Insulin Resistance Plays Role in Racial Disparities in Breast Cancer Prognosis

In patients with breast cancer, insulin resistance is a factor that contributes to the association between race and poor prognosis that impacts survival, according to a study of women with newly diagnosed invasive breast cancer conducted at Mount Sinai.¹

Overall, this cross-sectional study, which is the first to explore insulin resistance as a factor for disparities in this population, found that African American patients with breast cancer had a worse prognosis compared with Caucasian women.

“Our results raise a number of questions for future research and patient care. It will be important in future studies to explore whether lowering insulin levels or targeting IR signaling will improve breast cancer disparities,” said co-senior investigator Nina Bickell, MD, MPH, Associate Director of Community Engaged and Equity Research of The Tisch Cancer Institute and Co-Director of the Center for Health Equity and Community Engaged Research at the Icahn School of Medicine at Mount Sinai.

Investigators found a positive association between insulin resistance and Nottingham Prognostic Index (NPI) scores (r = 0.1; P =.02). Poor prognosis was also associated with both younger age (55.3 ± 12.7 vs 58.9 ± 12.3 years; P =.01) and a not “very good/excellent” diet (58% vs. 44%; P =.02). However, poor prognosis was not associated with metabolic syndrome, smoking, drinking, or exercise.²

The multivariate linear mediation model, adjusted for age, was used to evaluate whether insulin resistance mediated the effect on race on NPI. Investigators observed the total relationship between African American racial status and having a worse NPI was 0.54 (P <.0001), and the direct effect of being African American to NPI was 0.50 (P =.0001). The direct effect on insulin resistance on NPI was 0.067 (P =.04), and the indirect effect of race on NPI through insulin resistance was 0.04 (P =.002), adjusted for age.

Out of 196 available tumor specimens for IR and IGF-1R IHC staining, 34 were from African American patients (17%) and 162 from Caucasian patients (83%). ER-positivity was noted in 168 of these tumors, 12 were HER2-positive, and 11 were triple-negative. Additionally, 128 had high IGF-1R expression while 68 had low expression, and 112 had high IR expression while 84 had low expression. More of the ER-positive tumors had high IGF-1R expression (71%) compared with the ER-negative tumors (35%; P =.0006), which was consistent with previously published findings in breast cancer subtypes. Investigators did not observe differences in IR expression based on the ER status, and triple-negative breast cancer (TNBC) in comparison with other breast subtypes did not demonstrate a difference in intensity of IGF-1R (67% vs. 45%; P =.2) or IR staining (73% vs. 57%; P =.4), respectively.

No differences were observed between high expression of IGF-1R by race, but investigators noted more African American women had high expression of IR (79%) compared with Caucasian women (52%; P =.004). A significantly better prognosis was observed with tumors expressing low IGF-1R, which is indicated by lower NPI scores (3.6 vs. 4.1; P =.0002) and iNPI (2.9 vs. 3.6; { <.0001). No difference was observed in prognostic scores between IR expression levels, but women with tumors with high IR expression had larger waist circumference than women with low expression (100.4 ± 14.7 vs 93.1 ± 15.2; P =.002).

Approximately 515 patients with treatment-naïve breast cancer were enrolled to the study, of which 83% identified as non-Hispanic Caucasian women and 17% identified as African American. More Caucasian women were current smokers (48%) than African American women (36%; P =.04), and more Caucasian women (29%) consumed more than 2 alcoholic drinks per day compared with African American women (5%; P<.0001).

There was no difference in age at diagnosis or percentage of women with commercial health insurance. However, investigators noted that more African American women (73%) had an annual income of < $75,000 than the Caucasian population (31%), and they also had less than a college education (P <.0001).

No difference was observed in the rate of breast cancer screening between the 2 groups of patients, but 28% of African American patients had an NPI of > 4.4 compared with 15% in the Caucasian population. Rates of ER-positivity was also more common in the Caucasian group (91%) compared with the African American group (77%; P =.0003). Triple-negative disease was more common in the African American group (16%) compared with the Caucasian group (6%; P =.01).

This was a multicenter study conducted across 10 institutions in the United States. The primary outcome was to determine if insulin resistance mediated the effect of race on prognosis, and this was measured with a multivariate linear mediation model. Poor prognosis was also defined as an NPI of > 4.4. Women were recruited after their primary diagnosis of invasive breast cancer.

To be eligible, women had to be over the age of 21 years and identify as either African American or Caucasian. If patients had type 1/2 diabetes being treated with either oral or injectable medication, had previous bariatric surgery, glucocorticoid treatment within 2 weeks of blood testing/biopsy/surgical resection, they were unable to enroll to the study.

Investigators were unable to determine the duration of insulin resistance in the cross-sectional study prior to diagnosis, which led to their determination of prognosis through NPI, but the NPI was previously validated as a prognostic indicator among different patient populations. Another limitation of this study was that it predicted prognosis independent of any future differences in treatments that could possibly contribute to disparities in survival among patients with breast cancer.

_References

1. _{Insulin Resistance Contributes to Racial Disparities in Breast Cancer Prognosis in US Women, Mount Sinai Researchers Reveal [news release]. New York, NY: Mount Sinai; May 12, 2020. https://bit.ly/3dLkMxw. Accessed May 14, 2020.}
2. _{Gallagher EJ, Fei K, Feldman SM, et al. Insulin resistance contributes to racial dispartieis in breasdt cancer prognosis in US women [Published Online May 12, 2020]. Breast Cancer Research. DOI: 10.1186/s13058-020-01281-y.}