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      Long-term Clinical Outcomes and Biomarker Analyses of Atezolizumab Therapy for Patients With Metastatic Triple-Negative Breast Cancer : A Phase 1 Study

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          Abstract

          Atezolizumab (anti-programmed cell death ligand 1 [PD-L1]) is well tolerated and clinically active in multiple cancer types. Its safety and clinical activity in metastatic triple-negative breast cancer (mTNBC) has not been reported.

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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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            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.

            Carsten Denkert, Gunter von Minckwitz, Jan C Brase … (2015)
            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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              Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer.

              S. Muenst, A R Schaerli, F. Gao … (2014)
              Recent studies in multiple epithelial cancers have shown that the inhibitory receptor programmed cell death 1 (PD-1) is expressed on tumor-infiltrating lymphocytes and/or programmed death ligand 1 (PD-L1) is expressed on tumor cells, suggesting that antitumor immunity may be modulated by the PD-1/PD-L1 signaling pathway. In addition, phase 1 clinical trials with monoclonal antibodies targeting PD-1 or PD-L1 have shown promising results in several human cancers. The purpose of this study was to investigate the impact of PD-L1 expression in human breast cancer specimens. We conducted an immunohistochemistry study using a tissue microarray encompassing 650 evaluable formalin-fixed breast cancer cases with detailed clinical annotation and outcomes data. PD-L1 was expressed in 152 (23.4 %) of the 650 breast cancer specimens. Expression was significantly associated with age, tumor size, AJCC primary tumor classification, tumor grade, lymph node status, absence of ER expression, and high Ki-67 expression. In univariate analysis, PD-L1 expression was associated with a significantly worse OS. In multivariate analysis, PD-L1 expression remained an independent negative prognostic factor for OS. In subset analyses, expression of PD-L1 was associated with significantly worse OS in the luminal B HER2(-) subtype, the luminal B HER2(+) subtype, the HER2 subtype, and the basal-like subtype. This is the first study to demonstrate that PD-L1 expression is an independent negative prognostic factor in human breast cancer. This finding has important implications for the application of antibody therapies targeting the PD-1/PD-L1 signaling pathway in this disease.
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                Author and article information

                Journal
                Title: JAMA Oncology
                Abbreviated Title: JAMA Oncol
                Publisher: American Medical Association (AMA)
                ISSN (Print): 2374-2437
                Publication date (Electronic): September 13 2018
                Affiliations
                [1 ]Bloomberg-Kimmel Institute for Cancer Immunotherapy, Department of Oncology, Johns Hopkins University, Baltimore, Maryland
                [2 ]now with Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh
                [3 ]Medical Oncology Department, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Barcelona, Spain
                [4 ]Department of Medicine (Oncology), Yale Cancer Center, New Haven, Connecticut
                [5 ]Comprehensive Cancer Centers of Nevada, University of Nevada Las Vegas School of Medicine, Las Vegas
                [6 ]The Angeles Clinic and Research Institute, Los Angeles, California
                [7 ]Department of Medicine,Dana-Farber Cancer Institute, Boston, Massachusetts
                [8 ]Department of Medicine, Hematology/Oncology, Massachusetts General Hospital, Boston
                [9 ]Section of Hematology/Oncology, University of Chicago, Chicago, Illinois
                [10 ]Department of Medical Oncology, Centre Léon-Bérard, Lyon, France
                [11 ]Department of Medical Oncology, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France
                [12 ]HonorHealth Research Institute, Scottsdale, Arizona
                [13 ]Ventana Medical Systems, Inc, Tucson, Arizona
                [14 ]Genentech, Inc, South San Francisco, California
                [15 ]now with Bellicum Pharmaceuticals, Inc, South San Francisco, California
                [16 ]Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, England
                Article
                DOI: 10.1001/jamaoncol.2018.4224
                PMC ID: 6439773
                PubMed ID: 30242306
                SO-VID: 56591f39-4147-4129-b55c-8acc3d7dc32e
                Copyright © © 2018
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