Randomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer

Background: Fenretinide, a vitamin A analogue, has been shown to inhibit br east carcinogenesis in preclinical studies, We determined the efficacy of f enretinide in preventing a second breast malignancy in women with breast ca ncer. Methods: We randomly assigned 2972 women, aged 30-70 years, with surg ically removed stage I breast cancer or ductal carcinoma in situ to receive for 5 years either fenretinide orally (200 mg/day) or no treatment. The pr imary end point was the incidence of contralateral breast cancer or ipsilat eral breast cancer 7 years after randomization. Other end points considered post hoc were the same outcomes stratified by menopausal status, incidence of distant metastases, overall mortality, and tumors in other organs. The hazards of breast cancer occurrence mere determined by Cox proportional haz ards regression analysis. Statistical tests were two-sided. Results: At a m edian observation time of 97 months, there were no statistically significan t differences in the occurrence of contralateral breast cancer (P = .642) o r ipsilateral breast cancer (P = .177) between the two arms. However, an in teraction was detected between fenretinide treatment and menopausal status in both outcomes (P for interaction in both outcomes = .045), with a possib le beneficial effect in premenopausal women (contralateral breast cancer: a djusted hazard ratio [HR] = 0.66, and 95% confidence interval [CI] = 0.41-1 .07; ipsilateral breast cancer: adjusted HR = 0.65, and 95% CI = 0.46-0.92) and an opposite effect in postmenopausal women (contralateral breast cance r: adjusted HR = 1.32, and 95% CI = 0.82-2.15; ipsilateral breast cancer: a djusted HR = 1.19, and 95% CI = 0.75-1.89), There were no statistically sig nificant differences between the two arms in tumors in other organs, incide nce of distant metastasis, and all-cause mortality. Conclusions: Fenretinid e treatment of women with breast cancer for 5 years appears to have no stat istically significant effect on the incidence of second breast malignancies overall, although a possible benefit was detected in premenopausal women. These studies, particularly the post hoc analyses, are considered explorato ry and need to be confirmed.