Prognostic value of tumor–stroma ratio combined with the immune status of tumors in invasive breast carcinoma

Breast Cancer Research and Treatment, Dec 2017

Purpose Complex interactions occur between cancer cells and cells in the tumor microenvironment. In this study, the prognostic value of the interplay between tumor–stroma ratio (TSR) and the immune status of tumors in breast cancer patients was evaluated. Methods A cohort of 574 breast cancer patients was analyzed. The percentage of tumor stroma was visually estimated on Hematoxylin and Eosin (H&E) stained histological tumor tissue sections. Immunohistochemical staining was performed for classical human leukocyte antigen (HLA) class I, HLA-E, HLA-G, markers for regulatory T (Treg) cells, natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs). Results TSR (P < .001) and immune status of tumors (P < .001) were both statistically significant for recurrence free period (RFP) and both independent prognosticators (P < .001) in which tumors with a high stromal content behave more aggressively as well as tumors with a low immune status. Ten years RFP for patients with a stroma-low tumor and high immune status profile was 87% compared to 17% of patients with a stroma-high tumor combined with low immune status profile (P < .001). Classical HLA class I is the most prominent immune marker in the immune status profiles. Conclusions Determination of TSR is a simple, fast and cheap method. The effect on RFP of TSR when combined with immune status of tumors or expression of classical HLA class I is even stronger. Both are promising for further prediction and achievement of tailored treatment for breast cancer patients.

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Prognostic value of tumor–stroma ratio combined with the immune status of tumors in invasive breast carcinoma

Prognostic value of tumor-stroma ratio combined with the immune status of tumors in invasive breast carcinoma K. M. H. Vangangelt 0 1 G. W. van Pelt 0 1 C. C. Engels 0 1 H. Putter 0 1 G. J. Liefers 0 1 V. T. H. B. M. Smit 0 1 R. A. E. M. Tollenaar 0 1 P. J. K. Kuppen 0 1 W. E. Mesker 0 1 0 Department of Medical Statistics, Leiden University Medical Center , Leiden , The Netherlands 1 Department of Pathology, Leiden University Medical Center , Leiden , The Netherlands 2 W. E. Mesker Purpose Complex interactions occur between cancer cells and cells in the tumor microenvironment. In this study, the prognostic value of the interplay between tumor-stroma ratio (TSR) and the immune status of tumors in breast cancer patients was evaluated. Methods A cohort of 574 breast cancer patients was analyzed. The percentage of tumor stroma was visually estimated on Hematoxylin and Eosin (H&E) stained histological tumor tissue sections. Immunohistochemical staining was performed for classical human leukocyte antigen (HLA) class I, HLA-E, HLA-G, markers for regulatory T (Treg) cells, natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs). Results TSR (P < .001) and immune status of tumors (P < .001) were both statistically significant for recurrence free period (RFP) and both independent prognosticators (P < .001) in which tumors with a high stromal content behave more aggressively as well as tumors with a low immune status. Ten years RFP for patients with a stroma-low tumor and high immune status profile was 87% compared to 17% of patients with a stroma-high tumor combined with low immune status profile (P < .001). Classical HLA class I is the most prominent immune marker in the immune status profiles. Conclusions Determination of TSR is a simple, fast and cheap method. The effect on RFP of TSR when combined with immune status of tumors or expression of classical HLA class I is even stronger. Both are promising for further prediction and achievement of tailored treatment for breast cancer patients. Breast cancer; Tumor-stroma ratio; Immune cells; HLA; Prognosis Introduction Survival for patients with invasive breast cancer has increased in the last decade due to new and improved therapeutic options as well as new insights in molecular biology. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10549-017-4617-6) contains supplementary material, which is available to authorized users. Department of Surgery, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands Methods to select patients based on the tumor phenotype are important to reduce over- and undertreatment, for example, gene expression profiles that identify subtypes [ 1, 2 ] associated with higher risk of metastasis. Although these techniques result in prognostic and predictive valuable information for specific patient groups, optimization of risk assessment might benefit from further improvement. Despite an important update on the role of the microenvironment on cancer development by Hanahan et al. [ 3, 4 ], the classification system for predicting metastasis and disease-specific survival is still based on traditional tumor staging criteria (AJCC/UICC-TNM Classification) [ 5–7 ] which focus largely on the tumor cell autonomous processes and not on the microenvironment. Complex interactions occur between cancer cells and cells in the tumor microenvironment, such as immune and stromal cells. A high stromal content has been associated with worse prognosis in different solid cancer types including breast cancer and especially in triple negative breast cancer [ 8–14 ]. Together with the development of malignant tumor stroma, the connective tissue framework of the tumor becomes active. The collagen bundles degrade, the number of inflammatory cells increases, fibroblasts differentiate into myofibroblasts and proliferate and angiogenesis increases [ 15 ]. Also, the cellular immune response has a fundamental role in cancer development. An example of the prognostic value of the activity of the immune system is represented by the Immunoscore which analyzes the distribution of CD3+ lymphocytes and CD8+ cytotoxic T cells [ 16 ]. In breast cancer, especially in triple negative tumors, the increased presence of tumor-infiltrating lymphocytes has been associated with good prognosis [ 17, 18 ]. De Kruijf et al. showed that the immune status of tumors based on six cellular immune markers has a statistically significant effect on prognosis preferable for tumors with a high immune status [19]. These six cellular immune markers (HLA-E, HLA-G, classical HLA class I (HLA-A, HLA-B and HLA-C), natural killer (NK) cells, cytotoxic T-lymphocytes (CTLs) and regulatory T (Treg) cells) were selected based on biological rationale and the balance between their various interactions. Suggestions have been made about the influence of tumor stroma on suppression of the immune response [ 9, 20–23 ]. In (...truncated)


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K. M. H. Vangangelt, G. W. van Pelt, C. C. Engels, H. Putter, G. J. Liefers, V. T. H. B. M. Smit, R. A. E. M. Tollenaar, P. J. K. Kuppen, W. E. Mesker. Prognostic value of tumor–stroma ratio combined with the immune status of tumors in invasive breast carcinoma, Breast Cancer Research and Treatment, 2017, pp. 1-12, DOI: 10.1007/s10549-017-4617-6