Chair of Medical Oncology and Postgraduate Medical School in Oncology
Department of Medical Oncology B
National Cancer Research Institute
Chair of Medical Oncology
University of Genoa
For many years, tamoxifen represented the “gold standard” adjuvant treatment for endocrine-responsive early breast cancer.(1,2) This antioestrogen significantly reduces the risk of recurrence and death in virtually all patients with oestrogen receptor-positive (ER+) tumours receiving treatment for an appropriate period of time.(3)
However, several trials(4,5) and the recent Early Breast Cancer Trialists’ Collaborative Group overview(3) have confirmed that five years of tamoxifen treatment increases the risk of endometrial carcinoma and of other life-threatening conditions such as thromboembolic events. Moreover, many women with ER+ tumours do not benefit from tamoxifen because they are primarily resistant to tamoxifen or develop resistance to this treatment after initially benefiting from it.(6)
Therefore, new well-tolerated and effective approaches are required. Third-generation aromatase inhibitors are as effective as, if not superior to, tamoxifen when used as firstline treatment for advanced disease.(7–9) They are also of benefit to many women with advanced breast cancer who have been initially managed with tamoxifen.(10,11)
In view of these premises, the efficacy of aromatase inhibitors has been investigated in the adjuvant setting, head-to-head, as an alternative to or combined with tamoxifen, as a switch after a few years of tamoxifen or, finally, after a standard five-year course of this antioestrogen as postadjuvant treatment.(12–17)
Aromatase inhibitors as primary adjuvant endocrine therapy: ATAC and BIG 1-98 trials
The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial enrolled 9,366 postmenopausal women in a prospective, double-blind, randomised study comparing five years of tamoxifen treatment with anastrozole alone, or in combination with tamoxifen. The first planned analysis,(13) at a median follow-up of 33.3 months, showed that anastrozole, but not the combination, was superior to tamoxifen and was also better tolerated. An updated analysis of this trial (median follow-up of 68 months) confirmed the superiority of anastrozole, particularly in women with hormone receptor-positive tumours, where a 27% decrease in the risk of recurrence (hazard ratio [HR] 0.83, 95% CI 0.73–0.94, p=0.005) was observed. Significant benefits in favour of anastrozole were also seen in time-to-distant recurrence (HR 0.79, 95% CI 0.70–0.90, p=0.0005) and contralateral breast cancer (HR 0.58, 95% CI 0.38–0.88, p=0.01). However, overall survival was similar for anastrozole and tamoxifen (HR 0.97, p=0.7).(14)
The first results of the Breast InterGroup (BIG) 1-98 study(17) were presented at a conference in St Gallen (Switzerland) in 2005. This trial is an ongoing, four-arm, randomised study comparing tamoxifen and letrozole, either as monotherapy or in sequence, in 8,028 postmenopausal women. The analysis relative to the comparison of monotherapies was performed after a median follow-up of 26 months, while results relative to the comparison of the two sequential therapy arms are expected to be available by 2008. Of the 4,003 patients who received letrozole, 84% were disease-free at five years, compared with 81.4% of patients in the tamoxifen group (p=0.003).
Switching to aromatase inhibitors treatment
Switching women currently receiving tamoxifen to an aromatase inhibitor may offer advantages over continued tamoxifen treatment, as it allows women who have been receiving an established treatment to receive a second, different type of drug potentially able to prevent the development of tamoxifen resistance, thus reducing relapse rates. This approach may also offer tolerability benefits. In fact, patients have the opportunity to receive five years of endocrine treatment while limiting the exposure to both tamoxifen and the aromatase inhibitor. Several trials have evaluated the risks and benefits of switching from tamoxifen to an aromatase inhibitor.
Following a pivotal experience with a first-generation aromatase inhibitor,(18) a prospective trial(12) was launched in Italy to test the efficacy of switching to anastrozole after two to three years of tamoxifen treatment. Total duration of treatment was five years, both in women switched to anastrozole and in those continued to tamoxifen.
Among the 448 postmenopausal patients who were enrolled, all had undergone prior surgery, with or without postoperative radiotherapy and chemotherapy, for node-positive, ER+ tumours. After a median follow-up time of 36 months, significantly more events had been recorded in the tamoxifen group (p=0.0002). Disease-free and local recurrence-free survival were also significantly longer in this group (HR 0.35, 95% CI 0.18–0.68, p=0.001 and HR 0.15, 95% CI 0.03–0.65, p=0.003, respectively). These results were confirmed by an updated analysis (median follow-up time: 52 months) presented at the 2005 ASCO meeting.(19) A pooled analysis of the two Italian trials, including a total of 828 postmenopausal women assessed for a median follow-up time of 68 months, showed that switching also implied a significant mortality benefit, relative to both all-cause mortality (HR 0.60, 95% CI 0.41–0.87, p=0.007) and breast cancer-specific mortality (HR 0.62, 95% CI 0.39–0.97, p=0.03).(20)
Like the ITA trial, the ABCSG and ARNO trials(21) randomly assigned postmenopausal women with ER+ tumours who had been receiving adjuvant tamoxifen therapy for at least two years to continue tamoxifen or to switch to anastrozole for the remainder of the planned five-year treatment. The combined analysis of data from these trials, after a median follow-up of 28 months, confirmed a significant benefit in terms of relapse-free survival (HR 0.59, p<0.0018) and in addition showed a significant decrease of the risk of developing distant metastasis (HR 0.60, 95% CI 0.42–0.88, p=0.0067).
ITA, ARNO and ABCSG trials meta-analysis
The results of a pooled analysis(22) of the three switching trials with anastrozole have been recently presented at the 2005 San Antonio Breast Cancer Conference. This analysis included a total of 4,006 patients with a median follow-up time of 30 months and confirmed that switching from tamoxifen to anastrozole, in addition to a significant improvement in disease-free survival (HR 0.59, 95% CI 0.48–0.74, p<0.0001), event-free survival (HR 0.55, 95% CI 0.42–0.71, p<0.0001) and distant recurrence-free survival (HR 0.61, 95% CI 0.45–0.83, p<0.0015), also resulted in a 29% improvement in overall survival (HR 0.71, 95% CI 0.52–0.98, p<0.0377).
This trial adopted the same design of previous switching trials with exemestane in place of anastrozole.(16) Of the 4,742 patients who were accrued, 2,362 were randomly assigned to switch to exemestane and 2,380 to continue on tamoxifen until a total of five years of treatment.
The unadjusted disease-free HR in the exemestane group was 0.68 (95% CI 0.56–0.82, p<0.001), which corresponds to an absolute three-year benefit in disease-free survival of 4.7% (95% CI 2.6–6.8). Distant disease-free survival was also better in the exemestane group (HR 0.66, 95% CI 0.52, p=0.0004). However, no statistically significant difference in overall survival merged so far at the time of this analysis (HR 0.88, 95% CI 0.67–1.16, p=0.37).
Aromatase inhibitors treatment after five years of tamoxifen therapy
The MA-17 trial(15) was an international, multi-institutional worldwide trial sponsored by the National Cancer Research Institute of Canada. In total, 5,187 women who had received an average of five years of adjuvant tamoxifen were randomised to additional treatment for five years with either letrozole or placebo. However, an interim analysis showed that the HR for local recurrence, distant metastasis and new contralateral breast cancers favoured letrozole (95% CI 0.43–0.75, p=0.00008). Therefore, recruitment of patients ceased after a median follow-up of 2.4 years. The results of this trial were updated at the 2004 ASCO Meeting(23) and included survival data. Although there was no difference between the two groups in terms of overall survival (HR 0.76, 95% CI 0.48–1.21, p=0.25), a retrospective, unplanned analysis by nodal status disclosed a statistically significant survival benefit for node-positive women assigned to additional treatment with letrozole.
Discussion and conclusions
Several trials have shown that new-generation aromatase inhibitors can further decrease the risk of relapse for women with ER+ breast cancer. These trials cannot be compared due to different design, trial size, patient selection, aromatase inhibitor type and schedule and, last but not least, follow-up duration and results maturity. Nonetheless, a benefit consisting in an additional 20–40% decrease in the recurrence risk has been reported for women receiving upfront, sequential or extended treatment with an aromatase inhibitor. Moreover, a survival benefit has come out from the retrospective analysis of MA17 trial(23) and from two meta-analysis including switching trials.(20,22) On the basis of these results, recommendations for the use of tamoxifen, until now the endocrine therapy of choice in the adjuvant setting, have been revised. In 2004, the American Society of Clinical Oncology Health Services Research Committee panel experts(24) advanced the hypothesis that tamoxifen might not be the optimal adjuvant treatment for any patient candidate to receive endocrine therapy and that aromatase inhibitors should be preferred in selected cases. Guidelines from the 8th St Gallen Breast cancer Conference(25) suggest tamoxifen as the preferred option for patients intolerant to tamoxifen or when tamoxifen is contraindicated. Based on the results of ATAC, ITA, IES and MA-17 trials the 2005 National Comprehensive Cancer Network (NCCN)(26) Practice Guidelines recommend five years of anastrozole as initial adjuvant therapy or, after an initial two to three years of tamoxifen, switching to anastrozole or exemestane for a completed course of five years of hormonal therapy. Despite these indications, important areas of uncertainty remain to be defined. One of the most important questions is whether aromatase inhibitors should replace tamoxifen from the beginning or whether this option should be considered after a few years of tamoxifen treatment. There is no doubt that each strategy has its own putative advantages and disadvantages, even from an economic point of view. There is an absolute need for predictive factors able to identify patients who are most likely to benefit from aromatase inhibitors from the start. There is increasing evidence about the role of HER2 overexpression and PgR expression as putative prognostic factors of tamoxifen de novo resistance.(27) Patients with HER2+ and PGR- tumours have a very high risk of relapse if initially managed with tamoxifen, and probably could more appropriately receive an aromatase inhibitor at the outset.(28) Indeed, the benefit achieved by upfront use of aromatase inhibitors in the ATAC trial was bigger in patients with ER+ and PGR- tumours.(14) However, this trend was not confirmed by the preliminary subgroup analysis of the BIG 1-98 trial.(17) On the contrary, in the ATAC trial, the benefit achieved with anastrozole in patients with both ER+ and PGR+ tumours was only marginally significant.(14) According to the model developed by Burstein et al(28) these patients, who actually represent the majority of postmenopausal women with ER+ tumours, could derive a better outcome from switching. While looking for the best strategy it is also necessary to remember that, due to the relatively short follow-up periods of most adjuvant trials, no firm conclusions can be drawn at the moment about long-term safety of aromatase inhibitor treatment in the adjuvant setting. Whereas there is no doubt that aromatase inhibitors might affect lipid metabolism in a different way than tamoxifen,(29,30) it is still impossible to ascertain whether and how this different effect can impact on cardiovascular lethality. Similarly, it is still difficult to give a prognostic regarding the widespread effects on bone resorption or cognitive function of such a prolonged oestrogenic deprivation resulting from the use of these compounds for several years. Indeed, most previous studies have reported an increased frequency of bone fractures.
In view of these findings there is no doubt that, in addition to women who are intolerant to tamoxifen or for whom tamoxifen might be contraindicated, the proportion of women who might benefit from upfront treatment with an aromatase inhibitor or from switching is becoming larger. However, this does not automatically imply that tamoxifen should no longer be offered as a valuable option to women candidate to adjuvant endocrine therapy. In addition, a careful cost/benefit balance should still represent the main decision-making criterion in each individual patient. Thus, the time has not come yet for aromatase inhibitors to become the panacea in breast cancer treatment.
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