Abstract Background: The cost-benefit ratio of tamoxifen for breast ductal intraepithelial neoplasia (DIN) is unclear. Since low-dose tamoxifen showed a favorable safety profile and modulation of breast cancer biomarkers in phase II trials, we analyzed a large mono-institutional cohort of women with DIN treated with low-dose tamoxifen or no systemic treatment.Material and Methods: A total of 309 patients with ER positive DIN received either tamoxifen 5 mg/day or 20 mg/week, as part of clinical trials or institutional guidelines and were compared with 371 patients who received no systemic treatment after surgery with or without radiotherapy due to personal preference, allocation to placebo or contraindication to tamoxifen.Results: The 5-year cumulative incidence of recurrence was 14.5% (95% CI, 11.9-17.5), with a negative trend according to age. Women with ER/PgR >50% DIN who were untreated had a higher incidence of breast events than women on tamoxifen (HR 1.76; 95% CI, 1.00-3.12) or women with ER/PgR<50% DIN (HR 1.72; 95% CI, 1.14-2.58). Among untreated patients with ER>50% DIN, recurrence was higher in PgR ≥50% DIN than in PgR <50% DIN, whereas it was similar among low PgR (<50%) DIN against which tamoxifen had no effect. No difference in endometrial cancer incidence was noted.Discussion: High ER and especially high PgR expression is a significant adverse prognostic indicator of DIN against which low-dose tamoxifen appears to be a safe and active treatment. Conversely, women with low expression ER or PgR DIN do not seem to benefit from tamoxifen. A definitive clinical trial is warranted. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2113.