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

Discussion

This is the first study to examine in detail the role of insulin resistance in the disparities in breast cancer prognosis between Black women and White women. Herein, we found that insulin resistance was more prevalent in Black women with invasive breast cancer than White women, and insulin resistance mediated in part the link between race and breast cancer prognosis (determined by NPI). Additionally, we found that breast cancers from Black women had higher IR expression and were more likely to have an elevated IR/IGF-1R ratio than tumors from White women. These findings may indicate that Black women are not only more likely to have hyperinsulinemia, but are also more susceptible to the tumor promoting effects of elevated insulin by direct effects of insulin on tumor IR signaling.

We found no differences in breast cancer screening rates or in the AJCC stage at presentation between Black women and White women. Types of insurance were also similar between the two groups. However, despite these similarities, prognosis as quantified by the NPI score was worse in Black women, compared with White women. These data suggest that access to healthcare was not a major contributing factor to the differences in breast cancer prognosis in our study.

A number of lifestyle differences were noted. Black women had lower rates of smoking, alcohol consumption, exercise, and self-described healthy eating habits than White women. Significant differences in education and annual income were observed between the two groups, and Black women had more comorbidities than White women. Diet and exercise are considered to be modifiable risk factors for a number of metabolic diseases, and diet-induced weight loss has been found to improve insulin sensitivity similarly in Black and White women.[35] The differences in insulin resistance may also be related to differences in insulin metabolism between races. Previous studies have found that African American women have higher circulating insulin levels than European American women, due to reduced hepatic insulin clearance.[17,36] Similar results have been reported in children.[37] Furthermore, some studies have reported that African American women have earlier menopause than White women, which may also contribute to a higher prevalence of metabolic syndrome in Black women.[38,39] Based on these previous studies, and the results of our current study, it is possible that the Black women may have long-term exposure to high circulating insulin levels. These high insulin levels may contribute to the development of breast cancer subtypes that carry a poor prognosis.

Our examination of IR and IGF-1R by IHC found that high IGF-1R expression was found in ER-positive tumors and those with better prognosis by NPI. These findings are consistent with studies examining IGF1R expression at an RNA level and survival in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) datasets.[31,32] Similarly, high IGF-1R expression by IHC has previously been associated with ER positivity in breast cancer.[33,40–43] We found no association between IR expression and ER or HER2 status, which is also similar to previous findings.[33] Some previous studies have reported decreased survival in women with high tumor IR expression,[44,45] although not all studies have reported this association.[33] In our current study, we found no association between IR expression and prognosis; however, we did find having higher IR/IGF-1R ratio was associated with a worse prognosis. Preclinical studies have reported that higher IR/IGF-1R ratio may be indicative of cells that are more sensitive to the growth promoting effects of insulin, and resistance to therapies.[34,46] In our current study, we found that more Black women had tumors with high IR expression and high IR/IGF-1R ratio. In the context of previously published studies, these results suggest that Black women may be more susceptible to the cancer promoting effects of hyperinsulinemia, due to higher levels of circulating insulin and higher ratio of tumor IR/IGF-1R expression.

Limitations include the cross-sectional design, which meant we were unable to determine the duration of insulin resistance prior to breast cancer diagnosis and led us to determine prognosis through the NPI. However, the NPI has previously been well-validated as a prognostic indicator in different populations.[47] Additionally, it predicts prognosis independent of any future differences in breast cancer treatments that may contribute to disparities in breast cancer survival. We also had incomplete data on some breast cancer risk factors, including reproductive history and parity. The prevalence of obesity as defined by BMI in our study was lower than anticipated for a US population. Recent US population studies report that 35.5% of White women and 56.9% of Black women ages 20 years and over are obese.[48] The lower prevalence of obesity in our study is likely related to the geographical regions in which this study was performed. The prevalence of self-reported obesity by BMI among US adults in New York, New Jersey, and Connecticut are between 25 and 30%.[49] Our relatively low prevalence of obesity is also likely to explain the lower than anticipated HOMA-IR results. The NHANES III reported that 25% of US adults without diabetes have HOMA-IR scores > 2.8.[21] In our population, only 11% of White women and 17% of Black women had HOMA-IR scores of > 2.8. While the focus of our study was to examine the link between insulin resistance and disparities in prognosis in women with newly diagnosed breast cancer, we acknowledge that this is certainly just one of a number of complex factors that contribute to racial disparities in breast cancer prognosis.

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