Phase II clinical trial of N-(4-hydroxyphenyl)retinamide and tamoxifen administration before definitive surgery for breast neoplasia

Purpose: 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. Experimental Design: 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. Results: 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. Conclusion: 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.