Summary Tamoxifen may mediate its effect in early breast cancer in part via an oestrogen receptor (ER)-independent pathway by directly stimulating fibroblasts to produce the negative paracrine growth factor transforming growth factor (TGF)-f,. We have previously shown that secretion of this factor is induced 3-to 30-fold in human fetal fibroblasts in vitro, and by stromal fibroblasts in vivo following tamoxifen treatment of ERpositive and ER-negative breast cancer patients. Primary cultures of breast tumour fibroblasts have been exposed to tamoxifen for 48 h, and rates of secretion of TGF-fl, and TGF-fl2 measured using a quantitative immunoassay. Fibroblast strains derived from malignant and benign tumours produced and secreted similar amounts of TGF-flp, but benign breast tumour fibroblasts secreted significantly higher levels of TGF-f32 compared with fibroblasts of malignant origin. Tamoxifen did not induce any consistent increase in TGF-,B secretion into the conditioned medium, but immunofluorescence analysis for the intracellular form of TGF-f3, revealed evidence of increased immunoreactive protein in tamoxifen-treated fibroblasts, which is localised to the nucleus. Therefore synthesis of TGF-fl, appears to be stimulated by tamoxifen, but increased secretion may be abrogated in vitro. Furthermore, using immunocytochemistry and transient transfection with an ER-responsive reporter construct, no ER was demonstrable in these fibroblasts supporting the proposed ER-independent paracrine pathway.

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#5152 Introduction:
 Ensuring pathologically tumor free surgical margins reduces local recurrence rates following breast conserving surgery for breast cancer or DCIS. There is no general agreement regarding the definition of a clear margin but units with an agreed policy report reduced local recurrence rates. In our unit all patients with a surgical clearance of <5mm are offered further surgery either by mastectomy or by re-excision. We have examined factors that may predict residual disease in re-excised tissues.
 Method:
 All attempted breast conserving operations between 01/01/2004 to 31/09/2007 were identified from a dedicated database. Patient age, presentation (symptomatic or screening), surgeon (any of 4 surgeons), weight of tissue removed, tumour size, grade, presence of lymphovascular invasion (LVI) and the closest radial margin (categorised as involved, <2mm, 2-5mm) were examined.
 Results:
 Breast conservation was attempted in 605 women (mean age 60; 297 symptomatic, 308 screening). Further surgery was performed in 166 (27.4%) women, including 89 (14.7%) mastectomies. Median tumour size was 20mm (range 0-109). Residual disease was found in 83(50%) of re excisions (66/111 with involved margins, 16/40 for non involved margins up to 2mm, and 1/15 for margins over 2mm). On univariate analysis excision margin (OR=0.33, p=0.000) and total tumor size (OR=4.0 p=0.045 for the smallest size quartile versus the largest) were associated with residual disease. On multivariate analysis only tumor margin remained predictive (OR for <2mm vs involved: 0.46, p=0.043; OR for 2-5mm vs involved: 0.05, p=0.004).
 Conclusion:
 In a unit with an aggressive re-excision policy, involved or close surgical margins predict the presence of residual disease in re-excision specimens. A margin of greater than 2mm reduces the risk of residual disease to 1/20 of that seen with microscopically involved margins. This study supports a 2mm minimum radial margin policy when attempting breast conservation for breast malignancy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5152.