Several significant studies investigating the use of aromatase inhibitors for early stage breast cancer have been reported. The following is a summary of the studies and significant results to date. Those looking at upfront usage are mentioned first, followed by switching protocols, then by extended use.

The ATAC study recruited over 9000 women from 381 centres in 21 countries between July 1996 and March 2000. Patients in the study included some women with hormone receptor negative breast cancer, as at the time the study started it was thought that hormone receptor negative patients might still get some benefit from hormone therapy. Women in the study had varying lymph node status (60.9% lymph node negative, 33.5% positive and the rest unknown). Average age of those entering the study was 64.3 years. Of these women, 64.1% women had a tumour size of 2cm or less. Preliminary results indicated that anastrozole was well tolerated and was effective in the treatment of hormone receptor positive early stage breast cancer. Combination treatment (anastrozole and tamoxifen) was equivalent to tamoxifen alone and significantly worse than anastrozole alone (2). This arm was not considered in the more recent analysis.

After a median follow up of 68 months, there was a small but significant increase in disease free survival in those taking anastrozole compared with tamoxifen. The advantage was greater for hormone receptor positive breast cancers. Current practice is that hormone therapy is only given to women whose breast cancers are ER positive. Tamoxifen appears to be less effective for tumours which are ER+PR- so the greatest benefit of anastrozole was seen in women whose breast cancers were ER+ but PR-. With women whose breast cancers were ER+PR+ less difference was noted.

There was also a significant reduction in contralateral breast cancers and distant metastases. Overall survival was similar for both the tamoxifen and anastrozole groups. The study population had a relatively good prognosis anyway, so it may be too soon to say whether overall survival is better. However, the significant reductions in recurrences (both local and distant) suggest that there may possibly be an overall survival advantage for anastrozole with more mature follow-up(3,4).

There were fewer side effects with anastrozole, especially with regard to gynaecological problems and vascular events. However there were increased muscular skeletal events and bone fractures in women taking anastrozole.

The ATAC study shows that anastrozole is an effective and well tolerated treatment for post menopausal women with early stage breast cancer.

The Breast International Group (BIG) 1-98 trial has four different trial arms – tamoxifen for five years; letrozole for five years; tamoxifen for two years followed by letrozole for three years; and letrozole for two years followed by tamoxifen for three years.

Over 8000 women in 27 different countries are taking part in the trial. All women are either ER positive (the vast majority) or PR positive.  The initial results were presented in January 2005 after a median follow up of 25.8 months and described the comparison between letrozole and tamoxifen. Results were in favour of letrozole.

Letrozole significantly prolonged disease free survival for post-menopausal women with hormone dependent breast cancer. It especially reduced distant recurrences (5, 6). The benefit appears greatest in women who had received chemotherapy and had node positive disease.

Whereas the ATAC trial has suggested the greatest benefit for women with ER+ PR- tumours, the BIG 1-98 study has so far shown a benefit for all women with ER+ tumours, irrespective of PR status (6)

There were more episodes of thromboembolic events and vaginal bleeding in women taking tamoxifen. However, there were more reports of bone fractures, cardiac events and low level hypercholesterolaemia with letrozole than tamoxifen. Tamoxifen tends to have a cholesterol-lowering effect.

Results suggest there might be a survival advantage for letrozole with the BIG 1-98 trial – there has so far been a 14% reduction in death. Further follow up will clarify the situation (4).

The International Exemestane Study looked at whether switching to exemestane after two to three years of tamoxifen was more effective than remaining on tamoxifen for five years.

Over 4000 women entered this study between February 1998 and February 2003. They had confirmed invasive breast cancer. The breast cancers were either known to be hormone receptor positive or with unknown hormone receptor status. About 32% of patients had received chemotherapy as part of their adjuvant treatment.

There was a significant improvement in disease free survival at three years after randomisation and a reduction in contralateral breast cancer occurrence. Overall survival was not significantly different in the two groups, but was in favour of exemestane. With longer follow up it is likely that a survival advantage will be seen. Exemestane appeared to be equally effective in node positive and node negative breast cancers.  

Women treated with exemestane had a higher incidence of arthralgia and diarrhoea than women treated with tamoxifen. Gynaecological symptoms, vaginal symptoms, muscle cramps and thromboembolic events were more common in the group receiving tamoxifen. More fractures were reported in women taking exemestane, but these were not statistically significant. There was a slight numerical increase in the number of myocardial infarctions in those taking exemestane and this situation will need monitoring (4)

Once again, following interim results it was recommended by the data and safety monitoring committee that results be released early (7).

These two trials looked at switching from tamoxifen to anastrozole after two years.

In total, over 3200 post menopausal women were involved in these studies. All patients were given tamoxifen for two years. Half the patients continued with tamoxifen for another three years, while the remainder took anastrozole for three years. All patients had hormone receptor positive breast cancer. Most (75%) had node negative disease. 

There was a significant reduction in any breast cancer event (recurrence, local recurrence or contralateral breast cancer) in the cross over arm. This was especially so with regard to distant metastases. There has not, as yet, been any improvement shown in overall survival.

Side effects were only counted after two years. There was a greater fracture rate in the anastrozole group compared to tamoxifen (8).

This trial looked at giving letrozole (Femara) for five years following completion of five years of tamoxifen in post menopausal women – extended adjuvant treatment. It was a double blind, placebo controlled trial. The primary endpoint was disease free survival, with overall survival, safety and quality of life also being assessed. 

Over 5000 women were recruited into this study. All women had had tamoxifen previously, and had hormone receptor positive breast cancers with no evidence of metastatic disease at time of entry into the trial. Nodal status varied with 46% of women having node positive disease and 50% node negative; in 4% of women nodal status was unknown.

After a median follow up of 2.4 years, letrozole decreased the risk of recurrence by 43% compared with the placebo. The benefit in disease free survival increased as time progressed. There was also a reduction in the rate of distant metastases in the letrozole group compared to the placebo group. The rate of death due to breast cancer was nearly halved. There was also a decrease in the frequency of contralateral breast cancers (9). A survival advantage was also noted in an updated analysis, but only in women who had node positive disease (10).

With regard to side effects, letrozole was well tolerated. Hot flushes, arthritis, arthralgia and myalgia were more common with letrozole but were generally low grade. In the letrozole group, 4.5% of women discontinued treatment because of side effects, compared to 3.6% of women in the placebo group.

Following the interim results of this study, the data and safety monitoring committee recommended that the study be discontinued early and the patients informed of the results.

This study does not identify the optimal duration of treatment with letrozole; neither does it identify possible long-term toxicities.