International specialists discuss the evidence driving clinical practice  

by Stephen Pinn

Introduction

Until recently, a five-year period of endocrine treatment with tamoxifen was widely acknowledged as being the gold standard, adjuvant therapy for postmenopausal women with early breast cancer (EBC). Despite the clear benefits of tamoxifen, however, many patients still develop recurrent disease. Furthermore, patients on tamoxifen may experience serious side effects - such as thromboembolic/cerebrovascular events and endometrial cancer.

Recent clinical data suggest that the new generation of aromatase inhibitors (AIs) provide more effective protection against breast cancer recurring than tamoxifen - while at the same time reducing the risk of complications.

A group of 15 internationally renowned breast cancer specialists (oncologists, surgeons and gynaecologists) is so concerned that women with EBC are continuing to receive sub-optimal endocrine treatment that they met to discuss the prevailing evidence on the use of AIs as adjuvant treatment.

Meeting in the UK (April 25-26, 2008), members of this forum first considered why postmenopausal hormone receptor-positive women with EBC should be treated with endocrine therapy in the first place:
- to prevent recurrence
- to prolong survival
- to minimise life-threatening side-effects
- to maintain quality of life

The American Society of Clinical Oncology (ASCO) and the National Institute for Health and Clinical Excellence (NICE) both signal that AIs should be playing an essential part of treatment strategies in this vulnerable cohort of women. However, clear guidance as to the timing of AI initiation remains somewhat vague. While there is a steady take-up of AIs as the endocrine treatment of preference, there is still a reluctance to commit to AIs up-front in some countries.

What do the clinical trials tell us?

Many oncologists have been persuaded that 2-3 years of tamoxifen before switching to an AI provides the best available endocrine strategy - certainly better than persisting with tamoxifen for 5 years. But have they been seduced by switching trials such as the IES (Intergroup Exemestane Study)? In the IES, 4,724 postmenopausal women with EBC who were disease-free after 2-3 years on tamoxifen were randomly assigned to continue with tamoxifen for the remainder of a 5-year period of endocrine therapy or switched to an AI (exemestane).

After a median follow-up of 55.7 months, there was a significant benefit in terms of disease-free survival favouring the AI (HR 0.76, p=0.0001) - an absolute difference compared with tamoxifen of 3.3% (i). In addition, a "modest" improvement in overall survival (OS) was seen. However, what is not widely understood is that the observed benefit in OS may be due to an effect on non-breast cancer deaths rather than breast cancer-related events.

To date, the upfront trials ATAC (Arimidex, Tamoxifen, Alone or in Combination) and BIG1-98, have not demonstrated an OS benefit for AI therapy, and clinicians continue to be cautious about up-front AI therapy (ii, iii). However, the specialists who took part in the UK forum recognise that there are competing causes of mortality that increase with age which decrease the likelihood of being able to easily demonstrate a better survival outcome with AIs. "In a sense," said Dr Jack Cuzick (Wolfson Institute of Preventive Medicine, London, UK), "it means that these women are not dying from breast cancer, but from other causes. We must make sure that oncologists appreciate the significance of the difference in recurrence with an AI. It is totally unrealistic to expect a decrease in OS."

However, in the ATAC trial, fewer deaths after recurrence were seen