Tumor-infiltrating lymphocytes in triple negative breast cancer
DOI:
https://doi.org/10.14739/2310-1237.2020.3.221722Keywords:
triple negative breast cancer, tumor infiltrating lymphocytes, tumor microenvironment, prognosisAbstract
The aim of this retrospective study is to assess the prognostic value of tumor-infiltrating lymphocytes in triple negative breast carcinomas that lack both estrogen, progesterone receptors and Her2 amplification.
The group of triple negative carcinomas has worse survival rates than other molecular subgroups of breast cancer, but at the same time it is very heterogeneous, and therefore requires the search for additional prognostic factors to improve the prognosis of patients.
Materials and methods. The study included 350 samples of biopsies and surgical material from patients with stage I–III triple negative breast cancer who had not previously received chemotherapy. The median follow-up was 3.8 years for overall survival and 3.2 years for relapse-free survival. The prognostic value of tumor-infiltrating lymphocytes was evaluated by Kaplan–Meyer survival curves with a log-rank test, and one- and multifactor regression analysis according to the proportional risks Cox model.
Results. Kaplan–Meier survival curves showed statistically significant relationships between tumor-infiltrating lymphocytes and overall and recurrence-free survival with a general trend to improve data for tumors with high lymphocyte volume. Proportional risks Cox model showed that tumors with a high number of tumor-infiltrating lymphocytes have statistically significantly better overall and recurrence-free survival rates (compared with tumors with a low number of tumor-infiltrating lymphocytes). The Kappa coefficient for interobserver variability was 0.79. It indicates a high level of agreement between pathologists in the evaluation of histological material.
Conclusions. The high number of tumor-infiltrating lymphocytes in triple negative breast cancers is statistically significantly associated with better overall and recurrence-free survival rates. Assessment of tumor-infiltrating lymphocytes is rapid and does not require additional training, which makes this prognostic marker convenient to use.
References
Grybach, S. M., Polishchuk, L. Z., & Chekhun, V. F. (2018). Analysis of the survival of patients with breast cancer depending on age, molecular subtype of tumor and metabolic syndrome. Experimental oncology, 40(3), 243-248. https://doi.org/10.31768/2312-8852.2018.40(3):243-248
Gonçalves, H., Jr, Guerra, M. R., Duarte Cintra, J. R., Fayer, V. A., Brum, I. V., & Bustamante Teixeira, M. T. (2018). Survival Study of Triple-Negative and Non-Triple-Negative Breast Cancer in a Brazilian Cohort. Clinical Medicine Insights. Oncology, 12, 1179554918790563. https://doi.org/10.1177/1179554918790563
Tan, H. P., Ellis, I., Allison, K., Brogi, E., Fox, S. B., Lakhani, S., Lazar, A. J., Morris, E. A., Sahin, A., Salgado, R., Sapino, A., Sasano, H., Schnitt, S., Sotiriou, C., van Diest, P., White, V. A., Lokuhetty, D., Cree, I. A., & WHO Classification of Tumours Editorial Board (2020). The 2019 WHO classification of tumours of the breast. Histopathology, 10.1111/his.14091. Advance online publication. https://doi.org/10.1111/his.14091
Wahba, H. A., & El-Hadaad, H. A. (2015). Current approaches in treatment of triple-negative breast cancer. Cancer biology & medicine, 12(2), 106-116. https://doi.org/10.7497/j.issn.2095-3941.2015.0030
Denkert, C., von Minckwitz, G., Darb-Esfahani, S., Lederer, B., Heppner, B. I., Weber, K. E., … Loibl, S. (2018). Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. The Lancet. Oncology, 19(1), 40-50. https://doi.org/10.1016/S1470-2045(17)30904-X
García-Teijido, P., Cabal, M. L., Fernández, I. P., & Pérez, Y. F. (2016). Tumor-Infiltrating Lymphocytes in Triple Negative Breast Cancer: The Future of Immune Targeting. Clinical Medicine Insights. Oncology, 10(Suppl 1), 31-39. https://doi.org/10.4137/CMO.S34540
Yeong, J., Thike, A. A., Lim, J. C., Lee, B., Li, H., Wong, S. C., Hue, S. S., Tan, P. H., & Iqbal, J. (2017). Higher densities of Foxp3+ regulatory T cells are associated with better prognosis in triple-negative breast cancer. Breast cancer research and treatment, 163(1), 21-35. https://doi.org/10.1007/s10549-017-4161-4
Althobiti, M., Aleskandarany, M. A., Joseph, C., Toss, M., Mongan, N., Diez-Rodriguez, M., Nolan, C. C., Ashankyty, I., Ellis, I. O., Green, A. R., & Rakha, E. A. (2018). Heterogeneity of tumour-infiltrating lymphocytes in breast cancer and its prognostic significance. Histopathology, 73(6), 887-896. https://doi.org/10.1111/his.13695
Park, M. H., Kwon, S. Y., Choi, J. E., Gong, G., & Bae, Y. K. (2020). Intratumoral CD103-positive tumour-infiltrating lymphocytes are associated with favourable prognosis in patients with triple-negative breast cancer. Histopathology, 77(4), 560-569. https://doi.org/10.1111/his.14126
Angell, H. K., Bruni, D., Barrett, J. C., Herbst, R., & Galon, J. (2020). The Immunoscore: Colon Cancer and Beyond. Clinical cancer research, 26(2), 332-339. https://doi.org/10.1158/1078-0432.CCR-18-1851
Bibeau, F. (2016). Galon J., Mlecnik B., Marliot F., et al. (2016) Validation of the immunoscore (IM) as a prognostic marker in stage I/II/III colon cancer: Results of a worldwide consortium-based analysis of 1,336 patients. J. clin. oncol. 34(suppl): Abstr 3500. Colon and Rectum, 10(3), 197-199. https://doi.org/10.1007/s11725-016-0664-4
Greene, F. L., & Sobin, L. H. (2009). A worldwide approach to the TNM staging system: collaborative efforts of the AJCC and UICC. Journal of surgical oncology, 99(5), 269-272. https://doi.org/10.1002/jso.21237
Salgado, R., Denkert, C., Demaria, S., Sirtaine, N., Klauschen, F., Pruneri, G., Wienert, S., Van den Eynden, G., Baehner, F. L., Penault-Llorca, F., Perez, E. A., Thompson, E. A., Symmans, W. F., Richardson, A. L., Brock, J., Criscitiello, C., Bailey, H., Ignatiadis, M., Floris, G., Sparano, J., … International TILs Working Group 2014 (2015). The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Annals of oncology, 26(2), 259-271. https://doi.org/10.1093/annonc/mdu450
Kanda, Y. (2013). Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone marrow transplantation, 48(3), 452-458. https://doi.org/10.1038/bmt.2012.244
Soysal, S. D., Tzankov, A., & Muenst, S. E. (2015). Role of the Tumor Microenvironment in Breast Cancer. Pathobiology, 82(3-4), 142-152. https://doi.org/10.1159/000430499
Galvez, M., Castaneda, C. A., Sanchez, J., Castillo, M., Rebaza, L. P., Calderon, G., Cruz, M., Cotrina, J. M., Abugattas, J., Dunstan, J., Guerra, H., Mejia, O., & Gomez, H. L. (2018). Clinicopathological predictors of long-term benefit in breast cancer treated with neoadjuvant chemotherapy. World journal of clinical oncology, 9(2), 33-41. https://doi.org/10.5306/wjco.v9.i2.33
Hida, A. I., Sagara, Y., Yotsumoto, D., Kanemitsu, S., Kawano, J., Baba, S., Rai, Y., Oshiro, Y., Aogi, K., Sagara, Y., & Ohi, Y. (2016). Prognostic and predictive impacts of tumor-infiltrating lymphocytes differ between Triple-negative and HER2-positive breast cancers treated with standard systemic therapies. Breast cancer research and treatment, 158(1), 1-9. https://doi.org/10.1007/s10549-016-3848-2
Ohtani, H., Mori-Shiraishi, K., Nakajima, M., & Ueki, H. (2015). Defining lymphocyte-predominant breast cancer by the proportion of lymphocyte-rich stroma and its significance in routine histopathological diagnosis. Pathology international, 65(12), 644-651. https://doi.org/10.1111/pin.12355
Pagès, F., Mlecnik, B., Marliot, F., Bindea, G., Ou, F. S., Bifulco, C., Lugli, A., Zlobec, I., Rau, T. T., Berger, M. D., Nagtegaal, I. D., Vink-Börger, E., Hartmann, A., Geppert, C., Kolwelter, J., Merkel, S., Grützmann, R., Van den Eynde, M., Jouret-Mourin, A., Kartheuser, A., … Galon, J. (2018). International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet, 391(10135), 2128-2139. https://doi.org/10.1016/S0140-6736(18)30789-X
Nederlof, I., De Bortoli, D., Bareche, Y., Nguyen, B., de Maaker, M., Hooijer, G., Buisseret, L., Kok, M., Smid, M., Van den Eynden, G., Brinkman, A. B., Hudecek, J., Koster, J., Sotiriou, C., Larsimont, D., Martens, J., van de Vijver, M. J., Horlings, H. M., Salgado, R., Biganzoli, E., … Desmedt, C. (2019). Comprehensive evaluation of methods to assess overall and cell-specific immune infiltrates in breast cancer. Breast cancer research, 21(1), 151. https://doi.org/10.1186/s13058-019-1239-4
Hatfield, B., Idowu, M., Zot, P., & Robila, V. Interobserver Variability in Scoring Percentages of Tumor-Infiltrating Lymphocytes in Breast Core Needle Biopsies, American Journal of Clinical Pathology, 150(suppl_1), S27-S28, https://doi.org/10.1093/ajcp/aqy090.068
Criscitiello, C., Esposito, A., Trapani, D., & Curigliano, G. (2016). Prognostic and predictive value of tumor infiltrating lymphocytes in early breast cancer. Cancer treatment reviews, 50, 205-207. https://doi.org/10.1016/j.ctrv.2016.09.019
Ruan, M., Tian, T., Rao, J., Xu, X., Yu, B., Yang, W., & Shui, R. (2018). Predictive value of tumor-infiltrating lymphocytes to pathological complete response in neoadjuvant treated triple-negative breast cancers. Diagnostic pathology, 13(1), 66. https://doi.org/10.1186/s13000-018-0743-7
Kramer, C., Vangangelt, K., van Pelt, G. W., Dekker, T., Tollenaar, R., & Mesker, W. E. (2019). The prognostic value of tumour-stroma ratio in primary breast cancer with special attention to triple-negative tumours: a review. Breast cancer research and treatment, 173(1), 55-64. https://doi.org/10.1007/s10549-018-4987-4
Vangangelt, K., van Pelt, G. W., Engels, C. C., Putter, H., Liefers, G. J., Smit, V., Tollenaar, R., Kuppen, P., & Mesker, W. E. (2018). Prognostic value of tumor-stroma ratio combined with the immune status of tumors in invasive breast carcinoma. Breast cancer research and treatment, 168(3), 601-612. https://doi.org/10.1007/s10549-017-4617-6
Zhang, L., Wang, X. I., & Zhang, S. (2018). Tumor-infiltrating lymphocyte volume is a better predictor of neoadjuvant therapy response and overall survival in triple-negative invasive breast cancer. Human pathology, 80, 47-54. https://doi.org/10.1016/j.humpath.2018.05.024
Vaziri Fard, E., Ali, Y., Wang, X. I., Saluja, K., Covinsky, M. H., Wang, L., & Zhang, S. (2019). Tumor-Infiltrating Lymphocyte Volume Is a Better Predictor of Disease-Free Survival Than Stromal Tumor-Infiltrating Lymphocytes in Invasive Breast Carcinoma. American journal of clinical pathology, 152(5), 656-665. https://doi.org/10.1093/ajcp/aqz088
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