Prognostic role of serum total cholesterol and high-density lipoprotein cholesterol in cancer survivors: A systematic review and meta-analysis

Highlights

• 26 cohorts with over 9 cancer types including 24,655 individuals are included.

• High blood TC and HDL-C level is associated with better prognosis in cancer.

• Blood TC and HDL-C are strongly associated with prognosis in specific cancer types.

Abstract

Background

The alterations of lipid profile in cancer has been reported to be associated with cancer development. However, the prognostic value of serum lipid markers level in cancer is currently under debate. Here we performed a meta-analysis to investigate the prognostic significance of serum blood total cholesterol (TC), Triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) for cancer.

Methods

We systematically searched in PubMed and EMBASE for follow-up studies to evaluate the association between blood TC, TG, HDL-C, LDL-C and overall survival (OS) or disease-free survival (DFS) in patients with cancer. Pooled hazard ratio (HR) and 95% CIs were pooled using the random models. Subgroup and sensitivity analyses were also performed.

Results

Twenty-six studies including 24655 individuals were identified. For patients with higher TC before diagnosis, the summary HR were 0.82 (95% CI 0.75–0.90) for OS, 0.920 (95% CI, 0.849–0.997) for DFS. Patients with higher HDL-C had a 37% reduced risk of death compared with lower HDL-C (HR 0.63, 95%CI 0.47–0.86, P < 0.001). As for DFS, patients with higher HDL-C level had the risk of disease relapse reduced by 35% (HR 0.65, 95% CI, 0.48–0.89, P < 0.001) compared with patients with lower levels.

Conclusions

After pooled analysis, only TC and HDL-C were significantly associated with cancer survival. Our findings demonstrate for the first time that serum TC and HDL-C was identified as a protective factor for overall survival in cancer patients.

Introduction

Advances in understanding mechanisms underlying cancer biology have resulted in the identification of novel therapeutic targets that have prolonged the lives of some patients with cancer. Nevertheless, stratifying risk before giving treatments remain significant challenges for oncologists. Clinicians currently relies exclusively on the TNM staging system based on preoperative imaging or biopsy to do risk stratification [1], [2], [3], [4], [5], [6], which cannot always accurately predict the benefit from therapy and risk of disease recurrence in cancer patients [7], [8]. Therefore, finding new prognostic biomarkers which can contribute to better stratify cancer risk and select patients who can most benefit from treatments could be especially useful.

Currently, abnormal lipid metabolism is increasingly recognized as important mechanism of carcinogenesis, and it has been widely evaluated that disorders in lipid and lipoprotein metabolism as a result of metabolic syndrome, overweight and obesity, might be associated with cancer risk and impacts prognosis in cancer patients [9], [10], [11]. Cholesterol, localized in lipid rafts-membrane micro-domains, assembles the signal transduction machinery and cell biological studies support a critical involvement of cholesterol in the modulation of proteins implicated in key cellular signaling pathways. These pathways organization can result in malignant transformation, including breast, colon, and nasopharyngeal cancer, due to altered cytoskeleton, cell polarity and angiogenesis [12], [13], [14], [15], [16], [17], [18], [19]. However, the clinical data on cancer remains very limited and inconsistent. Several studies support the positive association between high level of total cholesterol (TC) and cancer incidence [20], [21], [22] and overall mortality in cancer patients [23]. On the contrary, no association or even inverse association between TC levels and incidence of cancer was observed [24], [25], [26], [27].

High and low density serum lipoproteins act as key lipoprotein carriers of cholesterol to cancer cells via receptor mediated mechanisms [28]. In addition, they also play an important role in regulating the signaling pathways of cancer cell. It was reported that low density lipoproteins (LDL) can promote cancer metastasis through regulating integrin transfer [29], [30]. It also has been found that patients with distant metastases had markedly higher levels LDL-C compared with patients without metastases [31]. However, retrospective studies have revealed that patients with lower LDL-C levels are associated with a greater risk of malignancy [32], [33]. Recent studies have investigated that serum high-density lipoprotein (HDL) is associated with the incidence of cancer especially breast cancer. These findings imply that HDL might play an important role in promoting tumor progression [34], [35], [36]. However, the exact mechanism of lipid metabolism in tumor development has not been completely stated. Previous research has reported that low HDL-C levels are in relation to increased post-menopausal breast cancer risk [37], [38], [39]. In addition, reduced pre-treatment HDL-C levels were associated with worse prognosis in NSCLC patients [40].

Given the substantial controversy in various cancers, such as breast cancer, gastric cancer, lung cancer, hepatocellular carcinoma and renal cell cancer, we perform a meta-analysis to investigate the prognostic values of the serum lipid parameters, including HDL-C, LDL-C, TC, and Triglyceride (TG) in cancer patients. To our knowledge, our study is the first meta-analysis to make research about the association of TC, TG, LDL-C, and HDL-C with oncologic outcomes in cancer.