Metformin and thiazolidinediones are associated with improved breast cancer-specific survival of diabetic women with HER2+ breast cancer

Abstract

Background: Insulin/insulin-like growth factor-I (IGF-I) signaling is a mechanism mediating the promoting effect of type 2 diabetes (DM2) on cancer. Human epidermal growth factor receptor (HER2), insulin receptor and IGF-I receptor involve the same PI3K/AKT/mTOR signaling, and different antidiabetic pharmacotherapy may differentially affect this pathway, leading to different prognoses of HER2+ breast cancer.

Methods: We reviewed 1983 consecutive patients with HER2+ breast cancer treated between 1 January 1998 and 30 September 2010. The overall survival, breast cancer-specific death rate, age, race, nuclear grade, stage, menopausal status, estrogen and progesterone receptor status, body mass index and classes of antidiabetic pharmacotherapy were analyzed.

Results: A Cox regression analysis showed that DM2 [P=0.026, hazard ratio (HR)=1.42, 95 % confidence interval (95 % CI) 1.04-1.94] predicted poor survival of stage≥2 HER2+ breast cancer. In Kaplan-Meier analysis, metformin predicted lengthened survival and so did thiazolidinediones. Analyzing only the diabetics, Cox regression showed that metformin (P=0.041, HR=0.52, 95 % CI 0.28-0.97) and thiazolidinediones (P=0.036; HR=0.41, 95% CI 0.18-0.93) predicted lengthened survival, and competing risk analysis showed that metformin and thiazolidinediones were associated with decreased breast cancer-specific mortality (P=0.023, HR=0.47, 95% CI 0.24-0.90 and P=0.044, HR=0.42, 95 % CI 0.18-0.98, respectively).

Conclusions: Thiazolidinediones and metformin users are associated with better clinical outcomes than nonusers in diabetics with stage≥2 HER2+ breast cancer. The choice of antidiabetic pharmacotherapy may influence prognosis of this group.

Figure 1

Insulin use is associated with decreased overall survival while metformin use and thiazolidinedione use are associated with improved survival of diabetic patients with stage ≥2 HER2+ breast cancer. Kaplan–Meier survival curves comparing users (red curves), diabetic nonusers (blue curves) and nondiabetic patients (black curves) are shown for insulins (A), insulin secretagogues (B), insulins and/or insulin secretagogues (C), metformin (D), thiazolidinediones (E), and metformin and/or thiazolidinediones (F).

Figure 2

Metformin and thiazolidinediones are associated with decreased cumulative incidence of breast cancer-specific mortality of diabetic patients with HER2+ breast cancer. Cumulative incidence curves of breast cancer-specific deaths comparing users (red curves) and diabetic nonusers (black curves) and those of non-breast cancer-specific deaths comparing users (blue curves) and diabetic nonusers (green curves) are shown for insulin (A), insulin secretagogues (B), insulin and/or insulin secretatgogues (C), metformin (D), thiazolidinediones (E) and metformin and/or thiazolidinediones (F). The P-values are as labeled close to the compared curves.