Introduction
Methods
Tumor samples
Description of molecular marker used for analysis
Statistical analysis
Results
Patient characteristics and correlation between clinical and molecular variables
Tamoxifen cohort 1 | Untreated | Low MKS | High MKS | Tamoxifen | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
High ERS | Low ERS | High ERS | Low ERS | cohort 2 | ||||||||||||
Characteristic | N | % | N | % |
P
a
| N | % | N | % | N | % | N | % |
P
b
| N | % |
Patients
| 683 | 559 | 373 | 248 | 248 | 373 | 282 | |||||||||
Age, years
| ||||||||||||||||
≤50 | 43 | 6.3 | 240 | 42.9 |
<0.0001
| 82 | 22.0 | 47 | 19.0 | 57 | 23.0 | 96 | 25.7 | 0.247 | 8 | 2.8 |
>50 | 498 | 72.9 | 306 | 54.8 | 240 | 64.3 | 172 | 69.3 | 160 | 64.5 | 233 | 62.5 | 176 | 62.4 | ||
Unknown | 142 | 20.8 | 13 | 2.3 | 51 | 13.7 | 29 | 11.7 | 31 | 12.5 | 44 | 11.8 | 98 | 34.8 | ||
Tumor (T) stage
| ||||||||||||||||
T1 | 214 | 31.3 | 199 | 35.6 |
<0.0001
| 145 | 38.9 | 102 | 41.1 | 74 | 29.8 | 92 | 24.7 |
0.003
| 109 | 38.7 |
T2/T3 | 293 | 42.9 | 140 | 25.0 | 126 | 33.8 | 82 | 33.1 | 84 | 33.9 | 141 | 37.8 | 168 | 59.5 | ||
Unknown | 176 | 25.8 | 220 | 39.4 | 102 | 27.3 | 64 | 25.8 | 90 | 36.3 | 140 | 37.5 | 5 | 1.8 | ||
Nodal status
| ||||||||||||||||
Negative | 403 | 59.0 | 559 | 100.0 |
<0.0001
| 295 | 79.1 | 192 | 77.4 | 191 | 77.0 | 284 | 76.1 | 0.962 | 147 | 52.1 |
Positive | 258 | 37.8 | 0 | 0.0 | 76 | 20.4 | 50 | 20.2 | 52 | 21.0 | 80 | 21.5 | 111 | 39.4 | ||
Unknown | 22 | 3.2 | 0 | 0.0 | 2 | 0.5 | 6 | 2.4 | 5 | 2.0 | 9 | 2.4 | 24 | 8.5 | ||
Grade
| ||||||||||||||||
1 | 108 | 15.8 | 66 | 11.8 |
0.0002
| 86 | 23.1 | 54 | 21.8 | 18 | 7.3 | 16 | 4.3 |
<0.0001
| 26 | 9.2 |
2 | 258 | 37.8 | 242 | 43.3 | 159 | 42.6 | 105 | 42.3 | 108 | 43.5 | 128 | 34.3 | 114 | 40.4 | ||
3 | 111 | 16.3 | 152 | 27.2 | 29 | 7.8 | 32 | 12.9 | 63 | 25.4 | 139 | 37.3 | 44 | 15.6 | ||
Unknown | 206 | 30.2 | 99 | 17.7 | 99 | 26.5 | 57 | 23.0 | 59 | 23.8 | 90 | 24.1 | 98 | 34.8 | ||
HER2 by gene
c
| ||||||||||||||||
HER2-positive | 27 | 4.0 | 44 | 7.9 | 0.169 | 1 | 0.3 | 8 | 3.2 | 7 | 2.8 | 55 | 14.8 |
<0.0001
| - | 0.0 |
HER2-negative | 647 | 94.7 | 515 | 92.1 | 371 | 99.4 | 239 | 96.4 | 239 | 96.4 | 313 | 83.9 | - | 0.0 | ||
Unknown | 9 | 1.3 | 0 | 0.0 | 1 | 0.3 | 1 | 0.4 | 2 | 0.8 | 5 | 1.3 | 282 | 100.0 | ||
Distant events, time cohorts
| ||||||||||||||||
0 to 10 yrs | 137 | 144 | - | 42 | 37 | 65 | 137 |
-
| 64 | |||||||
0 to 2.5 yrs | 46 | 55 | 8 | 9 | 17 | 67 | 26 | |||||||||
2.5 to 5 yrs | 48 | 55 | 19 | 10 | 21 | 53 | 20 | |||||||||
>5 yrs | 43 | 34 | 15 | 19 | 26 | 17 | 18 | |||||||||
Unknown | 10 | 6 | 2 | 6 | 3 | 5 | - |
Time-varying prognostic values of clinical and molecular variables in adjuvant tamoxifen-treated patients
Variable | 0 to 10 years DEFS | 0 to 5 years DEFS | 5 to 10 years DEFS | ||||||
---|---|---|---|---|---|---|---|---|---|
Hazard ratio (95% CI) |
P
a
|
P
b
| Hazard ratio (95% CI) |
P
a
|
P
b
| Hazard ratio (95% CI) |
P
a
|
P
b
| |
Age
| 1.02 (1.00, 1.04) |
0.021
| 0.657 | 1.02 (0.99, 1.04) | 0.153 | 0.214 | 1.04 (1.00, 1.08) |
0.042
| 0.168 |
Stage T2/3 vs T1
| 2.71 (1.76, 4.19) |
<0.0001
| 0.581 | 2.51 (1.47, 4.26) |
0.0007
| 0.211 | 3.14 (1.49, 6.64) |
0.003
| 0.164 |
Node-positive vs -negative
| 2.47 (1.75, 3.48) |
<0.0001
| 0.964 | 2.51 (1.65, 3.82) |
<0.0001
| 0.732 | 2.67 (1.44, 4.97) |
0.002
| 0.941 |
Grade
| |||||||||
Intermediate vs low | 2.19 (1.20, 3.99) |
0.011
| 0.11 | 3.97 (1.57, 9.99) |
0.003
| 0.175 | 1.04 (0.44, 2.45) | 0.934 | 0.192 |
High vs low | 2.96 (1.56, 5.62) |
0.0009
| 5.05 (1.92, 13.3) |
0.001
| 1.66 (0.67, 4.12) | 0.277 | |||
HER2-positive vs -negative
| 2.64 (1.43, 4.90) |
0.002
|
0.029
| 3.68 (1.91, 7.10) |
0.0001
| 0.369 | 0.72 (0.11, 5.26) | 0.75 | 0.141 |
High MKS vs low MKS
| 2.96 (2.07, 4.25) |
<0.0001
|
0.04
| 3.89 (2.42, 6.24) |
<0.0001
| 0.473 | 1.90 (1.04, 3.46) |
0.036
| 0.377 |
Low ERS vs high ERS
| 2.00 (1.41, 2.83) |
<0.0001
|
0.0008
| 3.26 (2.04, 5.19) |
<0.0001
| 0.091 | 0.91 (0.50, 1.66) | 0.763 | 0.728 |
MKS/ERS combined groups
| |||||||||
LowMKS/lowERS vs lowMKS/highERS | 2.37 (1.29, 4.35) |
0.005
|
<0.0001
| 1.98 (0.87, 4.51) | 0.104 | 0.285 | 3.36 (1.29, 8.73) |
0.013
| 0.862 |
HighMKS/highERS vs lowMKS/highERS | 3.66 (2.04, 6.57) |
<0.0001
| 2.46 (1.09, 5.54) |
0.029
| 6.59 (2.62, 16.6) |
<0.0001
| |||
HighMKS/lowERS vs lowMKS/highERS | 5.35 (3.12, 9.17) |
<0.0001
| 7.78 (3.97, 15.3) |
<0.0001
| 1.46 (0.45, 4.79) | 0.531 | |||
Other genomic signatures
| |||||||||
High GGI vs low GGI
| 2.73 (1.94, 3.86) |
<0.0001
|
0.005
| 3.81 (2.43, 5.97) |
<0.0001
| 0.296 | 1.64 (0.90, 2.99) | 0.109 |
0.02
|
Mammaprint poor vs good
| 2.93 (1.91, 4.49) |
<0.0001
| 0.22 | 3.59 (2.02, 6.30) |
<0.0001
| 0.768 | 2.30 (1.16, 4.56) |
0.017
| 0.184 |
Three-gene model SCMGENE
| |||||||||
ER+/HER2-highP vs ER+/HER2-lowP | 2.13 (1.47, 3.08) |
<0.0001
|
0.017
| 2.58 (1.59, 4.18) |
0.0001
| 0.585 | 1.60 (0.87, 2.95) | 0.127 | 0.197 |
HER2+ vs ER+/HER2-lowP | 4.06 (2.09, 7.86) |
<0.0001
| 6.63 (3.17, 13.9) |
<0.0001
| 0.89 (0.12, 6.64) | 0.909 | |||
ER-/HER2- vs ER+/HER2-lowP | 2.55 (1.01, 6.42) |
0.048
| 4.70 (1.79, 12.3) |
0.002
| NA | ||||
PAM50
| |||||||||
LumB vs lumA | 3.01 (2.01, 4.51) |
<0.0001
|
0.004
| 3.84 (2.21, 6.65) |
<0.0001
| 0.109 | 2.26 (1.20, 4.24) |
0.011
| 0.147 |
HER2 vs lumA | 8.88 (4.36, 18.1) |
<0.0001
| 14.4 (6.37, 32.8) |
<0.0001
| 2.37 (0.31, 17.9) | 0.403 | |||
Basal vs lumA | 3.03 (1.07, 8.58) |
0.036
| 6.48 (2.17, 19.4) |
0.0008
| NA |
Time-varying prognostic values of clinical and molecular variables in untreated patients
Prediction of early and late relapse in tamoxifen-treated patients
Tamoxifen-treated patients (cohort 1) | Untreated patients | |||||||
---|---|---|---|---|---|---|---|---|
0.0 to 2.5 yearsa | 5.0 to 10.0 yearsa,c | 0.0 to 2.5 yearsb | 5.0 to 10.0 yearsb,c | |||||
Variable | Hazard ratio (95% CI) |
P
| Hazard ratio (95% CI) |
P
| Hazard ratio(95% CI) |
P
| Hazard ratio(95% CI) |
P
|
Age, analyzed as a continuous variable | 1.04 (0.99, 1.08) | 0.071 | 1.02 (0.98, 1.07) | 0.279 | 1.01 (0.98, 1.05) | 0.357 | 1.04 (0.99, 1.08) | 0.063 |
Tumor (T) stage, T2/3 vs T1 | 2.29 (0.87, 6.08) | 0.094 | 2.90 (1.22, 6.91) |
0.016
| 1.88 (0.74, 4.80) | 0.183 | 1.22 (0.48, 3.12) | 0.677 |
Nodal status, positive vs negative | 2.92 (1.23, 6.88) |
0.014
| 2.46 (1.15, 5.23) |
0.021
| - | - | ||
Grade 2 or 3 vs 1 | 1.51 (0.33, 6.78) | 0.592 | 0.72 (0.31, 1.69) | 0.451 | 2.13 (0.28, 16.4) | 0.467 | 1.07 (0.29, 3.95) | 0.923 |
HER2-positive vs -negative | 1.42 (0.33, 6.78) | 0.528 | 1.63 (0.31, 1.69) | 0.667 | 4.24 (1.36, 13.1) |
0.013
| 2.89 (0.57, 14.6) | 0.198 |
MKS/ERS (ref lowMKS/highERS) | ||||||||
lowMKS/lowERS | 2.65 (0.48, 14.7) | 0.269 | 3.53 (1.21, 10.2) |
0.021
| 1.67 (0.10, 27.1) | 0.717 | 0.46 (0.09, 2.33) | 0.349 |
highMKS/highERS | 1.28 (0.18, 9.23) | 0.807 | 4.59 (1.56, 13.5) |
0.006
| 11.6 (1.41, 95.2) |
0.023
| 1.82 (0.53, 6.27) | 0.343 |
highMKS/lowERS | 10.0 (2.21, 45.5) |
0.003
| 0.95 (0.20, 4.70) | 0.947 | 9.56 (1.17, 77.8) |
0.035
| 1.51 (0.44, 5.14) | 0.508 |