Cyclooxygenase type-2 (COX-2) is overexpressed in malignant tumours including breast cancers, though the mechanism of upregulation is unclear. This study aimed to determine COX-2 expression in ductal carcinoma in situ (DCIS) in comparison to invasive breast cancer (IBC) and normal breast, and also to investigate the relationship of COX-2 expression with HER-2 expression, oestrogen receptor (ER), tumour grade and cellular proliferation (Ki67) in DCIS. Cyclooxygenase type-2, HER-2, ER and Ki67 expression were determined by immunohistochemistry on paraffin tissue sections of DCIS (n ¼ 187), IBC (n ¼ 65) and normal breast reduction tissue (n ¼ 60). Cyclooxygenase type-2 expression in DCIS (67%, Po0.001) and IBC (63%, Po0.001) was significantly greater than in normal breast (23%). There was no difference in COX-2 expression level between DCIS and IBC (P ¼ 0.87) or between normal breast from reduction mammoplasty tissue and normal breast ducts around DCIS (22%, P ¼ 0.29). In DCIS, COX-2 expression was associated with higher cellular proliferation rates (Po0.0001), nuclear grade (P ¼ 0.003), with ER negativity (P ¼ 0.003) and with HER-2 positivity (Po0.0001). Cyclooxygenase type-2 expression is upregulated in in situ breast cancer and is associated with surrogate markers of an aggressive DCIS phenotype including nonoestrogen-regulated signalling pathways. Cyclooxygenase type-2 inhibition may potentially prevent the development of ER-positive and ER-negative breast cancers.

The type 1 tyrosine kinase receptor HER2 (c-erbB2/neu) is associated with resistance to hormone therapy and poor survival in invasive breast cancer, whereas HER4 expression is associated with endocrine responsiveness. Patterns of tyrosine kinase receptor coexpression may aid prediction of recurrence risk after surgery for ductal carcinoma in situ (DCIS). Women who had undergone surgery for pure DCIS were studied. Out of 129 primary tumors, 39 had recurred and 90 had not recurred after 5 years of follow-up. Primary tumors were compared for HER2, HER3, and HER4, estrogen receptor, and Ki67 by immunohistochemistry. HER2 was expressed in 58%, HER3 in 49%, and HER4 in 63% of nonrecurrent DCIS, compared with HER2 expression in 82% (P = 0.008), HER3 expression in 71% (P = 0.04), and HER4 expression in 36% (P = 0.004) in DCIS that subsequently recurred. Dually expressing HER2/4 DCIS was more likely to be estrogen receptor positive than HER2-only-expressing DCIS (73% versus 53%; P = 0.05). HER2 expression was associated with a higher percentage and HER4 expression a significantly lower percentage of proliferating DCIS cells (median, 13.8% versus 8.4%; P = 0.001). Coexpression of HER2 with HER4 was associated with reduced recurrence compared with HER2-only positive DCIS (P = 0.003). This association remained significant when analyzing only high nuclear-grade DCIS (P = 0.015). Low nuclear grade, low proliferation rate and presence of HER4 expression were independent predictors of nonrecurrence. Potentially, HER4 expression may identify women who could avoid radiotherapy after breast-conserving surgery for DCIS.

Excision margin width is the most important predictor of local recurrence after breast-conserving surgery for DCIS. The VNPI lacked discriminatory power for guiding further patient management.

Tumour grade and comedo necrosis were not strong enough predictors to be used as surrogates for immunohistochemical assessment. ER status should be determined before commencing endocrine therapy.

Adjuvant antioestrogen therapy with tamoxifen is recommended for all women following breast-conserving surgery for ductal carcinoma in situ (DCIS) to reduce local recurrence, despite 50% of lesions being oestrogen receptor (OR) negative. We have investigated the response to hormone manipulation in DCIS by studying changes in epithelial proliferation and progesterone receptor (PR) expression as surrogate molecular markers of treatment effects in DCIS of known OR status. Women were identified who had undergone diagnostic core biopsy followed by surgery for DCIS 14 -41 days later. Ki67 (a measure of epithelial cell proliferation) and PR expression were determined by immunohistochemistry on paired paraffin sections of the core biopsy and operative specimens for each patient, with OR and HER-2 measured on the operative specimen. Women were divided into three groups according to whether they had changed hormone therapy (stopped hormone replacement therapy (HRT), group 1), continued taking HRT (group 2) or were not taking HRT (group 3) between core biopsy and surgery. In OR-positive (but not in OR-negative) DCIS after oestrogen withdrawal (group 1), a fall in the mean cell proliferation (Po0.01) was observed. A fall in PR expression between core biopsy and surgery was also seen in this group (P ¼ 0.02). No change in either mean cell proliferation or PR expression was seen in the other two groups in OR-positive or -negative DCIS. The fall in proliferation and PR expression occurred regardless of HER-2 status. In conclusion, a biological response to hormone manipulation is only seen in OR-positive DCIS tumours. Any clinical value of antioestrogen therapy is likely to be restricted to this group.