Insulin-like growth factor-1, insulin-like growth factor-binding protein-3, and breast cancer risk: observational and Mendelian randomization analyses with ∼430 000 women

Abstract

Background: Epidemiological evidence supports a positive association between circulating insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk, but both the magnitude and causality of this relationship are uncertain. We conducted observational analyses with adjustment for regression dilution bias, and Mendelian randomization (MR) analyses allowed for causal inference.

Patients and methods: We investigated the associations between circulating IGF-1 concentrations and incident breast cancer risk in 206 263 women in the UK Biobank. Multivariable hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. HRs were corrected for regression dilution using repeat IGF-1 measures available in a subsample of 6711 women. For the MR analyses, genetic variants associated with circulating IGF-1 and IGF-binding protein-3 (IGFBP-3) levels were identified and their association with breast cancer was examined with two-sample MR methods using genome-wide data from 122 977 cases and 105 974 controls.

Results: In the UK Biobank, after a median follow-up of 7.1 years, 4360 incident breast cancer cases occurred. In the multivariable-adjusted models corrected for regression dilution, higher IGF-1 concentrations were associated with a greater risk of breast cancer (HR per 5 nmol/l increment of IGF-1 = 1.11, 95% CI = 1.07-1.16). Similar positive associations were found by follow-up time, menopausal status, body mass index, and other risk factors. In the MR analyses, a 5 nmol/l increment in genetically-predicted IGF-1 concentration was associated with a greater breast cancer risk (odds ratio = 1.05, 95% CI = 1.01-1.10; P = 0.02), with a similar effect estimate for estrogen-positive (ER⁺) tumours, but no effect found for estrogen-negative (ER^-) tumours. Genetically-predicted IGFBP-3 concentrations were not associated with breast cancer risk (odds ratio per 1-standard deviation increment = 1.00, 95% CI = 0.97-1.04; P = 0.98).

Conclusion: Our results support a probable causal relationship between circulating IGF-1 concentrations and breast cancer, suggesting that interventions targeting the IGF pathway may be beneficial in preventing breast tumorigenesis.

Keywords: Mendelian randomization; breast cancer; insulin-like growth factor-1 (IGF-1); insulin-like growth factor-binding protein-3 (IGFBP-3); observational.

Figure 1

Subgroup analyses of the association between circulating insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk in the UK Biobank (per 5 nmol/l increment). Multivariable Cox regression model using age as the underlying time variable and stratified by Townsend deprivation index (fifths), region of the recruitment assessment centre, and age at recruitment (5-year categories). Models adjusted for total physical activity (<10, 10 to <20, 20 to <40, 40 to <60, ≥60 metabolic equivalent hours per week, unknown); height (per 10 cm); alcohol consumption frequency (never, special occasions only, one to three times per month, one to two times per week, three to four times per week, daily/almost daily, unknown); smoking status and intensity (never, former, current <15 per day, current ≥15 per day, current intensity unknown, unknown); educational level (CSEs/O-levels/GCSEs or equivalent, NVQ/HND/HNC/A-levels/AS-levels or equivalent, other professional qualifications, college/university degree, none of the above, unknown); ever use of hormone replacement therapy (no, yes, unknown); parity, age at first birth (nulliparous; 1–2, <25 years; 1–2, 25–30 years; 1–2, ≥30 years; 1–2, unknown; ≥3, <25 years; ≥3, 25–30 years; ≥3, ≥30 years; ≥3, unknown; unknown); the interaction between menopausal status and body mass index (kg/m²); and circulating concentrations (fifths, missing/unknown) of C-reactive protein (CRP; mg/l), glycated haemoglobin (HbA1c; mmol/mol), testosterone (nmol/l), and sex hormone binding globulin (SHBG; nmol/l). Median values: height = 162 cm; CRP = 1.3 mg/l; HbA1c = 35.1 mmol/mol; testosterone = 1 nmol/l; SHBG = 56.3 nmol/l. HRs per 5 nmol/l increment were additionally corrected for regression dilution using a regression dilution ratio (0.74) obtained from the subsample of women with repeat IGF-1 measurements. CI, confidence interval; HR, hazard ratio.