Italian Tamoxifen Anastrozole Research Articles

Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: Long term results of the Italian Tamoxifen Anastrozole trial

The Italian Tamoxifen Anastrozole (ITA) trial investigated the efficacy of switching to anastrozole for women who were already on adjuvant tamoxifen since 2–3years. Relapse-free survival (RFS) was the primary end-point; event-free survival (EFS), overall survival (OS) and safety were secondary end-points. Herein, we report an update on the long term results of this trial.At a median follow-up time of 128months (range14–168months), 94 events have been recorded in the tamoxifen group compared with 71 events in the anastrozole group (hazard ratio (HR)=0.71; 95% confidence interval (CI), 0.52–0.97; p=0.03). RFS was also significantly longer in the anastrozole group (HR=0.64; 95% CI, 0.44–0.94; p=0.023); no statistically significant difference between study arms concerning OS was shown, but the trial was not powered enough in respect to this end-point. The incidence of serious adverse events (SAE) like bone fractures was comparable (four in each arm), while gynaecological problems were still significantly more numerous among the women continued on tamoxifen (21 patients developed a SAE in this group, including eight endometrial cancers, compared to three patients who suffered from a SAE, including one endometrial cancer, in the anastrozole group: p<0.000).Present data confirm that switch is safe and can provide long-term gain in terms both of RFS and of EFS, which persists even several years since treatment discontinuation.

Expression of estrogen receptor (ER) in disseminated tumor cells of breast cancer patients

For more than 20 years, tamoxifen has been the mainstay of adjuvant endocrine therapy for women with hormone-sensitive early-stage breast cancer. However, not only does tamoxifen have potential side-effects such as an increased risk of endometrial cancer and thromboembolic events, but patients can also develop resistance to the drug. We aimed to investigate whether switching treatment of postmenopausal women with such breast cancer to anastrozole after 2–3 years of tamoxifen would be more effective than continuing on tamoxifen for a total of 5 years.We did a meta-analysis of three clinical trials—the Austrian Breast and Colorectal Cancer Study Group (ABCSG 8), Arimidex-Nolvadex (ARNO 95), and the Italian Tamoxifen Anastrozole (ITA) studies—in which postmenopausal women with histologically confirmed, hormone-sensitive early-stage breast cancer were randomised to 1 mg/day anastrozole (n=2009) after 2–3 years of tamoxifen treatment or to continued 20 or 30 mg/day tamoxifen (n=1997). We analysed the data with a stratified Cox proportional hazards model with the covariates of age, tumour size, nodal status, grade, surgery, and chemotherapy.Patients who switched to anastrozole had fewer disease recurrences (92 vs 159) and deaths (66 vs 90) than did those who remained on tamoxifen, resulting in significant improvements in disease-free survival (hazard ratiro 0·59 [95% CI 0·48–0·74]; p<0·0001), event-free survival (0·55 [0·42–0·71]; p<0·0001), distant recurrence-free survival (0·61 [0·45–0·83]; p=0·002), and overall survival (0·71 [0·52–0·98]; p=0·04).Our results show that the clinical benefits in terms of event-free survival seen in individual trials for those patients who switched to anastrozole translate into a benefit in overall survival. These findings confirm that clinicians should consider switching postmenopausal women who have taken adjuvant tamoxifen for 2–3 years to anastrozole.

Summary of aromatase inhibitor clinical trials in postmenopausal women with early breast cancer

Five years of adjuvant therapy with tamoxifen was considered the gold-standard treatment for postmenopausal women with estrogen receptor-positive breast cancer for many years. Data from a core group of clinical trials investigating the safety and efficacy of aromatase inhibitors (AIs) have challenged this perception. These studies were designed to evaluate the safety and efficacy of AIs in the following clinical settings: 1) as initial adjuvant therapy (the Arimidex, Tamoxifen, Alone or in Combination trial, Breast International Group Trial 1-98), 2) in a "switched setting" after 2 to 3 years of treatment with tamoxifen (Arimidex-Nolvadex 95, the Austrian Breast and Colorectal Cancer Study Group 8 [ABCSG 8] trial, the Italian Tamoxifen Anastrozole study, the Intergroup Exemestane Study), and 3) in extended settings (National Cancer Institute of Canada Trial MA.17, ABCSG 6a, National Surgical Adjuvant Breast and Bowel Project 33). The efficacy data from these studies suggested that AIs have added substantial benefit in terms of disease outcome. AIs were tolerated well, and patients who received them experienced fewer thrombolic events and less endometrial cancer, hot flashes, night sweats, and vaginal bleeding compared with patients who receive tamoxifen. However, patients who received tamoxifen had less skeletal events and accelerated bone resorption compared with women who received AIs. AIs should be considered when planning a patient's endocrine therapy, taking into account the differences in tolerability and end-organ effects of the classes of endocrine therapy. Outstanding issues to optimize AI therapy include identifying the optimal duration, agent, and patients for these therapies.

Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta-analysis

For more than 20 years, tamoxifen has been the mainstay of adjuvant endocrine therapy for women with hormone-sensitive early-stage breast cancer. However, not only does tamoxifen have potential side-effects such as an increased risk of endometrial cancer and thromboembolic events, but patients can also develop resistance to the drug. We aimed to investigate whether switching treatment of postmenopausal women with such breast cancer to anastrozole after 2-3 years of tamoxifen would be more effective than continuing on tamoxifen for a total of 5 years. We did a meta-analysis of three clinical trials--the Austrian Breast and Colorectal Cancer Study Group (ABCSG 8), Arimidex-Nolvadex (ARNO 95), and the Italian Tamoxifen Anastrozole (ITA) studies--in which postmenopausal women with histologically confirmed, hormone-sensitive early-stage breast cancer were randomised to 1 mg/day anastrozole (n=2009) after 2-3 years of tamoxifen treatment or to continued 20 or 30 mg/day tamoxifen (n=1997). We analysed the data with a stratified Cox proportional hazards model with the covariates of age, tumour size, nodal status, grade, surgery, and chemotherapy. Patients who switched to anastrozole had fewer disease recurrences (92 vs 159) and deaths (66 vs 90) than did those who remained on tamoxifen, resulting in significant improvements in disease-free survival (hazard ratio 0.59 [95% CI 0.48-0.74]; p<0.0001), event-free survival (0.55 [0.42-0.71]; p<0.0001), distant recurrence-free survival (0.61 [0.45-0.83]; p=0.002), and overall survival (0.71 [0.52-0.98]; p=0.04). Our results show that the clinical benefits in terms of event-free survival seen in individual trials for those patients who switched to anastrozole translate into a benefit in overall survival. These findings confirm that clinicians should consider switching postmenopausal women who have taken adjuvant tamoxifen for 2-3 years to anastrozole.

Adjuvant Endocrine Therapy for Postmenopausal Women with Early Breast Cancer

Results from multiple clinical trials involving aromatase inhibitors have added to the knowledge base relating to endocrine therapy of postmenopausal women with hormone receptor-positive early breast cancer. In the extended adjuvant setting, data from the Austrian Breast and Colorectal Cancer Study Group 6a trial showed an advantage for anastrozole following 5 years of tamoxifen treatment, consistent with the more robust MA.17 trial that examined letrozole versus placebo following 5 years of tamoxifen treatment. The combined analysis of the Austrian Breast and Colorectal Cancer Study Group 8 trial and the German Arimidex Nolvadex 95 trial, plus the Italian Tamoxifen Anastrozole trial, have shown the advantage of switching to anastrozole over continuing the tamoxifen to complete the full 5 years of adjuvant therapy. These trials support the previously reported larger and double-blind Intergroup Exemestane Study. The Arimidex, Tamoxifen, Alone or in Combination trial now has data out to 68 months of median follow-up showing the maintenance of a significant advantage of anastrozole over tamoxifen for disease-free survival. In this initial treatment setting, the Breast International Group 1-98 trial recently showed a significant advantage for letrozole over tamoxifen. The current debate is centered on whether the optimal strategy is to give an aromatase inhibitor initially or after several years of tamoxifen treatment. Multiple important questions remain, including the predictive value of molecular markers such as progesterone receptor, the optimal duration of aromatase inhibitor therapy, the long-term adverse effects, and the relative efficacy and toxicity of the different aromatase inhibitors.

The use of aromatase inhibitors in adjuvant therapy for early breast cancer

Clinical evidence supporting the use of aromatase inhibitors (AIs) in adjuvant therapy for hormone-sensitive early breast cancer (EBC) has grown rapidly over the past few years and is reviewed in this article. The results of two studies-the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial and the Breast International Group (BIG) 1-98 trial-support the use of AIs as primary adjuvant therapy for EBC, with significantly prolonged disease-free survival, time to recurrence, and time to distant recurrence for both anastrozole and letrozole over tamoxifen. Furthermore, anastrozole has an established beneficial risk:benefit ratio compared with tamoxifen with mature data over the full 5-year recommended treatment period. For women who have already received 2-3 years of tamoxifen, switching studies with anastrozole [the Italian Tamoxifen Anastrozole (ITA) trial and the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 8/Arimidex-Nolvadex (ARNO 95) trial] and exemestane [the Intergroup Exemestane Study (IES)] have also shown that 5 years of primary adjuvant tamoxifen therapy is not optimal and that switching to an AI should be considered. Finally, for those women who have completed 5 years of tamoxifen, based on the results of the MA 17 trial, extended adjuvant treatment with letrozole should be considered. Although no sequencing data are available yet, current evidence suggests that an AI should be the adjuvant treatment of choice over tamoxifen, and anastrozole is the only AI with mature adjuvant data to date.

O-111. Switching to anastrozole (ANA) vs continued Tamoxifen (TAM) treatment of early breast cancer (EBC). Updated results of the Italian Tamoxifen Anastrozole (ITA) trial

Women with breast hypertrophy often experience a number of physical symptoms and psychological difficulties. The breasts are very important for the psychological well-being of women, which might be affected negatively because of breast size and shape distortions. Self-body dissatisfaction and, in this background, the breasts can lead to low levels of self-confidence and self-esteem, which might affect sexuality.Thirty-five women with macromastia and their partners were evaluated for their sexual function and surgery satisfaction before and 6 months following reduction mammaplasty. Physical status and sexual satisfaction were assessed using a questionnaire. In addition, the sexual function of the women and their partners was evaluated using the Index of Female Sexual Function (IFSF) and the International Index of Erectile Function (IIEF).There was a significant improvement in the mean IFSF and IIEF scores after surgery in both patients and their partners. In addition, patients expressed high levels of satisfaction with the results of surgery in terms of physical and psychological scores.Reduction breast surgery has a positive impact on the health status and psychological function as well as on the sexual activity of patients and their partners.

Selective oestrogen receptor modulators, aromatase inhibitors and the female breast

Tamoxifen has been available for over 20 years and remains the most commonly recognized endocrine therapy. This review was prompted by a wealth of new data on several newer endocrine agents, including selective oestrogen receptor modulators, aromatase inhibitors and a new oestrogen receptor antagonist, fulvestrant, which unlike the selective oestrogen receptor modulators has no oestrogen agonist effects. Completed analysis of the 'Arimidex', Tamoxifen, Alone or in Combination trial demonstrated that anastrozole as initial adjuvant therapy significantly improved disease-free survival and time to recurrence compared with tamoxifen, as well as reducing the incidence of contralateral breast cancer deaths. The Italian Tamoxifen Anastrozole trial and the Austrian Breast and Colorectal Cancer Study Group 8/Arimidex Nolvadex 95 trial have indicated that anastrozole may also be beneficial in women who have already received 2-3 years of tamoxifen. Similarly, the Intergroup Exemestane Study demonstrated the efficacy of exemestane in this setting. Women who have completed a full 5-year course of tamoxifen may also benefit from aromatase inhibitor treatment as indicated by the MA 17 trial, which investigated letrozole as extended adjuvant therapy. Fulvestrant is effective in tamoxifen-resistant disease, and phase II trial data suggest that fulvestrant may also be effective following aromatase inhibitor failure. The introduction of the third-generation aromatase inhibitors has caused a paradigm shift in adjuvant endocrine treatment. Research into the optimal use of selective oestrogen receptor modulators continues and the evidence base for fulvestrant, the first in a new class of endocrine agents, continues to grow, confirming its value in the treatment of hormone-responsive breast cancer.

Switching to Anastrozole Versus Continued Tamoxifen Treatment of Early Breast Cancer: Preliminary Results of the Italian Tamoxifen Anastrozole Trial

Tamoxifen, which is actually the gold standard adjuvant treatment in estrogen receptor-positive early breast cancer, is associated with an increased risk of endometrial cancer and other life-threatening events. Moreover, many women relapse during or after tamoxifen therapy because of the development of resistance. Therefore new approaches are required. We conducted a prospective randomized trial to test the efficacy of switching postmenopausal patients who were already receiving tamoxifen to the aromatase inhibitor anastrozole. After 2 to 3 years of tamoxifen treatment, patients were randomly assigned either to receive anastrozole 1 mg/d or to continue receiving tamoxifen 20 mg/d, for a total duration of treatment of 5 years. Disease-free survival was the primary end point. Event-free survival, overall survival, and safety were secondary end points. Four hundred forty-eight patients were enrolled. All women had node-positive, estrogen receptor-positive tumors. At a median follow-up time of 36 months, 45 events had been reported in the tamoxifen group compared with 17 events in the anastrozole group (P = .0002). Disease-free and local recurrence-free survival were also significantly longer in the anastrozole group (hazard ratio [HR] = 0.35; 95% CI, 0.18 to 0.68; P = .001 and HR = 0.15; 95% CI, 0.03 to 0.65; P = .003, respectively). Overall, more adverse events were recorded in the anastrozole group compared with the tamoxifen group (203 v 150, respectively; P = .04). However, more events were life threatening or required hospitalization in the tamoxifen group than in the anastrozole group (33 of 150 events v 28 of 203 events, P = .04). Switching to anastrozole after the first 2 to 3 years of treatment is well tolerated and significantly improves event-free and recurrence-free survival in postmenopausal patients with early breast cancer.

Switching to anastrozole (ANA) vs continued tamoxifen (TAM) treatment of early breast cancer (EBC). Updated results of the Italian tamoxifen anastrozole (ITA) trial

526 Background: We have previously shown that switching to ANA after 2–3 years of TAM is well tolerated and significantly improves event-free (EFS) and progression-free survival (PFS) of postmenopausal ebc (Breast Cancer Res Treat 82, 2003). Here we report on an additional analysis at a median follow-up time of 52 mos (1–80 mos). Methods: This was an open phase III trial comparing 5 years of TAM vs 2–3 years of TAM followed by 3–2 years of ANA (total duration of treatment: 5 years). PFS was the primary end point. EFS, OS and safety were secondary end points. Results: 448 node positive, ER positive patients were enrolled. At the time of the present analysis 87 events had occurred and 26 deaths. The first site of recurrence was the ipsilateral breast or the thoracic wall or the loco-regional nodes in 16 patients. Distant metastasis were the first site of recurrence in 47 patients; 19 patients developed second primaries (including 5 controlateral breast cancers). The Hazard Ratios of patients switched to ANA for EFS, PFS, local (l) PFS and distant (d)PFS are summarized in the table (Hazards of previous analysis are reported for comparison).17 women continued on TAM died as compared to 9 of those switched to ANA (HR: 0.52; 95% CI 0.23–1.17; p=0.1). The percentages of women developing at least one AE were 40% and 46% in the two groups respectively (p=0.2). However there were 6 endometrial cancers in the TAM group compared to 1 in the ANA group. Conclusions:Safety and clinical benefits of switching to ANA following 2 or 3 years of TAM are confirmed by this updated analysis. No significant financial relationships to disclose.