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      Tumors with high-density tumor infiltrating lymphocytes constitute a favorable entity in breast cancer: a pooled analysis of four prospective adjuvant trials

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          Abstract

          Background

          Tumor infiltrating lymphocytes (TILs) are considered in the prognosis of breast cancer (BC) patients. Here, we investigated the prognostic/predictive effect of TILs in patients treated in the frame of four prospective trials with adjuvant anthracycline-based chemotherapy in the pre- and post-trastuzumab era.

          Methods

          TILs density was histologically assessed as percentage of stromal area on whole routine sections of 2613 BC (1563 Luminal A/B; 477 Luminal HER2; 246 HER2-enriched; 327 triple negative [TNBC]) and were evaluated as high/low at three cut-offs (c/o; 50% [lymphocytic predominance, LP], 35% and 25%), in separate training and validation sets.

          Results

          High TILs were present in 3.5%, 6.5% and 11.5% of all tumors, using the 50%, 35% and 25% c/o, respectively. TILs status did not interact with BC subtypes or trastuzumab treatment. LPBC patient outcome was not affected by nodal status, while high TILs were favorable in TNBC with unfavorable nodal status. When adjusted for standard clinicopathological parameters and treatment, high TILs independently predicted for favorable outcome, e.g., disease-free survival with the 35% c/o in the entire cohort (HR = 0.44, 95% CI 0.28-0.69, p < 0.001) and in specific subtypes.

          Conclusions

          High TILs tumors, especially LPBC seem worthy validating as a separate entity of favorable prognosis in breast cancer.

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          Most cited references 18

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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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              Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists.

              Breast cancer is a heterogeneous disease encompassing a variety of entities with distinct morphological features and clinical behaviors. Although morphology is often associated with the pattern of molecular aberrations in breast cancers, it is also clear that tumors of the same histological type show remarkably different clinical behavior. This is particularly true for 'basal-like cancer', which is an entity defined using gene expression analysis. The purpose of this article was to review the current state of knowledge of basal-like breast cancers, to discuss the relationship between basal-like and triple-negative breast cancers, and to clarify practical implications of these diagnoses for pathologists and oncologists.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                26 January 2016
                25 October 2015
                : 7
                : 4
                : 5074-5087
                Affiliations
                1 Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
                2 Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Thessaloniki, Greece
                3 Health Data Specialists Ltd, Department of Biostatistics, Athens, Greece
                4 Department of Medical Oncology, “Papageorgiou” Hospital, Thessaloniki, Greece
                5 Department of Clinical Therapeutics, “Alexandra” Hospital, Athens, Greece
                6 Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece
                7 First Department of Medicine, “Laiko” General Hospital, Athens, Greece
                8 Second Department of Medical Oncology, “Metropolitan” Hospital, Piraeus, Greece
                9 Department of Pathology, “Papageorgiou” Hospital, Thessaloniki, Greece
                10 Division of Oncology, Department of Medicine, University Hospital, Patras, Greece
                11 Second Department of Medical Oncology, “Agii Anargiri” Cancer Hospital, Athens, Greece
                12 Third Department of Medical Oncology, “Agii Anargiri” Cancer Hospital, Athens, Greece
                13 Division of Oncology, Second Department of Internal Medicine, Attikon University Hospital, Athens, Greece
                14 Department of Pathology, University Hospital of Patras, Rion, Greece
                15 Oncology Unit, “Hippokration” Hospital, Athens, Greece
                16 Second Department of Medical Oncology, Hygeia Hospital, Athens, Greece
                17 Oncology Section, Second Department of Internal Medicine, “Hippokration” Hospital, Athens, Greece
                Author notes
                Correspondence to: Vassiliki Kotoula, vkotoula@ 123456auth.gr
                Article
                6231
                10.18632/oncotarget.6231
                4826267
                26506242
                Copyright: © 2016 Kotoula et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Categories
                Clinical Research Paper

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