Table 2.
Adjuvant studies evaluating TILs and prognosis
| Reference | Study | Manner of sample collection | Regimen | Assay | Marker | Type of TILs | Sample size | Correlation with clinical outcome (multivariate analysis)a |
|---|---|---|---|---|---|---|---|---|
| West et al. (2011) [44] | Single institute | Retrospective | CMF, AC, CEF, or CAF | TMA | CD3 | CD3-IHC alone | 255 for anthracyclines | CD3+ T cells: HR 0.24 for DFS (p = .016, univariate) |
| Mahmoud et al. (2011) [5] | Single institute | Retrospective | CMF | TMA | CD8 | Total TIL identified by CD8 | 1,334 | CD8+ total TIL: |
| HR 0.55 for BCSS in training set (p = .001) | ||||||||
| HR 0.58 for BCSS in validation set (p = .002) | ||||||||
| Liu et al. (2012) [24] | Single institute | Retrospective | MF, AC, FAC, or no CTx | TMA | CD8 | sTIL, iTIL, and total TIL | 497 TNBC | CD8+ iTIL: HR 0.48 for BCSS (p < .001) |
| Loi et al. (2013) [45] | BIG 02-98 | Prospective | A followed by CMF or AC followed by CMF | H&E | TILs | sTIL | 2,009 Total | None |
| iTIL | 256 TNBC | sTIL (continuous): HR 0.83 for OS (p = .023) | ||||||
| LPBC (binary ≥ 50%): HR 0.29 for OS (p= .036) | ||||||||
| Adams et al. (2014) [46] | ECOG2197 | Prospective | AC vs AC | H&E | TILs | sTIL | 481 TNBC | sTIL (continuous, per 10% increase): HR 0.79 for OS (p = .003) |
| ECOG1199 | AC followed by D or P | iTIL | ||||||
| Liu et al. (2014) [47] | FINHER | Prospective | D or V followed by FEC or FEC with trastuzuamb if HER2+ | H&E | TILs | sTIL | 934 Total | None |
| iTIL | 134 TNBC | sTIL (continuous): HR 0.77 for DDFS (p = .02) | ||||||
| 209 HER2+ | sTIL (continuous): HR 0.82 of DDRS (p = .025, univariate) only for trastuzumab arm | |||||||
| Ali et al. (2014) [48] | Four cohorts including NEAT trial | Retrospective | Various regimen | TMA | CD8 | sTIL and iTIL identified by CD8 | 12,439 | CD8+ iTIL: HR 0.72 for BCSS (p = .00003) |
| CD8+ sTIL: HR 0.79 for BCSS (p = .004) | ||||||||
| Liu et al. (2012) [24] | Single institute | Retrospective | MF, AC, FAC, or no CTx | TMA | CD8, FOXP3 | sTIL, iTIL, and total TIL | 88 ER–/HER2+with CD8+TIL–positive | FOXP3+ iTIL: HR 0.48 for BCSS (p = .047) |
| Schalper et al. (2014) [49] | Single institute | Retrospective | Various regimen | mRNA assay | PD-L1 mRNA TILs | Nonspecific TILs | 328 | Positive PD-L1 mRNA expression: HR 0.27 for RFS (p = .009) |
| H&E | ||||||||
| Perez et al. [50] (abstract only) | N9831 arm A and C | Prospective | AC followed by P or P with trastuzumab | H&E | TILs | sTIL | 489 Treated without trastuzumab | LPBC (binary ≥ 60%): HR 0.20 for RFS (p = .007) |
| 456 Treated with trastuzumab | LPBC (binary ≥ 60%): HR 1.1 for RFS (p = .87) |
TIL, tumor-infiltrating lymphocyte; CMF, cyclophosphamide, methotrexate, 5-flourouracil; AC, doxorubin/cyclophosphamide; CEF, Canadian cyclophosphamide, epirubicin, 5-flourouracil; CAF, cyclophosphamide, doxorubicin, 5-flourouracil; TMA, tissue microarray; IHC, immunohistochemistry; HR, hazard ratio; DFS, disease-free survival; BCSS, breast cancer specific survival; MF, methotrexate, 5-fluorouracil; FAC, 5-floururacil, doxorubin, cyclophosphamide; CTx, chemotherapy; sTIL, stromal tumor-infiltrating lymphocyte; iTIL, intratumoral tumor-infiltrating lymphocyte; TNBC, triple-negative breast cancer; H&E, hematoxylin and eosin; OS, overall survival; LPBC, lymphocyte predominant breast cancer; D, docetaxel; P, paclitaxel; V, vinorelbine; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; HER2, human epidermal growth factor receptor 2; DDFS, distant disease-free survival; DDRS, distant disease relapse-free survival; FOXP3, forkhead box P3 protein; ER, estrogen receptor; RFS, recurrence-free survival.