The Journal of Steroid Biochemistry and Molecular Biology
DCIS and aromatase inhibitors
Introduction
Following the introduction of mammographic national screening programmes ductal carcinoma in situ (DCIS) currently comprises 20% or more of all screen detected ‘cancer’. The appropriate treatment for this disease is now an important issue. It is generally agreed that adequate local treatment comprising either mastectomy or local excision with clear margins with or without radiotherapy is important to maintain local disease control [1]. Adjuvant endocrine therapy has also been advocated after breast conserving therapy for DCIS and there are two trials that have addressed the effectiveness of tamoxifen in reducing subsequent breast cancer events. The National Surgical Adjuvant Breast Project (NSABP) Trial B24 looked at the value of giving tamoxifen to women with DCIS who had undergone breast conserving surgery and had also received radiotherapy [2]. There was a highly significant reduction in the recurrence rate with the addition of tamoxifen. However, the subsequent United Kingdom, Australian and New Zealand trial found no significant reduction in the rate of recurrence with the addition of tamoxifen [3]. In the American study, the greatest reduction in recurrence was in women younger than 50 years of age [2]. Benefits of tamoxifen were only evident in patients with oestrogen receptor positive DCIS; there was no significant effect in oestrogen receptor negative DCIS [4]. Tamoxifen also reduced DCIS events compared with placebo in both the NSABP and the IBIS 1 prevention studies [6], [7], [8].
Aromatase inhibitors are a class of compounds which act systemically to inhibit oestrogen synthesis. They prevent oestrogen production by inhibiting the aromatase enzyme which catalyses conversion of adrenal androgens to oestrogen. They have been specifically developed for use in postmenopausal women.
The aromatase inhibitors have been shown to be significantly better than tamoxifen in the metastatic setting, the neoadjuvant and adjuvant setting [9]. There are few data looking at the effects of aromatase inhibitors on DCIS.
The aim of this study was to investigate the effects of aromatase inhibitors on DCIS by reviewing current adjuvant endocrine therapy trials that have already published results and to look at our own data in Edinburgh from a preoperative study of the aromatase inhibitors anastrozole and letrozole to determine the effect of these drugs on hormone receptor expression and proliferation in DCIS.
Section snippets
Patients, materials and methods
The current published studies of the use of aromatase inhibitors in the adjuvant setting have been reviewed. This includes the arimidex, tamoxifen alone, or combination (ATAC) trial of anastrozole versus tamoxifen [10], the breast international group study (BIG 198) comparing letrozole with tamoxifen [11] and the ITA and ARNO/ABCSG combined analysis a randomised study of anastrozole versus continued tamoxifen after 2–3 years of tamoxifen therapy [12], the exemestane international study (EIS), a
ER expression
ER α expression was assessed within the Edinburgh Breast Unit laboratory of the University of Edinburgh. Cut sections from the formalin fixed paraffin embedded tissue specimens were dewaxed and rehydrated to PBS (pH 7.2–7.4). Endogenous peroxidase activity was neutralised by incubation in 3% hydrogen peroxide before being rinsed in running tap water and PBS. Sections were then placed in pre-prepared antigen retrieval buffer (Tris-EDTA pH 8.0) and microwaved in a pressure cooker at full power
DCIS in current adjuvant therapy trials
The incidence of new contralateral cancers in adjuvant studies is outlined in Table 1. In all studies the number of new primary invasive cancers in the aromatase inhibitor arm was approximately half that in the tamoxifen arm. There were only data on DCIS from the ATAC [9] and the MA17 studies [12]. Within the ATAC study there were five DCIS cases identified in patients in the anastrozole arm and five in the tamoxifen arm, with three and four respectively if the analysis is restricted to those
Discussion
During adjuvant trials of tamoxifen, which is a selective oestrogen receptor modulator, there was a reduction compared to women receiving no treatment in the number of contralateral breast cancers which developed suggesting that this drug may have a role in preventing breast cancer [5]. The NSABP study randomised 3338 women with a risk equal to a 60-year-old woman and showed a 47% reduction in the risk of invasive cancer and a 50% reduction in the risk of non-invasive breast cancer in women
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