A clinical trial to assess biomarker modulation by tamoxifen in normal and premalignant breast tissue

Prevention trials using incidence or mortality as endpoints require a large number of subjects and long followup. Trials using biomarkers as endpoints would potentially require less subjects, time and resources to test promising new agents for breast cancer prevention. To further test this idea, a randomized trial of tamoxifen for 1 year versus observation was conducted to determine whether tamoxifen can cause regression of hyperplastic breast tissue, whether it changes the biomarker phenotype of premalignant disease or normal breast epithelium, and if biomarkers can be used as early surrogate indicators of response to a prevention regimen. Women were identified by having an abnormal mammogram and a core needle or excisional biopsy with typical or atypical ductal hyperplasia. Image-directed core needle biopsy was repeated in the same site of the breast at one year. Approximately 3,000 patients were screened, 265 were eligible, and 230 were contacted. Sixty-three patients were randomized and 45 paired biopsies were available for analysis. Ethnicity reflected that of the community, with 65% of patients being Hispanic, 30% white, and 5% black. There was no evidence of substantial regression of hyperplasia - fewer samples showed hyperplasia on one-year follow-up, but this was seen in both untreated and tamoxifen-treated women. ER and PgR were relatively decreased and bcl-2 relatively increased in normal and hyperplastic tissue in the tamoxifen-treated arm, though these changes did not reach statistical significance. Conclusion: Prolonged tamoxifen appeared to down-regulate ER and PgR and up-regulate bcl-2 in both normal and hyperplastic breast tissue. Additional biomarker analysis is ongoing.