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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

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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.

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Acknowledgments

We thank the patients, physicians, nurses, and data managers who participated in the International Breast Cancer Study Group trials.

Author information

Authors and Affiliations

  1. IBCSG Central Pathology Laboratory, Department of Pathology and Laboratory Medicine, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy

    Giancarlo Pruneri, Andrea Vingiani & Giuseppe Viale

  2. University of Milan, Milan, Italy

    Giancarlo Pruneri, Andrea Vingiani & Giuseppe Viale

  3. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA

    Richard D. Gelber & Meredith M. Regan

  4. International Breast Cancer Study Group (IBCSG) Statistical Center, Boston, MA, USA

    Kathryn P. Gray, Karen N. Price, Richard D. Gelber & Meredith M. Regan

  5. Harvard T. H. Chan School of Public Health, Boston, MA, USA

    Kathryn P. Gray & Richard D. Gelber

  6. Division of Experimental Therapeutics, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy

    Giuseppe Curigliano & Carmen Criscitiello

  7. National Institute of Oncology, Ráth György u. 7/9, Budapest, 1122, Hungary

    István Láng

  8. Breast Center St. Gallen, Kantonsspital, St. Gallen, Switzerland

    Thomas Ruhstaller

  9. Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland

    Thomas Ruhstaller

  10. Divisione di Oncologia, Ospedale degli Infermi, Viale Settembrini 2, 47923, Rimini, Italy

    Lorenzo Gianni

  11. Program for Breast Health, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy

    Aron Goldhirsch

  12. International Breast Cancer Study Group, Translational Research Coordination and Central Pathology Office, IBCSG Coordinating Center, Effingerstrasse 40, 3008, Bern, Switzerland

    Roswitha Kammler

  13. Frontier Science and Technology Research Foundation, Boston, MA, USA

    Karen N. Price & Richard D. Gelber

  14. Division of Medical Senology, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy

    Giuseppe Cancello, Elisabetta Munzone & Marco Colleoni

  15. Harvard Medical School, Boston, MA, USA

    Richard D. Gelber & Meredith M. Regan

Authors
  1. Giancarlo Pruneri
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  2. Kathryn P. Gray
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  9. Lorenzo Gianni
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Corresponding author

Correspondence to Giancarlo Pruneri.

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Funding

This work was supported by the International Breast Cancer Study Group and participating centers. Support for central coordination, data management and statistics were provided by the Swedish Cancer League; The Cancer Council Australia; Australia & New Zealand Breast Cancer Trials Group; The Frontier Science and Technology Research Foundation; The Swiss Group for Clinical Cancer Research; the Swiss Cancer League/Oncosuisse; and the United States National Institutes of Health (CA-75362 to MMR).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Trial Registration

clinicaltrials.gov NCT00022516.

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Pruneri, G., Gray, K.P., Vingiani, A. et al. 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. Breast Cancer Res Treat 158, 323–331 (2016). https://doi.org/10.1007/s10549-016-3863-3

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  • DOI: https://doi.org/10.1007/s10549-016-3863-3

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