Insulin-like growth factor 1 (IGF-1) and its main binding protein (IGFBP-3) in blood have been associated with the risk of several types of cancer. However, epidemiological studies have inconsistent results regarding the association of circulating IGF-1/IGFBP-3 levels with ovarian cancer risk. A systematic review of the prospective studies was conducted using meta-analysis to evaluate the existing evidence. Pubmed and Embase databases were searched to identify the relevant studies published before May 1, 2014. Four highly qualified studies with a total of 627 cases and 1,358 controls were finally included in the meta-analysis. Random effects meta-analysis was conducted by combining study-specific odds ratios (ORs) of ovarian cancer for the highest verses lowest exposure levels. A dose-response association was further assessed by relating the log of ORs for different exposure levels. As a result, the pooled ORs for the highest verses lowest categories of IGF-1/IGFBP-3 were 0.85 [95% confidence interval (CI), 0.51–1.40]/0.78 (95% CI, 0.43–1.40). In the subgroup analyses, the pooled ORs of IGF-1/IGFBP-3 were 1.89 (95% CI, 0.64–5.59)/1.08 (95% CI, 0.50–2.32) for the subgroup with cases diagnosed at <55 years, and 0.74 (95% CI, 0.50–1.08)/0.98 (95% CI, 0.73–1.33) for the subgroup with cases diagnosed at ≥55 years. No linear association between circulating IGF-1/IGFBP-3 levels and ovarian cancer risk was identified. As no significant association of IGF-1/IGFBP-3 with ovarian cancer risk was identified in the present meta-analysis of existing studies, more studies with greater quality are required in the future.
The insulin-like growth factor (IGF) family is a complex molecular signaling pathway, which plays an important role in oncogenesis, tumor progression, metastasis and chemoresistance (
A systematic literature search of Pubmed and Embase databases was conducted to identify all the studies published before May 1, 2014, which investigated the association of circulating IGF-1 or IGFBP-3 with the ovarian cancer risk. The following keywords were used during the search: ‘Insulin-like growth factor’ and ‘ovarian cancer’. Reference lists of relevant studies and general reviews were also searched. No restriction of languages was imposed. The systematic review was performed following the guideline of the Meta-analysis Of Observational Studies in Epidemiology (
The eligibility of studies was assessed by two investigators (Q.W. and H.L.P.) independently. Studies were included into the meta-analysis when they met the following criteria: i) Cohort or case-control studies published in full texts; ii) researching the association of circulating IGF-1/IGFBP-3 with ovarian cancer risk; iii) categorizing circulating IGF-1/IGFBP-3 concentrations into tertile or quartile levels; and iv) reporting odds ratios (ORs) with 95% confidence intervals (CIs), with results from crude and adjusted (adjusted for confounders) models. Study quality was assessed using the nine-star Newcastle-Ottawa scale (
The two investigators mentioned performed data extraction independently and discussed the results to make a consensus. The following variables were recorded: First author's name, publication year, geographic region where the study was conducted, study period, study design, sample size, IGFs assay, categorizing and corresponding cut-points of IGF-1/IGFBP-3 levels, ORs with 95% CIs for each category verses reference (the lowest category) of IGF-1/IGFBP-3, the numbers of cases and controls in each exposure category, and confounders considered in the adjustment models. When necessary, the primary authors were contacted for additional information.
Considering that the IGF assays and categorizing cut-points differed across studies, a random effects model (
The degree of heterogeneity among studies was assessed via Q and I2 statistics. Subgroup analyses and meta-regression models (
All the statistical tests were performed with the Stata software (version 12.0; StataCorp, College Station, TX, USA). P<0.05 was considered to indicate a statistically significant difference.
A flow diagram of the literature search is shown in
The remaining four studies (
There were no statistically significant associations of circulating IGF-1 or IGFBP-3 with ovarian cancer risk when the maximally adjusted ORs for the highest verses lowest exposure levels in each study were pooled into meta-analysis [OR, 0.85 (95% CI, 0.51–1.40) for IGF-1 and OR, 0.78 (95% CI, 0.43–1.40) for IGFBP-3]. When participants in all the studies were analyzed as a whole, potential heterogeneity among the studies was represented in the analysis model (P=0.103, I2=51.5% in the IGF-1 model; and P=0.042, I2=63.4% in the IGFBP-3 model) (
In the subgroup analyses according to the age at diagnosis, the pooled ORs of IGF-1 were 1.89 (95% CI, 0.64–5.59) for the subgroup with cases diagnosed before 55 years (tests of heterogeneity: P=0.063, I2=63.7%) and 0.74 (95% CI, 0.50–1.08) for the subgroup with cases diagnosed at ≥55 years (tests of heterogeneity: P=0.362, I2=0.0%). The pooled ORs of IGFBP3 were 1.08 (95% CI, 0.50–2.32) for the subgroup cases diagnosed before 55 years (tests of heterogeneity: P=0.209, I2=36.1%) and 0.98 (95% CI, 0.73–1.33) for the subgroup with cases diagnosed at ≥55 years (tests of heterogeneity: P=0.617, I2=0.0%) (
In the meta-regression models, the residual variation due to heterogeneity was not changed by geographic regions, year of publication, sample type (serum or plasma), assays (immunoradiometric assay or ELISA), confounders (smoking status or ever use of hormones) or range of exposure levels. However, the Knapp-Hartung meta-regression model (
Three studies reporting the exact numbers of cases and controls in each exposure category were included in the random effects dose-response meta-analysis (
No significant association of circulating IGF-1/IGFBP-3 with ovarian cancer risk was indicated in the present meta-analysis or in the dose-response analysis. Potential heterogeneity was represented when regarding participants in all the studies as a whole. However, heterogeneity in the IGFBP-3 model was significantly diminished using subgroup analysis based on age at diagnosis. Furthermore, meta-regression models were conducted and it was found that inclusion of females that were using exogenous hormones at the time of blood donation in studies was the main source of heterogeneity in analysis of IGF-1. This could be explained by the complicated interactions between sex steroid hormones and the IGF system. A previous study (
In all the studies reviewed in the present analysis, two prospective nested case-control studies [Peeters
Compared to the above two studies, an inverse association of circulating IGF-1 with ovarian cancer risk was observed in the case-control study [Dal Maso
The present meta-analysis was conducted to comprehensively and precisely evaluate the association of circulating IGF-1/IGFBP-3 with ovarian cancer, by combining the inconsistent findings of independent but similar studies. However, the meta-analyses found no sufficient evidence to confirm that circulating IGF-1/IGFBP-3 levels are associated with ovarian cancer risk. This result may be limited by the small number of current relevant studies and sample size included. In addition, as the majority of control groups were set in hospitals and health care centers, controls were not definitely free of other benign diseases that may affect the circulating levels of IGFs (
Despite the limitations, the present meta-analysis currently represents the overall view regarding the association of circulating IGF-1/IGFBP-3 levels and ovarian cancer risk, which has not been systematically reviewed previously. Additionally, the review exhibits several important problems that should be considered in future research. Despite the importance of prospective study design and stratified analyses of age, which were already discussed in the previous studies and systematic review in associating IGF-1/IGFBP-3 with other cancers (
In conclusion, the present meta-analysis found no significant association of IGF-1/IGFBP-3 with ovarian cancer risk. However, a more precise analysis with larger sample sizes should be conducted if more studies with improved quality are available in the future.
Flow diagram of the literature search process. IGF-1, insulin-like growth factor 1; IGFBP-3, insulin-like growth factor binding protein 3; OC, ovarian cancer.
Maximally adjusted odds ratios for the highest verses lowest levels of circulating insulin-like growth factor 1. CI, confidence interval.
Maximally adjusted odds ratios for the highest verses lowest levels of circulating insulin-like growth factor binding protein 3. CI, confidence interval.
Study characteristics.
First author (year) | Region | Study period | Study design | No. of case/control | Matched | IGFs test | Measure/range of exposure (ng/ml) | Adjustment for covariates | Study quality |
(Refs.) |
---|---|---|---|---|---|---|---|---|---|---|
Peeters (2007) | Denmark, France, Greece, Germany, Italy, The Netherlands, Spain, UK | 1999–2003 | Prospective nested c/c | 214/388 | Yes | Serum, ELISA | <156 (tertfile 1) ≥216 (tertfile 3) | Parity, BMI, ever use of HRT or OCont and fertility problems | 9 | ( |
Lukanova (2002) | USA, Sweden, Italy | 1985–2000 | Prospective nested c/c | 132/263 | Yes | Serum/plasma, IRMA, blind test | Tertile | Parity, smoking status, BMI and IGFs system | 8 | ( |
Tworoger (2007) | USA | 1976–2004 | Prospective nested c/c | 222/599 | Yes | Plasma, ELISA, blind test | <139 (quartile 1) 169 to <212 (quartile 3) | Parity, ever use of HRT or OCont, simple hysterectomy, tubal ligation, physical activity, age at menarche and menopause, IGFs system | 8 | ( |
Dal Maso (2004) | Italy | 1999–2003 | c/c | 59/108 | NR | Plasma, ELISA | <103 (tertfile 1) ≥151 (tertfile 3) | Parity, HRT, OCont, smoking status and IGFs system | 7 | ( |
Study quality was assessed using the nine-star Newcastle-Ottawa scale. IGF, insulin-like growth factor; c/c, case-control study; ELISA, enzyme-linked immunosorbent assay; BMI, body mass index; HRT, hormone replacement therapy; OCont, oral contraceptive; IRMA, immunoradiometric assay; NR, not reported.