Breast Cancer Prevention With Fenretinide in Young Women at Genetic and Familil Risk. A Phase III Randomized Clinical Trial

Retinoids have been studied as chemo preventive compounds in clinical trials because of their acknowledged role in regulating cell growth, differentiation and apoptosis in preclinical models. Induction of apoptosis is a unique feature of fenretinide (4-hydroxyphenylretinamide, 4-HPR),(2) the most widely studied retinoid in clinical trials of breast cancer chemoprevention for its selective accumulation in the breast tissue and its very low toxicity. The fifteen-year follow up of a randomized phase III trial of fenretinide to prevent second breast cancer indicates that fenretinide induced a 17%, durable reduction of second breast cancer incidence. When stratified by menopausal status, the analysis showed a 38%, statistically significant reduction of second breast cancers in premenopausal women and this protective effect persisted for up to 15 years, i.e. 10 years after treatment cessation. Importantly, the younger were the women, the greater was the trend of benefit of fenretinide, with a remarkable 50% risk reduction in women aged 40 years or younger, whereas the benefit disappeared after age 55. One explanation for the different effects of fenretinide according to menopausal status or age is a different modulation of circulating IGF-I in premenopausal and postmenopausal women, with a reduction of IGF-I levels only in premenopausal subjects.

When considering the protective activity of fenretinide on second breast cancer in young women and a similar trend on ovarian cancer (the latter at least during intervention)(4, 5), it appears that young women at high risk such as those with germ line BRCA-1 and 2 mutations or those with a high family risk may be ideal candidates for further investigation on this retinoid. Indeed, fenretinide is highly effective in inhibiting the growth of BRCA-1 mutated breast cancer cell lines. Since a reduction of second breast cancer might be a surrogate marker of primary prevention, a favourable effect of fenretinide provides strong rationale for a primary prevention trial in unaffected women at high-risk for breast cancer.

Importantly, at clinically relevant doses, fenretinide has shown to induce NO-mediated apoptosis in human and murine BRCA-1 mutated cancer cells, and In this ability fenretinide was the most potent of the phenylretinamide analogues against BRCA-1 mutated breast cancer cells.

Additionally, recent studies have shown that 4-HPR modulates gene expression in ovarian cells, with an up-regulation of expression of proapoptotic genes in OVCA433 cells and down-regulation of mutant BRCA genes in IOSE (premalignant) cells and OVCA433 cells. This suggests a preventive effect in premalignant cells and a treatment effect in cancer cells.

Increasing evidence sustains a link between the rising prevalence of metabolic syndrome in the Western world and breast cancer incidence. The retinol-binding protein 4 (RBP4), an adipocyte-secreted molecule, is the only specific transport protein for retinol in the blood and correlates with components of the metabolic syndrome, including increased body-mass index, waist-to-hip ratio, serum triglycerides. Plasma concentrations of RBP4 are known to decrease proportionally with retinol during fenretinide administration and normalization of RBP4 by fenretinide in insulin-resistant obese mice has shown to improve insulin action and glucose tolerance.