Insulin Resistance Contributes to Racial Disparities in Breast Cancer Prognosis in US Women

Emily J. Gallagher; Kezhen Fei; Sheldon M. Feldman; Elisa Port; Neil B. Friedman; Susan K. Boolbol; Brigid Killelea; Melissa Pilewskie; Lydia Choi; Tari King; Anupma Nayak; Rebeca Franco; Daliz Cruz; Irini M. Antoniou; Derek LeRoith; Nina A. Bickell

Disclosures

Breast Cancer Res. 2020;22(40) 

In This Article

Abstract and Introduction

Abstract

Background: Racial disparities in breast cancer survival between Black and White women persist across all stages of breast cancer. The metabolic syndrome (MetS) of insulin resistance disproportionately affects more Black than White women. It has not been discerned if insulin resistance mediates the link between race and poor prognosis in breast cancer. We aimed to determine whether insulin resistance mediates in part the association between race and breast cancer prognosis, and if insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R) expression differs between tumors from Black and White women.

Methods: We conducted a cross-sectional, multi-center study across ten hospitals. Self-identified Black women and White women with newly diagnosed invasive breast cancer were recruited. The primary outcome was to determine if insulin resistance, which was calculated using the homeostatic model assessment of insulin resistance (HOMA-IR), mediated the effect of race on prognosis using the multivariate linear mediation model. Demographic data, anthropometric measurements, and fasting blood were collected. Poor prognosis was defined as a Nottingham Prognostic Index (NPI) > 4.4. Breast cancer pathology specimens were evaluated for IR and IGF-1R expression by immunohistochemistry (IHC).

Results: Five hundred fifteen women were recruited (83% White, 17% Black). The MetS was more prevalent in Black women than in White women (40% vs 20%, p < 0.0001). HOMA-IR was higher in Black women than in White women (1.9 ± 1.2 vs 1.3 ± 1.4, p = 0.0005). Poor breast cancer prognosis was more prevalent in Black women than in White women (28% vs 15%. p = 0.004). HOMA-IR was positively associated with NPI score (r = 0.1, p = 0.02). The mediation model, adjusted for age, revealed that HOMA-IR significantly mediated the association between Black race and poor prognosis (β = 0.04, 95% CI 0.005–0.009, p = 0.002). IR expression was higher in tumors from Black women than in those from White women (79% vs 52%, p = 0.004), and greater IR/IGF-1R ratio was also associated with higher NPI score (IR/IGF-1R > 1: 4.2 ± 0.8 vs IR/IGF-1R = 1: 3.9 ± 0.8 vs IR/IGF-1R < 1: 3.5 ± 1.0, p < 0.0001).

Conclusions: In this multi-center, cross-sectional study of US women with newly diagnosed invasive breast cancer, insulin resistance is one factor mediating part of the association between race and poor prognosis in breast cancer.

Introduction

The metabolic syndrome is a set of biological factors (abdominal obesity, hypertension, dyslipidemia, and dysglycemia), associated with an increased risk of a number of diseases including cancer.[1,2] In breast cancer, the metabolic syndrome has been associated with an increased risk of developing cancer, and a worse prognosis.[3,4] In the 2007–2012 US National Health and Nutrition Examination Survey (NHANES), the overall prevalence of the metabolic syndrome was 34%.[5] Non-Hispanic Black women were found to be 20% more likely to have the metabolic syndrome than non-Hispanic White women.[5]

Non-Hispanic Black women still experience 39% higher rates of breast cancer mortality than non-Hispanic White women, despite similar incidence.[6] Black women have higher rates of triple-negative breast cancer (TNBC)[7–10] and also experience higher mortality from estrogen receptor (ER)-positive breast cancers.[11] A number of complex factors have been proposed to contribute to the disparities in breast cancer mortality including access to care, screening, and treatment; socioeconomic factors; systemic metabolic conditions; tumor biology; and epigenetic and genetic factors.[12,13]

Insulin resistance and endogenous hyperinsulinemia are key features that underlie the development of the metabolic syndrome.[14] Studies have reported that women with early-stage breast cancer and endogenous hyperinsulinemia have decreased rates of recurrence-free survival.[9] Preclinical studies have found that hyperinsulinemia promotes the growth and metastasis of breast cancers by activating the insulin receptor (IR)/insulin-like growth factor 1 receptor (IGF-1R) signaling pathways.[15,16] Differences in hepatic insulin metabolism have been reported between African American and European American women, leading to higher circulating insulin levels in African American women.[17] Whether hyperinsulinemia and tumor IR expression contribute to the racial disparities in breast cancer prognosis has not previously been explored.

In this study, we aimed to determine whether insulin resistance (determined by the homeostatic model assessment of insulin resistance, HOMA-IR) mediates the association between race and breast cancer prognosis, which was determined by the Nottingham Prognostic Index (NPI). We additionally explored whether expression of the IR and IGF-1R in the breast cancer cells was associated with race and worse breast cancer prognosis.

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