Background
Methods
Study cohort and design
Variables and outcome measures
Statistical analyses
Bioinformatic analyses of TCGA-BRCA and METABRIC data
Results
Analysis of ABCCG cohort
Total (%) | Hormone receptor-positive (%) | Hormone receptor-negative (%) | |||||||
---|---|---|---|---|---|---|---|---|---|
HER2-zero (n = 16,020) | HER2low (n = 12,260) | P | HER2-zero (n = 12,712) | HER2-low (n = 10,791) | P | HER2-zero (n = 3272) | HER2-low (n = 1362) | P | |
Age at diagnosis, years | |||||||||
Below 35 | 787 (4.9) | 541 (4.4) | 0.071 | 528 (4.2) | 455 (4.2) | 0.014 | 256 (7.8) | 77 (5.7) | < 0.001 |
35–49 | 7448 (46.5) | 5798 (47.3) | 6131 (48.2) | 5244 (48.6) | 1291 (39.5) | 466 (34.2) | |||
50–64 | 5639 (35.2) | 4357 (35.5) | 4319 (34.0) | 3768 (34.9) | 1315 (40.2) | 581 (42.7) | |||
65 and over | 2146 (13.4) | 1564 (12.8) | 1734 (13.6) | 1324 (12.3) | 410 (12.5) | 238 (17.5) | |||
Ethnicity | |||||||||
Chinese | 5203 (32.5) | 4674 (38.1) | < 0.001 | 4344 (34.2) | 4183 (38.8) | < 0.001 | 853 (26.1) | 483 (35.5) | < 0.001 |
Malay | 374 (2.3) | 220 (1.8) | 301 (2.4) | 194 (1.8) | 73 (2.2) | 26 (1.9) | |||
Indian | 253 (1.6) | 149 (1.2) | 191 (1.5) | 123 (1.1) | 62 (1.9) | 26 (1.9) | |||
Korean | 6873 (42.9) | 5363 (43.7) | 5245 (41.3) | 4739 (43.9) | 1622 (49.6) | 613 (45.0) | |||
Japanese | 3182 (19.9) | 1782 (14.5) | 2516 (19.8) | 1488 (13.8) | 642 (19.6) | 206 (15.1) | |||
Others | 135 (0.8) | 72 (0.6) | 115 (0.9) | 64 (0.6) | 20 (0.6) | 8 (0.6) | |||
Year of diagnosis | |||||||||
2000–2005 | 2171 (13.6) | 906 (7.4) | < 0.001 | 1697 (13.4) | 714 (6.6) | < 0.001 | 466 (14.2) | 172 (12.6) | 0.002 |
2006–2010 | 6501 (40.6) | 3835 (31.3) | 5069 (39.9) | 3286 (30.5) | 1421 (43.4) | 538 (39.5) | |||
2011–2015 | 7348 (45.9) | 7519 (61.3) | 5946 (46.8) | 6791 (62.9) | 1385 (42.3) | 652 (47.9) | |||
Histology | |||||||||
IDCa | 14,090 (88.0) | 11,043 (90.1) | < 0.001 | 11,019 (86.7) | 9665 (89.6) | < 0.001 | 3040 (92.9) | 1277 (93.8) | 0.323 |
ILCa | 895 (5.6) | 688 (5.6) | 821 (6.5) | 654 (6.1) | 72 (2.2) | 32 (2.4) | |||
Others | 1035 (6.5) | 529 (4.3) | 872 (6.9) | 472 (4.4) | 160 (4.9) | 53 (3.9) | |||
T-stage | |||||||||
T1 | 8828 (55.1) | 6815 (55.6) | 0.003 | 7413 (58.3) | 6112 (56.6) | 0.002 | 1392 (42.5) | 635 (46.6) | 0.100 |
T2 | 6011 (37.5) | 4629 (37.8) | 4472 (35.2) | 4008 (37.1) | 1528 (46.7) | 594 (43.6) | |||
T3 | 719 (4.5) | 557 (4.5) | 528 (4.2) | 478 (4.4) | 189 (5.8) | 75 (5.5) | |||
T4 | 309 (1.9) | 167 (1.4) | 209 (1.6) | 131 (1.2) | 100 (3.1) | 30 (2.2) | |||
Othersb | 103 (0.6) | 58 (0.5) | 46 (0.4) | 30 (0.3) | 57 (1.7) | 27 (2.0) | |||
Unknown | 50 (0.3) | 34 (0.3) | 44 (0.4) | 32 (0.3) | 6 (0.2) | 1 (0.1) | |||
N-stage | |||||||||
N0 | 10,412 (65.0) | 7679 (62.6) | 0.001 | 8199 (64.5) | 6754 (62.6) | 0.042 | 2191 (67.0) | 855 (62.8) | 0.005 |
N1 | 3865 (24.1) | 3101 (25.3) | 3118 (24.5) | 2760 (25.6) | 735 (22.5) | 319 (23.4) | |||
N2 | 1081 (6.8) | 920 (7.5) | 887 (7.0) | 810 (7.5) | 194 (5.9) | 102 (7.5) | |||
N3 | 647 (4.0) | 543 (4.4) | 494 (3.9) | 453 (4.2) | 151 (4.6) | 83 (6.1) | |||
NX | 15 (0.1) | 17 (0.1) | 14 (0.1) | 14 (0.1) | 1 (0.0) | 3 (0.2) | |||
Overall stage | |||||||||
Stage 1 | 6782 (42.3) | 5217 (42.6) | 0.159 | 5732 (45.1) | 4712 (43.7) | 0.050 | 1034 (31.6) | 452 (33.2) | 0.033 |
Stage 2 | 6881 (43.0) | 5154 (42.0) | 5206 (41.0) | 4485 (41.6) | 1657 (50.6) | 636 (46.7) | |||
Stage 3 | 2357 (14.7) | 1889 (15.4) | 1774 (14.0) | 1594 (14.8) | 581 (17.8) | 274 (20.1) | |||
ER receptor status | |||||||||
Positive | 12,338 (77.0) | 10,578 (86.3) | < .0001 | 12,338 (97.1) | 10,578 (98.0) | < 0.001 | 0 (–) | 0 (–) | - |
Negative | 3643 (22.7) | 1574 (12.8) | 371 (2.9) | 210 (2.0) | 3272 (100) | 1362 (100) | |||
Unknownc | 39 (0.2) | 108 (0.9) | 3 (0.0) | 3 (0.0) | 0 (–) | 0 (–) | |||
PR receptor status | |||||||||
Positive | 10,832 (67.6) | 9296 (75.8) | < 0.001 | 10,832 (85.2) | 9296 (86.2) | 0.050 | 0 (–) | 0 (–) | – |
Negative | 5136 (32.1) | 2853 (23.3) | 1864 (14.7) | 1488 (13.8) | 3272 (100) | 1362 (100) | |||
Unknownb | 52 (0.3) | 111 (0.9) | 16 (0.1) | 7 (0.1) | 0 (–) | 0 (–) | |||
Tumour grade | |||||||||
Grade 1 | 3586 (22.4) | 2745 (22.4) | < 0.001 | 3471 (27.3) | 2657 (24.6) | < 0.001 | 104 (3.2) | 47 (3.5) | 0.028 |
Grade 2 | 6544 (40.9) | 5601 (45.7) | 5882 (46.3) | 5277 (48.9) | 648 (19.8) | 291 (21.4) | |||
Grade 3 | 4879 (30.5) | 3219 (26.3) | 2552 (20.1) | 2296 (21.3) | 2321 (70.9) | 914 (67.1) | |||
Unknown | 1011 (6.3) | 695 (5.7) | 807 (6.4) | 561 (5.2) | 199 (6.1) | 110 (8.1) | |||
Received radiotherapyd | |||||||||
Applicable—no | 2487 (15.5) | 1957 (16.0) | < 0.001 | 2045 (16.1) | 1742 (16.1) | < 0.001 | 432 (13.2) | 189 (13.9) | 0.267 |
Applicable—yes | 6302 (39.3) | 4114 (33.6) | 5015 (39.5) | 3583 (33.2) | 1272 (38.9) | 495 (36.3) | |||
Not applicable | 7231 (45.1) | 6189 (50.5) | 5652 (44.5) | 5466 (50.7) | 1568 (47.9) | 678 (49.8) | |||
Received endocrine therapyc,d | |||||||||
Applicable—no | 1214 (7.6) | 978 (8.0) | < 0.001 | 1214 (9.6) | 978 (9.1) | 0.208 | 0 (–) | 0 (–) | – |
Applicable—yes | 11,498 (71.8) | 9813 (80.0) | 11,498 (90.5) | 9813 (90.9) | 0 (–) | 0 (–) | |||
Not applicable | 3272 (20.4) | 1362 (11.1) | 0 (–) | 0 (–) | 3272 (100) | 1362 (100) | |||
Unknown | 36 (0.2) | 107 (0.9) | 0 (–) | 0 (–) | 0 (–) | 0 (–) | |||
Received chemotherapyc,d | |||||||||
Applicable—no | 2065 (12.9) | 1624 (13.3) | 0.677 | 1760 (13.9) | 1446 (13.4) | 0.003 | 296 (9.1) | 154 (11.3) | 0.048 |
Applicable—yes | 7507 (46.9) | 5744 (46.9) | 5455 (42.9) | 4879 (45.2) | 2041 (62.4) | 836 (61.4) | |||
Not applicable | 5695 (35.6) | 4297 (35.1) | 4925 (38.7) | 3959 (36.7) | 756 (23.1) | 287 (21.1) | |||
Unknown | 753 (4.7) | 595 (4.9) | 572 (4.5) | 507 (4.7) | 179 (5.5) | 85 (6.2) |
Centre-adjusted | Multivariable-adjusteda | |||||
---|---|---|---|---|---|---|
Hazard ratio (95% CI) | P | P(int) | Hazard ratio (95% CI) | P | P(int) | |
Relapse-free survival | ||||||
Overall: HER2-low vs HER2-zero | 0.88 (0.82–0.93) | < 0.001 | – | 0.90 (0.85–0.96) | 0.002 | – |
Hormone receptor-positive: HER2-low vs HER2-zero | 0.92 (0.86–0.99) | 0.022 | 0.973 | 0.90 (0.84–0.97) | 0.004 | 0.715 |
Hormone receptor-negative: HER2-low vs HER2-zero | 0.92 (0.81–1.05) | 0.226 | 0.92 (0.81–1.05) | 0.244 | ||
Overall: HER2 IHC1+ vs HER2-zero | 0.85 (0.79–0.91) | < 0.001 | – | 0.89 (0.83–0.96) | 0.001 | – |
Overall: HER2 IHC2+ ISH− vs HER2-zero | 0.96 (0.87–1.06) | 0.421 | 0.94 (0.85–1.05) | 0.280 | ||
Hormone receptor-positive: HER2 IHC1+ vs HER2-zero | 0.89 (0.82–0.96) | 0.004 | 0.962 | 0.89 (0.82–0.96) | 0.003 | 0.934 |
Hormone receptor-positive: HER2 IHC2+ ISH− vs HER2-zero | 1.01 (0.90–1.13) | 0.898 | 0.94 (0.83–1.05) | 0.280 | ||
Hormone receptor-negative: HER2 IHC1+ vs HER2-zero | 0.88 (0.76–1.03) | 0.107 | 0.91 (0.78–1.05) | 0.206 | ||
Hormone receptor-negative: HER2 IHC2+ ISH− vs HER2-zero | 1.04 (0.83–1.30) | 0.735 | 0.97 (0.78–1.22) | 0.807 | ||
Overall survival | ||||||
Overall: HER2-low vs HER2-zero | 0.82 (0.76–0.89) | < 0.001 | – | 0.86 (0.79–0.93) | < 0.001 | – |
Hormone receptor-positive: HER2-low vs HER2-zero | 0.89 (0.81–0.97) | 0.012 | 0.401 | 0.87 (0.79–0.96) | 0.004 | 0.538 |
Hormone receptor-negative: HER2-low vs HER2-zero | 0.82 (0.69–0.96) | 0.017 | 0.82 (0.70–0.97) | 0.018 | ||
Overall: HER2 IHC1+ vs HER2-zero | 0.79 (0.73–0.87) | < 0.001 | – | 0.85 (0.78–0.93) | 0.001 | – |
Overall: HER2 IHC2+ ISH− vs HER2-zero | 0.91 (0.79–1.04) | 0.148 | 0.88 (0.76–1.01) | 0.062 | ||
Hormone receptor-positive: HER2 IHC1+ vs HER2-zero | 0.86 (0.78–0.96) | 0.005 | 0.627 | 0.86 (0.78–0.95) | 0.004 | 0.811 |
Hormone receptor-positive: HER2 IHC2+ ISH− vs HER2-zero | 0.96 (0.82–1.12) | 0.632 | 0.89 (0.76–1.05) | 0.171 | ||
Hormone receptor-negative: HER2 IHC1+ vs HER2-zero | 0.78 (0.65–0.94) | 0.009 | 0.82 (0.68–0.99) | 0.035 | ||
Hormone receptor-negative: HER2 IHC2+ ISH− vs HER2-zero | 0.94 (0.71–1.24) | 0.654 | 0.83 (0.62–1.09) | 0.178 |