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Evaluation of the prognostic and predictive value of tumor-infiltrating lymphocytes (TILs) in a phase III randomized adjuvant breast cancer (BC) trial (BIG 2-98) of node-positive (N+) BC comparing the addition of docetaxel to doxorubicin (A-T) with doxorubicin (A)-only chemotherapy (CT).

556 Background: Previous clinical and preclinical data suggest a contribution of the immune system to prognosis and response to anthracycline CT, however clinical utility is yet to be established in BC. We hypothesized that TILs would be associated with prognosis and would predict increased benefit from A-based over A-T CT regimens in the triple negative (TN) and HER2+BC.


METHODS
We investigated the relationship between percentage of TILs (both intratumoral and peristromal) at diagnosis in 2016 N+ BC samples from the BIG 2-98 adjuvant phase III trial and clinical outcome from A-based (AC-CMF;A-CMF) or combination A-T (AT-CMF; A-T-CMF) CT (Francis et al., 2008). TILs were independently evaluated by two pathologists. Disease-free and overall survival (DFS, OS) associations were studied in a multivariate Cox model adjusted for other prognostic markers. Median FU is 93.6 months.


RESULTS
Correlation between pathologists was 0.67, p<0.001. There was no significant prognostic association in ER+/HER2- disease or Luminal-A or B phenotypes (central Ki67< or ≥14%). As a continuous variable (per 10% increments) TILs were an independent marker of better survival in TN BC regardless of CT type (DFS HR 0.89 [95%CI:0.81-0.99], p=0.03). For those TN BC with ≥50% TILs (10.5% of TN) the 5-yr DFS was 89% vs. 62% (p=0.018, HR 0.29 [0.11-0.81]). However, in HER2+ BC, TILs were associated with a better outcome with A-based over A-T CT (continuous variable interaction p=0.056). Those HER2+ BCs with ≥50% TILs (11% of HER2+) had a 5-yr DFS of 79% with A-only CT vs. 47% with A-T (HR 0.45 [0.12-1.71] and those HER2+ BCs with <50% had a 5-yr DFS of 58% vs. 73% respectively (HR 2.05 [1.41-2.97], test for interaction p=0.032). OS results were similar.


CONCLUSIONS
The presence of TILs was associated with a better prognosis in N+ TN BC. However women with HER2+ BC and TILs at diagnosis had a significantly better outcome from A-alone based CT, compared with the addition of T. Evaluation of TILs should be considered in future clinical trials evaluating new therapies in TN and HER2+ BC.