Fenretinide, a synthetic retinoid, improves insulin sensitivity in premenopausal women at increased risk for breast cancer

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Background: The prevalence of metabolic syndrome is increasing along with breast cancer (BC) incidence worldwide. Normalization of serum retinol-binding protein 4 by fenretinide (N-4-hydroxyphenylretinamide; 4-HPR) leads to improved insulin action and glucose tolerance in insulin-resistant obese mice. We investigated the insulin sensitizing properties of 4-HPR in a randomized BC prevention trial.

Patients and Methods: A total of 235 premenopausal women at risk for BC according to the Gail model or because of a prior I.E.N. or microinvasive BC, were randomized to receive either low dose tamoxifen (TAM; 5 mg/daily), or 4-HPR (200 mg/daily), their combination or placebo for two years. Fasting blood samples were drawn at baseline (B), 12 and 24 months (M), and stored at -80°C. We employed the homeostasis model assessment (HOMA), developed by Matthews et al. (Diabetologia, 1985), as a surrogate index of insulin resistance. Women were considered to improve insulin sensitivity when they passed from a HOMA status > 2.8 to a HOMA < 2.8. This cut-off corresponds to the lower limit of the highest quintile in a population-based study conducted in 888 subjects randomly selected from the general population in Bruneck, Italy (Bonora et al., Diabetes, 1998). We performed an exploratory analysis on a subgroup of 59 women having a BMI > 25 kg/m². The difference in improvement of insulin sensitivity from B to 24 M between treatment groups was evaluated by HOMA, categorized as previously described, and assessed by a logistic model.

Results: No interaction between treatments arms was observed, thus treatment was evaluated pooling the effect of 4-HPR vs no 4-HPR and TAM versus no TAM. Women taking 4-HPR had a 23% chance to improve insulin sensitivity after 24 M (OR=22.9, 95%CI: 2.4-220; P=0.007), as compared to women who did not take 4-HPR.

The subjects showed the following distribution during the study:

a) 4-HPR (n=27):

HOMA > 2.8: 22 at B, 19 after 12 M, and 14 after 24 M;

HOMA < 2.8: 5 at B, 8 after 12 M, and 13 after 24 M

b) No 4-HPR (n=32):

HOMA > 2.8: 14 at B, 18 after 12 M, and 16 after 24 M;

HOMA < 2.8: 18 at B, 14 after 12 M, and 16 after 24 M

TAM-treated subjects did not show an improvement. The analysis will be extended to all participants regardless of BMI.

Conclusions: 4-HPR improved insulin sensitivity in overweight subjects with insulin resistance as defined by HOMA > 2.8. These subjects are at increased risk for metabolic disorders which may influence BC risk, as recently suggested from several prospective studies. The favourable effect of 4-HPR on insulin sensitivity may positively balance the metabolic profile and ultimately prevent BC. Further studies are warranted to address this important issue.