Table 2. Extracted data from biomarker articles.
| IHC target | N | Positive cases | Primary antibody (dilution) | Reference group | Uni or Multivariate | Survival | HR | CI | P-value | |
|---|---|---|---|---|---|---|---|---|---|---|
|
Evasion of growth supressors | ||||||||||
| Evangelou et al, 2008 | Caspase-3 | 35 | NA | Cell signalling Bioline (1 : 100) | Labelling index | Univariate | DFS | <0.01a | 0.298–3.302a | 0.990 |
| Evangelou et al, 2008 | E2f-1 | 35 | 23 (66%) | Santa Cruz (1 : 100) | >35% cells labelling index | Univariate | DFS | 3.908 | 0.153–0.992a | 0.048 |
| Cavazzola et al, 2009 | p53 | 38 | 24 (52%) | Sigma Biosciences (1 : 100) | >10% | Multivariate | CSS | 1.429 | 0.429–4.725 | 0.514 |
| Moskaluk et al, 1996 | p53 | 88 | 40 (45%) | Novocastra (NA) | >50% | Univariate | OS | 1.46 | 0.87–2.46 | 0.155 |
| Madani et al, 2010 | p53 | 142 | 48 (34%) | Dako (1 : 50) | +2 to +8 | Univariate | OS | 1.64 | 1.1–2.45 | 0.014 |
|
Sustained Proliferative signalling | ||||||||||
| Langer et al, 2006 | EGFR | 137 | 72 (53%) | Cytomed (1 : 60) | >10% cells +ve. | Univariate | OS | 0.99 | 0.98–1.00a | 0.039 |
| Ong et al, 2013 | EGFR | 359 | 36 (10%) | Novocastra (1 : 10) | +2, +3 | Univariate | OS | 1.520 | 1.03–2.26 | 0.040 |
| Ong et al, 2013b | EGFR | 663 | NA | Novocastra (1 : 10) | +1 | Univariate | OS | 0.83 | 0.66–1.04 | .10 |
| 100 (15%) | +2 | 1.41 | .05–1.91 | 0.02 | ||||||
| +3 | 0.94 | 0.58–1.52 | 0.80 | |||||||
| Wang et al, 2007 | EGFR | 103 | 33 (32%) | Dako (NA) | >5% | Univariate | OS | 1.93 | 1.24–3.02 | 0.004 |
| Nakamura et al, 1994 | HER2 | 62 | 15 (19%) | Boehringer Mannheim Biochemica (NA) | +2 | Univariate | OS | 4.100 | 1.4–11.8 | 0.015 |
| Yoon et al, 2012 | HER2 | 708 | 119 (17%) | Herceptest (NA) | +2, +3 | Univariate | OS | 0.760 | 0.59–0.96 | 0.024 |
| Phillips et al, 2013 | HER2 | 135 | 31 (23%) | Ventana (NA) | +2, +3 | Multivariate | OS | 0.840 | 0.53–1.33 | 0.470 |
| Dutta et al, 2012 | Ki67 | 98 | NA | Dako (1 : 50) | Slidepath scoring algorithm. Tertiles. | Univariate | CSS | 1.460 | 1.01–2.12 | 0.048 |
| Evangelou et al, 2008 | Ki67 | 35 | NA | Dako (1 : 100) | <35% cells +ve, labelling index | Univariate | DFS | 3.757 | 0.986–11.68 | 0.050 |
| Falkenback et al, 2008 | Ki67 | 59 | 50 (85%) | Dako (1 : 1000) | 0–10% | Univariate | CSS | 3.900 | 1.7–9.1 | <0.001 |
| Tuynman et al, 2008 | MET | 145 | 78 (54%) | Zymed (1 : 100) | +2, +3 | Univariate | DFS | 2.300 | 1.3–4.1 | 0.004 |
| Prins et al, 2013 | p-mTOR | 147 | 29 (19.7%) | Cell Signalling Technology (1 : 50) | 2+, 3+ | Univariate | CSS | 1.648 | 1.019–2.664 | 0.042 |
| Ong et al, 2013 | PAPSS2 | 337 | 216 (64%) | Abcam (1 : 600) | +2, +3 | Univariate | OS | 1.240 | 0.96–1.61 | 0.100 |
| Schoppmann et al, 2012 | pSTAT3 | 179 | 72 (40%) | Cell Signalling Technology (1 : 100) | >10 (>median) | Univariate | OS | 1.982 | 1.186–3.311 | 0.050 |
| Bettstetter et al, 2013 | PTEN | 117 | 101 (86%) | Cell Signalling Technology (1 : 50) | >75% | Multivariate | OS | 0.451 | 0.233–0.873 | 0.018 |
|
Escape from immune surveillance | ||||||||||
| Loos et al, 2011 | B7-H1 | 101 | 74 (73%) | Abcam (NA) | >+4 (Intensity+proportion of cells) | Univariate | OS | 2.92 | 1.50–5.66 | <0.001 |
| Rauser et al, 2010 | CD3 | 99 | 57 (58%) | NeoMarkers (1 : 100) | >2.0 Labelling indices | Univariate | OS | 0.49 | 0.28–0.85 | 0.012 |
| Zingg et al, 2010 | CD3 central | 105 | NA | Dako (1 : 50) | >563 (>median count) | Univariate | OS | 0.53 | 0.33–0.84 | 0.008 |
| Zingg et al, 2010 | CD4 central | 105 | 58 (55%) | NeoMarkers (1 : 40) | >30 (>median count) | Univariate | OS | 0.74 | 0.47–1.16 | 0.187 |
| Zingg et al, 2010 | CD25 central | 105 | NA | NeoMarkers (1 : 10) | >33 (>median count) | Univariate | OS | 0.76 | 0.48–1.22 | 0.262 |
| Zingg et al, 2010 | CD8 central | 105 | 51 (49%) | Dako (1 : 50) | >225 (>median count) | Univariate | OS | 0.44 | 0.27–0.69 | <0.001 |
| Dutta et al, 2012 | CD8 tertiles | 98 | NA | Dako (1 : 100) | Slidepath scoring algorithm | Univariate | CSS | 0.69 | 0.48–0.99 | 0.048 |
| Rauser et al, 2010 | CD45RO | 110 | 93 (85%) | Dako (1 : 1200) | >0.9 Labelling indices | Univariate | DFS | 0.44 | 0.23–0.84 | 0.013 |
| Dutta et al, 2012 | CD68 | 98 | NA | Dako (1 : 200) | Slidepath scoring algorithm. Tertiles. | Univariate | CSS | 1.38 | 0.99–1.94 | 0.061 |
| Zingg et al, 2010 | FoxP3 central | 105 | 46 (43%) | eBioscience (1 : 50) | >117 (>median count) | Univariate | OS | 0.65 | 0.40–1.05 | 0.079 |
|
Deregulation of cellular energetics | ||||||||||
| Birner et al, 2011 | CAIX | 182 | 85 (47%) | Abcam (1 : 1000) | >median score (20 out of score 0–300) | Univariate | OS | 1.844 | 1.11–3.08 | 0.007 |
|
Tumour promoting inflammation | ||||||||||
| Wang et al, 2006 | ANXA1 | 104 | 41 (39%) | BD Biosciences (1 : 100) | >25% | Univariate | OS | 1.930 | 1.25–2.99 | 0.003 |
| Bhandari et al, 2006 | COX-2 | 90 | NA | Cayman Chemical (1 : 100) | >200 | Univariate | CSS | 3.530 | 2.11–5.89 | <0.001 |
| Buskens et al, 2002 | COX-2 | 145 | 115 (79%) | Cayman Chemical (1 : 200) | +2, +3 | Univariate | OS | 3.200 | 1.5–7.1 | 0.002 |
| Prins et al, 2012 | COX-2 | 147 | 39 (27%) | Cayman Chemical (1 : 100) | +3 | Univariate | OS | 1.700 | 1.07–2.69 | 0.023 |
| Tuynman et al, 2008 | COX-2 | 145 | 78 (54%) | Cayman Chemical (1 : 200) | +2, +3 | Univariate | DFS | 1.400 | 0.8–2.6 | 0.234 |
|
Evasion of apoptosis | ||||||||||
| Ong et al, 2013 | DCK | 355 | 126 (36%) | Lifespan Biosciences (1 : 10) | +2, +3 | Univariate | OS | 0.980 | 0.75–1.28 | 0.860 |
| Chandra et al, 2002 | GSTπ | 15 | 6 (40%) | Vector laboratories | 3+ | Univariate | DFS | 2.250 | 0.71–7.17 | 0.350 |
| Ong et al, 2013 | MTMR9 | 356 | 88 (25%) | Novus (1 : 350) | +2, +3 | Univariate | OS | 1.140 | 0.87–1.51 | 0.340 |
| Ong et al, 2013 | NEIL2 | 357 | 198 (55%) | Sigma-Aldrich (1 : 50) | +2, +3 | Univariate | OS | 1.120 | 0.87–1.43 | 0.390 |
| Ong et al, 2013 | SIRT2 | 359 | 156 (44%) | Atlas Antibodies (1 : 100) | +2, +3 | Univariate | OS | 1.310 | 1.03–1.67 | 0.030 |
| Ong et al, 2013b | SIRT2 | 663 | NA | Atlas Antibodies (1 : 100) | 2 | Univariate | OS | 1.69 | 1.10–2.60 | 0.02 |
| 290 (44) | 1 | 1.81 | 1.24–2.64 | <0.01 | ||||||
| 0 | 1.37 | 0.96–1.97 | 0.08 | |||||||
| Ong et al, 2013 | WT1 | 358 | 19 (5%) | Dako (1 : 800) | +2, +3 | Univariate | OS | 0.710 | 0.39–1.30 | 0.270 |
|
Inducing angiogenesis | ||||||||||
| Dutta et al, 2012 | CD34 | 98 | NA | Dako (1 : 150) | Slidepath scoring algorithm. Tertiles. | Univariate | CSS | 0.94 | 0.67–1.34 | 0.736 |
| Cavazzola et al, 2009 | VEGF | 38 | 22 (48%) | Santa Cruz (1 : 400) | >30% cells stained | Multivariate | CSS | 0.369 | 0.095–1.436 | 0.115 |
| Prins et al, 2012 | VEGF | 143 | 90 (63%) | R&D systems (1 : 50) | >+1 | Univariate | CSS | 1.900 | 1.22–2.96 | 0.005 |
| Xie et al, 2013 | VEGF-C | 128 | 96 (75%) | Santa Cruz (1 : 50) | >0.18 Mean optical density | Multivariate | DFS | 3.491 | 2.156–5.652 | <0.0001 |
|
Tissue invasion and metastasis | ||||||||||
| Hector et al, 2010 | AXL | 92 | 56 (61%) | R&D systems (1 : 100) | +3 | Multivariate | OS | 1.91 | 1.04–3.49 | 0.036 |
| Falkenback et al, 2008 | E-cadherin | 59 | 44 (75%) | Dako (1 : 100) | Absent/reduced | Univariate | CSS | 3.900 | 1.2–12.9 | 0.017 |
| Becker et al, 2010 | LgR5 | 24 | NA | MBL Internation Co (1 : 50) | >5 (Intensity+proportion) | Univariate | OS | 2.860 | 1.08–7.61 | 0.040 |
| von Rahden et al, 2011 | LgR5 | 60 | 51 (85%) | Abcam (NA) | >15% | Univariate | OS | 2.418 | 1.17–4.99 | 0.033 |
| Grimm et al, 2010 | MMP-1 | 60 | 33 (55%) | Hiddenhausen (NA) | >46% | Univariate | OS | 1.453 | 0.7101–2.9718 | 0.307 |
| Streppel et al, 2012 | Mucin 16 | 95 | 66 (70%) | Abcam (1 : 200) | Moderate/Diffuse | Univariate | NA | 1.410 | 0.734–2.709 | 0.303 |
| Wijnhoven et al, 2005 | p120 | 96 | 65 (67%) | Transduction laboratories (1 : 1000) | <90% | Multiivariate | OS | 2.100 | 1.1–4.2 | 0.006 |
| Schoppmann et al, 2013b | Podoplanin (lymphovascular invasion) | 194 | 81 (42%) | Ventana (NA) | Tumour cluster in podoplanin decorated space | Univariate | OS | 1.863 | 1.086–0.195a | <0.01 |
| Schoppmann et al, 2013a | Podoplanin (CAFs) | 200 | 118 (59%) | Venatana (1 : 300) | >10% CAFs | Univariate | OS | 1.843 | 1.097–3.096 | 0.001 |
| Birner et al, 2012 | RKIP | 179 | NA | Upstage/Millipore (1 : 1000) | >80 out of score 0–300 (>median score) | Multivariate | DFS | 0.494 | 0.278–0.878 | 0.016 |
| Ong et al, 2013 | TRIMM44 | 349 | 197 (56%) | Protein Tech group (1 : 50) | +2, +3 | Univariate | OS | 1.310 | 1.01–1.70 | 0.040 |
| Ong et al, 2013b | TRIMM44 | 655 | NA | Protein Tech group (1 : 50) | +1 | Univariate | OS | 1.46 | 0.89–2.44 | 0.4 |
| 442 (67%) | +2 | 1.59 | 0.96–2.63 | 0.07 | ||||||
| +3 | 1.94 | 1.09–3.44 | 0.02 | |||||||
| Laerum et al, 2012 | uPAR (Cancer cells) | 60 | 37 (62%) | Raised in-house | +2, +3, +4 | Univariate | OS | 2.020 | 1.11–3.66 | 0.021 |
| Laerum et al, 2012 | uPAR (Macrophages) | 60 | 57 (95%) | Raised in-house | +2, +3, +4 | Univariate | OS | 1.120 | 0.62–2.01 | 0.710 |
| Laerum et al, 2012 | uPAR (myofibroblasts) | 60 | 39 (65%) | Raised in-house | +2, +3, +4 | Univariate | OS | 1.600 | 0.86–2.99 | 0.140 |
Abbreviations: CI=confidence interval; CSS=cancer-specific survival; DFS=disease-free survival; IHC=immunohistochemical; HR=hazard ratio; OS=overall survival.
a
Values as documented in original articles. Incorrect values excluded from meta-analysis.
b
Validation cohorts from same study not used in meta-analysis due to differences in cut-offs.