Biological and clinical effects of aromatase inhibitors in neoadjuvant therapy

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Abstract

Postmenopausal women with large primary oestrogen receptor-rich (>20 fmol/mg protein or 80 histoscore) breast cancers have been treated neoadjuvantly with either letrozole (2.5 or 10 mg daily n=12 in each case) or anastrozole (1 or 10 mg daily n=12 and 11, respectively). Tumour was available for analysis before treatment (wedge biopsy) and 3 months later at definitive surgery (wide local excision or mastectomy). Clinical response to treatment was assessed by sequential measurements of tumour volume based on caliper assessment, ultrasound and mammography. Results showed that in these selected groups of patients a reduction in tumour volume with treatment was observed in 43 of 47 cases (91%). Pathological responses, i.e. clear decrease in tumour cellularity or increased fibrosis was evident in 32 cases (68%). Furthermore, there was a decrease with therapy in immunohistochemical staining for Ki67 in all tumours. Staining for progesterone receptor (PgR) was reduced in all 21 PgR-positive cancers treated with letrozole and in 16 of 17 positive cancers treated with anastrozole. These effects are at least as great as those seen in a non-randomised group of patients treated with tamoxifen over the same time period (additionally tamoxifen treatment was often associated with an increase in PgR staining). The results suggest that potent specific aromatase inhibitors will be valuable in treating hormone-dependent cancers.

Introduction

Primary systemic or neoadjuvant treatment for breast cancer is given with the primary tumours still present in situ within the breast. This form of therapy offers several advantages to the patient in that large tumours may be down-staged following successful treatment allowing more conservative surgery [1] and knowledge of tumour sensitivity to agents which may be subsequently used in an adjuvant setting, can be more precisely assessed by monitoring the volume/size of the primary tumour [2]. Additionally, however, the relatively easy access to tumour within the breast makes sequential sampling possible so that the effects of treatment on tumour biology and histopathology may be followed [3], [4]. In the present study the effect of new aromatase inhibitors (anastrozole/letrozole) given neoadjuvantly have been assessed on clinical/pathological response and histological expression of Ki67 and progestogen receptors in primary breast cancers from postmenopausal women; these have been compared with the effects of tamoxifen given in a neoadjuvant setting to another cohort of patients.

Section snippets

Patients

Postmenopausal patients with large (>3 cm) oestrogen receptor-positive (>20 fmol/mg cytosol protein or 80 histoscore) primary breast cancers (staged as T2, T3, T4b, N0 or N1, M0) were entered into the study. None had received prior treatment with hormonal agents for breast cancer or were taking hormone preparations at the time of study. Tumour size was monitored clinically (by calipers) and by breast ultrasound before and at monthly intervals during treatment. All patients received primary

Clinical response

Tumour volumes were measured monthly by ultrasound in 24 patients receiving letrozole and 23 women taking anastrozole. Over the same time period 65 women were recruited to treatment with neoadjuvant tamoxifen. Clinical response as assessed by % reduction in tumour volume over 3 months is depicted in Table 1. All drug regimes were capable of producing measurable tumour shrinkage (>25% reduction in tumour volume) in most cases. Furthermore major tumour shrinkage (>50% reduction in volume) was

Discussion

The present study confirms the efficacy of two third-generation aromatase inhibitors (anastrozole and letrozole) when given neoadjuvantly to treat ER-rich breast cancer [8], [9], [10]. The results also highlight differences between aromatase inhibitors and tamoxifen when given in the same setting.

It was possible to demonstrate tumour volume reduction as assessed by ultrasound in most cases, irrespective of the nature of the endocrine agents (volume reduction >25% were seen in 87 and 98% of

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    For PgR, changes from a positive to a negative result occur more commonly than seen for ER. This is particularly marked after aromatase inhibitor treatment, as reported in 2 studies in which 70% and 94% of cancers lost PgR expression.53,54 In contrast, fewer than 10% of tamoxifen treated cancers lost PgR expression and some cancers had an increase in the degree of positivity.

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Proceedings of the Symposium: ‘Aromatase 2000 and the Third Generation’ (Port Douglas, Australia, 3–7 November 2000).

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