Prognostic Value of Anti-Chlamydia Trachomatis IgG in Breast Cancer and the Modification Effects of Pro-Inflammatory Cytokines: A 13-Year Prospective Cohort Study

Introduction

Breast cancer is the most prevalent malignancy among women worldwide and is an important public health issue.1,2 In 2020, breast cancer in women has surpassed lung cancer as the leading cause of cancer incidence worldwide, with an estimated 2.3 million new cases, representing 11.7% of all cancer cases. It is the fifth leading cause of cancer death globally, with 685,000 deaths.3 The burden of disease due to breast cancer remains substantial around the world.4 Therefore, improving the prognosis of breast cancer is of great importance for public health.

A variety of risk factors have been found to be associated with breast cancer prognosis, including demographic characteristics, clinicopathological features, therapeutic methods, and lifestyles.5–7 Current evidence suggests associations between chronic infections with viral or bacterial pathogens and the progression of various cancers, including breast cancer.8,9 Predominantly, Chlamydia trachomatis (C. trachomatis) has emerged as a pathogen of interest, given its established association with cervical and ovarian cancers.10–13 Importantly, both breast and ovarian cancers exhibit hormone sensitivity, particularly to estrogen. The infectivity of C. trachomatis, known to be modulated by hormonal variations and heightened by estrogen, posits a hormonal nexus potentially influencing breast cancer. Despite these associations, the impact of C. trachomatis on the prognosis of breast cancer remains unknown. This existing gap in our understanding calls for more in-depth research to clarify the potential influence of C. trachomatis on breast cancer prognosis.

In addition, C. trachomatis infection may trigger immune responses, notably the production of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor alpha (TNF-α).14,15 Persistent C. trachomatis infection leads to sustained cytokine secretion, contributing to a chronic inflammatory state, which in turn plays a significant role in tumor metastasis and invasion.16–18 Therefore, the present study aimed to evaluate the association of C. trachomatis infection with overall survival (OS) and progression-free survival (PFS) in women with breast cancer, with specific emphasis on the modification effects of pro-inflammatory cytokines, which could provide evidence for tailoring treatment plans and prognostic evaluation in breast cancer patients.

Materials and Methods Study Population

A total of 1121 women with breast cancer were recruited from October 2008 to January 2018 derived from a subset of the Guangzhou Breast Cancer Study (GZBCS) cohort.19 Briefly, patients who were pathologically diagnosed with primary invasive breast cancer from the First and the Second Affiliated Hospitals of Sun Yat-sen University in Guangzhou, China were enrolled. Women with metastasized breast cancer or previous history of other cancers were excluded. Blood samples were collected immediately after the patients were admitted to the hospitals or after the interview and stored at −80°C before detection. Of them, 1755 patients had serum samples collected at diagnosis. We excluded patients with missing data on the following variables: clinical stage, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) status, or follow-up. Additionally, 204 patients with poor serum quality were excluded. This study was approved by the Ethics Committee of the School of Public Health at Sun Yat-sen University. Informed consent was obtained from each participant before the interview.

Data Collection

The baseline information was collected using a structured questionnaire. Trained and qualified investigators conducted face-to-face interviews with patients in the hospital wards. The collected information included the general demographic characteristics, family history of breast cancer, menstrual history, and reproductive history. Clinicopathological characteristics were extracted from medical records. Immunohistochemistry test was used to determine the ER, PR, and HER2 status. The definitions of ER, PR, and HER2 statuses have been described in detail in a previous study.20

Follow-Up

Patients were followed up by telephone or out-patient visits every 3 months during the first-year post-diagnosis, semiannually in the second and third year, and annually thereafter. The endpoints of this study were OS and PFS. OS was defined as the duration from the date of diagnosis to the date of death from any cause. PFS was defined as the interval from diagnosis to the occurrence of disease progression, which includes recurrence, metastasis, or death. The survival status of patients was ascertained on the latest follow-up date or December 31, 2021.

Serological Tests

Immunoglobulin G (IgG) antibody against C. trachomatis and total IgG were measured using commercial enzyme-linked immunosorbent assay kits (Savyon diagnostics, Israel and Cusabio Biotech Co, China, respectively). The tests were performed in strict accordance with the manufacturers’ instructions. To ensure consistency in the optical density (OD) values across the different test plates, a reference sample provided with each kit was included in each 96-well plate. Seropositivity for C. trachomatis IgG was defined by a cut-off index (COI) greater than 1.1. The COI was calculated based on the ratio of the OD value from each sample and to the OD value of the cut-off control in the corresponding plate. In addition, serum concentrations of IL-6, TNF-α, IL-8, and IL-1β were measured using a commercially available cytokine panel from Bio-Rad Laboratories (Cat. No. M500KCAF0Y), following the provided instructions. Analysis was performed on the Luminex xMAP 200 platform (Luminex Corporation, Austin, TX, USA). Standard curves for these measurements were generated using the known concentrations of each cytokine. The data were collected and processed with Bio-Plex Manager 6.0 (Bio-Rad Laboratories).

Statistical Analysis

Seropositivity to IgG against C. trachomatis was assessed and total IgG levels were quantified in terms of concentration (g/L). To compare the distribution differences in general demographic and clinicopathological characteristics between the C. trachomatis positive and negative groups, continuous variables were expressed as medians and interquartile ranges (IQR). These differences were evaluated using Mann–Whitney U-test. Categorical variables were presented by frequency and constituent ratio, with the χ2 test applied to compare differences between groups. The levels of pro-inflammatory cytokines were categorized into tertiles for analysis. Univariate and multivariate Cox proportional hazards regression models were used to explore the association of general demographic and clinicopathological characteristics, C. trachomatis, and pro-inflammatory cytokines with breast cancer prognosis. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated. Variables adjusted in the multivariable Cox proportional hazards regression models were determined based on previous studies and the factors known to affect breast cancer prognosis. These included age at diagnosis, menopausal status, education, ER status, HER2 status, clinical stage, and total IgG levels. The association between C. trachomatis infection and breast cancer prognosis was analyzed using pro-inflammatory cytokine levels as stratification factors. Stratified analyses were also performed based on clinical pathological characteristics. Multiplicative interactions were analyzed by including product term into the multivariate Cox regression analysis. All statistical analyses were performed using R 3.6.1, and a two-sided P-value of less than 0.05 was considered statistically significant.

Results Demographic and clinicopathological characteristics and the associations with breast cancer prognosis and C. trachomatis infection.

A total of 1121 patients with breast cancer were included in this study, 182 (16.2%) of whom were C. trachomatis IgG positivity. Table 1 shows that the median age at diagnosis was 48 years (interquartile range: 42–57 years), and 63.7% of women were 41–60 years old. More than half of the subjects were premenopausal (57.9%) and nearly half of them had an education level of junior middle school or below (40.9%). In terms of clinicopathological characteristics, most patients were diagnosed with ER+ (76.8%), PR+ (67.4%), HER2- (58.0%), and early clinical stage (stage I/II: 79.1%). C. trachomatis IgG positive breast cancer patients were more likely to be premenopausal, age 41–60 years old at diagnosis, ER-positive, and PR-positive compared to negative ones (Table 1).

Table 1 Demographic and Clinicopathological Characteristics by C. trachomatis Infection Status

Univariate Cox regression analysis showed that age at diagnosis, menopausal status, education level, ER status, PR status, HER2 status, tumor size, lymph node metastasis, distant metastasis, and TNM stage were significantly associated with breast cancer prognosis (Supplementary Table 1).

Prognostic Effects of C. trachomatis on Breast Cancer

Of the 1121 subjects, 150 died, and 241 showed disease progression during the follow-up period (median follow-up time: 63.91 months, interquartile range: 39.16–90.08 months). Five-year OS rate and PFS rate were 88.3% and 80.1%, respectively. Table 2 presents the results of univariate and multivariate analyses of the association between C. trachomatis IgG levels and breast cancer prognosis. No association of C. trachomatis IgG positivity with the risks of death and disease progression (adjusted HR=1.09, 95% CI: 0.67–1.78 for OS; adjusted HR=1.24, 95% CI: 0.87–1.78 for PFS) was found.

Table 2 Association Between C. trachomatis IgG Levels and Breast Cancer Prognosis

Furthermore, stratified analyses according to age at diagnosis revealed that compared with C. trachomatis IgG negativity, the positivity was related to a significantly poorer PFS among patients aged 50 years or younger (HR=1.79, 95% CI: 1.16–2.77), while it was associated with a better PFS among those aged over 50 years (HR=0.62, 95% CI: 0.31–1.25); the interaction was significant (Pinteraction=0.013, Supplementary Table 2). For OS, a similar pattern was observed and the HRs and 95% CIs were 1.43 (0.79–2.58) and 0.59 (0.23–1.50) in ≤ 50 and >50 age groups, respectively, though the interaction did not reach a significance (Pinteraction=0.169, Supplementary Table 2).

Modification effects of pro-inflammatory cytokines on the relationship between C. trachomatis and breast cancer OS and PFS.

We then assessed the differential associations between C. trachomatis and breast cancer prognosis stratified by cytokine levels. The results showed that C. trachomatis IgG positivity obviously elevated the risk of death and disease progression among breast cancer patients with a higher level of IL-6 (HR=6.46, 95% CI: 2.47–16.88 for OS; HR=2.96, 95% CI: 1.45–6.02 for PFS), while there were decreased risks among patients with a lower level of IL-6 (HR=0.23, 95% CI: 0.07–0.76 for OS; HR=0.52, 95% CI: 0.27–1.03 for PFS), and the interactions were significant (P interaction < 0.001 for OS; P interaction=0.001 for PFS), as shown in Table 3. For IL-8, the effects of C. trachomatis infection on breast cancer prognosis were similar to those of IL-6, and the interactive effect tended to be significant (P interaction=0.074 for OS; P interaction=0.101 for PFS). For TNF-α and IL-1β, however, the interactions were not significant.

Table 3 Modification Effects of Pro-Inflammatory Cytokines on the Association of C. trachomatis with Breast Cancer OS and PFS

We further divided the participants into two subgroups by age (≤ 50 and > 50 years) to examine the interactions between C. trachomatis and the cytokines on the prognosis (Supplementary Tables 3 and 4). Significant interactions between the four cytokines (IL-6, TNF-α, IL-8, and IL-1β) and C. trachomatis on the prognosis were observed in patients with aged 50 years or younger, whereas these interactive effects were absent (TNF-α, IL-8, and IL-1β) or weak (IL-6) in patients with aged over 50 years.

Discussion

In this study, we found that C. trachomatis IgG positivity was associated with increased risks of death and progression in breast cancer patients aged ≤ 50 years or with higher levels of the four pro-inflammatory cytokines (IL-6, TNF-α, IL-8, and IL-1β).

C. trachomatis, the most prevalent pathogen infecting the genital tract in women worldwide,21 is involved in persistent long-term chronic infections of the reproductive tract in humans, which can be clinically insidious.22 This infection, a common sexually transmitted infection (STI), can ascend from the cervix to the uterus and fallopian tubes, leading to complications such as pelvic inflammatory disease, chronic pelvic pain, infertility, and ectopic pregnancy.23,24 Animal studies have demonstrated that murine C. trachomatis in mice can spread from the reproductive tract to the gastrointestinal tract through systemic routes other than oral or rectal-anal contact, suggesting that C. trachomatis might gain access to the bloodstream through the rich submucosal vessels in the endometrial tissue for dissemination.25,26

As a Gram-negative obligate intracellular pathogen, C. trachomatis replicates in a specialized membrane compartment, utilizes a large arsenal of secreted effectors to survive in the host, and strictly relied on the host for many of their metabolic requirements.27 After infecting host cells, C. trachomatis generates an environment conducive to malignant transformation by interfering with host chromatin, DNA double-strand break repair, and cell-cycle regulation.28 Furthermore, C. trachomatis alters metabolic program of the host by aerobic glycolysis and an accumulation of certain metabolites (such as acetyl-coenzyme A, glutamate and malate), fostering rapid tumor cell proliferation.29 Additionally, C. trachomatis has been implicated in inhibiting apoptosis in infected tumor cells, further supporting its role in tumor proliferation.30–35 These in vitro findings align with our observation that C. trachomatis infection correlates with increased risks of death and progression in breast cancer patients to some extent.

Previous studies have shown that estrogen enhances the attachment and infectivity of chlamydiae,34,36–38 potentially leading to the accumulation of C. trachomatis in estrogen-rich breast tissues. Guseva et al found that estrogen-responsive MCF-7 cells were more susceptible to C. trachomatis than estrogen-negative breast epithelial clone HCC-1806 cells;34 Bose et al reported that treatment of HeLa 229 cultures with a synthetic estrogen analogue prior to infection with C. trachomatis enhanced chlamydial inclusion formation by 50% to 60%.36 Given that younger women had a higher level of estrogen than the elders, C. trachomatis was more likely to adhere to and infect breast cancer cells in younger women, resulting in a greater risk of recurrence, metastasis or death in younger breast cancer patients. Therefore, the observed stronger association between C. trachomatis infection and progression-free survival in breast cancer patients aged 50 years or younger may be attributed to these findings.

Interestingly, our study revealed that the impact of C. trachomatis IgG on the risk of death and progression was more profound in breast cancer patients with higher levels of pro-inflammatory cytokines (IL-6, TNF-α, IL-8, and IL-1β). Higher levels of pro-inflammatory cytokines, indicative of chronic inflammation, are associated with promoting the process of epithelial-mesenchymal transition (EMT),39 leading to the loss of cell polarity and adhesion capacity in epithelial cells and subsequently promoting cell migration and invasion.40 Meanwhile, C. trachomatis can promote EMT.41,42 Thereafter, C. trachomatis and pro-inflammatory cytokines can jointly facilitate EMT, resulting in an apparent interaction on the prognosis of breast cancer. Nevertheless, the exact mechanism remained to be explored.

Our study has several potential limitations. First, information on the treatment related to the outcome was not collected, which may potentially confound the results. As the treatment was determined based on clinicopathological characteristics, adjusting these characteristics in the analysis was able to control the confounding effects of the treatment to a large extent. Second, only patients with serum samples were included, which may be difficult to avoid the selection bias. However, the distribution of clinicopathological features of the subjects in this study was similar to those in the same cohort we reported previously.43 Third, participants were recruited from Guangdong Province, China, potentially introducing geographical limitations that could limit the generalizability of the findings. Nevertheless, upon reviewing the existing literature, it is observed that our findings align with cytological experiments, suggesting that the geographic limitation does not undermine the validity of our results. Furthermore, there is no evidence indicating that the association between Chlamydia trachomatis infection and breast cancer prognosis varies by ethnicity or region. Nonetheless, to enhance the generalizability of our findings, future studies should aim to validate these results in more diverse populations, including different ethnic and regional groups. Finally, considering that the concentrations of pro-inflammatory cytokines were also measured with serum samples collected at the time of diagnosis, we were unable to infer the temporal sequence between C. trachomatis and inflammation in this study, which meant that C. trachomatis may lead to an increase of the cytokines or the cytokines may reactivate chronic infection of C. trachomatis. Thus, relevant biological experiments were needed to clarify this issue.

In conclusion, our study revealed the adverse prognostic roles of C. trachomatis infection in breast cancer patients with higher levels of pro-inflammatory cytokines (IL-6, TNF-α, IL-8, and IL-1β) or those aged ≤ 50 years. Taking measures to control C. trachomatis infection may potentially reduce the risks of death and disease progression in younger patients with breast cancer or those with higher levels of pro-inflammatory cytokines. Further studies are needed to explore the underlying mechanisms.

Abbreviations

C. trachomatis, Chlamydia trachomatis; CI, confidence interval; COI, cut-off index; ELISA, enzyme-linked immunosorbent assay; EMT, epithelial-mesenchymal transition; ER, estrogen receptor; GZBCS, Guangzhou Breast Cancer Study; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; IgG, immunoglobulin G; IL, interleukin; IQR, interquartile range; OD, optical density; OS, overall survival; PFS, progression-free survival; PR, progesterone receptor; STI, sexually transmitted infection; TNF-α, tumor necrosis factor alpha.

Data Sharing Statement

All data produced in the present study are available upon reasonable request to the corresponding author.

Ethics Approval and Informed Consent

All participants provided informed consent prior to study inclusion. This study was approved by the Ethics Committee of the School of Public Health at Sun Yat-sen University (number of Institutional Review Board approval:2012-8) and performed in accordance with the Declaration of Helsinki.

Acknowledgments

We sincerely thank all the patients who participated in this study, the staff who conducted the baseline and the follow-up data collection, and the medical staff in the breast departments of the First and Second Affiliated Hospital of Sun Yat-Sen University.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This work was funded by the Natural Science Foundation of China (No. 82373661).

Disclosure

The authors report no conflicts of interest in this work.

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