When I Stop Anastrozole How Big Is the Change That I Get Breast Cancer Again?
INTRODUCTION
Department:
For many years, tamoxifen has represented the gold standard adjuvant treatment for endocrine-responsive early chest cancer.ane,2 Treatment with this agent significantly reduces the risk of recurrence and death in almost all patients with estrogen receptor–positive tumors receiving treatment for an appropriate period of time.iii Nonetheless, several trialsfour,5 and the most recent Early Breast Cancer Trialists' Collaborative Group overviewiii have confirmed that 5 years of tamoxifen treatment increases risk of endometrial carcinoma and other life-threatening conditions such as thromboembolic events. Moreover, many women with estrogen receptor–positive tumors do not benefit from tamoxifen because they are primarily resistant to tamoxifen or develop resistance to this treatment subsequently initially benefiting from information technology.6 Tamoxifen resistance and, in particular, tamoxifen-induced tumor growth, which is a course of resistance well documented in experimental models,seven are likely reasons why prior attempts to amend the efficacy of tamoxifen adjuvant therapy past prolonging treatment across 5 years accept failed.8,9
Aromatase inhibitors inhibit breast cancer growth past reducing systemic and tumor estradiol levels.10 The tertiary-generation aromatase inhibitors are every bit effective as, if not superior to, tamoxifen when used as start-line treatment for advanced disease.xi-13 They are also of benefit to many women with avant-garde breast cancer who accept been initially treated with tamoxifen.14,15 After the positive results in the treatment of advanced disease, the efficacy of aromatase inhibitors has besides been investigated in the adjuvant setting, including caput to head equally an culling to tamoxifen, combined with tamoxifen, or as a switch after a few years of tamoxifen or after a standard 5-year course of tamoxifen every bit postadjuvant handling.16-xx Switching women currently receiving tamoxifen to an aromatase inhibitor may offer advantages over continued tamoxifen treatment considering it allows women who have been receiving an established treatment to receive a 2nd different blazon of drug that may pre-empt the evolution of tamoxifen resistance and, thus, reduce relapse rates and may also offer tolerability benefits. Therefore, patients take the opportunity to receive 5 years of endocrine treatment while limiting the exposure to both tamoxifen and the aromatase inhibitor.
A preliminary study was conducted to investigate the efficacy of this approach using a sequence of tamoxifen and aminoglutethimide (the only available aromatase inhibitor at that fourth dimension).16 Although no issue on recurrence charge per unit was observed in the aminoglutethimide grouping,sixteen the effects on pattern of recurrence and mortality encouraged us to recruit patients into a companion trial using the third-generation aromatase inhibitor anastrozole.
PATIENTS AND METHODS
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Report Design
The Italian Tamoxifen Anastrozole (ITA) trial was a phase III, randomized, multicenter trial including postmenopausal women who had already received ii to three years of tamoxifen handling. Patients were randomly assigned to receive connected tamoxifen treatment (20 mg/d) or to be switched to anastrozole (ane mg/d) for a menses of time that would result in a total of 5 years of endocrine handling. Before randomization, women were stratified according to prior chemotherapy and participating centre.
Written report Population
Eligible patients were postmenopausal women (ie, women missing regular menses for at least 1 year) or women more than 50 years of historic period who had undergone hysterectomy. Women who were confirmed to be amenorrheic as a upshot of chemotherapy were also permitted. When menopausal status was unclear, plasma follicle-stimulating hormone and estradiol levels were evaluated before inclusion. Other inclusion criteria were histologically confirmed primary breast cancer, tumor estrogen receptor positivity (confirmed by immunohistochemical analysis; progesterone receptor assessment was not required), positive axillary nodes, and no evidence of recurrent or metastatic disease (assessed using imaging studies and claret tests).
Patients with a history or presence of whatsoever other cancer (except adequately treated pare cancer or carcinoma-in-situ of the cervix) and patients with any condition that may jeopardize their compliance to treatment or follow-up were excluded. The ethics committee at each center approved the written report protocol, and written informed consent was obtained from all patients.
Study Protocol Evaluations
During the first year after random assignment, patients underwent clinical examinations every three months; subsequent examinations were performed every 6 months. At each visit, patients were asked to report any tolerability issues; blood counts and biochemical tests were also performed up to five years after randomization. Ultrasound exam of the liver, os browse, and chest 10-rays were usually performed on an annual basis. Mammography of the ipsilateral and/or the contralateral breast was performed annually or every two years, according to local policy.
Written report End Points
The primary stop betoken was illness recurrence, including both locoregional and distant recurrences (except contralateral breast cancer). Locoregional recurrences had to be cytologically and/or hystologically confirmed and included tumor relapse in the ipsilateral chest, thoracic wall, axilla, and other locoregional nodes. For estimates of event-free survival, events included any of the post-obit: locoregional recurrence (equally previously divers), distant metastases, 2d primary tumors (including contralateral breast cancer), and breast cancer–unrelated deaths (ie, deaths occurring in the absence of affliction recurrence).
The incidence of deaths, whatever the cause, and agin events were secondary end points. All second main tumors (except contralateral breast cancer) were included amongst serious adverse events. Serious adverse events included all lethal or life-threatening events or those events causing disability or requiring hospitalization.
Statistical Methods
Affliction-gratis survival and effect-free survival were divers as the time from random assignment to the occurrence of disease recurrence or whatsoever of the previously defined events. Survival was defined as the time from random consignment to expiry, independently of crusade. Curves were constructed using the Kaplan-Meier method21 and compared using the log-rank exam.22 All P values were 2-tailed. Multivariate models were constructed including variables known to be predictive of risk of relapse in univariate models.23 Forest plot was performed to describe the interaction of each treatment with the variables within each strata.24 The χtwo test or Fisher's verbal test were used to compare the incidence of adverse events in each group.
Sample Size
Aromatase inhibitors are known to benefit women with advanced breast cancer who feel failure with start-line treatment with tamoxifen. Approximately 50% of women formerly responsive to tamoxifen derive clinical do good (tumor response or stable disease ≥ 24 weeks) from subsequent treatment with aromatase inhibitors.25 Therefore, we hypothesized that switching patients to anastrozole may result in a 50% reduction in the take a chance of recurrence. Originally, a more bourgeois thirty% decrease in the annual hazard of recurrence was assumed to calculate the sample size. Nether these conditions and with an α = .05, information technology was estimated that a total of 996 patients (498 per arm) would be required to give the trial a statistical ability of an eighty% chance of detecting such a departure in favor of anastrozole. Yet, this study accrued approximately half this number of patients considering of the beingness of competitive trials in Italian republic that discouraged the participation of some of the centers that had, in principle, agreed to participate in the ITA trial.
RESULTS
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Patients
A total of 448 patients were enrolled onto the trial between March 1998 and Dec 2002, and all of the patients were included in an intent-to-care for assay. The median follow-up (from randomization) was 36 months (range, ane to 70 months). Nineteen patients in the tamoxifen group and 18 patients in the anastrozole group were withdrawn from treatment. Patient baseline demographics are listed in Tabular array 1. One patient in each group was institute to have no histologic involvement of axillary nodes, and two patients in the anastrozole group had estrogen receptor–negative tumors. Hormone receptor status was unknown for 14% of the patients continued on tamoxifen and for 8% of patients who were switched to anastrozole. Prior radiotherapy mostly consisted of irradiation of the residual breast in women who had undergone conservative surgical procedures (approximately half of the patients in each treatment group). Few women (seven in the tamoxifen group and two in the anastrozole group) had received thoracic wall irradiation afterwards mastectomy. There were no significant differences betwixt groups regarding variables.
Efficacy
At the time of this assay, 32 women (fourteen.2%) in the tamoxifen group had illness recurrence compared with 12 women (v.4%) in the anastrozole group. Women in the tamoxifen group also developed more than second primary tumors compared with the anastrozole grouping (10 v five tumors, respectively), including five endometrial cancers, and 3 women in this group died in the absence of clinically detectable affliction recurrence. Thus, in total, at that place were 45 events in the tamoxifen group and 17 events in the anastrozole group (Tabular array 2). There were 10 deaths in the tamoxifen group, seven of which were a result of breast cancer, and four deaths in the anastrozole grouping, all of which were chest cancer related (P = .one). Pregnant benefits in terms of result-free (Fig 1 ) and recurrence-gratuitous survival (Fig 2 ) were observed in the women switched to anastrozole (hazard ratio [HR] = 0.35; 95% CI, 0.xx to 0.63; P = .0002 and Hour = 0.35; 95% CI, 0.18 to 0.68; P = .001, respectively). The iii-twelvemonth difference in recurrence-free survival was 5.8% (95% CI, 5.two% to half-dozen.4%). Women in the anastrozole group also had significantly longer locoregional recurrence-complimentary survival (Hr = 0.fifteen; 95% CI, 0.03 to 0.65; P = .003), whereas the deviation in afar metastases–gratuitous survival approached statistical significance (60 minutes = 0.49; 95% CI, 0.22 to one.05; P = .06; Figs 3 and iv ).
Multivariate analysis confirmed that switching to anastrozole resulted in a significant reduction in the risk of developing an outcome or a disease recurrence and that this event was independent of the other variables (Tabular array 3). The benefit (in terms of risk of recurrence) of switching to anastrozole seemed to exist consequent across the strata analyzed (Fig five ).
Safety
Adverse events occurring in each treatment group are listed in Table 4. 80-one patients in the tamoxifen group (36.0%) and 98 patients in the anastrozole group (43.ix%) experienced i or more agin events (P = .ane). More patients treated with anastrozole, compared with the tamoxifen group, experienced more than than one agin issue (47 v 32 patients, respectively; P = .06), and overall, more events were recorded in this group (203 5 150 events, respectively; P = .04). However, more patients in the tamoxifen group experienced serious adverse events than patients in the anastrozole group (29 of 225 patients, 12.nine% five 24 of 223 patients, 10.8%, respectively). Although this difference was not statistically significant (P = .v), in total, significantly more serious adverse events occurred in the tamoxifen group than the anastrozole group (33 of 150 events, 22.0% v 28 of 203 events, xiii.9%, respectively; P = .04). It is worth noting that the percentage of patients requiring treatment discontinuation considering of agin events was small and comparable in the two groups (4.0% and 4.four% in the tamoxifen and anastrozole groups, respectively).
Discussion
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Aromatase inhibitors are condign increasingly important in the management of early chest cancer.16-20 Our group was the first one to excogitate the idea of switching women already on treatment with adjuvant tamoxifen to an aromatase inhibitor and to show that this approach might produce a valuable benefit.sixteen This preliminary experience prompted us to go on testing the potentialities of the new strategy with new-generation aromatase inhibitors. Unfortunately, the new trial was airtight before we were able to enroll the number of patients originally planned for the reasons that are described in the post-obit paragraph.
Although only interim analyses of safety were originally planned, an interim efficacy analysis was performed in Oct 2002, when 443 patients had been enrolled onto the written report. This analysis, which included the first 426 assessable patients, was decided by all participants in view of the preliminary results of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial, which had get available in 2001, suggesting the putative superiority of anastrozole over tamoxifen in hormone-naive, hormone receptor–positive women.17 The acting analysis confirmed that switching to anastrozole might provide additional benefit over continuing on tamoxifen, namely concerning recurrence-costless survival, with a P = .015. Because information technology had taken approximately 5 years to accumulate half of the patients who were originally thought to be required, it seemed that it would not be realistic and probably would non be ethical to continue to recruit patients for another 5 years to reach the expected size. Withal, although preliminary and express to a substantially smaller number of patients than expected, the interim analysis had the statistical power (81%) that was originally accounted to be necessary. Therefore, all investigators unanimously decided that recruitment should exist closed, and December 31 of the same year was arbitrarily stock-still, without adopting whatsoever specific stopping rule. This allowed 5 more patients to be randomly assigned.
Information technology was decided that the preliminary nature of results and the missing of whatever statistically significant bear witness of a survival benefit would not allow for automatically switching to anastrozole the patients who had been randomly assigned to keep with tamoxifen and who were all the same on written report. These patients represented approximately 25% of the patients randomly assigned to continue on tamoxifen up to the fifth year, and all of these patients were really maintained on tamoxifen treatment. The results of the subsequent analysis, which was performed 1 year later and forms the bailiwick of the nowadays article, confirmed the trends of the interim analysis with an fifty-fifty college statistical power (89%). Nonetheless, these results are nevertheless premature, and we should be cautious in extrapolating them to all women currently receiving adjuvant tamoxifen treatment because of the minor size of this trial. All the same, information are provocative and deserve some comment in the context of previous trials.
With respect to our previous switching trial,16 we expected anastrozole treatment to be more effective than aminoglutethimide. The two trials had similar designs and patient choice criteria; notwithstanding, the median follow-upward was longer in the previous trial. The previous trial as well used a depression aminoglutethimide dose (250 mg/d) and a shorter duration of handling. Nonetheless, the results of both trials suggest benefits for patients switching to the aromatase inhibitor. In particular, women who were switched to anastrozole in the ITA trial gained significant benefits in terms of take a chance of recurrence, which is a difference that was non observed in the Gruppo di Ricerca in Oncologia Clinica e Terapie Associate 04 trial.16 However, a more favorable pattern of relapse (fewer visceral failures and longer survival after recurrence) was observed in women who were switched to aminoglutethimide in the previous trial.16 Because of the relatively pocket-sized size of both trials, it is possible that the observed differences in disease recurrence may be a result of run a risk. Notwithstanding, the results of trials comparing the new imidazolic aromatase inhibitors with aminoglutethimide in women with advanced affliction25,26 and the proven superiority of these compounds over aminoglutethimide in inhibiting aromatase activeness and estradiol synthesis27 support the assumption that observed differences may reverberate the superior biologic and clinical activeness of anastrozole.
We besides expected anastrozole to exist better tolerated than aminoglutethimide and to allow better compliance with treatment. Indeed the number of withdrawals caused by agin events was considerably higher with aminoglutethimide16 (14.0%) compared with anastrozole (4.0%). Although anastrozole was better tolerated than aminoglutethimide, even in the present trial, switching was associated with some side furnishings in approximately 40% of patients. Compared with patients who were continued on tamoxifen, more patients in the anastrozole group experienced lipid disorders and gastrointestinal complaints, but 5 of these patients had hiatus hernia at baseline. These effects were somewhat expected in view of previous findings with these agents in advanced breast cancer11,12 and the differential furnishings on lipid metabolism exerted by tamoxifen28 and the aromatase inhibitors.29 Because tamoxifen treatment results in reduced plasma cholesterol levels and anastrozole has been shown to exist lipid neutral,xxx,31 it is likely that the changes in serum lipids in the anastrozole group are a upshot of the effects of tamoxifen withdrawal. No differences in the incidence of musculoskeletal disorders or os fractures were evident in the present trial; even so, our results are preliminary, based on a modest number of events, and follow tamoxifen therapy, so differences may arise after longer follow-up. Furthermore, switching to anastrozole resulted in a significant reduction in the incidence of gynecologic changes, especially endometrial cancer; and in total, serious adverse events were less common in this group.
Three other contempo trials suggest that aromatase inhibitors have a valuable role to play in the management of early chest cancer.17-xx The ATAC trial enrolled nine,366 postmenopausal women in a prospective, double-bullheaded, randomized report comparing 5 years of tamoxifen treatment with anastrozole alone or in combination with tamoxifen. The first analysis showed that anastrozole alone, only not the combination, was superior to tamoxifen and also better tolerated.17 An updated analysis of this trial (median follow-up of 47 months) confirmed the superiority of anastrozole, particularly in women with hormone receptor–positive tumors, in whom a 22% decrease in the chance of recurrence (P = .007) was observed.xviii
The ITA data presented here are supportive of the overall results seen in ATAC, illustrating the efficacy and tolerability benefits of anastrozole over tamoxifen. However, differences in trial blueprint, trial size, and patient demography preclude full comparison of the two trials.
The MA-17 trial, which was performed by the National Cancer Research Plant of Canada, recruited five,187 women who had received an boilerplate of v years of adjuvant tamoxifen.19 These women were randomly assigned to a further 5 years of treatment with either letrozole or placebo. However, an interim analysis showed that the HR for local recurrence, afar metastasis, and new contralateral breast cancers favored letrozole (P = .00008), and so recruitment of patients ceased after a median follow-upwardly of 2.4 years.19 Once more, differences in study pattern and size render it difficult to compare ITA with MA-17; however, both trials show the do good of aromatase inhibitor treatment after tamoxifen in postmenopausal women with early breast cancer (although the results were preliminary for both trials and the comparison is against a placebo, rather than an active drug, in the MA-17 trial).
More recently, the results of an international cooperative trial of exemestane subsequently 2 or 3 years of tamoxifen therapy in postmenopausal women (Intergroup Exemestane Study [IES]) take been reported.twenty This trial accrued 4,742 patients, of whom ii,362 have been randomly assigned to switch to exemestane and 2,380 have been assigned to keep to receive tamoxifen.
The unadjusted 60 minutes in the exemestane group compared with the tamoxifen group was 0.68 (95% CI, 0.56 to 0.82; P < .001), implying an absolute 3-year benefit in disease-free survival of 4.7% (95% CI, 2.6% to 6.eight%). Although this trial shares exactly the same design as our trial, information technology is too difficult to compare the ii trials. The ii trials differ in regard to their size (the IES trial accrued approximately ten-fold the patients recruited in the ITA trial), patient option (approximately half of the patients enrolled onto the IES trial were node negative), the proportion of patients previously treated with adjuvant chemotherapy (which was more than twice larger in our trial), and the type of aromatase inhibitor. Indeed, no major differences are likely to be expected between anastrozole and exemestane in terms of efficacy. Withal, there is no doubt that the two drugs act via different mechanisms,10,25 are partially not–cross resistant,x,25 and have unlike pharmacodynamic furnishings and toxicologic profiles.32 Unfortunately, directly comparisons between the two drugs are non available all the same, and indirect comparisons are non reliable.
Despite previous differences, the ii trials produced comparable results. Information technology is interesting to note that the size of the benefit observed in both trials was in the same range of that reported in the MA-17 trial, and, on boilerplate, the benefit achieved in the ITA, IES, and MA-17 trials (all of which tested the value of an aromatase inhibitor later 2, three, or more years of tamoxifen) was apparently superior to the benefit accomplished by anastrozole in the ATAC trial, in which the aromatase inhibitor was used as an culling to tamoxifen since the starting time.
Currently, there are no clinical data direct comparing switching with initiating handling with an aromatase inhibitor. However, contempo research on tamoxifen action and resistance suggests that, biologically, timing and sequencing of treatments may be crucial. Berstein et al33 have reviewed the results of several experiments that suggest that tamoxifen resistance can exist the outcome of either genetic or adaptive changes. According to their model, different stages can exist identified relating to time-dependent increases in aromatase activities in chest cancer jail cell lines exposed to tamoxifen. Aromatase activity is depression in the early on stages of exposure, just it progressively increases upwards to the fourth month and tends to turn down thereafter. These changes may help explicate the differences in size of the furnishings achieved with aromatase inhibitors in previous trials. For example, in the present trial and in the IES trial,20 the aromatase inhibitor was administered, on boilerplate, afterward 2.4 years of tamoxifen treatment. According to Bernstein'due south model, a meaning proportion of the tumor cells will testify increased aromatase activeness at this stage. The elegant experiment performed by Brodie34 in the aromatase-overexpressing MCF-7 chest cancer xenograft model shows that switching to an aromatase inhibitor after 16 weeks of tamoxifen treatment reduces the charge per unit of tumor growth by more than than eighty% compared with animals that receive tamoxifen up to week 28.34 This confirms the effectiveness of switching in a model where aromatase activity is artificially increased and is highly evocative of the situation that may accept occurred in the switching studies performed in breast cancer patients.
Larger, recently closed and ongoing adjuvant trials will be crucial not simply to further define the role of aromatase inhibitors in the treatment of early breast cancer only also in defining whether sequencing aromatase inhibitors and tamoxifen might actually be superior to monotherapy with aromatase inhibitors from the offset.35 While awaiting for the results of these trials, both the ITA and IES trial results seem to provide enough evidence to suggest that switching to an aromatase inhibitor is a valuable option for women currently treated with tamoxifen. Yet, the prematurity of results with respect to bloodshed and long-term safe require some caution and propose limiting this option to women who accept become intolerant to tamoxifen and/or have developed clinical conditions (ie, venous disorders, gynecologic changes, ocular problems, so on) that might contraindicate the continued use of tamoxifen.
Authors' Disclosures of Potential Conflicts of Interest
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Although all authors have completed the disclosure annunciation, the following authors or their immediate family members have indicated a financial involvement. No conflict exists for drugs or devices used in a report if they are non being evaluated equally office of the investigation. For a detailed description of the disclosure categories, or for more information most ASCO'southward disharmonize of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
| Authors | Employment | Leadership | Consultant | Stock | Honoraria | Enquiry Funds | Testimony | Other |
|---|---|---|---|---|---|---|---|---|
| Francesco Boccardo | AstraZeneca (A) | |||||||
| Dino Amadori | Intalfarmaco (A); Novartis (A); Eli-Lilly (B) | Bristol-Myers Squibb (A); Bayer (A); Elan (A) | Elan (A) |
Department:
Fig ane. Kaplan-Meier estimates of event gratis-survival. Run across Results for run a risk ratios.
Fig 2. Kaplan-Meier estimates of recurrence-gratis (locoregional plus distant) survival. Run into Results for hazard ratios.
Fig iii. Kaplan-Meier estimates of locoregional recurrence-free survival. Encounter Results for hazard ratios.
Fig 4. Kaplan-Meier estimates of distant metastases–free survival. See Results for adventure ratios.
Fig 5. Subgroup analysis of the risk of recurrence. The hazard ratio given for all patients was adjusted for tumor size, tumor grade, number of involved nodes, and treatment of primary tumor. The size of the squares is proportional to the size of the subgroups.
 | Tabular array i. Patient Baseline Demographics |
| | Table 2. No. and Distribution of Events |
| | Table three. Hazard of Developing Any Event or Disease Recurrence Afterward Multivariate Analysis |
| | Table four. Blazon and Incidence of Adverse Events |
| | Tabular array |
© 2005 by American Society of Clinical Oncology
Presented in function at the 26th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, Dec 3-half dozen, 2003. Authors' disclosures of potential conflicts of involvement are found at the end of this article.
Nosotros thank AstraZeneca (Milan, Italy) for providing the trial drugs and for funding the study. Nosotros also admit the support of CM PANSID (Milan, Italy) for trial monitoring and data management. Finally, we thank Simona Barozzi (University of Genoa, Genoa, Italy) for her good secretarial assistance.
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Source: https://ascopubs.org/doi/10.1200/JCO.2005.04.120
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