Abstract
ObjectiveTo evaluate whether the genetic susceptibility of T2D was associated with overall survival (OS) and disease-free survival (DFS) outcomes for breast cancer (BC).MethodsIncluded in the study were 6346 BC patients who participated in three population-based epidemiological studies of BC and were genotyped with either GWAS or Exome-chip. We constructed a genetic risk score (GRS) for diabetes using risk variants identified from the GWAS catalog (http://genome.gov/gwastudies) that were associated with T2D risk at a minimum significance level of P ≤ 5.0E-8 among Asian population and evaluated its associations with BC outcomes with Cox proportional hazards models.ResultsDuring a median follow-up of 8.08 years (range, 0.01–16.95 years), 1208 deaths were documented in 6346 BC patients. Overall, the diabetes GRS was not associated with OS and DFS. Analyses stratified by estrogen receptor status (ER) showed that the diabetes GRS was inversely associated with OS among women with ER- but not in women with ER+ breast cancer; the multivariable adjusted HR was 1.38 (95% CI: 1.05–1.82) when comparing the highest to the lowest GRS quartiles. The association of diabetes GRS with OS varied by diabetes status (P for interaction <0.01). In women with history of diabetes, higher diabetes GRS was significantly associated with worse OS, with HR of 2.22 (95% CI: 1.28–3.88) for the highest vs. lowest quartile, particularly among women with an ER- breast cancer, with corresponding HR being 4.59 (95% CI: 1.04–20.28). No significant association between the diabetes GRS and OS was observed across different BMI and PR groups.ConclusionsOur study suggested that genetic susceptibility of T2D was positively associated with total mortality among women with ER- breast cancer, particularly among subjects with a history of diabetes. Additional studies are warranted to verify the associations and elucidate the underlying biological mechanism.
Highlights
Breast cancer is the most common cancer diagnosis in women in China and worldwide[1]
We constructed a genetic risk score (GRS) for diabetes using risk variants identified from the genome-wide association studies (GWAS) catalog that were associated with type 2 diabetes (T2D) risk at a minimum significance level of P 5.0E-8 among Asian population and evaluated its associations with breast cancer (BC) outcomes with Cox proportional hazards models
Analyses stratified by estrogen receptor status (ER) showed that the diabetes GRS was inversely associated with overall survival (OS) among women with ER- but not in women with ER+ breast cancer; the multivariable adjusted hazard ratios (HRs) was 1.38 when comparing the highest to the lowest GRS quartiles
Summary
Breast cancer is the most common cancer diagnosis in women in China and worldwide[1]. Survival after breast cancer diagnosis is influenced by tumor characteristics such as disease stage, tumor grades, hormonal status, and treatment. Recent epidemiological studies, including our own study, the Shanghai Breast Cancer Survival Study (SBCSS) [2], have shown that comorbidities, such as diabetes and hypertension, influence breast cancer outcomes [3, 4, 5, 6]. Few studies [11, 13] have evaluated the association of diabetes on outcomes of breast cancer by estrogen receptor status, the most important prognostic factor. Studies have shown that under-diagnosis of diabetes is common, ranging from 27% in the US to 60% in China [16, 17]. It has been recently recognized that diabetes treatments, the use of metformin, may mitigate the negative influence of diabetes on mortality, and may even reduce the risk of recurrence [18, 19], making it difficult to interpret the diabetes and breast cancer outcomes associations
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