Hypertension and diabetes treatment and risk of adverse outcomes among breast cancer patients

Background: Management of comorbidities is a critical issue among 2.9 million breast cancer survivors in the U.S. Hypertension and diabetes are two common chronic conditions affecting this patient population. Despite the generally good safety profile of widely used antihypertensive medications and diabetes treatments, few studies have examined their relationships with adverse breast cancer outcomes. In particular, metformin, a first line diabetes treatment, is hypothesized to lower the risk of incident breast cancer, but it is unclear whether metformin influences breast cancer progression. The purpose of this dissertation was to characterize how commonly prescribed classes of antihypertensive medications and diabetes treatments relate to adverse breast cancer outcomes. Methods: We conducted a retrospective cohort study of women between ages 66 and 80 years newly diagnosed with stage I or II breast cancer during 2007-2011. A total of 14,766 eligible women were identified in the linked Surveillance, Epidemiology and End-Results (SEER)-Medicare database. Medicare Part D Prescription Drug Event data were obtained to characterize women’s use of commonly used antihypertensive medications (angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), β-blockers, calcium channel blockers and diuretics) and diabetes treatments (metformin, sulfonylureas, insulin therapy and other diabetes treatments) after their breast cancer diagnosis. Primary outcomes were any second breast cancer events (SBCEs, recurrence or second primary breast cancer, n=791), recurrence per se (n=627), and breast cancer-specific mortality (n=327). Time varying Cox proportional hazard models, adjusted for demographic characteristics, tumor characteristics, first course treatment and a history of diabetes and hypertension, were used to estimate hazard ratios (HRs) and their associated 95% confidence intervals (CIs). Results: Use of diuretics (n=8,517) after breast cancer diagnosis was associated with 40% (95% CI: 1.20-1.64), 41% (95% CI: 1.18-1.67) and 78% (95% CI: 1.32-2.40) higher risks of a SBCE, recurrence and breast cancer death, respectively, compared to nonusers of diuretics. Use of β-blockers (n=7,145) was associated with a 1.63-fold (95% CI: 1.24-2.13) higher risk of breast cancer death compared to women who did not use this class of drug. Use of angiotensin II receptor blockers was associated with 1.26-fold (95% CI: 1.08-1.48) higher risk of a SBCE. Use of calcium channel blockers and angiotensin-converting enzyme inhibitors were generally not associated with an altered risk of adverse breast cancer outcomes. With respect to diabetes treatments, use of metformin after breast cancer (n=2,558) was associated with a 22% (95% CI: 0.62-0.98), 26% (95% CI: 0.57-0.96), and 40% (95% CI: 0.40-0.90) lower risk of a SBCE, breast cancer recurrence, and breast cancer death, respectively, compared to metformin nonusers. Use of sulfonylureas and insulin were associated with 1.58 (95% CI: 1.08-2.30) and 2.64-fold (95%CI: 1.78-3.92) higher risks of breast cancer death, respectively, than women who did not use these drugs. Conclusions: Use of certain types of antihypertensive medications after breast cancer diagnosis, including diuretics and β-blockers, may increase risk of adverse breast cancer outcomes among older women while use of metformin is associated with reduced risks of adverse outcomes. Additional research is warranted to clarify these potential associations.