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
].
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