A total of 880 subjects were registered and 586 were screened for eligibility; 190 were not eligible and 161 refused to participate, leaving 235 participants (). The main subject characteristics have previously been reported,21
with no differences among groups. There were two randomization strata of the same age and BMI: at-risk women by the Gail model (23%) and women with either prior IEN (68%) or pT1mic/T1a (9%). Baseline values of the primary end point measures are reported in ; subjects in the IEN/pT1mic/pT1a strata had 9.4% (95% CI, −0.6% to 20.5%) higher mean levels of IGF-I (P
= .07) and 9.7% higher IGF-I/IGFBP-3 (95% CI, −1.1% to 21.9%; P
= .08) than those in the Gail strata, whereas IGFBP-3 and mammographic density had comparable values. Mammographic % density was not correlated with IGFs but negatively correlated with age (r
= −0.21; P
= .004) and BMI (r
= −0.38; P
< .001). Age was negatively correlated with IGF-I (r
= −0.25; P
< .001), but not with IGFBP-3 (not shown).
CONSORT diagram (participant flow diagram). AEs, adverse events.
Baseline Levels of the Main Outcome Measures by Disease Status
Mean pill count compliance over 2 years ranged between 80% and 90% in all four arms. shows the blood concentrations of tamoxifen and endoxifen (upper panels), and retinol and fenretinide (lower panels) during treatment. Subjects taking tamoxifen had mean serum drug and metabolite levels around 20 and 15 ng/mL, respectively. Subjects taking fenretinide exhibited a 50% reduction in plasma retinol levels, which recovered to baseline levels at month 36.
Circulating levels of (A) tamoxifen (T), (B) endoxifen, (C) retinol, and (D) fenretinide (F) during the trial according to treatment arm. Data on T and F concentrations were pooled into two groups (T- and non–T-containing arms). P, placebo.
(upper part) shows the yearly changes in IGF-I during treatment. Tamoxifen lowered IGF-I from baseline by approximately 10% at 6 months and plateaued thereafter, with a return to baseline values after drug cessation (P < .0001 for the time × tamoxifen interaction), whereas IGF-I was not significantly lowered by fenretinide (P = .35). The combination arm induced a nearly 20% reduction of IGF-I, without evidence for a synergistic interaction (P = .29). Overall, tamoxifen decreased IGF-I by 16.6% (95% CI, 11.6% to 21.5%). Qualitatively similar results were noted on IGF-1:IGFBP-3 ratio (not shown). The effects on mammographic % density are presented in (lower two parts). Tamoxifen induced a 20% reduction over 2 years, fenretinide induced a nonsignificant decline of 11%, whereas their combination induced a 22% reduction, with placebo alone a nonsignificant 12% reduction. There was no evidence of any interaction between tamoxifen and fenretinide (P = .22), nor of any main effect of fenretinide (P = .43). There was an effect of tamoxifen (P = .003) but this was not different according to baseline mammographic density level (P = .16 for the interaction). Qualitatively similar results were obtained using analog mammograms only.
Percentage Changes From Baseline in IGF-I, Mammographic % Density in All Women, and Mammographic % Density in Women With Analog Mammography Only, According to Treatment Arm
The results of endometrial thickness are presented in . There was a three-way interaction between tamoxifen, menopausal status, and time on study (P = .013). While tamoxifen had little effect among premenopausal women at 12 months, there was a borderline increase at 24 and 36 months relative to placebo (P = .09 tamoxifen × time interaction). The proportion of women undergoing natural menopause during the 2 years of the study was evenly distributed among the four arms: 25%, 27%, 33%, and 28% in the tamoxifen, fenretinide, combination, and placebo arms, respectively. Among women who became postmenopausal during study, tamoxifen increased endometrial thickness relative to placebo (tamoxifen × menopausal status interaction P = .02), which did not persist into month 36, however. While on tamoxifen, postmenopausal women had an endometrial thickness which was 80.6% thicker than on placebo (95% CI, 46.3% to 123%). Fenretinide decreased endometrial thickness by 10.9% (95% CI, 1.9% to 19.0%; P = .021) compared to placebo up to month 36 and counteracted tamoxifen-induced endometrial thickness increase, although the effect modification was not significant (P = .15 for the tamoxifen × fenretinide interaction). Qualitatively similar results were obtained on uterine volume, whereas there was no effect of either agent on ovarian cysts (data not shown).
Endometrial Thickness (mm) According to Treatment Arm, Separately for Women Remaining Premenopausal (upper part) and Women Becoming Postmenopausal (lower part) During the Trial
Adverse events were not significantly different among groups, including menopausal symptoms and endometrial polyps (Appendix , online only). Grade 1 cardiac arrhythmia (mainly palpitations) were slightly more frequent in the tamoxifen arm (n = 6) versus the other three arms (n = 1, 1, and 2, respectively; P = .02). There were three serious adverse events, one instance of deep vein thrombosis, and one instance of optic neuritis on tamoxifen, and one instance endometrial cancer on fenretinide.
As at November 1, 2007, after a median follow-up of 5.5 years (range, 0 to 9.2 years), there were 48 women with breast neoplasms (plus three cases of LCIS): 11 with tamoxifen (mean ± standard deviation annual rate = 3.5% ± 1.0%), seven with fenretinide (2.1% ± 0.8%), 14 with the combination (5.1% ± 1.3%), and 16 with placebo (4.7% ± 1.3%). All events but one (n = 47; 98%) were second breast neoplasms in women with prior IEN (n = 46) or pT1mic/T1a (n = 2), 19 were second IEN (DCIS), one with sarcoma and 28 stage I breast cancers, 37 were ipsilateral and 11 contralateral neoplasms. The Cox regression analysis in shows a trend to a reduced hazard of breast neoplasms for each single agent, particularly fenretinide, relative to placebo, but a similar effect for their combination (HR, 0.96; 95% CI, 0.46 to 1.99), with an antagonistic interaction for the addition of fenretinide to tamoxifen compared with tamoxifen alone (P = .03). Baseline plasma IGF-I did not significantly predict breast neoplasms (P = .08), nor did IGF-I during treatment (P = .64). Neither IGFBP-3 (P = .98), nor IGF-1:IGFBP-3 ratio (P = .39), nor baseline mammographic density (P = .45), nor its change (P = .40) predicted breast neoplasms. Older women had a lower risk of breast neoplasm (P = .01), whereas BMI had no effect (P = .79). Adjusting for IGF-I and treatment group, women age 44 or older were less likely to have an event (HR, 0.64, 95% CI, 0.36 to 1.14) compared to women age 30 to 43 years.
Multivariate Cox Regression Analysis of Breast Neoplastic Events
Tumor receptor characteristics occurring during treatment are presented in . The rates of disease were similar according to major receptor status at baseline as there were nine of 34 initial HER2–positive neoplasms and 40 ER/progesterone receptor (PgR) positive events of 139 in the initial neoplasms (assuming all unknowns are ER/PgR positive). The antagonistic interaction trend between tamoxifen and fenretinide was not explained by ER/PgR and HER2 status of the original neoplasm as there was no statistical evidence of imbalance in ER/Pgr positive neoplasms (χ2, 1.36; P = .71), nor in HER2-positive neoplasms over the four treatment groups (χ2, 4.1; P = .25).
Receptor Characteristics of Second Breast Neoplasms During the Trial Among Women in the IEN/pT1mic/pT1a Strata Only