title: 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.
abstract: 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.
authors.affiliation: IBCSG Central Pathology Laboratory, Department of Pathology and Laboratory Medicine, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy. giancarlo.pruneri@ieo.it.|University of Milan, Milan, Italy. giancarlo.pruneri@ieo.it.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pruneri
authors.affiliation: International Breast Cancer Study Group (IBCSG) Statistical Center, Boston, MA, USA.|Harvard T. H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Gray
authors.affiliation: IBCSG Central Pathology Laboratory, Department of Pathology and Laboratory Medicine, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.|University of Milan, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vingiani
authors.affiliation: IBCSG Central Pathology Laboratory, Department of Pathology and Laboratory Medicine, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.|University of Milan, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.affiliation: Division of Experimental Therapeutics, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Curigliano
authors.affiliation: Division of Experimental Therapeutics, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Criscitiello
authors.affiliation: National Institute of Oncology, Ráth György u. 7/9, Budapest, 1122, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Láng
authors.affiliation: Breast Center St. Gallen, Kantonsspital, St. Gallen, Switzerland.|Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruhstaller
authors.affiliation: Divisione di Oncologia, Ospedale degli Infermi, Viale Settembrini 2, 47923, Rimini, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Gianni
authors.affiliation: Program for Breast Health, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
authors.affiliation: International Breast Cancer Study Group, Translational Research Coordination and Central Pathology Office, IBCSG Coordinating Center, Effingerstrasse 40, 3008, Bern, Switzerland.
authors.forename: Roswitha
authors.initials: R
authors.lastname: Kammler
authors.affiliation: International Breast Cancer Study Group (IBCSG) Statistical Center, Boston, MA, USA.|Frontier Science and Technology Research Foundation, Boston, MA, USA.
authors.forename: Karen N
authors.initials: KN
authors.lastname: Price
authors.affiliation: Division of Medical Senology, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cancello
authors.affiliation: Division of Medical Senology, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Munzone
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.|International Breast Cancer Study Group (IBCSG) Statistical Center, Boston, MA, USA.|Harvard T. H. Chan School of Public Health, Boston, MA, USA.|Frontier Science and Technology Research Foundation, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gelber
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.|International Breast Cancer Study Group (IBCSG) Statistical Center, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Meredith M
authors.initials: MM
authors.lastname: Regan
authors.affiliation: Division of Medical Senology, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Colleoni
mesh_terms: D059250:Administration, Metronomic; D000328:Adult; D000368:Aged; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology*; D060046:Maintenance Chemotherapy; D008727:Methotrexate / Q000008:administration & dosage* / Q000627:therapeutic use; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D003520:Cyclophosphamide; D008727:Methotrexate
keywords: Breast cancer; Low-dose maintenance chemotherapy; Prognosis; Triple negative; Tumor-infiltrating lymphocytes