Breast cancer survivors who were treated with either tamoxifen or an aromatase inhibitor (AI) for hormone receptor-positive breast cancer were significantly more likely to develop diabetes during a median follow-up of 5.9 years compared with women who did not have hormonal therapy, a case-control study found.
In a study of 2,246 female breast cancer patients with no history of diabetes before their diagnosis or in the first year thereafter, Israeli investigators found that hormone therapy increased the risk of diabetes by almost 2.5 times on multivariable-adjusted analysis compared with those who did not have hormone therapy, according to Rola Hamood, MD, of the University of Haifa, and colleagues.
The study, online in the Journal of Clinical Oncology, showed a Hazard Ratio (HR) of 2.40 (95% CI, 1.26 to 4.55; P=0.008). Some 48% of the diabetes that did occur in the entire diabetes cohort during follow-up could also have been prevented had patients not received hormonal therapy, the investigators reported. The risk of diabetes also persisted during the entire time women received hormone therapy.
The team emphasized that "breast cancer survivors should not be denied this treatment, because the survival benefits outweigh the risks." Still, the "dramatic increase" in prevalence within a relatively brief time, and the establishment of hormone therapy as a risk factor that accounts for >45% of diabetes incidence in breast cancer survivors means that survivors who receive hormone therapy should be closely monitored.
The study included women diagnosed with primary nonmetastatic invasive breast cancer between 2002 and 2012. The primary outcome was diabetes-free survival, which was defined as the time from study entry (1 year after breast cancer diagnosis) to a first diagnosis of diabetes.
Of the total cohort of women analyzed, 324 developed diabetes over the follow-up interval. Analyzed by the type of hormonal therapy taken, the risk for diabetes was over twice as high among women who had tamoxifen compared with those who did not — HR of 2.25 (95% CI, 1.19 to 4.26; P=0.013).
The risk of developing diabetes among women who took an AI was considerably higher — HR of 4.27 (95% CI, 1.42 to 12.84; P=0.010) — compared with women not exposed to an AI during their treatment for breast cancer. Furthermore, after 13 years of observation, "the crude cumulative incidence rate of diabetes in the presence of death as a competing risk was 20.9% (95% CI, 18.3% to 23.7%)," the authors reported.
The study’s senior author, Hatem Hamood, MD, of Leumit Health Services in Karmiel, Israel, noted via email that if patients died before developing diabetes, they were not included in the analysis, since they were no longer at risk of diabetes. However, by doing this, "the cumulative incidence of diabetes will be overestimated, as it will be applied on survivors only. Thus, assessment of the cumulative incidence without taking into account the completing risk of death will likely lead to upward estimates, and thus the necessary adjustment was made to arrive at unbiased results."
The prevalence rates of diabetes in the population of breast cancer survivors analyzed in the study increased from 6% in 2002 to 28% in 2015.
The researchers also analyzed a subcohort of 570 participants that included women with diabetes who were alive at the time the study was carried out; the mean time that had elapsed since breast cancer diagnosis was 6.4 years. Looking specifically at those who developed diabetes over time, the investigators found that participants who eventually developed diabetes made more frequent outpatient visits, were exposed to more drugs known to promote diabetes, and had received hormone therapy for longer periods of time than women who did not develop diabetes over the course of follow-up.
Following the diagnosis of diabetes, the same group of women were more likely to be obese, to consume an unhealthy diet, and to be physically inactive — all risk factors for diabetes. "Our findings demonstrate that diabetes management in our cohort was clearly suboptimal, as diabetes cases led an unhealthy lifestyle, characterized by obesity, lack of exercise, and poor nutrition," Hamood said.
"Therefore, we believe that strategies should be targeted to the prevention of diabetes, which maximizes survival and minimizes the net health and economic burden of diabetes. A first step to realization of this goal is lifestyle modification targeting both dietary and physical activity behavior and by screening for diabetes."
Asked for her perspective, Maryam Shafaee, MD, of the Dan L. Duncan Comprehensive Cancer Center of Baylor College of Medicine in Houston, pointed out that obesity in and of itself is a risk factor for breast cancer.
Because women in the current analysis who developed diabetes were significantly more likely to be obese than those who did not (P<0.001), they may have already been predisposed to develop diabetes independent of any effect that hormonal therapy might have had on their diabetes risk, Shafaee explained. Women who developed diabetes in the study were also significantly less likely to engage in any physical activity than women who did not (P<0.001), and being active appears to be protective against the development of both breast cancer and diabetes in general. Nevertheless, "I think the findings were noteworthy.
"We see a lot of breast cancer survivors in our clinics, and these are the kinds of issues they often struggle with. First, because treatment with an AI often causes joint pain, making exercise difficult, and second, because treatment with tamoxifen often causes hot flushes, making it unpleasant to exercise. Life after diagnosis and treatment of breast cancer is not the same as the way it was before, so a lot of things change in these patients’ lives — in their work as well as what they are able or willing to do after the diagnosis.
"But given that not only obesity but diabetes are huge risk factors for morbidity in breast cancer survivors, these issues need to be better addressed, and lifestyle modification and education are something our society as a whole needs to be more aware of and implement."
The study was supported in part upported in part by grants from the Council for Higher Education in collaboration with the Graduate Studies Authority at the University of Haifa.
The researchers, as well as Shafaee, reported having no conflicts of interest.