Fernandez et al., pp. 1862–1868 Breast cancer is the most frequent neoplasm in women, and epidemiological evidence has pointed to estrogen, in particular 17β-estradiol (E2), as one of the most important factors in its development. The estrogen link in breast cancer has been associated mostly with the estrogen receptor that mediates cell proliferation. However, E2 and its metabolites also lead to DNA damage and these genotoxic effects are also thought to participate in the pathogenesis of breast cancer. In this issue of the IJC, Fernandez and colleagues have studied the genotoxic activity of E2 and its metabolites 4-hydroxy-estradiol (4-OHE2) and 2-hydroxyestradiol (2-OHE2). They report that treatment of immortalized breast epithelial cells (MCF-10F) with E2 or its metabolites induces phenotypical changes indicative of neoplastic transformation. To determine whether phenotypical transformation is associated with genotoxic changes, they analyzed E2-treated cells using microsatellite markers. MCF-10F cells treated with E2 or with 4-OHE2 showed loss of heterozygosity in the region 13q12.3 (the BRCA2 site), a region that is frequently altered in breast carcinoma. They also observed that cells treated with E2 or with 4-OHE2 exhibited a 5-bp deletion in p53 exon 4, another lesion on chromosome 17 frequently observed in breast carcinoma. Importantly, these genomic alterations were not inhibited by the antiestrogen agent ICI182780, indicating that the genotoxic activity of E2 occurs mainly through its reactive metabolites 4-OHE2 and 2-OHE2. These observations confirm the genotoxic activity of E2 and demonstrate that this activity is sufficient to induce the alterations in vitro that are frequently observed in breast carcinoma. Wiedswang et al., pp. 2013–2019 While the presence of disseminated tumor cells (DTC) in bone marrow is well established as an independent prognostic marker for breast cancer, the value of circulating tumor cells (CTC) in blood is less clear. Theoretically, tumor cells localized in the bone marrow should have free access to peripheral blood circulation and can be expected in both compartments with similar frequencies. Wiedswang and colleagues from the University of Oslo tested this hypothesis by systematically matching DTC and CTC values from 341 Norwegian women with breast cancer. They focused on asymptomatic patients 3 years after surgery to test the strength of the two assays to predict relapses. Although DTC and CTC statuses were both significantly associated with disease-free survival, the analysis of blood cells was overall inferior to bone marrow examinations in detecting patients at risk of cancer recurrence. One important hindrance was the low number of tumor cells isolated from blood, which impaired precise quantification and monitoring. The authors point out that they analyzed 5 times more mononuclear cells isolated from blood than from bone marrow to overcome this obstacle, but that new technologies for CTC detection are required to improve the method in the future. Fracheboud et al., pp. 2020–2025 In several countries, including the Netherlands, women over the age of 70 years are invited for screening mammograms. However, concerns exist about the costs, possible low attendance and risk of overdiagnosis of cancers that would have not become manifest during lifetime. Dutch researchers have now addressed this controversy. They compared data obtained from the nationwide breast cancer-screening program for women aged 70–75 with women aged 50–69. They found high participation among elderly women in the screening program (65.6%). Detection rates of breast cancer increased steadily with age, consistent with a model that the so-called sojourn time augments with age. Soujourn time is defined as the time in which a cancer is still asymptomatic, but already detectable by a screening test. There was also a significant trend towards a prognostically more favorable tumor size distribution, suggesting a slower tumor growth in older women. The authors estimate that up to age 75, overdiagnosis of cancers by the screening program is limited (6.1% in women aged 70–75). They also conclude that above this age the program loses its benefit and will lead to overtreatment of breast cancers without additional benefits in survival time.