Prospective studies on insulin-like growth factor I (IGF-I) and epithelial ovarian cancer (EOC) risk are inconclusive. Data suggest risk associations vary by tumour characteristics.
We conducted a nested case–control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate IGF-I concentrations and EOC risk by tumour characteristics (n=565 cases). Multivariable conditional logistic regression models were used to estimate associations.
We observed no association between IGF-I and EOC overall or by tumour characteristics.
In the largest prospective study to date was no association between IGF-I and EOC risk. Pre-diagnostic serum IGF-I concentrations may not influence EOC risk.
Insulin-like growth factor I (IGF-I)-related signalling pathways are implicated in the aetiology of epithelial cancer at various sites (e.g., prostate, colon and breast cancer), including ovarian cancer (reviewed in Bruchim and Werner, 2013; Singh et al, 2014). Insulin-like growth factor I drives cellular proliferation in several cell lines of epithelial neoplasms (reviewed in Pollak, 2008) and is additionally associated with invasion and angiogenesis in epithelial ovarian cancer cells (reviewed in Beauchamp et al, 2010). Recently, IGF-I was shown to be overexpressed in low-grade, but not high-grade, serous ovarian cancer cell lines, suggesting IGF-I may be differentially associated with risk across ovarian cancer subtypes (King et al, 2011). Further, low-grade ovarian cancer cells expressing IGF-I were more responsive to IGF-I stimulation and IGF-I receptor (IGF-IR) inhibition compared with high-grade serous ovarian cancer cells (King et al, 2011).
Prior prospective studies on the association between pre-diagnostic circulating IGF-I and epithelial invasive ovarian cancer (EOC) were inconclusive and evaluated EOC as a single disease entity, without addressing associations in EOC subgroups (i.e., histologic subtype, dualistic model of ovarian carcinogenesis) (Lukanova et al, 2002; Peeters et al, 2007; Tworoger et al, 2007). This is the largest prospective study to date (n=565 cases; 1097 controls) investigating the role of IGF-I and EOC risk, and the first prospective investigation to assess IGF-I and EOC by tumour characteristics (histology, grade, stage and type I/II status).
Materials and methods
The European Prospective Investigation into Cancer and Nutrition (EPIC) is an ongoing multicentre prospective cohort study. Descriptions of study design, population and baseline data collection of the cohort (Riboli et al, 2002) and this nested case–control study (Ose et al, 2014) have been reported in detail. Briefly, 519 978 participants (366 521 women) aged 25–70 years were enrolled from 1992 to 2000 in 10 European countries. Data on diet, reproductive factors, use of exogenous hormones (oral contraceptives (OC) and hormone replacement therapy (HRT)), disease history and anthropometric measures were collected at baseline. A total of 226 673 women provided a baseline blood sample.
Women not using exogenous hormones at blood donation and with no history of cancer at recruitment (with the exception of non-melanoma skin cancer) were eligible for this study.
A total of 565 eligible cases with biological samples and incident epithelial invasive ovarian, fallopian tube or primary peritoneal cancer were 1:2 matched to 1097 controls. An incidence density sampling protocol was used. We included 201 cases and 372 matched controls from a prior analysis in EPIC (phase 1; Peeters et al, 2007) and additional 364 cases (725 matched controls) subsequently diagnosed during follow-up (phase 2).
Information on tumour characteristics (histologic subtype (serous, endometrioid, clear cell, mucinous and not otherwise specified (NOS)), grade (well, moderately or poorly/undifferentiated) and stage (local, regional and metastatic)) was available from pathology reports and from cancer registries. Tumours were classified on the basis of histology and the proposed dualistic pathway of ovarian carcinogenesis (type I/II; Kurman and Shih, 2011). Clear cell carcinomas (n=28) were excluded from type I/II analyses as they show unique clinical behaviour (Penson et al, 2013). All participants gave written informed consent. The Ethical Review Board of the International Agency for Research on Cancer and the Institutional Review Board of each EPIC centre approved these analyses.
Pre-diagnostic concentrations of IGF-I (nmol l−1) were analysed with enzyme-linked immunosorbent assays at IARC (phase 1 (Peeters et al, 2007): DSL, Webster, TX, USA) and at the Division of Cancer Epidemiology at the German Cancer Research Center (phase 2: Immunodiagnostics Systems, Frankfurt, Germany). Cases and matched controls were analysed within the same analytical batch by laboratory technicians blinded to case–control status and identity of quality control samples. Intra- and inter-batch coefficients of variation from replicate quality control (QC) samples were 2.50% and 12.20% (phase 1: triplicate QCs), and 9.42% and 8.93% (phase 2: duplicate QCs).
Insulin-like growth factor I values were log2 transformed and centred to a mean value of zero in each phase. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Insulin-like growth factor I was examined continuously on the log2 scale and in tertiles with phase-specific cut-offs based on the distribution in controls.
The final model included full-term pregnancy (never/ever), as other covariates (BMI, height, smoking, physical activity, diabetes, alcohol, age at menarche, age at first birth, number of births, age at menopause, OC use and HRT use) did not change the OR by >10% (i.e., by a factor 1.10 or its reciprocal; Maldonado and Greenland, 1993).
Heterogeneity in the associations between IGF-I and EOC by tumour characteristics was assessed using likelihood ratio tests comparing logistic regression models with and without corresponding interaction terms (Rothman et al, 2008).
Sensitivity analyses included stratification by menopausal status at blood donation and age at diagnosis (<55 and ⩾55 years); exclusion of women providing a blood sample <2 years before diagnosis (to ensure any observed associations were not due to cancers influencing circulating concentrations of IGF-I, but not yet diagnosed) and women who had a prior hysterectomy.
All statistical tests were two-tailed and significant at the P<0.05 level. SAS 9.2 (SAS Institute Inc., Cary, NC, USA) was used for all statistical analysis.
Cases and controls were similar with respect to most characteristics, except for established reproductive risk factors (e.g., cases were less likely to be parous, P<0.01 or to use OCs, P<0.01; Table 1). We observed no case–control differences in IGF-I concentrations overall or by study phase.
There was no association between EOC and IGF-I concentrations for doubling of hormone concentrations or comparing top to bottom tertiles in overall analyses (all histological subtypes combined (ORlog2=0.88; 95% CI 0.71–1.08)). A similar pattern was observed in subgroup analyses by tumour characteristics (e.g., serous tumours: ORlog2=0.98; 95% CI 0.74–1.30; Table 2). We did not observe heterogeneity between risk associations by tumour characteristics (e.g., Phet for histological subtypes=0.12). Overall, risk estimates were similar when analyses were restricted to study phase 2 (data not shown).
Results were similar in sensitivity analyses by age at diagnosis (<55 vs ⩾55) and menopausal status at blood donation (pre- vs postmenopausal at blood donation). Excluding women with unilateral oophorectomy/hysterectomy (n=116) or women diagnosed within 2 years after blood donation (n=84) led to results comparable to overall results (data not shown).
This is the largest prospective study on the relationship between IGF-I and EOC to date and the first to assess risk associations by tumour characteristics. We observed no association between IGF-I and EOC overall. The same pattern was observed in analyses stratified by tumour characteristics, age at diagnosis or menopausal status at blood donation.
Three prospective studies (range: 132 cases (Lukanova et al, 2002) to 222 cases (Tworoger et al, 2007)) have evaluated this association previously. Two of these studies observed a positive association between IGF-I and EOC in women <55 at diagnosis (Lukanova et al, 2002; Peeters et al, 2007); however, sample size in these subgroups was limited (n⩽66 younger than 55 at diagnosis) and confidence intervals were wide (i.e., ORQ3-Q1=5.10; 95% CI 1.50–18.20 (Peeters et al, 2007)). In a US-based study, no association was observed in women diagnosed before the age of 55, but there was an inverse association in women diagnosed after the age of 55 (ORQ4-Q1=0.52; 95% CI 0.28–0.95 (Tworoger et al, 2007)). Slightly different exclusion criteria might contribute to inconsistent results across studies (e.g., exclusion of: cases diagnosed within 1 year after blood donation (Lukanova et al, 2002), fallopian tube cancers (Tworoger et al, 2007), unilateral oophorectomy/hysterectomy (EPIC phase 1; Peeters et al, 2007). In the current study including 565 EOC cases, we observed no association between IGF-I and ovarian cancer risk regardless of the age at diagnosis.
Elevated IGF-I concentrations may lead to the development of a malignant cell rather than to apoptotic cell death in the early phases of carcinogenesis (reviewed in Pollak, 2008). Insulin-like growth factor I signalling is predominantly mediated by the IGF-IR; higher IGF-IR expression is associated with development of epithelial neoplasms through anti-apoptotic and mitogenic activities and its role in oncogenic transformation (reviewed in Pollak, 2008). We hypothesised that circulating IGF-I would be differentially associated with ovarian cancer subtypes given the differential expression of IGF-I in low- and high-grade serous tumours. Insulin-like growth factor I has been shown to be overexpressed in low-grade serous ovarian cancer cell lines (i.e., type I), which were more responsive to IGF-I stimulation and IGF-IR inhibition compared with high-grade serous ovarian cancer cell lines (i.e., type II) (King et al, 2011). We did not observe the hypothesised associations; however, we had small sample size in some subgroups (i.e., low-grade serous tumours, n=35).
Our study has important strengths and limitations. We investigated pre-diagnostic serum IGF-I and EOC risk in a large, well-characterised nested case–control study. However, circulating IGF-I may not be reflective of IGF-I exposure in the ovary. Although the data on this association are mixed (Rabinovici et al, 1990; Thierry van Dessel et al, 1996), there is evidence to suggest that follicular fluid concentrations are well correlated with serum concentrations (r=0.77, P<0.001; Dorn et al, 2003). In addition, the current analysis is based on a single biomarker in the IGF signalling axis. However, data to date suggest IGF-I and the IGF-IR are the most relevant members of the IGF family for ovarian carcinogenesis (reviewed in Beauchamp et al, 2010). In line with other epidemiologic studies, a single measurement was used to evaluate risk associations. However, relatively high intra-individual reproducibility of IGF-I measurements has been consistently shown (2–3 years; premenopausal women: ICC=0.86 (Missmer et al, 2006), up to 5 years; pre- and postmenopausal women: ICC=0.71 (Borofsky et al, 2002)).
The sample size for subgroup analyses by tumour characteristics (e.g., histology, grade or type I/type II) may have been too small to detect an association, with the exception of the group of serous tumours (cases n=302). For subgroup analyses by grade as well as type I/type II classification a considerable proportion of data was missing (>39%), further limiting sample size in those subgroups.
Despite evidence suggesting that IGF-I could be involved in EOC development (reviewed in Bruchim and Werner, 2013; Singh et al, 2014), our study shows no association between circulating IGF-I and EOC risk. Larger, pooled prospective studies are needed to confirm our results and to address the associations in small subgroups with more statistical power and assess risk associations with expression of IGF receptors.
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We thank all the EPIC participants for their invaluable contribution to the study. The German Cancer Research Center, Division of Cancer Epidemiology (Principal Investigator: Rudolf Kaaks) funded the analysis of IGF-I for this study. The European Prospective Investigation into Cancer and Nutrition is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); Deutsche Krebshilfe (70-2488), Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany; Grant 01-EA-9401); Hellenic Health Foundation (Greece) and the Stavros Niarchos Foundation; Italian Association for Research on Cancer (AIRC) and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health. (Norway); Health Research Fund (FIS) of the Spanish Ministry of health (Exp 96/0032), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK, Medical Research Council (United Kingdom).
The authors declare no conflict of interest.
The sponsors had no role in the study design, data collection, and analysis, interpretation of results or writing of the paper.
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Ose, J., Fortner, R., Schock, H. et al. Insulin-like growth factor I and risk of epithelial invasive ovarian cancer by tumour characteristics: results from the EPIC cohort. Br J Cancer 112, 162–166 (2015). https://doi.org/10.1038/bjc.2014.566
- ovarian cancer
- histological subtypes
- type I/type II
- dualistic pathway
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