DCIS and aromatase inhibitors

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Abstract

In patients with hormone receptor positive DCIS tamoxifen reduces recurrence rates by almost 50%. Few data are available with aromatase inhibitors from randomised studies. In the ATAC study there were three DCIS lesions in the anastrozole arm and four in the tamoxifen arm in the women with ER positive invasive cancer. In the MA17 study which randomised patients to up to 5 years of letrozole or placebo there was only one DCIS event in the contralateral breast in patients taking letrozole and five on placebo. There were also four patients in this study who had DCIS in the conserved breast on placebo and none in the letrozole treated group. The few clinical data that are available therefore suggest the aromatase inhibitors are likely to be effective in DCIS. A histological review of a study of 206 postmenopausal women with invasive oestrogen receptor positive breast cancer who were randomised as part of a 14 day preoperative study to receive 2.5 mg of letrozole or 1 mg of anastrozole identified 27 patients with 28 pairs of tumours in whom there was sufficient ER positive DCIS in invasive cancer in the initial core biopsy and in the subsequent surgery specimen, to evaluate for PgR activity and proliferation. Within the DCIS both aromatase inhibitors significantly reduced PgR expression and both drugs also produced a significant fall in proliferation. There was a moderate degree of agreement between the fall in PgR in both the invasive cancer and DCIS (Kappa = 0.5; p = 0.0013) and between the fall in proliferation and between the invasive and in situ components (correlation coefficient = 0.68; p < 0.001). This study has shown significant effects of aromatase inhibitors on DCIS indicating that these agents are therapeutically active in this condition.

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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