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      Tumor infiltrating lymphocytes in triple negative breast cancer receiving neoadjuvant chemotherapy

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          Abstract

          AIM

          To determine influence of neoadjuvant-chemotherapy (NAC) over tumor-infiltrating-lymphocytes (TIL) in triple-negative-breast-cancer (TNBC).

          METHODS

          TILs were evaluated in 98 TNBC cases who came to Instituto Nacional de Enfermedades Neoplasicas from 2005 to 2010. Immunohistochemistry staining for CD3, CD4, CD8 and FOXP3 was performed in tissue microarrays (TMA) sections. Evaluation of H/E in full-face and immunohistochemistry in TMA sections was performed in pre and post-NAC samples. STATA software was used and P value < 0.05 was considered statistically significant.

          RESULTS

          Higher TIL evaluated in full-face sections from pre-NAC tumors was associated to pathologic-complete-response (pCR) ( P = 0.0251) and outcome ( P = 0.0334). TIL evaluated in TMA sections showed low level of agreement with full-face sections (ICC = 0.017-0.20) and was not associated to pCR or outcome. TIL in post-NAC samples were not associated to response or outcome. Post-NAC lesions with pCR had similar TIL levels than those without pCR ( P = 0.6331). NAC produced a TIL decrease in full-face sections ( P < 0.0001). Percentage of TIL subpopulations was correlated with their absolute counts. Higher counts of CD3, CD4, CD8 and FOXP3 in pre-NAC samples had longer disease-free-survival (DFS). Higher counts of CD3 in pre-NAC samples had longer overall-survival. Higher ratio of CD8/CD4 counts in pre-NAC was associated with pCR. Higher ratio of CD4/FOXP3 counts in pre-NAC was associated with longer DFS. Higher counts of CD4 in post-NAC samples were associated with pCR.

          CONCLUSION

          TIL in pre-NAC full-face sections in TNBC are correlated to longer survival. TIL in full-face differ from TMA sections, absolute count and percentage analysis of TIL subpopulation closely related.

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          Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer.

          Carsten Denkert, Sibylle Loibl, Aurelia Noske … (2010)
          PURPOSE Preclinical data suggest a contribution of the immune system to chemotherapy response. In this study, we investigated the prespecified hypothesis that the presence of a lymphocytic infiltrate in cancer tissue predicts the response to neoadjuvant chemotherapy. METHODS We investigated intratumoral and stromal lymphocytes in a total of 1,058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline/taxane-based studies (GeparDuo, n = 218, training cohort; and GeparTrio, n = 840, validation cohort). Molecular parameters of lymphocyte recruitment and activation were evaluated by kinetic polymerase chain reaction in 134 formalin-fixed, paraffin-embedded tumor samples. Results In a multivariate regression analysis including all known predictive clinicopathologic factors, the percentage of intratumoral lymphocytes was a significant independent parameter for pathologic complete response (pCR) in both cohorts (training cohort: P = .012; validation cohort: P = .001). Lymphocyte-predominant breast cancer responded, with pCR rates of 42% (training cohort) and 40% (validation cohort). In contrast, those tumors without any infiltrating lymphocytes had pCR rates of 3% (training cohort) and 7% (validation cohort). The expression of inflammatory marker genes and proteins was linked to the histopathologic infiltrate, and logistic regression showed a significant association of the T-cell-related markers CD3D and CXCL9 with pCR. CONCLUSION The presence of tumor-associated lymphocytes in breast cancer is a new independent predictor of response to anthracycline/taxane neoadjuvant chemotherapy and provides useful information for oncologists to identify a subgroup of patients with a high benefit from this type of chemotherapy.
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            Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.

            David DeNardo, Donal Brennan, Elton Rexhepaj … (2011)
            Immune-regulated pathways influence multiple aspects of cancer development. In this article we demonstrate that both macrophage abundance and T-cell abundance in breast cancer represent prognostic indicators for recurrence-free and overall survival. We provide evidence that response to chemotherapy is in part regulated by these leukocytes; cytotoxic therapies induce mammary epithelial cells to produce monocyte/macrophage recruitment factors, including colony stimulating factor 1 (CSF1) and interleukin-34, which together enhance CSF1 receptor (CSF1R)-dependent macrophage infiltration. Blockade of macrophage recruitment with CSF1R-signaling antagonists, in combination with paclitaxel, improved survival of mammary tumor-bearing mice by slowing primary tumor development and reducing pulmonary metastasis. These improved aspects of mammary carcinogenesis were accompanied by decreased vessel density and appearance of antitumor immune programs fostering tumor suppression in a CD8+ T-cell-dependent manner. These data provide a rationale for targeting macrophage recruitment/response pathways, notably CSF1R, in combination with cytotoxic therapy, and identification of a breast cancer population likely to benefit from this novel therapeutic approach. These findings reveal that response to chemotherapy is in part regulated by the tumor immune microenvironment and that common cytotoxic drugs induce neoplastic cells to produce monocyte/macrophage recruitment factors, which in turn enhance macrophage infiltration into mammary adenocarcinomas. Blockade of pathways mediating macrophage recruitment, in combination with chemotherapy, significantly decreases primary tumor progression, reduces metastasis, and improves survival by CD8+ T-cell-dependent mechanisms, thus indicating that the immune microenvironment of tumors can be reprogrammed to instead foster antitumor immunity and improve response to cytotoxic therapy.
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              Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199.

              Sylvia Adams, Robert J Gray, Sandra Demaria … (2014)
              Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter.
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                Author and article information

                Journal
                Journal ID (nlm-ta): World J Clin Oncol
                Journal ID (publisher-id): WJCO
                Title: World Journal of Clinical Oncology
                Publisher: Baishideng Publishing Group Inc
                ISSN (Electronic): 2218-4333
                Publication date (Print): 10 October 2016
                Publication date (Electronic): 10 October 2016
                Volume: 7
                Issue: 5
                Pages: 387-394
                Affiliations
                Carlos A Castaneda, Miluska Castillo, Patricia Arboleda, Ketty Dolores-Cerna, Carolina Belmar-Lopez, Department of Research, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
                Carlos A Castaneda, Henry L Gomez, Tatiana Vidaurre, Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
                Elizabeth Mittendorf, Department of Surgical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
                Sandro Casavilca, Patricia Arboleda, Teresa Nunez, Henry Guerra, Carlos Barrionuevo, Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
                Yun Wu, Department of Pathology, Division of Pathology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
                Julio Abugattas, Gabriela Calderon, Miguel De La Cruz, Manuel Cotrina, Jorge Dunstan, Department of Breast Cancer Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
                Author notes

                Author contributions: Castaneda CA, Mittendorf E, Casavilca S and Wu Y contributed to the conception and design of the study and performed data analysis and interpretation; Castaneda CA, Casavilca S, Castillo M, Nunez T and Guerra H performed data acquisition, as well as providing administrative, technical, and material support; all authors drafted the article and made critical revisions related to the intellectual content of the manuscript, and approved the final version of the article to be published.

                Correspondence to: Carlos A Castaneda, MD, MSc, Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplasicas, Av. Angamos Este 2520 Surquillo, Lima 15038, Peru. carloscastanedaaltamirano@ 123456yahoo.com

                Telephone: +51-1-2157220 Fax: +51-1-6204991

                Article
                Other ID: jWJCO.v7.i5.pg387
                DOI: 10.5306/wjco.v7.i5.387
                PMC ID: 5056330
                PubMed ID: 27777881
                SO-VID: 12f60b15-5975-4e81-835b-ce738bcbdd7f
                Copyright © ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
                License:

                This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

                History
                Date received : 18 April 2016
                Date revision received : 13 August 2016
                Date accepted : 21 September 2016
                Categories
                Subject: Basic Study

                Keywords: triple-negative breast cancer,survival,tumor-infiltrating lymphocytes,neoadjuvant therapy
                Data availability:
                Keywords: triple-negative breast cancer, survival, tumor-infiltrating lymphocytes, neoadjuvant therapy

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