Abstract
BackgroundObservational studies have investigated the association of risk factors with breast cancer prognosis. However, the results have been conflicting and it has been challenging to establish causality due to potential residual confounding. Using a Mendelian randomisation (MR) approach, we aimed to examine the potential causal association between breast cancer-specific survival and nine established risk factors for breast cancer: alcohol consumption, body mass index, height, physical activity, mammographic density, age at menarche or menopause, smoking, and type 2 diabetes mellitus (T2DM).MethodsWe conducted a two-sample MR analysis on data from the Breast Cancer Association Consortium (BCAC) and risk factor summary estimates from the GWAS Catalog. The BCAC data included 86,627 female patients of European ancestry with 7054 breast cancer-specific deaths during 15 years of follow-up. Of these, 59,378 were estrogen receptor (ER)-positive and 13,692 were ER-negative breast cancer patients. For the significant association, we used sensitivity analyses and a multivariable MR model. All risk factor associations were also examined in a model adjusted by other prognostic factors.ResultsIncreased genetic liability to T2DM was significantly associated with worse breast cancer-specific survival (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.03–1.17, P value [P] = 0.003). There were no significant associations after multiple testing correction for any of the risk factors in the ER-status subtypes. For the reported significant association with T2DM, the sensitivity analyses did not show evidence for violation of the MR assumptions nor that the association was due to increased BMI. The association remained significant when adjusting by other prognostic factors.ConclusionsThis extensive MR analysis suggests that T2DM may be causally associated with worse breast cancer-specific survival and therefore that treating T2DM may improve prognosis.
Highlights
Observational studies have investigated the association of risk factors with breast cancer prognosis
Relationships between body mass index (BMI), type 2 diabetes mellitus (T2DM), and breast cancer survival To ensure that the effects of BMI and T2DM were independent, we identified Single-nucleotide polymorphism (SNP) that overlapped between the genetic instruments for these risk factors
We found a significant association between genetic liability to T2DM and breast cancer-specific survival (P < 0.05, Table 2)
Summary
Observational studies have investigated the association of risk factors with breast cancer prognosis. Many observational studies have evaluated the association of breast cancer risk and survival with other patient characteristics and lifestylerelated risk factors [3,4,5]. Due to their observational nature, it is difficult for these studies to establish causation. In theory, randomised control trials (RCTs) provide a reliable method to evaluate the causal relationship between risk factors and survival [6, 7], but they are often not feasible as they can be prohibitively expensive, time-consuming, and even unethical. If an RCT cannot be performed to assess the causal effect between a risk factor and the outcome of interest, methods using instrumental variables may be an alternative
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