Introduction
Methods
Study population
Tissue microarrays and immunohistochemistry
Definition and subtype | ER | PR | HER2 | Ki-67 | CK5/6 | EGFR |
---|---|---|---|---|---|---|
Definition of positive result | >1% of tumor nuclei | >1% tumor nuclei | HercepTest score 3+ or 2+ with CISH amplification ratio >2.2 | ≥14% of tumor nuclei | Any cytoplasmic or membranous staining | Any cytoplasmic or membranous staining |
Subtype 4 biomarkers | ||||||
Luminal A | ER + or PR+ | Negative | Negative | – | – | |
Luminal B | ER + or PR+ | Negative | Positive | – | – | |
HER2-enriched | Any | Any | Positive | Any | – | – |
Triple-negative | Negative | Negative | Negative | Any | – | – |
Subtype 6 biomarkers | ||||||
Luminal A | ER + or PR+ | Negative | Negative | Any | Any | |
Luminal B | ER + or PR+ | Negative | Positive | Any | Any | |
Luminal HER2 | ER + or PR+ | Positive | Any | Any | Any | |
HER2-enriched | Negative | Negative | Positive | Any | Any | Any |
Basal-like | Negative | Negative | Negative | Any | CK5/6-positive EGFR-positive | |
TNP nonbasal | Negative | Negative | Negative | Any | Negative | Negative |
Statistical analysis methods
Results
Patient cohort
Luminal A and luminal B (N = 916) | HER2-enriched (N = 151) | Triple-negative (N = 182) | |||||||
---|---|---|---|---|---|---|---|---|---|
Characteristics | Ki-67 <14% (N = 540) | Ki-67 ≥14% (N = 376) |
P
b
| Ki-67 <14% (N = 42)c | Ki-67 ≥14% (N = 107)c |
P
b
| Ki-67 <14% (N = 38)d | Ki-67 ≥14% (N = 143)d |
P
b
|
Age (years), n (%) | |||||||||
<40 | 33 (6.1) | 32 (8.5) | NS | 4 (9.5) | 15 (14.0) | NS | 5 (13.2) | 22 (15.4) | NS |
40 to 55 | 197 (36.5) | 139 (37.1) | 14 (33.3) | 49 (45.8) | 9 (23.7) | 58 (40.6) | |||
>55 | 310 (57.3) | 205 (54.4) | 24 (57.1) | 43 (40.2) | 24 (63.2) | 63 (44.1) | |||
Menopausal status, n (%) | |||||||||
Premenopausal | 172 (31.9) | 130 (34.7) | NS | 15 (35.7) | 53 (49.5) | NS | 12 (31.6) | 59 (41.3) | NS |
Postmenopausal | 360 (66.6) | 242 (64.3) | 26 (61.9) | 54 (50.5) | 26 (68.4) | 83 (58.0) | |||
NA | 8 (1.5) | 4 (1.1) | 1 (2.4) | – | – | 1 (0.7) | |||
Tumor size (cm), n (%) | |||||||||
<2 | 250 (46.4) | 158 (42.1) | NS | 14 (33.3) | 29 (27.1) | NS | 8 (21.1) | 36 (25.2) | NS |
2 to 5 | 261 (48.2) | 198 (52.5) | 23 (54.8) | 67 (62.6) | 27 (71.1) | 89 (62.2) | |||
>5 | 22 (4.1) | 14 (3.7) | 4 (9.5) | 10 (9.3) | 1 (2.6) | 13 (9.1) | |||
NA | 7 (1.3) | 6 (1.6) | 1 (2.4) | 1 (0.9) | 2 (5.3) | 5 (3.5) | |||
Tumor grade, n (%) | |||||||||
1 | 144 (26.7) | 39 (10.4) | <0.0001 | 2 (4.8) | 2 (1.9) | 0.0036 | 1 (2.6) | 1 (0.7) | 0.003 |
2 | 311 (57.5) | 226 (60.0) | 27 (64.3) | 43 (40.2) | 19 (50.0) | 38 (26.6) | |||
3 | 47 (8.7) | 91 (24.3) | 10 (23.8) | 55 (51.4) | 13 (34.2) | 90 (62.9) | |||
NA | 38 (7.1) | 20 (5.3) | 3 (7.1) | 7 (6.5) | 5 (13.2) | 14 (9.8) | |||
Lymph nodes, n (%) | |||||||||
0 | 293 (54.2) | 192 (50.9) | NS | 15 (35.7) | 48 (44.9) | NS | 13 (34.2) | 77 (53.8) | NS |
1 to 3 | 145 (26.9) | 109 (29.1) | 16 (38.1) | 28 (26.2) | 13 (34.2) | 36 (25.2) | |||
≥4 | 101 (18.7) | 73 (19.5) | 11 (26.2) | 30 (28.0) | 11 (28.9) | 27 (18.9) | |||
NA | 1 (0.2) | 2 (0.5) | – | 1 (0.9) | 1 (2.6) | 3 (2.1) | |||
Chemotherapy, n (%) | |||||||||
No | 275 (50.8) | 174 (46.1) | NS | 10 (23.8) | 27 (25.2) | NS | 9 (23.7) | 20 (14.0) | NS |
Yes | 260 (48.2) | 199 (53.1) | 31 (73.8) | 79 (73.8) | 29 (76.3) | 121 (84.6) | |||
NA | 5 (0.9) | 3 (0.8) | 1 (2.4) | 1 (0.9) | – | 2 (1.4) | |||
Hormonotherapy, n (%) | |||||||||
No | 106 (19.5) | 67 (17.6) | NS | 22 (52.4) | 45 (42.1) | NS | 19 (50.0) | 100 (69.9) | NS |
Yes | 432 (80.1) | 307 (81.9) | 20 (47.6) | 62 (57.9) | 19 (50.0) | 43 (30.1) | |||
NA | 2 (0.4) | 2 (0.5) | – | – | – | – | |||
Local therapy, n (%) | |||||||||
Mastectomy alone | 172 (31.9) | 105 (28.0) | 19 (45.2) | 30 (28.0) | 20 (52.6) | 36 (25.2) | |||
Mastectomy + RT | 61 (11.3) | 36 (9.6) | NS | 7 (16.7) | 16 (15.0) | NS | 7 (18.4) | 23 (16.1) | NS |
Lumpectomy alone | 28 (5.2) | 13 (3.5) | 1 (2.4) | 8 (7.5) | – | 5 (3.5) | |||
Lumpectomy + RT | 279 (51.6) | 222 (58.9) | 15 (35.7) | 53 (49.5) | 11 (28.9) | 79 (55.2) |
Characteristics | Luminal A and luminal B (N = 916) | Luminal HER2 (N = 77) | HER2-enriched (N = 74) | Basal-like (N = 133) | TNP nonbasal (N = 49) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Ki-67 <14% (N = 540) | Ki-67 ≥14% (N = 376) |
P
b
| Ki-67 <14% (N = 18)c | Ki-67 ≥14% (N = 57)c |
P
b
| Ki-67 <14% (N = 24) | Ki-67 ≥14% (N = 50) |
P
b
| Ki-67 <14% (N = 13) | Ki-67 ≥14% (N = 120) |
P
b
| Ki-67 <14% (N = 25)d | Ki-67 ≥14% (N = 23)d |
P
b
| |
Age (years), n (%) | |||||||||||||||
<40 | 33 (6.1) | 32 (8.5) | NS | 2 (11.1) | 10 (17.5) | NS | 2 (8.3) | 5 (10.0) | NS | 1 (7.7) | 18 (15.0) | NS | 4 (16.0) | 4 (17.4) | NS |
40 to 55 | 197 (36.5) | 139 (37.1) | 5 (27.8) | 24 (42.1) | 9 (37.5) | 25 (50.0) | 3 (23.1) | 47 (39.2) | 6 (24.0) | 11 (47.8) | |||||
>55 | 310 (57.3) | 205 (54.4) | 11 (61.1) | 23 (40.4) | 13 (54.2) | 20 (40.0) | 9 (69.2) | 55 (45.8) | 15 (60.0) | 8 (34.8) | |||||
Menopausal status, n (%) | |||||||||||||||
Premenopausal | 172 (31.9) | 130 (34.7) | NS | 6 (33.3) | 25 (43.9) | NS | 9 (37.5) | 28 (56.0) | NS | 4 (30.8) | 50 (41.7) | NS | 8 (32.0) | 9 (39.1) | NS |
Postmenopausal | 360 (66.6) | 242 (64.3) | 11 (61.1) | 32 (56.1) | 15 (62.5) | 22 (44.0) | 9 (69.2) | 70 (58.3) | 17 (68.0) | 13 (56.5) | |||||
NA | 8 (1.5) | 4 (1.1) | 1 (5.6) | – | – | – | – | – | – | 1 (4.3) | |||||
Tumor size (cm), n (%) | |||||||||||||||
<2 | 250 (46.4) | 158 (42.1) | NS | 8 (44.2) | 18 (31.6) | NS | 6 (25.0) | 11 (22.0) | NS | 2 (15.4) | 30 (25) | NS | 6 (24.0) | 6 (26.1) | NS |
2 to 5 | 261 (48.2) | 198 (52.5) | 9 (50.0) | 36 (63.2) | 14 (58.3) | 31 (62.0) | 10 (76.9) | 77 (64.2) | 17 (68.0) | 12 (52.2) | |||||
>5 | 22 (4.1) | 14 (3.7) | – | 3 (5.3) | 45 (16.7) | 7 (14.0) | – | 8 (6.7) | 1 (4.0) | 5 (21.7) | |||||
NA | 7 (1.3) | 6 (1.6) | 1 (5.6) | – | – | 1 (2.0) | 1 (7.7) | 5 (4.2) | 1(4.0) | – | |||||
Tumor grade, n (%) | |||||||||||||||
1 | 144 (26.7) | 39 (10.4) | <.0001 | 1 (5.9) | 2 (3.8) | .004 | 1 (4.2) | – | NS | – | 1 (0.8) | NS | 1 (4.0) | – | .005 |
2 | 311 (57.5) | 226 (60.0) | 15 (88.2) | 26 (50.0) | 12 (50.0) | 17 (34.0) | 4 (30.8) | 32 (26.7) | 15 (60.0) | 6 (26.1) | |||||
3 | 47 (8.7) | 91 (24.3) | 1 (5.9) | 24 (46.2) | 9 (37.5) | 31 (62.0) | 8 (61.5) | 75 (625) | 5 (20.0) | 15 (65.2) | |||||
NA | 38 (7.1) | 20 (5.3) | – | – | 2 (8.3) | 2 (4.0) | 1 (7.7) | 12 (10.0) | 4 (16.0) | 2 (8.7) | |||||
Lymph nodes, n (%) | |||||||||||||||
0 | 293 (54.2) | 192 (50.9) | NS | 9 (50.0) | 31 (54.4) | NS | 6 (25.0) | 17 (34.0) | NS | 3 (23.1) | 64 (53.3) | NS | 10 (40.0) | 13 (56.5) | NS |
1 to 3 | 145 (26.9) | 109 (29.1) | 7 (38.9) | 18 (31.6) | 9 (37.5) | 10 (20.0) | 5 (38.5) | 32 (26.7) | 8 (32.0) | 4 (17.4) | |||||
≥4 | 101 (18.7) | 73 (19.5) | 2 (11.1) | 8 (14.0) | 9 (37.5) | 22 (44.0) | 5 (38.5) | 23 (19.2) | 6 (24.0) | 4 (17.4) | |||||
NA | 1 (0.2) | 2 (0.5) | – | – | – | 1 (2.0) | – | – | 1 (4.0) | 2 (8.7) | |||||
Chemotherapy, n (%) | |||||||||||||||
No | 275 (50.8) | 174 (46.1) | NS | 8 (44.4) | 16 (28.1) | NS | 2 (8.3) | 11 (22.0) | NS | 2 (15.4) | 16 (13.3) | NS | 7 (28.0) | 7 (17.4) | NS |
Yes | 260 (48.2) | 199 (53.1) | 10 (55.6) | 41 (71.9) | 21 (87.5) | 38 (76.0) | 11 (84.6) | 102 (85.0) | 18 (72.0) | 19 (82.6) | |||||
NA | 5 (0.9) | 3 (0.8) | – | – | 1 (4.2) | 1 (2.0) | – | 2 (1.7) | – | – | |||||
Hormonotherapy, n (%) | |||||||||||||||
No | 106 (19.5) | 67 (17.6) | NS | 4 (22.2) | 13 (22.8) | NS | 18 (75.0) | 32 (64.0) | NS | 9 (69.2) | 86 (71.7) | NS | 10 (40) | 14 (60.9) | |
Yes | 432 (80.1) | 307 (81.9) | 14 (77.8) | 44 (77.2) | 6 (25.0) | 18 (36.0) | 4 (30.8) | 34 (28.3) | 15 (60) | 9 (39.1) | |||||
NA | 2 (0.4) | 2 (0.5) | – | – | – | – | – | – | – | – | |||||
Local therapy, n (%) | |||||||||||||||
Mastectomy alone | 172 (31.9) | 105 (28.0) | 7 (38.9) | 14 (24.6) | 12 (50.0) | 16 (32.0) | 5 (38.5) | 28 (23.3) | 15 (60.0) | 8 (34.8) | |||||
Mastectomy + RT | 61 (11.3) | 36 (9.6) | NS | 1 (5.6) | 5 (8.8) | NS | 6 (25.0) | 11 (22.0) | NS | 3 (23.1) | 17 (14.2) | NS | 4 (16.0) | 6 (26.1) | NS |
Lumpectomy alone | 28 (5.2) | 13 (3.5) | 1 (5.6) | 4 (7.0) | – | 4 (8.0) | – | 5 (4.2) | – | – | |||||
Lumpectomy + RT | 279 (51.6) | 222 (58.9) | 9 (50.0) | 34 (59.6) | 6 (25.0) | 19 (38.0) | 5 (38.5) | 70 (58.3) | 6 (24.0) | 9 (39.1) |
Analysis of actuarial breast cancer–free survival by intrinsic subtype and proliferation rate
Intrinsic subtype | 2-year BCFS | 95% CI | 3-year BCFS | 95% CI | 5-year BCFS | 95% CI |
---|---|---|---|---|---|---|
Luminal A | 96.7% | 95.2% to 98.3% | 92.8% | 90.6% to 95.0% | 85.8% | 82.7% to 88.9% |
Luminal B | 91.5% | 88.6% to 94.4% | 85.2% | 81.6% to 89.0% | 77.1% | 72.8% to 81.7% |
HER2-enriched | 81.2% | 75.0% to 87.8% | 73.3% | 66.4% to 81.0% | 68.7% | 61.4% to 76.8% |
Triple-negative | 83.0% | 77.7% to 88.8% | 74.5% | 68.3% to 81.2% | 68.4% | 61.8% to 75.7% |
Intrinsic subtype | 2-year BCFS | 95% CI | 3-year BCFS | 95% CI | 5-year BCFS | 95% CI |
---|---|---|---|---|---|---|
Luminal A | 96.7% | 95.2% to 98.3% | 92.8% | 90.6% to 95.0% | 85.8% | 82.7% to 88.9% |
Luminal B | 91.5% | 88.6% to 94.4% | 85.2% | 81.6% to 89.0% | 77.1% | 72.8% to 81.7% |
Luminal HER2 | 89.2% | 82.5% to 96.6% | 81.0% | 72.4% to 90.5% | 77.1% | 68.8% to 72.4% |
HER2-enriched | 72.4% | 62.5% to 83.8% | 63.9% | 53.5% to 76.3% | 58.3% | 47.6% to 71.5% |
Basal-like | 80.8% | 74.3% to 87.9% | 72.2% | 64.9% to 80.4% | 68.1% | 60.5% to 76.7% |
TNP nonbasal | 89.3% | 80.9% to 98.6% | 80.6% | 70.0% to 92.8% | 66.7% | 54.2% to 82.1% |
Analysis of recurrence prognostic factors and variations in recurrence risk over time
Variables | HR | 95% CI |
P
b
|
---|---|---|---|
Tumor size, cm | |||
<2 | 1.0 | ||
2 to 5 | 1.6 | 1.2 to 2.1 | 0.0004 |
>5 | 1.9 | 1.2 to 3.1 | 0.005 |
Lymph nodes | |||
0 | 1.0 | ||
1 to 3 | 1.4 | 1.0 to 1.8 | 0.01 |
≥4 | 2.8 | 2.1 to 3.7 | <0.0001 |
Local therapy | |||
Mastectomy alone | 1.0 | ||
Mastectomy + RT | 1.1 | 0.7 to 1.5 | 0.6 |
Lumpectomy alone | 1.2 | 0.6 to 2.1 | 0.5 |
Lumpectomy + RT | 0.6 | 0.4 to 0.8 | 0.0005 |
Endocrine therapy | |||
Yes | 1.0 | ||
No | 0.7 | 0.5 to 0.9 | 0.01 |
Subtype | |||
Luminal A | 1.0 | ||
Luminal B | 1.3 | 1.0 to 1.7 | 0.02 |
HER2-enriched | 1.4 | 1.0 to 2.0 | 0.04 |
Triple-negative | 1.3 | 0.9 to 1.8 | 0.09 |
Years after surgery | Luminal A hazard rateb | HR | Luminal B hazard rate | HR | HER2-enriched hazard rate | HR | Triple-negative hazard rate | HR |
---|---|---|---|---|---|---|---|---|
2 | 0.26 (0.2 to 0.3) | 1 | 0.50 (0.4 to 0.6) | 1.9 | 1.26 (0.8 to 2.0) | 4.8 | 0.78 (0.6 to 1.0) | 3.0 |
3 | 0.32 (0.2 to 0.4) | 1 | 0.54 (0.4 to 0.6) | 1.7 | 0.63 (0.3 to 1.3) | 2.0 | 0.60 (0.4 to 0.8) | 1.9 |
4 | 0.33 (0.2 to 0.4) | 1 | 0.43 (0.3 to 0.5) | 1.3 | 0.28 (0.1 to 0.9) | 0.8 | 0.39 (0.2 to 0.5) | 1.2 |
5 | 0.30 (0.2 to .04) | 1 | 0.29 (0.2 to 0.4) | 1.0 | 0.14 (.02 to 1.0) | 0.4 | 0.24 (0.1 to 0.4) | 0.8 |
6 | 0.23 (0.1 to 0.3) | 1 | 0.26 (0.2 to 0.5) | 1.1 | 0.62 (0.2 to 1.7) | 2.6 | 0.17 (.06 to 0.3) | 0.7 |
7 | 0.23 (0.1 to 0.3) | 1 | 0.31 (0.2 to 0.6) | 1.4 | NA | NA | 0.11 (.04 to 0.3) | 0.5 |
8 | 0.17 (0.1 to 0.2) | 1 | 0.35 (0.2 to 0.7) | 2.0 | NA | NA | 0.11 (.04 to 0.3) | 0.6 |
9 | 0.15 (0.1 to 0.3) | 1 | 0.38 (0.2 to 0.7) | 2.5 | NA | NA | 0.10 (.03 to 0.3) | 0.7 |
10 | 0.19 (0.1 to 0.4) | 1 | 0.28 (0.1 to 0.6) | 1.5 | NA | NA | 0.16 (.06 to 0.4) | 0.8 |
Variable | HR | 95% CI |
P
b
|
---|---|---|---|
Tumor size, cm | |||
<2 | 1.0 | ||
2 to 5 | 1.6 | 1.2 to 2.1 | 0.0003 |
>5 | 2.0 | 1.2 to 3.2 | 0.005 |
Lymph nodes | |||
0 | 1.0 | ||
1 to 3 | 1.4 | 1.0 to 1.8 | 0.01 |
≥4 | 2.8 | 2.1 to 3.7 | <0.0001 |
Local therapy | |||
Mastectomy alone | 1.0 | ||
Mastectomy + RT | 1.1 | 0.8 to 1.5 | 0.6 |
Lumpectomy alone | 1.2 | 0.7 to 2.1 | 0.5 |
Lumpectomy + RT | 0.6 | 0.5 to 0.8 | 0.0009 |
Hormonotherapy | |||
Yes | 1.0 | ||
No | 0.7 | 0.5 to 0.9 | 0.01 |
Subtype | |||
Luminal A | 1.0 | ||
Luminal B | 1.4 | 1.1 to 1.7 | 0.02 |
Luminal HER2 | 1.4 | 0.8 to 2.2 | 0.2 |
HER2-enriched | 1.5 | 0.9 to 2.2 | 0.08 |
Basal-like | 1.2 | 0.8 to 1.8 | 0.3 |
TNP nonbasal | 1.6 | 0.9 to 2.6 | 0.06 |
Years after surgery | Luminal A hazard rateb | HR | Luminal B hazard rate | HR | Luminal HER2 hazard rate | HR | HER2-enriched hazard rate | HR | Basal-like hazard rate | HR | TNP nonbasal hazard rate | HR |
---|---|---|---|---|---|---|---|---|---|---|---|---|
2 | 0.24 (0.2 to 0.3) | 1 | 0.50 (0.4 to 0.6) | 2.05 | 0.56 (0.3 to 0.9) | 2.30 | 1.83 (1.1 to 3.1) | 7.53 | 0.84 (0.6 to 1.2) | 3.46 | 0.60 (0.3 to 1.1) | 2.46 |
3 | 0.32 (0.2 to 0.4) | 1 | 0.54 (0.4 to 0.6) | 1.68 | 0.46 (0.2 to 0.8) | 1.43 | 0.45 (0.1 to 1.4) | 1.41 | 0.58 (0.4 to 0.8) | 1.83 | 0.66 (0.4 to 1.1) | 2.06 |
4 | 0.33 (0.2 to 0.4) | 1 | 0.43 (0.3 to 0.5) | 1.32 | 0.27 (0.1 to 0.5) | 0.82 | 0.41 (0.1 to 1.6) | 1.27 | 0.29 (0.2 to 0.5) | 0.90 | 0.60 (0.3 to 1.1) | 1.84 |
5 | 0.29 (0.2 to 0.3) | 1 | 0.29 (0.2 to 0.4) | 1.00 | 0.20 (0.07 to 0.5) | 0.68 | 0.32 (0.06 to 1.6) | 1.09 | 0.14 (0.05 to 0.3) | 0.47 | 0.51 (0.3 to 1.0) | 1.75 |
6 | 0.26 (0.1 to 0.3) | 1 | 0.26 (0.1 to 0.4) | 1.02 | 0.19 (0.05 to 0.6) | 0.72 | 0.55 (0.1 to 2.2) | 2.12 | 0.08 (0.03 to 0.2) | 0.29 | 0.39 (0.2 to 0.9) | 1.51 |
7 | 0.21 (0.1 to 0.3) | 1 | 0.31 (0.2 to 0.5) | 1.43 | 0.13 (0.03 to 0.5) | 0.59 | NA | NA | 0.05 (0.01 to 0.3) | 0.24 | 0.25 (0.08 to 0.8) | 1.16 |
8 | 0.18 (0.1 to 0.2) | 1 | 0.35 (0.2 to 0.6) | 1.95 | 0.01 (0.00 to 0.04) | 0.06 | NA | NA | 0.09 (0.02 to 0.3) | 0.49 | 0.15 (0.04 to 0.6) | 0.86 |
9 | 0.16 (0.1 to 0.3) | 1 | 0.38 (0.2 to 0.7) | 2.33 | NA | NA | NA | NA | 0.14 (0.04 to 0.4) | 0.84 | 0.05 (0.01 to 0.2) | 0.30 |
10 | 0.21 (0.1 to 0.3) | 1 | 0.28 (0.1 to 0.6) | 1.33 | NA | NA | NA | NA | 0.21 (0.08 to 0.6) | 1.00 | NA | NA |