Prognostic role of serum soluble ST2 of advanced breast cancer patients: a retrospective cohort study

Introduction

Breast cancer (BC) is the most common and serious malignant tumor endangering the health of women in the world. In China, according to statistics, there were an estimated 2.3 million breast cancer cases and 685,000 deaths in 2020, and the number of cases is expected to reach 4.4 million by 2070 (1). Breast cancer has overtaken lung cancer as the fifth leading cause of death from cancer worldwide. Yet, its development is multifactorial and involves factors such as estrogen levels, genetic factors, living environment, and lifestyle. The incidence of breast cancer is increasing every year, and thus, there is an urgent need to determine which biomarkers are needed, rapidly and effectively evaluate the treatment effects, accurately predict patient prognosis, and identify recurrence (2). Although the risk of recurrence or death related to breast cancer is very different between different subgroups and related to the quality of treatments performed, some evidence showed that the recurrence rate of patients with invasive breast cancer can reach up to 85% 10 years after surgery (3).

A combination of surgery, radiotherapy, and systemic therapy is now the most common treatment for breast cancer patients, and the application of this treatment modality has greatly improved the survival and prognosis of breast cancer patients. Currently, the prognostic indicators that routinely predict the prognosis of breast cancer patients include pathological type, tumor node metastasis (TNM) stage, histological type, molecular typing, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), tumor proliferation index (Ki-67), lymph node metastasis, and D-dimer (1). However, the prognosis of patients is not satisfactory, so it is critical to find laboratory indicators related to the efficacy and prognosis of breast cancer treatment.

Homsak et al. (4) reported that the soluble suppression of tumorigenicity 2 receptor (ST2) is a member of the interleukin (IL)-1 receptor family, encoded by the IL-1 receptor-like 1 (IL1RL1) gene, which is modified and processed to produce four isoforms: ST2 ligand (ST2L), soluble ST2 (sST2), ST2 variant (ST2V), and ST2 ligand variant (ST2LV). ST2L is a membrane receptor containing an IL1R1-like intramembrane domain, a transmembrane domain, and three immunoglobulin (Ig)-like extracellular domains, while sST2 is the soluble form of ST2 (4). ST2 is mainly expressed by immune cells, including t-helper (Th) 2 cells, regulatory T cells (Tregs) cells, and innate lymphoid cells (ILCs). The only ligand for ST2 is IL-33; under normal conditions, IL-33 is constitutively expressed in the nucleus of endothelial and epithelial cells in vivo and is a chromatin-associated nuclear factor that can be released from the nucleus when the organism suffers injury or exogenous pathogen infection resulting in cell damage or death. The released IL-33 seeks out ST2-expressing cells or free ST2, binds to it, and the resulting IL-33/ST2 signaling pathway plays an important role in several immune system diseases and inflammatory responses. For example, the IL-33/ST2 signaling pathway can exacerbate asthma by activating immune cells such as mast cells and Th2 to produce cytokines such as IL-4, IL-5, and IL-13, and can exacerbate rheumatoid arthritis by activating mast cells to produce cytokines such as IL-6. IL-33/ST2 signaling pathway can also exert a protective effect by tilting the immune response to Th2 cells, thereby reducing atherosclerosis and inhibiting cardiomyocyte hypertrophy and myocardial fibrosis (5).

sST2, a “decoy” receptor, is mostly found in peripheral circulating blood and binds to IL-33, competitively inhibiting the IL-33/ST2 signaling pathway, thereby exerting the opposite effect of this signaling pathway (6). When cardiomyocyte injury occurs, the serum sST2 level can increase significantly, which acts as a decoy receptor to competitively bind IL-33 to ST2L, thereby inhibiting the IL-33/ST2 signaling pathway and leading to further myocardial injury. Therefore, sST2 can be used as an indicator of cardiac injury (4).

Previous reports have shown that the IL-33/ST2 signaling pathway also plays an important role in colorectal, liver, gastric, non-small cell lung, and ovarian cancers. For example, Cui et al. (6) found that the IL-33/ST2 pathway plays a role in promoting the progression of human colorectal adenomas to colorectal cancer (CRC), with higher levels of IL-33 and ST2 in CRC tissues compared to surrounding normal tissues. These reports highlight the importance of the IL-33/ST2 signaling pathway, which has also been reported in breast cancer. For example, Lu et al. (7) found that serum sST2 levels in ER-positive breast cancer patients were significantly associated with poor prognostic factors. However, we found that in the treatment of breast cancer patients, anthracycline chemotherapeutic drugs are often applied for treatment; although such drugs are clinically effective, can induce cardiotoxicity, usually irreversible. Cardiomyocyte damage can lead to an increase in serum sST2 levels, and thus, breast cancer patients could have increased levels of serum sST2 after chemotherapy with anthracycline. However, whether sST2 can assess the prognosis of breast cancer patients has not yet been investigated. Therefore, this paper focuses on whether there are differences in serum sST2 levels in patients with different molecular staging of breast cancer and whether sST2 could be used as a prognostic indicator for advanced breast cancer patients.

In this paper, we collected sera from patients diagnosed with advanced breast cancer at the Tianjin Medical University Cancer Institute and Hospital from 2008 to 2021 during their first hospitalization and measured the serum sST2 expression levels of patients with different molecular subtypes of breast cancer using magnetic particle chemiluminescence. We present this article in accordance with the REMARK reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-792/rc).

Methods

Patients

Ninety-one patients who were admitted to the Tianjin Medical University Cancer Institute and Hospital and were first diagnosed with advanced breast cancer from 2008 to 2021 were selected.

• Inclusion criteria: (I) patients with clear pathological data and complete clinical information; (II) first diagnosis of advanced breast cancer; and (III) serum was collected from patients admitted for the first time.
• Exclusion criteria: (I) metastatic breast cancer; (II) other diseases such as a history of hypertension and heart disease; and (III) other concurrent tumors.

Patients with advanced breast who met the enrollment requirements were 25–78 years old, with a mean age of 51.2±10.3 years. There were 17 HER2-positive patients, 11 Luminal-like A patients, 35 Luminal-like B patients, and 28 triple-negative breast cancer (TNBC) patients. All patients were diagnosed by imaging or histopathology. The 91 included breast cancer patients had never undergone mastectomy or breast-conserving surgery, or received anti-cancer drug treatment, and were followed up for a certain period and recorded. All patients were treated with the neoadjuvant chemotherapy (NACT) regimen (4 cycles of doxorubicin 60 mg/m² or cyclophosphamide 600 mg/m² followed by 12 cycles of weekly paclitaxel 80 mg/m²). In our study, HER2-positive patients were administered adjuvant trastuzumab. The collected sera were stored in a −80 ℃ refrigerator. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Tianjin Medical University Cancer Institute and Hospital (No. BC2018024) and informed consent was taken from all the patients.

Laboratory test indexes

All laboratory indicators were obtained from the results of serum tests before the first inpatient surgery or chemotherapy. The laboratory tests included D-dimer, CA153, CA125, TPSA, CEA, and sST2. The D-dimer level was assessed by enzyme-linked fluorescent immunoassay using a mini-VIDAS device (Bio-Mérieux SA, Craponne, France), and CA153, CA125, and CEA were detected by employing the electrochemiluminescence method using Roche cobas8000 equipment at the biochemistry laboratory in our hospital.

TPSA was detected by enzyme-linked immunosorbent assay (ELISA) provided by CanAg to reagents and sST2 was detected by the magnetic particle chemiluminescence method using Lidman equipment and supporting reagents at the biochemistry laboratory in our hospital, and the data presented herein correspond to baseline (before treatment and treatment-associated cardiotoxicity) sST2 levels.

Evaluation criteria

Each item was grouped separately according to the threshold value of the reference interval. There were 53 cases in the D-dimer normal group (D-dimer ≤500 ng/mL) and 38 cases in the D-dimer abnormal group (D-dimer >500 ng/mL); 58 cases in the TPSA normal group (TPSA 0–80 U/L) and 33 cases in the TPSA abnormal group (TPSA >80 U/L); 65 cases in the CA153 normal group (CA153 ≤25 U/mL) and 26 cases in the CA153 abnormal group (CA153 >25 U/mL); 71 cases in the CEA normal group (CEA ≤5 µg/L) and 20 cases in the CEA abnormal group (CEA >5 µg/L); and 68 cases in the CA125 normal group (CA125 ≤35 U/mL) and 23 cases in the CA125 abnormal group (CA125 >35 U/mL).

Statistical analysis

Data were evaluated using the SPSS software, Version 16 (IBM, Armonk, NY, USA). and the mean ± standard deviation (Std) was used for measurement data. The t-test was used for comparisons between groups. Subgroup analysis of the different molecular typologies was performed using Bonferroni correction. Logistic multivariate regression was employed to analyze the influencing factors, and P<0.05 is two-sided, which was considered a statistically significant difference.

Results

Comparison of serum sST2 levels in breast cancer patients with different clinical profiles

By analyzing the sST2 serum levels in different breast cancer patients, we found that sST2 was significantly higher in the subgroup of breast cancer patients with cardiotoxicity after chemotherapy. The differences between the different age, pathological type, with bone metastasis, HER2⁺, ER, PR, and Ki-67 (P>0.05) subgroups were not statistically significant. Moreover, there were no statistically significant differences in sST2 levels between patients with different molecular subtypes overall; however, sST2 levels were significantly higher in those with TNBC compared to the other three groups (Table 1).

Comparison of serum sST2 levels in different molecular types of breast cancer

We analyzed the tumor markers related to breast cancer according to previous studies, CEA, CA153, CA125, TPSA, and D-dimer, and found that only the CEA level in TNBC patients was higher than that in Luminal B patients (Figure 1A), but there were no statistical differences between CA153, CA125, TPSA, and D-dimer of different molecular types (Figure 1B-1E). sST2 was highly expressed in the serum of TNBC patients, which was significantly higher than in those with HER2⁺, Luminal A, and Luminal B types (P<0.05). However, the difference between patients with Luminal A and Luminal B breast cancer was not statistically significant (P>0.05) (Figure 1F).

Figure 1 Comparison of various laboratory indices in breast cancer patients with different molecular types. These laboratory indices in breast cancer patients contain TPSA, CA125, CEA, CA153, D-dimer and sST2. **, P<0.01; ***, P<0.001; NS, no significance. TNBC, triple-negative breast cancer; TPSA, tissue polypeptide specific antigen; CA125, carbohydrate antigen 125; CEA, carcinoembryonic antigen; CA153, carbohydrate antigen 153; sST2, soluble suppression of tumorigenicity 2 receptor.

Comparison of survival in advanced breast cancer patients with different sST2 groupings in serum

The previously reported biomarkers related to survival in advanced breast cancer patients, CEA, CA153, CA125, D-dimer, and TPSA, were selected as controls to compare the survival of advanced breast cancer patients with different serum sST2 levels. The results showed that there was no statistical difference in the survival of breast cancer patients with different CEA, CA153, D-dimer, and TPSA levels (P>0.05) (Figure 2A-2D). However, there was a statistically significant difference between the survival of advanced breast cancer patients in the various CA125 and sST2 groups (P<0.05) (Figure 2E-2F), and the survival of patients in the sST2 abnormal group was significantly lower than that in the normal group (P<0.001) (Figure 2F).

Figure 2 Comparison of survival in breast cancer patients with normal and abnormal laboratory indices. These laboratory indices in breast cancer patients contain TPSA, CA125, CEA, CA153, D-dimer and sST2. TPSA, tissue polypeptide specific antigen; CA125, carbohydrate antigen 125; CEA, carcinoembryonic antigen; CA153, carbohydrate antigen 153; sST2, soluble suppression of tumorigenicity 2 receptor.

Logistic multivariate regression analysis affecting the serum sST2 levels

The possible influencing factors of serum sST2 level in advanced breast cancer patients, including pathological type, clinical stage, molecular classification, ER, PR, HER2, Ki-67, cardiotoxicity, bone metastasis, D-dimer, TPSA, CA153, CEA, and CA125, were selected. These factors were analyzed using logistic regression, and the results showed that high or low sST2 expression levels were correlated with cardiotoxicity and clinical stage but not with the other factors (Table 2).

Discussion

ST2, also known as IL-1R4, is a member of the IL-1 receptor family and was originally isolated and purified from murine fibroblasts. Two main isoforms exist, a membrane-bound form (ST2L) and a soluble form formed by selective splicing (sST2). ST2L is the ligand-binding chain for the IL-33 receptor; until recently, ST2 was known as an orphan receptor, and IL-33 is now known to be the only ligand for ST2. ST2 binds covalently to IL-33 and is coupled to the IL-1 receptor accessory protein (IL-1RAcP, also known as IL-1R3, a common receptor for IL-1a, IL-1b, IL-33, and the three IL-36 isoforms), which is a signal transduction chain that together with ST2 forms a heterodimer as a receptor for IL-33. ST2 is predominantly expressed on the surface of immune cells and is a selective marker for Th2 cells in human and mouse cells (8). IL-33 was first identified as a nuclear factor with high endothelial venation and in 2005, was classified as a member of the IL-1 cytokine family due to the structural similarity of its protein structure to that of members of the IL-1 family, such as IL-1α. IL -IL-33 is stably expressed in the nuclei of normal tissues in humans and mice and is expressed in almost all human tissues, and can be expressed primarily by non-immune cells, such as endothelial cells, epithelial cells, and fibroblasts (8).

IL-33 can be released from the nucleus when an organism suffers an injury or exogenous pathogen infection leading to cell damage or death, and thus, it can act as an alarmin or damage-associated molecular pattern (DAMP) for tissue damage (6,9). Full-length IL-33 is synthesized in the nucleus, and when cells are damaged or necrotic, full-length IL-33 can be processed by caspase-1 to mature IL-33, which is released with cell death. Previous studies have found that the activity of mature IL-33 after processing was 30 times higher than that of full-length IL-33. IL-33 can also be cleaved into inactive fragments by caspase-3 and caspase-7 when apoptosis occurs. Mature IL-33 binds to the cell surface receptor, ST2, via its C-terminal IL-1-like cytokine structural domain, and ST2L, which binds to IL-33, interacts with IL-1RAcP to form a heterodimeric receptor complex. This complex initiates the recruitment of adapter molecules, including myeloid differentiation primary response protein 88 (MyD88), IL-1 receptor-associated kinases (IRAK-1 and IRAK-4), and TNF receptor-associated factor 6 (TRAF6), which subsequently activate the p38 MAPK, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and NF-κB pathways. These signaling pathways direct the expression and secretion of cell-specific cytokines (such as IL-4, IL-5, IL-13) and chemokines as well as a series of downstream effects, including cell proliferation, survival, and amphiregulin (AREG) expression (10). Thus, IL-33 is involved in the development of inflammatory diseases, trauma, metaplasia, autoimmune diseases, cardiovascular diseases, and tumors (11). sST2 can inhibit IL-33-mediated signaling by competing with the membrane-bound form of ST2.

In this study, we investigated whether there were differences in sST2 expression in breast cancer patients with different molecular staging and whether sST2 could be used as an indicator of poor prognosis in patients with advanced breast cancer. We used magnetic particle chemiluminescence to detect serum sST2 levels; electrochemiluminescence to detect CEA, CA153, and CA125 in serum; and ELISA to detect TPSA and D-dimer. We first analyzed sST2 in breast cancer patients by age, type of pathology, the presence of bone metastases and post-chemotherapy cardiotoxicity, and HER2⁺, ER, PR, and Ki-67 in different subgroups and found that there were differences only in the presence or absence of post-chemotherapy cardiotoxicity. Meanwhile, the differences in the remaining subgroups were not statistically significant.

Anthracyclines are very active drugs and still widely used in the treatment of breast cancer. Despite the efficacy of anthracyclines, they are potentially cardiotoxic and can lead to the development of progressive and irreversible cardiomyopathies, influencing the quality of life and prognosis of patients with serious impact on the quality of life of breast cancer survivors. Indeed, it can be said that chemotherapy with anthracyclines is rightfully included among the cardiovascular risk factors. The myocardial pull stimulus caused by myocardial injury induces the release of sST2 in cardiomyocytes, which acts as a “decoy receptor” and competitively binds IL-33 to ST2L, thereby inhibiting the IL-33/ST2 signaling pathway. Elevated sST2 levels serve as an indicator of myocardial injury, and elevated sST2 can further contribute to myocardial injury (12). This is consistent with our findings that serum sST2 levels were significantly and statistically elevated in breast cancer patients with cardiotoxicity after chemotherapy.

We also analyzed and compared the differences in the expressions of CEA, CA153, CA125, D-dimer, TPSA (13), and sST2 in the peripheral blood of breast cancer with different molecular typing. The results showed that CEA, CA153, CA125, D-dimer, and TPSA were not statistically significant in breast cancer patients with different molecular typing; only sST2 was statistically significant in breast cancer patients with different molecular typing. This suggests that the expression levels of sST2 are different in different molecular types of breast cancer, with patients who have advanced TNBC being significantly higher than the other three groups. Thus, serum sST2 may provide a new idea for the clinical diagnosis of patients with TNBC. Comparing the differences in survival between the different CEA, CA153, D-dimer, TPSA, CA125, and sST2 groups of advanced breast patients, we found that only patients in the normal and abnormal CA125 and sST2 groups had statistically significant survival differences (P<0.05). Furthermore, the differences in survival between breast cancer patients in different sST2 groups were more significant (P<0.001), suggesting that ST2 can be used as an independent indicator to predict breast cancer prognosis, with high sST2 levels signifying a poor prognosis and low sST2 levels reflecting a relatively good prognosis. This is consistent with Lu et al., who concluded that serum sST2 levels in ER-positive breast cancer patients are significantly associated with poor prognosis (7), and is also consistent with Yang et al., who reported that IL-33 and sST2 are significantly correlated with matrix metalloproteinase 11 (MMP-11) or platelet-derived growth factor-C (PDGF-C), indicating a poorer prognosis in breast cancer patients (14). However, the specific mechanism remains unclear; one possible mechanism of ST2 protein-mediated immune tolerance in breast cancer may be that tumor tissue escapes the surveillance of the host immune system by modifying it with a chemical structure similar to that of the body’s own tissue (15). Another possible mechanism is through the promotion of immunosuppressive cells, such as Tregs, myeloid-derived suppressive cells (MDSC), the soluble factor major histocompatibility complex class I chain related gene A (MICA), tumor-associated macrophage (TAM), etc., which produces an immunosuppressive tumor microenvironment and promotes the growth and metastasis of breast cancer (3,15-19).

Follow-up multifactorial regression analysis of the clinical impact on serum sST2 levels revealed that cardiotoxicity occurs after chemotherapy, and later clinical staging may become an important factor for serum sST2 levels. Anthracyclines can act on cardiomyocytes through various mechanisms, such as oxygen free radicals, iron ion chelate formation, calcium overload, and cellular conduction pathways, affecting cardiac structure and function. Cardiotoxicity leading to increased sST2 levels interferes with the ability of serum sST2 to predict the prognosis of patients with advanced breast cancer (14,20). However, the number of cases of cardiotoxicity after chemotherapy in advanced breast cancer patients was too small to be considered in the present study. For this reason, this paper focused on the differences in sST2 levels in patients with different molecular staging of breast cancer and its value in assessing the prognosis of breast cancer patients. We found that serum sST2 was higher in patients with TNBC than in patients with other molecular subtypes, and that patients with high levels of sST2 had a worse prognosis than those with low levels.

In conclusion, serum sST2 contributes to the clinical diagnosis of patients with TNBC and may be a potential indicator to assess the prognosis of advanced breast cancer, subject to the exclusion of clinical staging and cardiotoxicity. However, due to the limited number of included samples, the threshold for determining the level of serum sST2 may need to be defined by including more samples to improve the accuracy of sST2 in predicting prognosis (14,21). Also, the influence of cardiotoxicity and clinical staging should be fully considered when using serum sST2 levels to assess the prognosis of patients with advanced breast cancer.

Conclusions

In this study, we found that sST2 could be used as a prognostic indicator of advanced breast cancer progression. To improve the postoperative survival rate of breast cancer patients and guarantee their quality of life, early and accurate prognostic assessment and determination of recurrence is critical. This will ensure early intervention in tumor progression and guide timely and effective clinical treatment. This study provides a basis for the possible use of serum sST2 as a prognostic indicator for pre-stage breast cancer, especially as a novel biomarker for TNBC patients.

Acknowledgments

Funding: This study was sponsored by the Tianjin health research project (No. TJWJ2021MS010 to C Chen).

Footnote

Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-792/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-792/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-792/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-792/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Tianjin Medical University Cancer Institute and Hospital (No. BC2018024) and informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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