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Challenge in the Treatment of Estrogen-Receptor–Negative Ductal Carcinoma in Situ

Hacettepe University Faculty of Medicine, Department of Medical Oncology, Ankara, Turkey

To the Editor:

I read with great interest the review article by Dunn et al¹ that presents updated knowledge about the prevention of breast cancer. Regarding this subject, I would like to comment on the challenge of treating estrogen receptor (ER) –negative ductal carcinoma in situ (DCIS).

Barnes et al² reported on the incidence of ER and progesterone-receptor expression as a function of DCIS grade. They found that most DCIS lesions were ER-positive, especially in well and moderately differentiated (grades 1 and 2) tumors. However, a large fraction of grade 3 DCIS lacked ER expression. ER expression was also less marked among cases with comedonecrosis.² Diab³ determined the concordance between ER status of DCIS and invasive disease in the same patient. Diab identified 187 patients who had known ER status of both DCIS and the invasive disease. In general, there was high concordance between ER status in DCIS and subsequent invasive breast cancer (83%); ER-negative DCIS was associated with ER-negative invasive disease in 60% of the cases.³

Patients with ER-negative DCIS are not candidates for tamoxifen treatment. However, a preventive strategy is needed for reducing the incidence of ER-negative tumors, which contribute disproportionately to breast cancer–related mortality. Recent studies suggest that the administration of cyclooxygenase (COX) -2 inhibitors to patients with ER-negative DCIS may be such a strategy. Moderate-to-high levels of COX-2 expression have been reported in invasive breast carcinomas (43%), in DCIS (63%),⁴ and in breast cancers overexpressing HER2.⁵ Boland et al⁶ determined COX-2 expression levels by immunohistochemistry on paraffin tissue sections of DCIS (n = 187), invasive breast cancer (n = 65), and normal breast reduction tissue (n = 60). They found that COX-2 expression in DCIS (67%; P < .001) and in invasive breast cancer (63%; P < .001) was significantly greater than COX-2 expression in normal breast tissue (23%). In DCIS, COX-2 expression was also associated with higher cellular proliferation rates (P < .0001) and nuclear grade (P = .003), with ER negativity (P = .003), and with HER-2 positivity (P < .0001). Eighty percent of ER-negative DCIS tumors showed COX-2 positivity, compared with 58% of ER-positive DCIS tumors (P = .003). These findings, together with the association of COX-2 with HER-2 expression, are important because these factors are surrogate markers of an aggressive DCIS phenotype and link nonestrogen growth factor–signaling pathways with COX-2 overexpression. Therefore, COX-2 inhibitors and trastuzumab may have a role in preventing invasive breast cancer in patients with ER-negative DCIS.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

REFERENCES

1. Dunn BK, Wickerham DL, Ford LG: Prevention of hormone-related cancers: Breast cancer. J Clin Oncol 23:357-367, 2005[Abstract/Free Full Text]

2. Barnes NLP, Boland G, Davenport A, et al : A prospective study of estrogen and progesterone receptor status in ductal carcinoma-in-situ. Breast Cancer Res Treat 82:S34, 2003 (suppl 1)

3. Diab SG: Concordance between estrogen receptor status of ductal carcinoma-in-situ and invasive disease: Analysis of the Surveillance, Epidemiology, and End Results program. Breast Cancer Res Treat 82:S62, 2003 (suppl 1)

4. Half E, Tang XM, Gwyn K, et al: Cyclooxygenase-2 expression in human breast cancers and adjacent ductal carcinomas in situ. Cancer Res 62:1676-1681, 2002[Abstract/Free Full Text]

5. Subbaramaiah K, Norton L, Gerald W, et al: Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: Evidence for involvement of AP-1 and PEA3. J Biol Chem 277:18649-18657, 2002[Abstract/Free Full Text]

6. Boland GP, Butt IS, Prasad R, et al: COX-2 expression is associated with an aggressive phenotype in ductal carcinoma-in-situ. Br J Cancer 90:423-429, 2004[CrossRef][Medline]

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