Tumour-infiltrating lymphocytes (TILs) are predictive for response
to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC)
and HER2-positive breast cancer, but their role in luminal breast
cancer and the effect of TILs on prognosis in all subtypes is less
clear. Here, we assessed the relevance of TILs for chemotherapy
response and prognosis in patients with TNBC, HER2-positive breast
cancer, and luminal-HER2-negative breast cancer.
Patients with primary breast cancer who were treated with
neoadjuvant combination chemotherapy were included from six
randomised trials done by the German Breast Cancer Group.
Pretherapeutic core biopsies from 3771 patients included in these
studies were assessed for the number of stromal TILs by standardised
methods according to the guidelines of the International TIL working
group. TILs were analysed both as a continuous parameter and in
three predefined groups of low (0-10% immune cells in stromal tissue
within the tumour), intermediate (11-59%), and high TILs (≥60%).
We used these data in univariable and multivariable statistical
models to assess the association between TIL concentration and
pathological complete response in all patients, and between the
amount of TILs and disease-free survival and overall survival in
2560 patients from five of the six clinical trial cohorts.
In the luminal-HER2-negative breast cancer subtype, a pathological
complete response (pCR) was achieved in 45 (6%) of 759 patients with
low TILs, 48 (11%) of 435 with intermediate TILs, and 49 (28%) of
172 with high TILs. In the HER2-positive subtype, pCR was observed
in 194 (32%) of 605 patients with low TILs, 198 (39%) of 512 with
intermediate TILs, and 127 (48%) of 262 with high TILs. Finally, in
the TNBC subtype, pCR was achieved in 80 (31%) of 260 patients with
low TILs, 117 (31%) of 373 with intermediate TILs, and 136 (50%) of
273 with high TILs (p<0·0001 for each subtype, χ test
for trend). In the univariable analysis, a 10% increase in TILs was
associated with longer disease-free survival in TNBC (hazard ratio
[HR] 0·93 [95% CI 0·87-0·98], p=0·011)
and HER2-positive breast cancer (0·94
[0·89-0·99], p=0·017), but not in
luminal-HER2-negative tumours (1·02
[0·96-1·09], p=0·46). The increase in TILs was
also associated with longer overall survival in TNBC (0·92
[0·86-0·99], p=0·032), but had no association
in HER2-positive breast cancer (0·94
[0·86-1·02], p=0·11), and was associated with
shorter overall survival in luminal-HER2-negative tumours
(1·10 [1·02-1·19], p=0·011).
Increased TIL concentration predicted response to neoadjuvant
chemotherapy in all molecular subtypes assessed, and was also
associated with a survival benefit in HER2-positive breast cancer
and TNBC. By contrast, increased TILs were an adverse prognostic
factor for survival in luminal-HER2-negative breast cancer,
suggesting a different biology of the immunological infiltrate in
this subtype. Our data support the hypothesis that breast cancer is
immunogenic and might be targetable by immune-modulating therapies.
In light of the results in luminal breast cancer, further research
investigating the interaction of the immune system with different
types of endocrine therapy is warranted.
Deutsche Krebshilfe and European Commission.
Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner B I,
Weber K E, Budczies J, Huober J, Klauschen F, Furlanetto J, Schmitt
W D, Blohmer J U, Karn T, Pfitzner B M, Kümmel S, Engels K,
Schneeweiss A, Hartmann A, Noske A, Fasching P A, Jackisch C, van
Mackelenbergh M, Sinn P, Schem C, Hanusch C, Untch M, Loibl S.
Tumour-infiltrating lymphocytes and prognosis in different subtypes
of breast cancer: a pooled analysis of 3771 patients treated with
neoadjuvant therapy. Lancet Oncol 2017; 19:40-50.