@article{0bd530512e504d178bb6bec93d19fcfc,
title = "Prognostic implications of residual disease tumor-infiltrating lymphocytes and residual cancer burden in triple-negative breast cancer patients after neoadjuvant chemotherapy: Annals of Oncology",
abstract = "Background For primary triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC), higher pretreatment tumor-infiltrating lymphocytes (TILs) correlates with increased pathologic complete response (pCR) rates, and improved survival. We evaluated the added prognostic value of residual disease (RD) TILs to residual cancer burden (RCB) in predicting survival post-NAC. Patients and methods We combined four TNBC NAC patient cohorts who did not achieve pCR. RD TILs were investigated for associations with recurrence-free survival (RFS), and overall survival (OS) using Cox models with stromal TILs as a continuous variable (per 10% increment). The likelihood ratio test was used to evaluate added prognostic value of RD TILs. Results A total of 375 RD TNBC samples were evaluable for TILs and RCB. The median age was 50 years, with 62% receiving anthracycline/taxane chemotherapy. The RCB class after NAC was 11%, 50%, and 39% for I, II, and III, respectively. The median RD TIL level was 20% (IQR 10-40). There was a positive correlation between RD TIL levels and CD8+ T-cell density ({\"I} = 0.41). TIL levels were significantly lower with increasing post-NAC tumor (P = 0.005), nodal stage (P = 0.032), but did not differ by RCB class (P = 0.84). Higher RD TILs were significantly associated with improved RFS (HR: 0.86; 95% CI 0.79-0.92; P <0.001), and improved OS (HR: 0.87; 95% CI 0.80-0.94; P <0.001), and remained significant predictors in multivariate analysis (RFS P = 0.032; OS P = 0.038 for OS). RD TILs added significant prognostic value to multivariate models including RCB class (P <0.001 for RFS; P = 0.021 for OS). The positive prognostic effect of RD TILs significantly differed by RCB class for RFS (P Int =0.003) and OS (P Int =0.008) with a greater magnitude of positive effect observed for RCB class II than class III. Conclusions TIL levels in TNBC RD are significantly associated with improved RFS and OS and add further prognostic information to RCB class, particularly in RCB class II. {\textcopyright} The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology.",
keywords = "Neoadjuvant, Prognosis, Rcb, Tils, Tnbc, anthracycline, taxane derivative, adult, aged, Article, cancer combination chemotherapy, cancer prognosis, cancer survival, CD8+ T lymphocyte, cell density, clinical evaluation, cohort analysis, disease association, drug effect, human, human cell, human tissue, major clinical study, minimal residual disease, neoadjuvant chemotherapy, overall survival, priority journal, recurrence free survival, triple negative breast cancer, tumor associated leukocyte, tumor volume",
author = "S.J. Luen and R. Salgado and M.V. Dieci and A. Vingiani and G. Curigliano and R.E. Gould and C. Castaneda and T. D'Alfonso and J. Sanchez and E. Cheng and E. Andreopoulou and M. Castillo and S. Adams and S. Demaria and W.F. Symmans and S. Michiels and S. Loi",
note = "Cited By :10 Export Date: 27 February 2020 CODEN: ANONE Correspondence Address: Loi, S.; Peter MacCallum Cancer Centre, University of MelbourneAustralia; email: sherene.loi@petermac.org Funding details: University of Melbourne Funding details: National Breast Cancer Foundation Funding details: Breast Cancer Research Foundation, number-16-199 Funding details: Breast Cancer Research Foundation Funding details: Novartis Funding details: Pfizer Australia Funding text 1: The authors wish to acknowledge Vassilena Tsvetkova for her role in preparation and evaluation of immunohistochemistry samples in this study. SJL is supported by the University of Melbourne. SL is supported by National Breast Cancer Foundation (NBCF) of Australia and the John Colebatch Cancer Council Victoria Clinical fellowship. Funding text 2: This work was supported by the Breast Cancer Research Foundation (BRCF NY) (BCRF grant number-16-199). Funding text 3: SJL reports receipt of travel funding from Pfizer; honoraria from Novartis. RS reports research funding from Roche, Puma, Merck; participates on the advisory board for BMS; travel funding from Roche, Merck, and Astra Zeneca. MVD reports consulting or advisory role for Eli Lilly, Genomic Health, Celgene. SD receives research funding to her institution from Lytix Biopharma and Nanobiotix. She reports consulting or advisory role for Eisai, Lytix Biopharma, EMD Serono, AstraZeneca, AbbVie, Cytune Pharma. SM is a co-inventor of a patent describing the prognostic value of a four-gene signature for predicting high levels of TILs after anthracycline-containing NACT and outcome in patients with triple-negative breast cancer. SL receives research funding to her institution from Novartis, Bristol Meyers Squibb, Merck, Roche-Genentech, Puma Biotechnology and Pfizer. She has acted as consultant (not compensated) to Seattle Genetics, Pfizer, Novartis, BMS, Merck and Roche-Genentech. All remaining authors have declared no conflicts of interest. References: Masuda, N., Lee, S.-J., Ohtani, S., Adjuvant capecitabine for breast cancer after preoperative chemotherapy (2017) N Engl J Med, 376 (22), pp. 2147-2159; Cortazar, P., Zhang, L., Untch, M., Pathological complete response and long-term clinical benefit in breast cancer: The ctneobc pooled analysis (2014) Lancet, 384 (9938), pp. 164-172; Symmans, W.F., Peintinger, F., Hatzis, C., Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy (2007) JCO, 25 (28), pp. 4414-4422; Symmans, W.F., Wei, C., Gould, R., Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype (2017) JCO, 35 (10), pp. 1049-1060; Denkert, C., Von Minckwitz, G., Darb-Esfahani, S., Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: A pooled analysis of 3771 patients treated with neoadjuvant therapy (2018) Lancet Oncol, 19 (1), pp. 40-50; Loi, S., Drubay, D., Adams, S., Abstract s1-03: Pooled individual patient data analysis of stromal tumor infiltrating lymphocytes in primary triple negative breast cancer treated with anthracycline-based chemotherapy (2016) Cancer Res, 76, p. S10303; Dieci, M.V., Criscitiello, C., Goubar, A., Prognostic value of tumorinfiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: A retrospective multicenter study (2014) Ann Oncol, 25 (3), pp. 611-618; Salgado, R., Denkert, C., Demaria, S., The evaluation of tumorinfiltrating lymphocytes (tils) in breast cancer: Recommendations by an international tils working group (2014) Ann Oncol 2015, 26 (2), pp. 259-271; Dieci, M.V., Radosevic-Robin, N., Fineberg, S., Update on tumorinfiltrating lymphocytes (tils) in breast cancer, including recommendations to assess tils in residual disease after neoadjuvant therapy and in carcinoma in situ: A report of the international immuno-oncology biomarker working group on breast cancer (2017) Semin Cancer Biol, 52, pp. 16-25; Criscitiello, C., Bayar, M.A., Curigliano, G., A gene signature to predict high tumor-infiltrating lymphocytes after neoadjuvant chemotherapy and outcome in patients with triple-negative breast cancer (2018) Ann Oncol, 29 (1), pp. 162-169; Huang, A.C., Postow, M.A., Orlowski, R.J., T-cell invigoration to tumour burden ratio associated with anti-pd-1 response (2017) Nature, 545 (7652), pp. 60-65; Savas, P., Virassamy, B., Ye, C., Single-cell profiling of breast cancer t cells reveals a tissue-resident memory subset associated with improved prognosis (2018) Nat Med, 24, pp. 986-993; Simoni, Y., Becht, E., Fehlings, M., Bystander cd8(p) t cells are abundant and phenotypically distinct in human tumour infiltrates (2018) Nature, 557 (7706), pp. 575-579; Asano, Y., Kashiwagi, S., Goto, W., Prediction of survival after neoadjuvant chemotherapy for breast cancer by evaluation of tumor-infiltrating lymphocytes and residual cancer burden (2017) BMC Cancer, 17, p. 888",
year = "2019",
doi = "10.1093/annonc/mdy547",
language = "English",
volume = "30",
pages = "236--242",
journal = "Ann. Oncol.",
issn = "1569-8041",
publisher = "NLM (Medline)",
number = "2",
}