fenretinide and Carcinoma--Intraductal--Noninfiltrating

Tamoxifen and fenretinide are active in reducing premenopausal breast cancer risk and work synergistically in preclinical models. The authors assessed their combination in a two-by-two biomarker trial.. A total of 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), or intraepithelial neoplasia (IEN, n = 160), or 5-year Gail risk > or = 1.3% (n = 54) were randomly allocated to either tamoxifen 5 mg/d, fenretinide 200 mg/d, their combination, or placebo. We report data for plasma insulin-like growth factor I (IGF-I), mammographic density, uterine effects, and breast neoplastic events after 5.5 years.. During the 2-year intervention, tamoxifen significantly lowered IGF-I and mammographic density by 12% and 20%, respectively, fenretinide by 4% and 10% (not significantly), their combination by 20% and 22%, with no evidence for a synergistic interaction. Tamoxifen increased endometrial thickness principally in women becoming postmenopausal, whereas fenretinide decreased endometrial thickness significantly. The annual rate of breast neoplasms (n = 48) was 3.5% +/- 1.0%, 2.1% +/- 0.8%, 4.7% +/- 1.3%, and 5.2% +/- 1.3% in the tamoxifen, fenretinide, combination, and placebo arms, respectively, with hazard ratios (HRs) of 0.70 (95% CI, 0.32 to 1.52), 0.38 (95% CI, 0.15 to 0.90), and 0.96 (95% CI, 0.46 to 1.99) relative to placebo (tamoxifen x fenretinide adverse interaction P = .03). There was no clear association with tumor receptor type. Baseline IGF-I and mammographic density did not predict breast neoplastic events, nor did change in mammographic density.. Despite favorable effects on plasma IGF-I levels and mammographic density, the combination of low-dose tamoxifen plus fenretinide did not reduce breast neoplastic events compared to placebo, whereas both single agents, particularly fenretinide, showed numerical reduction in annual odds of breast neoplasms. Further follow-up is indicated.

Topics: Adult; Anticarcinogenic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Lobular; Double-Blind Method; Drug Administration Schedule; Drug Synergism; Female; Fenretinide; Humans; Incidence; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Mammography; Middle Aged; Multivariate Analysis; Odds Ratio; Premenopause; Proportional Hazards Models; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Selective Estrogen Receptor Modulators; Tamoxifen; Treatment Outcome; Vitamin A

Topics: Adult; Aged; Anticarcinogenic Agents; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Female; Fenretinide; Follow-Up Studies; Humans; Middle Aged; Neoplasms, Second Primary; Treatment Outcome

Surrogate end point biomarkers (SEBs) that can be measured in ductal carcinoma in situ or early-stage invasive cancer are needed to improve the efficiency and reduce the cost of chemoprevention trials.. We conducted a prospective study to develop SEBs for tamoxifen and N-[4-hydroxyphenyl]retinamide by administering either a placebo or both drugs for 2-4 weeks to women with ductal carcinoma in situ or early invasive cancers in the interval between the initial diagnostic core biopsy and definitive surgery. The major statistical end point of the study was pre- versus posttreatment change in cell proliferation, as measured by changes in Ki67 labeling indices. In addition, estrogen receptor (ER), HER2/neu, p53, retinoid receptors, and DNA index were measured.. Between February 1997 and April 200, 52 patients were registered on the study, and 36 (20 in the placebo arm and 16 in the treatment arm) were available for analysis. No statistically significant pre- versus posttreatment differences in Ki67 labeling index or in the other markers were observed in the treatment arm compared with the placebo arm. There was a trend toward increased treatment response in ER-positive versus ER-negative patients, but this could not be rigorously analyzed because of the low sample size and the unequal distribution of ER-positive patients in the two study arms.. Future SEB trials for breast carcinoma must (a) incorporate information about patient hormonal status into the study design and (b) resolve problems in patient accrual.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Chemotherapy, Adjuvant; Combined Modality Therapy; DNA, Neoplasm; Female; Fenretinide; Humans; Ki-67 Antigen; Mastectomy; Middle Aged; Neoplasm Proteins; Premedication; Prodrugs; Prospective Studies; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Retinoic Acid; Tamoxifen; Treatment Outcome; Tumor Suppressor Protein p53

Topics: Adult; Anticarcinogenic Agents; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Lobular; Disease Progression; Female; Fenretinide; Humans; Insulin-Like Growth Factor I; Mammography; Middle Aged; Neoplasm Recurrence, Local; Predictive Value of Tests; Premenopause; Research Design; Selective Estrogen Receptor Modulators; Tamoxifen