Introduction
Patients and methods
Data collection and study population
End-points
Prognostic factors
Statistical analysis
Results
Characteristic | No recurrence (N = 7489) | First recurrence DM (N = 1343) | First recurrence LR/RR (N = 510) | Second recurrence LR/RR (N = 52) | Total (N = 9342) | |||||
---|---|---|---|---|---|---|---|---|---|---|
N
| % |
N
| % |
N
| % |
N
| % |
N
| % | |
Age at diagnosis | ||||||||||
<40 | 410 | 5.5 | 126 | 9.4 | 57 | 11.2 | 3 | 5.8 | 593 | 6.4 |
40–49 | 1455 | 19.4 | 293 | 21.8 | 106 | 20.8 | 6 | 11.5 | 1854 | 19.9 |
60–74 | 4625 | 61.8 | 749 | 55.8 | 296 | 58.0 | 37 | 71.2 | 5670 | 60.7 |
≥75 | 999 | 13.3 | 175 | 13.0 | 51 | 10.0 | 6 | 11.5 | 1225 | 13.1 |
Tumour size | ||||||||||
≤2 cm | 4772 | 63.7 | 523 | 38.9 | 285 | 55.9 | 24 | 46.2 | 5580 | 59.7 |
2–5 cm | 2484 | 33.2 | 728 | 54.2 | 201 | 39.4 | 24 | 46.2 | 3413 | 36.5 |
>5 cm | 177 | 2.4 | 77 | 5.7 | 15 | 2.9 | 3 | 5.8 | 269 | 2.9 |
Unknown | 56 | 0.8 | 15 | 1.1 | 9 | 1.8 | 1 | 1.9 | 80 | 0.9 |
Grade | ||||||||||
I | 1660 | 22.2 | 96 | 7.2 | 91 | 17.8 | 3 | 5.8 | 1847 | 19.8 |
II | 3006 | 40.1 | 534 | 39.8 | 187 | 36.7 | 22 | 42.3 | 3727 | 39.9 |
III | 2122 | 28.3 | 602 | 44.8 | 180 | 35.3 | 25 | 48.1 | 2904 | 31.1 |
Unknown | 701 | 9.4 | 111 | 8.3 | 52 | 10.2 | 2 | 3.9 | 864 | 9.3 |
Histology | ||||||||||
Invasive ductal | 5948 | 79.4 | 1096 | 81.6 | 408 | 80.0 | 43 | 82.7 | 7452 | 79.8 |
Invasive lobular | 801 | 10.7 | 158 | 11.8 | 57 | 11.2 | 6 | 11.5 | 1016 | 10.9 |
Other | 740 | 9.9 | 89 | 6.6 | 45 | 8.8 | 3 | 5.8 | 874 | 9.4 |
Lymph nodes | ||||||||||
Negative | 4772 | 63.7 | 509 | 37.9 | 318 | 62.4 | 24 | 46.2 | 5599 | 59.9 |
1–3 positive | 1972 | 26.3 | 424 | 31.6 | 138 | 27.1 | 21 | 40.4 | 2534 | 27.1 |
4–9 positive | 607 | 8.1 | 401 | 29.9 | 41 | 8.0 | 7 | 13. | 1049 | 11.2 |
Unknown | 138 | 1.8 | 9 | 0.7 | 13 | 2.6 | 0 | 0.0 | 160 | 1.7 |
Hormone status | ||||||||||
ER and PR− | 1152 | 15.4 | 325 | 24.2 | 130 | 25.5 | 14 | 26.9 | 1607 | 17.2 |
ER/PR+ | 6025 | 80.5 | 960 | 71.5 | 366 | 71.7 | 38 | 73.1 | 7351 | 78.7 |
Unknown | 312 | 4.2 | 58 | 4.3 | 14 | 2.8 | 0 | 0.0 | 384 | 4.1 |
Multifocality | ||||||||||
No | 6269 | 83.7 | 1061 | 79.0 | 434 | 85.1 | 41 | 78.9 | 7764 | 83.1 |
Yes | 693 | 9.25 | 187 | 13.9 | 46 | 9.0 | 6 | 11.5 | 926 | 9.9 |
Unknown | 527 | 7.0 | 95 | 7.1 | 30 | 5.9 | 5 | 9.6 | 652 | 7.0 |
Surgery type | ||||||||||
BCS | 4246 | 56.7 | 581 | 43.3 | 279 | 54.7 | 22 | 42.3 | 5106 | 54.7 |
Mastectomy | 3243 | 43.3 | 762 | 56.7 | 231 | 45.3 | 30 | 57.7 | 4236 | 45.3 |
Microscopic residue | ||||||||||
No | 7083 | 94.6 | 1231 | 91.7 | 479 | 93.9 | 50 | 96.2 | 8793 | 94.1 |
Yes | 250 | 3.3 | 50 | 3.7 | 16 | 3.1 | 1 | 1.9 | 316 | 3.4 |
Unknown | 156 | 2.1 | 62 | 4.6 | 15 | 2.9 | 1 | 1.9 | 233 | 2.5 |
Chemotherapy | ||||||||||
No | 5057 | 67.5 | 660 | 49.1 | 350 | 68.6 | 34 | 65.4 | 6067 | 64.9 |
Yes | 2432 | 32.5 | 683 | 50.9 | 160 | 31.4 | 18 | 34.6 | 3275 | 35.1 |
Radiation therapy | ||||||||||
No | 2631 | 35.1 | 421 | 31.4 | 207 | 40.6 | 26 | 50.0 | 3259 | 34.9 |
Yes | 4858 | 64.9 | 922 | 68.7 | 303 | 59.4 | 26 | 50.0 | 6083 | 65.1 |
Endocrine therapy | ||||||||||
No | 4370 | 58.4 | 643 | 47.9 | 368 | 72.2 | 30 | 57.7 | 5381 | 57.6 |
Yes | 3119 | 41.7 | 700 | 52.1 | 142 | 27.8 | 22 | 42.3 | 3961 | 42.4 |
Patterns of first recurrence
Patterns of second and third recurrence
Prognostic factors for first and subsequent recurrences
Characteristic | LR (362 events) | RR (148 events) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Univariable | Multivariable | Univariable | Multivariable | |||||||||
HR | 95% CI |
p
| HR | 95% CI |
p
| HR | 95% CI |
p
| HR | 95% CI |
p
| |
Age (years) | ||||||||||||
<40 | Ref | Ref | Ref | Ref | ||||||||
40–49 | 0.67 | 0.45–0.99 | 0.045 | 0.59 | 0.40–0.88 | 0.009 | 0.34 | 0.19–0.61 | <.001 | 0.35 | 0.19–0.63 | <.001 |
50–74 | 0.54 | 0.38–0.78 | 0.001 | 0.43 | 0.30–0.61 | <.001 | 0.44 | 0.27–0.70 | 0.001 | 0.42 | 0.25–0.71 | 0.001 |
≥75 | 0.72 | 0.46–0.12 | 0.141 | 0.62 | 0.39–0.99 | 0.043 | 0.25 | 0.11–0.54 | <.001 | 0.13 | 0.05–0.32 | <.001 |
Tumour size | ||||||||||||
≤2 cm | Ref | Ref | Ref | |||||||||
2–5 cm | 1.09 | 0.88–1.35 | 0.441 | 2.05 | 1.47–2.86 | <.001 | 2.18 | 1.51–3.15 | <.001 | |||
>5 cm | 0.92 | 0.45–1.86 | 0.814 | 2.65 | 1.22–5.77 | 0.014 | 2.72 | 1.13–6.57 | 0.026 | |||
Grade | ||||||||||||
I | Ref | Ref |
Ref*
| |||||||||
II | 0.95 | 0.72–1.26 | 0.731 | 1.69 | 0.96–2.99 | 0.069 |
1.18
|
0.81–1.72
|
0.398
| |||
III | 1.05 | 0.79–1.39 | 0.751 | 3.35 | 1.94–5.77 | <.001 |
1.28
|
0.84–1.96
|
0.254
| |||
Lymph nodes | ||||||||||||
Negative | Ref |
Ref*
| Ref | Ref | ||||||||
1–3 positive | 1.04 | 0.82–1.32 | 0.738 |
1.16
|
0.95–1.42
|
0.133
| 0.95 | 0.65–1.39 | 0.796 | 0.86 | 0.57–1.29 | 0.464 |
>3 positive | 0.91 | 0.62–1.34 | 0.626 |
0.88
|
0.64–1.21
|
0.420
| 0.89 | 0.49–1.62 | 0.693 | 1.00 | 0.51–1.96 | 0.999 |
Endocrine status | ||||||||||||
ER&PR negative | Ref |
Ref*
| Ref |
Ref*
| ||||||||
ER/PR positive | 0.67 | 0.52–0.86 | 0.001 |
1.59
|
1.27–2.00
|
0.001
| 0.35 | 0.25–0.49 | <.001 |
0.85
|
0.61–1.20
|
0.364
|
Histology | ||||||||||||
Ductal | Ref | Ref | Ref |
Ref*
| ||||||||
Lobular | 1.17 | 0.85–1.60 | 0.329 | 1.21 | 0.88–1.66 | 0.246 | 0.69 | 0.38–1.24 | 0.213 |
1.03
|
0.69–1.53
|
0.890
|
Other | 1.05 | 0.74–1.48 | 0.797 | 0.99 | 0.69–1.41 | 0.950 | 0.58 | 0.30–1.14 | 0.116 |
0.85
|
0.53–1.37
|
0.505
|
Multifocality | ||||||||||||
No | Ref | Ref | Ref | Ref | ||||||||
Yes | 0.98 | 0.69–1.39 | 0.908 | 1.12 | 0.77–1.62 | 0.562 | 0.78 | 0.43–1.41 | 0.41 | 0.62 | 0.34–1.13 | 0.120 |
Surgery type | ||||||||||||
Breast conserving | Ref |
Ref*
| Ref | |||||||||
Mastectomy | 0.87 | 0.70–1.08 | 0.197 |
0.74
|
0.63–0.87
| <.001
| 2.17 | 1.56–3.02 | <.001 | |||
Residual disease | ||||||||||||
No | Ref | Ref | Ref | |||||||||
Microscopic | 0.92 | 0.51–1.68 | 0.794 | 0.99 | 0.40–2.41 | 0.979 | 1.44 | 0.58–3.57 | 0.437 | |||
Chemotherapy | ||||||||||||
No | Ref | Ref | Ref | |||||||||
Yes | 0.77 | 0.61–0.97 | 0.024 | 1.07 | 0.77–1.50 | 0.673 | 0.67 | 0.42–1.05 | 0.081 | |||
Radiation therapy | ||||||||||||
No | Ref | Ref | Ref | |||||||||
Yes | 0.9 | 0.72–1.11 | 0.331 | 0.43 | 0.31–0.60 | <.001 | 0.42 | 0.29–0.60 | <.001 | |||
Endocrine therapy | ||||||||||||
No | Ref |
Ref*
| Ref | |||||||||
Yes | 0.47 | 0.37-0.59 | <.001 |
0.62
|
0.51–0.75
| <.001
| 0.67 | 0.47–0.94 | <.001 |
Characteristic | DM (1343 events) | All (1853 events) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Univariable | Multivariable | Univariable | Multivariable | |||||||||
HR | 95% CI |
p
| HR | 95% CI |
p
| HR | 95% CI |
p
| HR | 95% CI |
p
| |
Age (years) | ||||||||||||
<40 | Ref | Ref |
Ref*
| |||||||||
40–49 | 0.69 | 0.56–0.85 | <.001 | 0.65 | 0.54–0.77 | <.001 |
0.83
|
0.73–0.95
|
0.007
| |||
50–74 | 0.58 | 0.48–0.70 | <.001 | 0.55 | 0.47–0.65 | <.001 |
0.84
|
0.74–0.96
|
0.008
| |||
≥75 | 0.82 | 0.65–1.03 | 0.087 | 0.73 | 0.60–0.89 | 0.002 |
0.81
|
0.68–0.96
|
0.016
| |||
Tumour size | ||||||||||||
≤2 cm | Ref |
Ref*
| Ref |
Ref*
| ||||||||
2–5 cm | 2.60 | 2.33–2.91 | <.001 |
1.27
|
1.16–1.39
| <.001
| 2.15 | 1.95–2.36 | <.001 |
1.22
|
1.14–1.32
| <.001
|
>5 cm | 3.71 | 2.92–4.72 | <.001 |
1.23
|
1.01–1.51
|
0.036
| 2.87 | 2.31–3.56 | <.001 |
1.31
|
1.09–1.56
|
0.003
|
Grade | ||||||||||||
I | Ref |
Ref*
| Ref |
Ref*
| ||||||||
II | 2.70 | 2.18–3.34 | <.001 |
1.42
|
1.25–1.63
| <.001
| 1.93 | 1.64–2.26 | <.001 |
1.24
|
1.12–1.37
| <.001
|
III | 4.22 | 3.43–5.19 | <.001 |
1.50
|
1.30–1.73
| <.001
| 2.89 | 2.48–3.38 | <.001 |
1.22
|
1.09–1.36
| <.001
|
Lymph nodes | ||||||||||||
Negative | Ref |
Ref*
| Ref |
Ref*
| ||||||||
1–3 positive | 1.94 | 1.71–2.21 | <.001 |
1.25
|
1.14–1.37
| <.001
| 1.59 | 1.43–1.77 | <.001 |
1.20
|
1.11–1.31
| <.001
|
>3 positive | 5.45 | 4.78–6.22 | <.001 |
1.78
|
1.59–1.99
| <.001
| 3.71 | 3.30–4.16 | <.001 |
1.61
|
1.44–1.79
| <.001
|
Endocrine status | ||||||||||||
ER and PR negative | Ref |
Ref*
| Ref | |||||||||
ER/PR positive | 0.56 | 0.50–0.63 | <.001 |
1.40
|
1.23–1.60
| <.001
| 0.56 | 0.50–0.62 | <.001 | |||
Histology | ||||||||||||
Ductal | Ref |
Ref*
| Ref | |||||||||
Lobular | 1.05 | 0.89–1.24 | 0.582 |
1.03
|
0.91–1.17
|
0.61
| 1.04 | 0.90–1.20 | 0.590 | |||
Other | 0.67 | 0.54–0.83 | <.001 |
0.89
|
0.77–1.04
|
0.155
| 0.73 | 0.61–0.87 | <.001 | |||
Multifocality | ||||||||||||
No | Ref | Ref | Ref | Ref | ||||||||
Yes | 1.5 | 1.29–1.75 | <.001 | 1.19 | 1.01–1.40 | 0.037 | 1.34 | 1.16–1.53 | <.001 | 1.25 | 1.09–1.44 | 0.002 |
Surgery type | ||||||||||||
Breast conserving | Ref | Ref | Ref | |||||||||
Mastectomy | 1.79 | 1.61–1.99 | <.001 | 1.41 | 1.25–1.58 | <.001 | 1.58 | 1.44–1.73 | <.001 | |||
Residual disease | ||||||||||||
No | Ref | |||||||||||
Microscopic | 1.16 | 0.87–1.53 | 0.311 | |||||||||
Chemotherapy | ||||||||||||
No | Ref | Ref |
Ref*
| |||||||||
Yes | 1.93 | 1.74–2.15 | <.001 | 1.56 | 1.42–1.71 | <.001 |
0.88
|
0.80–0.96
|
0.006
| |||
Radiation therapy | ||||||||||||
No | Ref | Ref | ||||||||||
Yes | 1.09 | 0.97–1.22 | 0.161 | 0.97 | 0.88–1.06 | 0.478 | ||||||
Endocrine therapy | ||||||||||||
No | Ref | Ref | ||||||||||
Yes | 1.47 | 1.32–1.63 | <.001 | 1.12 | 1.03–1.23 | 0.012 |
Characteristic | Event after LR (n = 362, 102 events) | Event after RR (n = 148, 74 events) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Univariable | Multivariable | Univariable | Multivariable | |||||||||
HR | 95% CI |
p
| HR | 95% CI |
p
| HR | 95% CI |
p
| HR | 95% CI |
p
| |
Age (years) | ||||||||||||
<40 | Ref. | Ref | Ref | Ref | ||||||||
40–49 | 0.9 | 0.44–1.85 | 0.772 | 1.06 | 0.50–2.24 | 0.889 | 1 | 0.43–2.31 | 0.999 | 0.89 | 0.38–2.11 | 0.793 |
50–74 | 0.83 | 0.43–1.58 | 0.567 | 1.04 | 0.52–2.09 | 0.904 | 1.19 | 0.61–2.35 | 0.609 | 1.87 | 0.90–3.88 | 0.093 |
≥75 | 1.75 | 0.80–3.83 | 0.158 | 1.47 | 0.62–3.46 | 0.378 | 0.21 | 0.03–1.67 | 0.141 | 0.29 | 0.04–2.29 | 0.240 |
Tumour size | ||||||||||||
≤2 cm | Ref. | Ref | Ref | Ref | ||||||||
2–5 cm | 3.28 | 2.17–4.95 | <.001 | 3.01 | 1.91–4.74 | 0.000 | 1.04 | 0.65–1.67 | 0.865 | 0.83 | 0.50–1.38 | 0.467 |
>5 cm | 7.85 | 3.29–18.74 | <.001 | 2.60 | 0.95–7.10 | 0.062 | 1.34 | 0.41–4.38 | 0.625 | 1.64 | 0.49–5.54 | 0.426 |
Grade | ||||||||||||
I | Ref. | Ref | Ref | |||||||||
II | 2.31 | 1.06–5.04 | 0.036 | 1.25 | 0.55–2.83 | 0.595 | 0.91 | 0.41–2.04 | 0.825 | |||
III | 5.72 | 2.71–12.07 | <.001 | 3.31 | 1.49–7.37 | 0.003 | 1.04 | 0.48–2.23 | 0.922 | |||
Lymph nodes | ||||||||||||
Negative | Ref. | Ref | Ref | |||||||||
1–3 positive | 2.98 | 1.92–4.64 | <.001 | 1.94 | 1.20–3.14 | 0.007 | 1.07 | 0.62–1.82 | 0.816 | |||
>3 positive | 7.03 | 4.05–12.21 | <.001 | 3.23 | 1.65–6.30 | 0.001 | 2.25 | 1.01–4.98 | 0.047 | |||
Hormone status | ||||||||||||
ER&PR− | Ref. |
Ref*
| Ref | Ref | ||||||||
ER/PR+ | 0.41 | 0.27–0.62 | <.001 |
0.6
|
0.41–0.96
|
0.032
| 0.58 | 0.36–0.92 | 0.021 | 0.6 | 0.31–1.13 | 0.111 |
Histology | ||||||||||||
Ductal | Ref. | Ref | Ref | |||||||||
Lobular | 0.77 | 0.42–1.46 | 0.436 | 0.73 | 0.37–1.42 | 0.352 | 1.56 | 0.71–3.43 | 0.266 | |||
Other | 0.15 | 0.04–0.62 | 0.009 | 0.14 | 0.03–0.60 | 0.008 | 1.09 | 0.40–3.01 | 0.867 | |||
Multifocality | ||||||||||||
No | Ref. | Ref | Ref | Ref | ||||||||
Yes | 0.98 | 0.52–1.87 | 0.961 | 1.20 | 0.76–2.01 | 0.398 | 1.07 | 0.47–0.89 | 0.880 | 1.59 | 0.66–3.82 | 0.297 |
Surgery type | ||||||||||||
BCS | Ref. | Ref | ||||||||||
Mastectomy | 2.67 | 1.79–3.97 | <.001 | 0.87 | 0.55–1.39 | 0.557 | ||||||
Residual disease | ||||||||||||
No | Ref. | Ref | ||||||||||
Microscopic | 0.31 | 0.04–2.17 | 0.236 | 0.79 | 0.19–1.17 | 0.743 | ||||||
Chemotherapy | ||||||||||||
No | Ref. | Ref | ||||||||||
Yes | 3.07 | 2.07–4.54 | <.001 | 1.1 | 0.68–1.76 | 0.696 | ||||||
Radiation therapy | ||||||||||||
No | Ref. | Ref | ||||||||||
Yes | 0.58 | 0.39–0.86 | 0.007 | 1.56 | 0.98–2.46 | 0.058 | ||||||
Endocrine therapy | ||||||||||||
No | Ref. |
Ref*
| Ref | Ref | ||||||||
Yes | 1.94 | 1.30–2.91 | 0.001 |
1.60
|
1.08–2.42
|
0.020
| 0.98 | 0.60–1.59 | 0.930 | 1.3 | 0.73–2.31 | 0.381 |
DFI (years) | ||||||||||||
0–1.9 | Ref. | Ref |
Ref*
| |||||||||
2.0–3.9 | 0.58 | 0.37–0.91 | 0.02 | 0.98 | 0.57–1.68 | 0.930 |
0.97
|
0.59–1.59
|
0.899
| |||
4.0–5.9 | 0.35 | 0.19–0.65 | <.001 | 0.7 | 0.36–1.36 | 0.298 |
2.07
|
1.04–4.16
|
0.040
| |||
6.0–7.9 | 0.15 | 0.05–0.41 | <.001 | 0.58 | 0.25–1.33 | 0.198 |
3.94
|
1.42–10.96
|
0.009
| |||
8.0–10.0 | 0.29 | 0.10–0.82 | 0.02 | 0.25 | 0.03–1.83 | 0.170 |
4.34
|
0.24–76.81
|
0.317
| |||
Surgery of recurrence | ||||||||||||
No | Ref. | Ref | Ref | Ref | ||||||||
Yes | 0.33 | 0.20–0.55 | <.001 | 0.40 | 0.21–0.75 | 0.005 | 0.52 | 0.33–0.82 | 0.005 | 0.42 | 0.26–0.70 | 0.001 |
Chemotherapy of recurrence | ||||||||||||
No | Ref. | Ref | Ref | |||||||||
Yes | 1.03 | 0.60–1.76 | 0.92 | 0.66 | 0.37–1.19 | 0.170 | 1.31 | 0.83–2.08 | 0.245 | |||
Radiation therapy of recurrence | ||||||||||||
No | Ref. | Ref | Ref | |||||||||
Yes | 2.02 | 1.37–2.98 | <.001 | 1.51 | 0.96–2.39 | 0.076 | 1.4 | 0.87–2.26 | 0.169 | |||
Endocrine therapy of recurrence | ||||||||||||
No | Ref. | Ref | Ref | |||||||||
Yes | 0.69 | 0.46–1.04 | 0.07 | 0.61 | 0.38–0.98 | 0.040 | 0.64 | 0.36–1.17 | 0.148 |