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

Results

Patient Characteristics

Five hundred fifteen women with newly diagnosed breast cancer were consented for inclusion in the study. Patient characteristics are shown in Table 1. Eighty-three percent (n = 428) self-identified as non-Hispanic White women, and 17% (n = 87) self-identified as Black women. There was no difference in age at breast cancer diagnosis between Black and White women. More White women (48%) than Black women (36%) were current smokers (p = 0.04). Additionally, more White women (29%) consumed more than 2 alcoholic drinks per week than Black women (5%), p < 0.0001. There was no difference in the percent of Black women and White women with commercial health insurance. More Black women (75%) than White women (31%) had an annual income of <$75,000 (p < 0.0001) and had less than a college education (p < 0.0001). Sixty-eight percent of Black women had a Charlson Comorbidity Index of 1 or more, compared with 53% of White women (p = 0.01).

Obesity was more prevalent in Black women than in White women, whether defined by BMI (47% vs 19%, p < 0.0001) or as waist circumference (96% vs 67%, p < 0.0001). The metabolic syndrome was also more prevalent in Black women than in White women (40% vs 20%, p < 0.0001). HOMA-IR was higher in Black women (1.9 ± 1.2) than in White women (1.3 ± 1.4), p = 0.0005. Seventeen percent of Black women had HOMA-IR > 2.8, compared with 9% of White women (p = 0.03). More White women than Black women reported that their diet was "very good/excellent" (59% vs 30%, p < 0.0001), and engaged in moderate or more physical activity (53% vs 40%, p = 0.02).

Breast Cancer Screening and Tumor Characteristics

There was no difference in the rate of breast cancer screening or the AJCC stage at diagnosis between Black women and White women. However, 28% of Black women had an NPI of > 4.4, compared with 15% of White women (p = 0.004). Rates of ER-positive breast cancer were higher in White women than in Black women (91% vs 77%, p = 0.0003). There were no differences in the percent of women with HER2-positive breast cancer. TNBC was more common in Black women than in White women (16% vs 6%, p = 0.01).

Association Between Insulin Resistance and Breast Cancer Prognosis

Insulin resistance (HOMA-IR) was positively associated with NPI scores (r = 0.1; p = 0.02). Poor prognosis was associated with younger age (55.3 ± 12.7 vs 58.9 ± 12.3 years; p = 0.01), and a diet that was not "very good/excellent" (58% vs 44%, p = 0.02), but was not associated with metabolic syndrome, smoking, drinking, or exercise. To evaluate whether HOMA-IR mediated the effect of race on NPI, the multivariate linear mediation model was used, adjusting for age. The total relationship between being a Black woman and having a worse NPI was 0.54, p < 0.0001; the direct effect of being a Black woman to NPI was 0.50, p < 0.0001; and the direct effect of HOMA-IR on NPI was 0.067, p = 0.04, The indirect effect of race on NPI through HOMA-IR was 0.04 (p = 0.002) adjusting for age (Figure 1). This model indicates that insulin resistance (measured by HOMA-IR) significantly mediated the association between race and poor prognosis, measured by NPI score.

Figure 1.

The linear mediation model showing the direct and indirect effects of race on breast cancer prognosis. The total effect (c path) of race on prognosis (NPI) and the direct (c' path) and indirect (ab paths) are shown. HOMA-IR homeostatic model assessment of insulin resistance, NPI Nottingham Prognostic Index, β parameter estimate, SE standard error. Proportion of the effect that was mediated (PEM) = ab/c = 0.5532 × 0.0666/0.5364 = 7%

Breast Cancer Insulin Receptor and Insulin-like Growth Factor Receptor Expression

IR and IGF-1R IHC staining was performed on 196 available tumor specimens (Table 2). Of them, 34 tumor specimens were from Black women (17%) and 162 (83%) were from White women. One hundred sixty-eight were ER positive, 12 (6.2%) were HER2 positive by IHC, and 11 (5.7%) were TNBCs. One hundred twenty-eight (65%) specimens had high IGF-1R expression, and 68 (35%) had low IGF-1R expression. One hundred twelve (57%) of tumors exhibited high IR expression, and 84 (43%) specimens had low expression (representative images Figure 2). More ER-positive than ER-negative tumors had high IGF-1R expression (71% vs 35%, p = 0.0006). These findings were consistent with previously published studies examining IGF1R RNA and protein expression in breast cancer subtypes.[31–33] No differences in IR expression were seen based on ER. TNBC exhibited no difference in intensity of IGF-1R (67% vs 45%, p = 0.2) or IR staining (73% vs 57%, p = 0.4) compared with other breast cancer subtypes, although there were only 11 cases of TNBC in the group.

Figure 2.

Representative images of high and low IGF-1R and IR expression by IHC. a High IGF-1R expression. b Low IGF-1R expression. c High IR expression. d Low IR expression

There was no difference in high expression of IGF-1R by race (Black women 59% vs White women 67%, p = 0.38), but more Black women than White women had tumors with high IR expression (79% vs 52%, p = 0.004). Tumors with high IGF-1R expression had significantly better prognosis compared with tumors with low IGF-1R expression, as indicated by lower NPI scores (3.6 vs 4.1, p = 0.0002) and iNPI (2.9 vs 3.6, p < 0.0001). There was no difference in prognostic scores between IR expression categories. Women with tumors that had high IR expression had larger waist circumference than women that had tumors with low IR expression (100.4 ± 14.7 vs 93.1 ± 15.2, p = 0.002).

Previous studies have reported that the ratio of IR/IGF-1R expression is important in determining the sensitivity of the cancer cells to the effects of insulin.[34] We found that more Black women than White women had an IR/IGF-1R ratio > 1. Additionally, an IR/IGF-1R ratio of > 1 was associated with highest NPI (4.3) and iNPI (3.8), those with similar levels of expression IR and IGF-1R (ratio = 1) had NPI 3.9 and iNPI 3.3, and those with an IR/IGF-1R ratio < 1 had the lowest NPI (3.5) and iNPI (2.8) scores, p < 0.0001 for both NPI and iNPI comparisons.

processing....