaemic heart disease rate after internal mammary chain and chest wall irradiation, results are shown here for ≥10 years after breast cancer treatment. No increased ischaemic heart disease rates were seen in the period <10 years after treatment. These results are presented in Supplementary Table 5.
bHeart failure included both cardiomyopathy and congestive heart failure; diagnoses I42 and I50 International Classification of Diseases, 10th revision.
cHazard ratios estimated using one multivariable model containing radiation fields (right breast, right-sided chest wall, right-sided internal mammary chain field, left breast, left-sided chest wall, left-sided internal mammary chain field, no radiation therapy, unknown radiation fields), chemotherapy (no chemotherapy, CMF-like regimen, anthracycline-based regimen), endocrine therapy (no, yes), age at breast cancer treatment (<40, 40–49, 50–61 years), cardiovascular risk factor at breast cancer diagnosis yes/no (hypertension, hypercholesterolemia or diabetes), smoking (ever, never or unknown) and other cardiovascular diseases (time-dependent). Hazard ratios for the covariates, estimates for patients with unknown radiation fields and estimates for patients irradiated to the internal mammary chain separately for patients additionally irradiated to the breast/chest wall are shown in Supplementary Table 2.
dAnalyses included all patients with at least 1 day of cardiovascular follow-up after start of time at risk (n = 12,355). Patients with a specific cardiovascular diagnosis before start of time at risk were excluded from analysis with that specific diagnosis as end point (n = 138 for any cardiovascular event [including also 27 diagnoses of arrhythmia and 3 of pericarditis], n = 50 for ischaemic heart disease, n = 18 for valvular heart disease and n = 36 for heart failure). Numbers at risk differs by end point due to time-dependency of the treatment variables.
eFor some women who were treated with direct electrons with the chest wall as the target, the internal mammary chain received a therapeutic dose.
fMutually exclusive treatment categories, taking into account primary treatment, as well as treatment for (loco)regional recurrences and second breast cancers.
gHazard ratios estimated using one multivariable model containing one variable for the joint effect of radiation therapy and anthracycline-based chemotherapy (breast irradiation without anthracycline-based chemotherapy, internal mammary chain irradiation without anthracycline-based chemotherapy, breast irradiation with anthracycline-based chemotherapy, internal mammary chain irradiation with anthracycline-based chemotherapy), age at breast cancer (<40, 40–50, 50–61 years), cardiovascular risk factor at breast cancer diagnosis yes/no (hypertension, hypercholesterolaemia or diabetes), smoking (ever, never or unknown) and other cardiovascular diseases (time-dependent). Patients not irradiated to either the breast or internal mammary chain were excluded from these analyses.
hHazard ratios estimated using one multivariable model containing radiation fields (right breast, right-sided chest wall, left breast, left-sided chest wall, internal mammary chain [left- or right-sided], no radiation therapy, unknown radiation fields), chemotherapy (no chemotherapy, CMF-like regimen, anthracycline-based regimen), endocrine therapy (no, yes), age at breast cancer treatment (<40, 40–49, 50–61 years), cardiovascular risk factor at breast cancer diagnosis yes/no (hypertension, hypercholesterolemia or diabetes), smoking (ever, never or unknown) and other cardiovascular diseases (time-dependent)