PMID- 27372069
OWN - NLM
STAT- MEDLINE
DCOM- 20171117
LR  - 20210102
IS  - 1573-7217 (Electronic)
IS  - 0167-6806 (Print)
IS  - 0167-6806 (Linking)
VI  - 158
IP  - 2
DP  - 2016 Jul
TI  - Tumor-infiltrating lymphocytes (TILs) are a powerful prognostic marker in 
      patients with triple-negative breast cancer enrolled in the IBCSG phase III 
      randomized clinical trial 22-00.
PG  - 323-31
LID - 10.1007/s10549-016-3863-3 [doi]
AB  - The purpose of this study was to assess the prognostic and predictive value of 
      tumor-infiltrating lymphocytes (TILs) in the triple-negative breast cancer (TNBC) 
      cohort of the phase III IBCSG trial 22-00, comparing low-dose oral 'metronomic' 
      cyclophosphamide-methotrexate maintenance chemotherapy (CM-maintenance) to 
      no-CM-maintenance in early breast cancer. TILs were evaluated in full-face 
      hematoxylin-and-eosin-stained sections of tumor samples confirmed centrally as 
      TNBC (< 1 % of ER and PgR immunoreactivity and absence of HER2 overexpression or 
      amplification). Mononuclear cells were evaluated in the stromal area within the 
      borders of the invasive tumor. The primary endpoint was breast cancer-free 
      interval (BCFI). Cox proportional hazards regression model assessed the 
      association of BCFI and secondary endpoints with TILs score. In the 647 tumor 
      samples, the median percentage of TILs was 18 % (IQR = 8-40 %), with 18 % having 
      TILs >/= 50 % (lymphocyte-predominant breast cancer, LPBC). At a median follow-up 
      of 6.9 years, TILs were associated with better prognosis. For every 10 % increase 
      of TILs, BCFI risk reduction was 13 % (HR 0.87, 95 % CI 0.79-0.95,P = 0.003). 
      DFS, DRFI, and OS risk reductions were 11 % (P = 0.005), 16 % (P = 0.003), and 
      17 % (P < 0.001), respectively. Multivariable analysis confirmed the independent 
      prognostic value of TILs. No significant TILs-by-treatment interaction was 
      observed (P = 0.39) for associations of TILs with BCFI, although patients with 
      LPBC receiving CM-maintenance had a greater breast cancer risk reduction (HR 
      0.64,95 % CI 0.23-1.78) than those with non-LPBC (TILs < 50 %) (HR 0.96, 95 % CI 
      0.67-1.40). TILs score is a potent prognostic factor in patients with TNBC. 
      Low-dose chemotherapy confers a greater (not statistically significant) clinical 
      benefit in patients with LPBC.
FAU - Pruneri, Giancarlo
AU  - Pruneri G
AD  - IBCSG Central Pathology Laboratory, Department of Pathology and Laboratory 
      Medicine, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy. 
      giancarlo.pruneri@ieo.it.
AD  - University of Milan, Milan, Italy. giancarlo.pruneri@ieo.it.
FAU - Gray, Kathryn P
AU  - Gray KP
AD  - International Breast Cancer Study Group (IBCSG) Statistical Center, Boston, MA, 
      USA.
AD  - Harvard T. H. Chan School of Public Health, Boston, MA, USA.
FAU - Vingiani, Andrea
AU  - Vingiani A
AD  - IBCSG Central Pathology Laboratory, Department of Pathology and Laboratory 
      Medicine, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
AD  - University of Milan, Milan, Italy.
FAU - Viale, Giuseppe
AU  - Viale G
AD  - IBCSG Central Pathology Laboratory, Department of Pathology and Laboratory 
      Medicine, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
AD  - University of Milan, Milan, Italy.
FAU - Curigliano, Giuseppe
AU  - Curigliano G
AD  - Division of Experimental Therapeutics, European Institute of Oncology, Via 
      Ripamonti 435, 20141, Milan, Italy.
FAU - Criscitiello, Carmen
AU  - Criscitiello C
AD  - Division of Experimental Therapeutics, European Institute of Oncology, Via 
      Ripamonti 435, 20141, Milan, Italy.
FAU - Lang, Istvan
AU  - Lang I
AD  - National Institute of Oncology, Rath Gyorgy u. 7/9, Budapest, 1122, Hungary.
FAU - Ruhstaller, Thomas
AU  - Ruhstaller T
AD  - Breast Center St. Gallen, Kantonsspital, St. Gallen, Switzerland.
AD  - Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland.
FAU - Gianni, Lorenzo
AU  - Gianni L
AD  - Divisione di Oncologia, Ospedale degli Infermi, Viale Settembrini 2, 47923, 
      Rimini, Italy.
FAU - Goldhirsch, Aron
AU  - Goldhirsch A
AD  - Program for Breast Health, European Institute of Oncology, Via Ripamonti 435, 
      20141, Milan, Italy.
FAU - Kammler, Roswitha
AU  - Kammler R
AD  - International Breast Cancer Study Group, Translational Research Coordination and 
      Central Pathology Office, IBCSG Coordinating Center, Effingerstrasse 40, 3008, 
      Bern, Switzerland.
FAU - Price, Karen N
AU  - Price KN
AD  - International Breast Cancer Study Group (IBCSG) Statistical Center, Boston, MA, 
      USA.
AD  - Frontier Science and Technology Research Foundation, Boston, MA, USA.
FAU - Cancello, Giuseppe
AU  - Cancello G
AD  - Division of Medical Senology, European Institute of Oncology, Via Ripamonti 435, 
      20141, Milan, Italy.
FAU - Munzone, Elisabetta
AU  - Munzone E
AD  - Division of Medical Senology, European Institute of Oncology, Via Ripamonti 435, 
      20141, Milan, Italy.
FAU - Gelber, Richard D
AU  - Gelber RD
AD  - Department of Biostatistics and Computational Biology, Dana-Farber Cancer 
      Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.
AD  - International Breast Cancer Study Group (IBCSG) Statistical Center, Boston, MA, 
      USA.
AD  - Harvard T. H. Chan School of Public Health, Boston, MA, USA.
AD  - Frontier Science and Technology Research Foundation, Boston, MA, USA.
AD  - Harvard Medical School, Boston, MA, USA.
FAU - Regan, Meredith M
AU  - Regan MM
AD  - Department of Biostatistics and Computational Biology, Dana-Farber Cancer 
      Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.
AD  - International Breast Cancer Study Group (IBCSG) Statistical Center, Boston, MA, 
      USA.
AD  - Harvard Medical School, Boston, MA, USA.
FAU - Colleoni, Marco
AU  - Colleoni M
AD  - Division of Medical Senology, European Institute of Oncology, Via Ripamonti 435, 
      20141, Milan, Italy.
LA  - eng
GR  - U24 CA075362/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160702
PL  - Netherlands
TA  - Breast Cancer Res Treat
JT  - Breast cancer research and treatment
JID - 8111104
RN  - 8N3DW7272P (Cyclophosphamide)
RN  - YL5FZ2Y5U1 (Methotrexate)
SB  - IM
MH  - Administration, Metronomic
MH  - Adult
MH  - Aged
MH  - Cyclophosphamide/*administration & dosage/therapeutic use
MH  - Disease-Free Survival
MH  - Female
MH  - Humans
MH  - Lymphocytes, Tumor-Infiltrating/*pathology
MH  - Maintenance Chemotherapy
MH  - Methotrexate/*administration & dosage/therapeutic use
MH  - Middle Aged
MH  - Prognosis
MH  - Survival Analysis
MH  - Treatment Outcome
MH  - Triple Negative Breast Neoplasms/*drug therapy/pathology
PMC - PMC4977583
MID - NIHMS800248
OTO - NOTNLM
OT  - Breast cancer
OT  - Low-dose maintenance chemotherapy
OT  - Prognosis
OT  - Triple negative
OT  - Tumor-infiltrating lymphocytes
COIS- Conflict of Interest: The authors declare that they have no conflict of interest.
EDAT- 2016/07/04 06:00
MHDA- 2017/11/29 06:00
PMCR- 2017/07/02
CRDT- 2016/07/04 06:00
PHST- 2016/06/07 00:00 [received]
PHST- 2016/06/09 00:00 [accepted]
PHST- 2016/07/04 06:00 [entrez]
PHST- 2016/07/04 06:00 [pubmed]
PHST- 2017/11/29 06:00 [medline]
PHST- 2017/07/02 00:00 [pmc-release]
AID - 10.1007/s10549-016-3863-3 [pii]
AID - 10.1007/s10549-016-3863-3 [doi]
PST - ppublish
SO  - Breast Cancer Res Treat. 2016 Jul;158(2):323-31. doi: 10.1007/s10549-016-3863-3. 
      Epub 2016 Jul 2.