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      PD-1/PD-L1 Targeting in Breast Cancer: The First Clinical Evidences are Emerging—A Literature Review

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          Abstract

          Recently, the development of immunotherapy through the immune checkpoint blockade led to long-lasting responses in several types of cancers that are refractory to conventional treatments, such as melanoma or non-small cell lung cancer. Immunotherapy has also demonstrated significant improvements in various other types of cancers. However, breast cancer remains one of the tumors that have not experienced the explosion of immunotherapy yet. Indeed, breast cancer was traditionally considered as being weakly immunogenic with a lower mutational load compared to other tumor types. In the last few years, anti-PD1/PD-L1 (Programmed death-ligand 1) agents have been evaluated in breast cancer, particularly in the triple negative subtype, with promising results observed when delivered as monotherapy or in combination with conventional treatments. In this review, we will report the results of the most recent studies evaluating immune checkpoint inhibitors in breast cancer. In addition, we will discuss the concomitant development of possible biomarkers, which is required for improving the selection of patients with the highest probability of benefiting from these agents.

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          Most cited references52

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

          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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            Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers.

            Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy. To investigate the immunogenicity of human epidermal growth factor receptor 2 (HER2) -positive and triple-negative (TN) breast cancers (BCs), we evaluated tumor-infiltrating lymphocytes (TILs) and immunologically relevant genes in the neoadjuvant GeparSixto trial.
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              Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients.

              T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                22 July 2019
                July 2019
                : 11
                : 7
                : 1033
                Affiliations
                [1 ]Department of Medical Oncology, Aix-Marseille University, Inserm U1068, CNRS UMR7258, Institute Paoli-Calmettes, 13009 Marseille, France
                [2 ]CRCM—Tumor Immunology Laboratory, Aix-Marseille University, Inserm U1068, CNRS UMR7258, Institute Paoli-Calmettes, 13009 Marseille, France
                [3 ]CRCM—Predictive Oncology Laboratory, Aix-Marseille University, Inserm U1068, CNRS UMR7258, Institute Paoli-Calmettes, 13009 Marseille, France
                Author notes
                [* ]Correspondence: goncalvesa@ 123456ipc.unicancer.fr ; Tel.: +33-491-223-789
                Author information
                https://orcid.org/0000-0001-7932-0530
                https://orcid.org/0000-0003-1511-1048
                https://orcid.org/0000-0002-5821-682X
                https://orcid.org/0000-0001-7570-7439
                Article
                cancers-11-01033
                10.3390/cancers11071033
                6679223
                31336685
                07b2fa4d-7b23-41f3-98ee-4e7fda2a5979
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 May 2019
                : 17 July 2019
                Categories
                Review

                breast cancer,immunotherapy,pd1,pdl1,triple-negative breast cancer

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