ARTICLES |
Ovarian Ablation or Suppression in Premenopausal Early Breast Cancer: Results From the International Adjuvant Breast Cancer Ovarian Ablation or Suppression Randomized Trial
The Adjuvant Breast Cancer Trials Collaborative GroupCorrespondence to: Judith Bliss, MSc, The Institute of Cancer Research—Clinical Trials and Statistics Unit, Section of Clinical Trials, Sir Richard Doll Bldg, Cotswold Rd, Sutton, Surrey SM2 5NG, UK (e-mail: abc-icrctsu{at}icr.ac.uk).
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ABSTRACT |
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Background: Substantial survival benefits exist for patients with early-stage breast cancer who undergo treatment with single-modality tamoxifen, ovarian ablation or suppression, or chemotherapy. To determine whether additional benefits exist with combined treatment, the Adjuvant Breast Cancer (ABC) Trials were undertaken.
Methods: The ABC Ovarian Ablation or Suppression Trial randomly assigned pre- and perimenopausal patients with early-stage breast cancer who were receiving prolonged (5 years) tamoxifen treatment with or without chemotherapy to ovarian ablation or suppression (by oophorectomy, ovarian irradiation, or treatment with luteinizing hormone–releasing hormone agonist) versus no ovarian ablation or suppression. Trial endpoints included relapse-free and overall survival. Hazard ratios (HRs) were derived from Cox models, and all statistical tests were two-sided.
Results: Between 1993 and 2000, 2144 (1063 ovarian ablation or suppression, 1081 no ovarian ablation or suppression) patients were randomly assigned. A total of 942 (89%) received ovarian ablation or suppression as allocated. Overall, no evidence of a benefit for ovarian ablation or suppression was observed for relapse-free survival (relapse in the ovarian ablation/suppression versus no ovarian ablation/suppression group, 290 events versus 306 events, HR = 0.95, 95% confidence interval [CI] = 0.81 to 1.12; P = .56) or overall survival (death from any cause in the ovarian ablation or suppression versus no ovarian ablation/suppression group, 215 events versus 230 events, HR = 0.94, 95% CI = 0.78 to 1.13; P = .44), nor were differences seen after adjustment for age, nodal status, or estrogen receptor (ER) status.
Conclusion: Overall, no added effect of ovarian ablation or suppression was seen on relapse-free survival or overall survival of premenopausal women who were treated for early-stage breast cancer. However, the role of ovarian ablation or suppression in young (<40 years) women with ER-positive tumors, especially those not receiving chemotherapy, requires further study.
Prior knowledge Women with early-stage breast cancer have improved outcomes after treatment with either tamoxifen, ovarian suppression or ablation, or chemotherapy. Study design Randomized controlled phase III clinical trial of tamoxifen treatment in combination with chemotherapy among premenopausal women who did or did not undergo ovarian ablation or suppression. Contributions Rates of relapse-free survival and overall survival were similar among women who underwent ovarian ablation or suppression and those who did not. Implications Ovarian ablation or suppression may not improve outcomes of combined tamoxifen and chemotherapy treatment for premenopausal women with early-stage breast cancer. Limitations Patients were treated with tamoxifen and ovarian ablation or suppression regardless of tumor estrogen receptor status. The chemotherapy regimen used may have had effects similar to those of ovarian ablation or suppression, possibly masking the effects of the latter.
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In 1992, the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) systematic overview of randomized trials (1) reported that chemotherapy and ovarian ablation or suppression were of similar efficacy when given as single-modality treatments in pre- and perimenopausal women with early breast cancer. Ovarian ablation and suppression were defined as ablation of ovarian function by oophorectomy or irradiation of the ovaries or as suppression of ovarian function by treatment with luteinizing hormone–releasing hormone (LH-RH) agonists. In addition, the EBCTCG overview demonstrated that the effects of prolonged tamoxifen treatment (>2 years) in young women (aged <50 years) were consistent with the benefit that was already recognized for older women. Subsequently, prolonged tamoxifen (usually 5 years) became an alternative or adjunct to chemotherapy or ovarian ablation or suppression.
The EBCTCG overview included trials conducted in the era before the introduction of routine testing of estrogen receptor (ER) status. The overview did not include information on the addition of ovarian ablation or suppression to tamoxifen and included data on only 939 patients to evaluate ovarian ablation or suppression in addition to chemotherapy. Among patients who did not receive other systemic therapy, benefits of ovarian ablation or suppression were clear—30% reduction in the annual odds of recurrence and a 28% reduction in the annual odds of death from any cause. However, in those treated with chemotherapy, a suggestion of benefit for ovarian ablation or suppression was also observed, although the results did not reach statistical significance (21% reduction in the annual odds of recurrence and a 19% reduction in the annual odds of death from any cause). These data prompted the question of whether ovarian ablation or suppression added to elective tamoxifen would lead to worthwhile survival gains, including in patients with retained or recovered ovarian function who had been prescribed cytotoxic chemotherapy. Because ovarian ablation or suppression as a sole systemic modality is associated with considerable side effects, it was recognized that potential survival gains from its combination with tamoxifen would need to outweigh any corresponding increase in adverse effects.
In the early 1990s, ovarian ablation or suppression was commonly achieved via surgery or radiation therapy, although the use of LH-RH agonists was emerging. Additionally, at that time in the United Kingdom, testing for ER status was not routinely available, at least in part, because the EBCTCG overview at that time suggested a benefit for tamoxifen in both ER-positive (+) and ER-negative (–) breast cancer.
Therefore, in late 1992, the Adjuvant Breast Cancer (ABC) Trials were initiated to assess long-term outcomes, particularly overall survival, of combined modality therapy for women with early breast cancer. The ABC Chemotherapy (CT) Trial compared combination treatment with tamoxifen and chemotherapy with prolonged tamoxifen only, with or without elective ovarian ablation or suppression (in pre- and perimenopausal women). Here we present the results of the ABC Ovarian Ablation or Suppression (OAS) Trial, which assessed the addition of ovarian ablation or suppression to prolonged tamoxifen (with or without elective chemotherapy).
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Subjects and Methods |
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Design
The ABC (OAS) Trial aimed to identify the added benefits of prescribing ovarian ablation or suppression in addition to prolonged tamoxifen or prolonged tamoxifen accompanied by chemotherapy in pre- and perimenopausal women with early breast cancer. All patients were scheduled to receive prolonged tamoxifen [5 years unless patient was entered into the Adjuvant Tamoxifen Longer Against Shorter (2) or Does Adjuvant Tamoxifen Treatment Offer More? (3) trials of tamoxifen duration] and were randomly assigned to ovarian ablation or suppression. Use of chemotherapy was at the clinician's discretion (including the option for the patient to be entered into the ABC [CT] Trial), but with a requirement to declare such treatment before random assignment into the ABC (OAS) Trial. A total of 281 patients were entered into both the ABC (CT) and ABC (OAS) Trials.
The primary endpoint for this study was overall survival, based on all-cause mortality. Secondary endpoints were breast cancer–specific mortality (not reported here) and relapse-free survival.
Eligibility
Eligible patients were women who were pre- or perimenopausal with histologically confirmed early-stage operable (T1-3a N0-1 M0) invasive breast cancer. Women were defined as pre- or perimenopausal if their last menstrual period had occurred within the 12 months preceding breast diagnostic surgery. Patients could have had no previous malignancy (except cervical cancer in situ or basal cell carcinoma) and no previous systemic therapy for their current breast cancer and had to be available for follow-up. The trial was open to recruitment from January 7, 1993, to September 27, 2000.
Evaluation of Estrogen Receptor Status
For patients who had unknown ER status at randomization, retrospective testing of the ER has subsequently been carried out centrally on the majority of tumor samples from women residing in the United Kingdom (and some non-UK women). Testing was carried out by using immunohistochemistry using paraffin-embedded tissue, as described previously (4). Alternatively, results were obtained from local hospitals where information on ER status is now available.
Treatment
The method of achieving ovarian ablation or suppression was at the clinician's discretion but was to be according to center policy and declared before randomization (thus avoiding bias). Specific recommendations for radiation ablation and LH-RH agonists were defined in the protocol. For radiation-induced menopause, 1600 cGy in four fractions was to be delivered to the midplane by the anteroposterior fields of the pelvis after ultrasound localization of the ovaries. If LH-RH agonists were to be used, goserelin (Zoladex) at 3.6 mg or leuprorelin acetate (Prostap SR) at 3.75 mg was recommended every 28 days for at least 2 years.
Surgery and radiotherapy were carried out according to local policy but within protocol-specified recommendations. Tamoxifen (20 mg/day) was prescribed for a minimum of 5 years in all patients starting within 4 weeks of primary surgery and concurrently with chemotherapy, if given. Chemotherapy and ovarian ablation or suppression were scheduled according to local practice. Random assignment to the ABC (OAS) Trial was permitted before chemotherapy commenced or while chemotherapy was ongoing. Of the 1529 patients with known date of first chemotherapy cycle, 637 (41.7%) were randomly assigned before commencing chemotherapy and 685 (44.8%) within 3 months of commencing chemotherapy. The remaining 207 (13.5%) of patients were randomly assigned 3 or more months after commencing chemotherapy. No assessment or selection based on postchemotherapy menopausal status was required because it was recognized that a proportion of patients resume substantial ovarian estrogen production over the course of the first year post-chemotherapy.
Ethics and Governance
A Patient Information Sheet was provided, and all patients gave consent, according to the requirements of the participating institution. Ethics committee approval was sought initially from each local research ethics committee, and subsequently, once established, from a UK multicenter research ethics committee. The trial was conducted in accordance with the UK Medical Research Council's principles of Good Clinical Practice. The trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN31514446 [controlled-trials.com] .
Trial Management
Randomization and data management were carried out at four academic trials units in the United Kingdom (The Institute of Cancer Research, Clinical Trials and Statistics Unit [ICR-CTSU], Sutton; Information & Statistics Division Cancer Clinical Trials Team, Edinburgh; Cancer Research UK Clinical Trials Unit, Birmingham; and the Clinical Trials Research Unit, University of Leeds, Leeds) and at the Ministry of Health Clinical Trials and Epidemiology Research Unit, Singapore. Data were collated annually at the ICR-CTSU, where interim and final analyses were conducted.
Data Collection and Follow-up
Patients were followed up annually via their participating hospital. All UK patients were flagged through the Office for National Statistics. Case report forms included a minimum defined dataset required to assess the main endpoints and a summary assessment of treatment compliance. Analysis was based on follow-up received by the trials units to June 30, 2004. Annual follow-up continues for all patients who are available for follow-up.
Relapses were diagnosed according to local practice. Local relapse was defined as cancer recurrence in or on the ipsilateral chest wall/breast, and all other sites were classified as distant metastases.
No individual adverse event data was recorded because the toxicity profile of trial treatments was considered to be well characterized; however, patient-reported symptomatology was recorded in the subset of patients in an associated Quality of Life study.
Quality of Life
The associated Quality of Life study was initiated in 1997 in 31 UK centers. All patients who entered the main trial from these centers were invited to participate in the Quality of Life study. Detailed methodology and results from this substudy will be published separately.
Statistical Analysis
Randomization was performed using randomly permuted blocks that were stratified by hospital and elective chemotherapy treatment. A 1:1 treatment allocation ratio was used. Among women who were to receive single-modality systemic therapy, 5-year overall survival was envisaged to be approximately 75% (1). If 5-year overall survival improved from 75% to 80% by the addition of ovarian ablation or suppression to prolonged tamoxifen (with or without chemotherapy), it was judged to be of clinical benefit. Based on this assumption and using a two-sided log-rank test (
= 0.05), 492 events were required for 80% power. It was estimated that approximately 2000 patients would need to be recruited to achieve this number of events.
Median follow-up was calculated using the reverse Kaplan–Meier estimator (5). Analyses were according to the intention-to-treat principle, included all randomly assigned patients, and were performed using STATA 8.0 (6). Overall survival was defined as time from date of random assignment to date of death. Relapse-free survival was defined as time from date of random assignment to date of first recurrence or death from breast cancer with no known date of relapse. In the relapse-free survival analysis, patients were censored on the occasion of an intercurrent death. Cumulative survival curves were constructed as Kaplan–Meier time-to-event plots (5,6), with unadjusted comparisons between groups based on the log-rank test (two-sided). Cox regression models were used to estimate treatment effects, with adjustment for age, nodal status, and ER status. Proportionality of hazards was verified according to Schoenfeld residuals. Estimates of treatment effect are presented as hazard ratios (HRs) with their associated 95% confidence intervals (CIs), with ratios of less than 1.0 favoring the addition of ovarian ablation or suppression. Descriptive subgroup analyses by age with or without chemotherapy and ER status are presented as forest plots. Chi-square tests (for trend, if appropriate) were used to test for heterogeneity between subgroups. Results for the QL study are based on complete data available to 30 months. These longitudinal data were analyzed by general linear models for panel data using the generalized estimating equations approach (7) via the xtgee command in STATA 8.0.
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Results |
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Between January 7, 1993, and September 27, 2000, 2144 patients from 106 UK and 16 non-UK centers were entered into the ABC (OAS) Trial (Fig. 1). Ten patients (seven allocated to ovarian ablation or suppression, three allocated to no ovarian ablation or suppression) were deemed to be ineligible for the following reasons: not early-stage breast cancer (n = 9) and previous other cancer (n = 1). Mean age of eligible patients was 43 (standard deviation = 5.7) years, 1298 (61%) had node-positive disease, 838 (39%) had confirmed ER+ tumors, 391 (18%) had ER– tumors, and 915 (43%) had tumors with unknown ER status. The two groups had well-balanced baseline characteristics (Table 1).
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Analysis was based on follow-up received by the trials units to June 30, 2004. At this time, 11152 women-years of follow-up had accrued. Median follow-up was 5.9 years (interquartile range [IQR] = 4.2 to 7.7). Completeness of follow-up was 80.0% (8).
Nine hundred forty-two (88.6%) patients who were randomly assigned to ovarian ablation or suppression received allocated treatment (Table 2). Compliance with treatment was lower among younger women (<35 years, 77.1%) than in older women and among women from non-UK centers (78.3%) compared with those from UK centers. Of patients who received ovarian ablation or suppression, 68.8% had radiation-induced menopause, 22.8% surgical ablation, and 8.4% LH-RH agonists. The majority of patients also received chemotherapy (78.5%). Among patients who received both treatments, 14% received ovarian ablation before chemotherapy, 37% received it during chemotherapy, and the remaining 49% received it after chemotherapy.
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At the time of analysis, 1401 (65%) patients were no longer taking tamoxifen, of whom nine patients never took the drug. Median tamoxifen treatment duration (after censoring patients who stopped due to recurrence) was 5.0 years (IQR = 3.4 to 5.6 years).
To date, 445 deaths (21% of patients) and 596 recurrences have been reported (Table 3). The unadjusted hazard ratio for relapse among patients in the ovarian ablation or suppression group was 0.95 (95% CI = 0.81 to 1.12, P = .56) (Fig. 2) compared with those who did not undergo ovarian ablation or suppression. Five-year relapse-free survival was 73.7% (95% CI = 70.7% to 76.3%) in the ovarian ablation or suppression group compared with 72.8% (95% CI = 69.8% to 75.5%) in the group randomly assigned to no ovarian ablation or suppression, translating into an estimated absolute difference of 0.9% (95% CI = –3.1% to 4.9%).
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The unadjusted hazard ratio for death from any cause among patients in the ovarian ablation or suppression group compared with those in the no ovarian ablation or suppression group was 0.94 (95% CI = 0.78 to 1.13, P = .44) (Fig. 3). Five-year survival was 82.6% (95% CI = 80.0% to 84.9%) in the ovarian ablation or suppression group compared with 80.3% (95% CI = 77.5% to 82.9%) in the no–ovarian ablation or suppression group, for an estimated absolute difference of 2.3% (95% CI = –1.2% to 5.9%). There were very few intercurrent deaths, so the analysis of time to breast cancer death produces almost identical results to that of overall survival (data not shown).
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Adjusting for prognostic factors (age, nodal status, and ER status) made little difference to the hazard ratios for either relapse-free or overall survival (Table 4). As expected, there was a greater effect of ovarian ablation or suppression in women with ER+ tumors (Fig. 4), but there was no statistically significant evidence of heterogeneity for either overall or relapse-free survival among any of the subgroups investigated. Adjusting for use of chemotherapy did not materially alter the estimate of effect (overall survival, HR = 0.94, P = .50; relapse-free survival, HR = 0.95, P = .56), and the interaction test was not statistically significant (P = .68 for overall survival, P = .85 for relapse-free survival). In younger women (aged <40 years, n = 56) who did not receive chemotherapy, the group considered biologically to have the most to gain from ovarian ablation or suppression, there was a suggestion of a potentially useful clinical benefit that was slightly greater if patients with tumors known to be ER– are excluded (increasing the proportion known to be ER+ from 32.1% to 40.9%). However, the above results are based on very small numbers (n = 56, Fig. 5; n = 44; Supplementary Fig. 1, available online).
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Of the 1290 UK patients who were included in the ovarian ablation comparison, 246 (118 with ovarian ablation or suppression, 128 no ovarian ablation or suppression) agreed to take part in the Quality of Life substudy, and detailed results will be published elsewhere. In summary, patients who received ovarian ablation or suppression recorded more menopausal symptoms, e.g., night sweats (P = .005), day sweats (P<.001), and vaginal dryness (P = .001) than patients who did not receive ovarian ablation or suppression. The effect of ovarian ablation or suppression on menopausal symptoms was seen in women receiving tamoxifen alone and in those who had received chemotherapy in addition to tamoxifen (Fig. 6).
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Discussion |
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In this trial, ovarian ablation or suppression did not add to the benefits of 5 years of tamoxifen treatment or to those of tamoxifen plus chemotherapy in terms of relapse-free survival or overall survival rates. No heterogeneity was observed across subgroups, although in the small subgroup of women younger than 40 years who did not receive chemotherapy, the data were consistent with a therapeutic benefit for ovarian ablation or suppression. However, this subgroup is too small to investigate any additional effect of ER status. Despite the apparent lack of therapeutic efficacy, the addition of ovarian ablation caused a considerable increase in acute and chronic side effects, e.g., hot flushes, sweats, and sleep disturbance.
Results of the EBCTCG overview (9) indicate that the benefits of ovarian ablation or suppression on relapse-free survival only become apparent after several years and that overall survival gains appear at 8–10 years follow-up, but there is no evidence for the emergence of such effects in the ABC (OAS) Trial. The trial has collected more than 11000 women-years of follow-up, but it is possible that benefits of ovarian ablation or suppression will emerge after further follow-up data have accrued.
The study has several potential limitations. First, tamoxifen and ovarian ablation or suppression were prescribed to patients regardless of ER status, whereas it is now clear that endocrine manipulation does not benefit patients with ER– tumors. Although women with ER+ tumors would be considered for ovarian ablation today, we believe it appropriate to conduct the primary analysis in the intent-to-treat population. In addition, given that ER testing was not routinely assessed in these centers at the time the trial was conducted, there is little reason to suspect that women with tumors of unknown ER status were not representative of premenopausal breast cancer patients in general. Therefore, it can be assumed that approximately 65% of such patients will have had ER+ disease (10). Exclusion of the large group of patients with unknown ER status would have detracted from the overall statistical power to test the underlying hypothesis. As expected, the estimate of effect for the group of women with tumors of unknown ER status appears to be an appropriate "average" of the effects in the ER+ and ER– subgroups. It is also noteworthy that ER status was unknown in the original trials that demonstrated an effect of ovarian ablation (9). Nevertheless, no evidence was observed of benefit for ovarian ablation or suppression in the subgroup of 838 patients known to be ER+ either (Fig. 4).
A second limitation of the study relates to the probability of chemotherapy-induced castration in a majority of patients, which may have precluded the identification of an ovarian ablation or suppression associated benefit. The risk of chemotherapy-induced amenorrhea is directly related to age and varies with the chemotherapy regimen used and the total duration of chemotherapy (11,12). The average rates of amenorrhea for classic oral cyclophosphamide, methotrexate, and 5 fluorouracil (CMF) and standard adiramycin and cytoxan are 68% and 43%, respectively, and 80% patients in the ABC (OAS) Trial received CMF. More than 50% women aged 40 years and older experience chemotherapy-induced amenorrhea, whereas this rate is less than 50% for women younger than 40 years. Even in the subgroup of women younger than 40 years who received chemotherapy, the majority of whom would have retained ovarian function, there appears to be no gain from ovarian ablation or suppression in combination with 5 years of tamoxifen treatment.
A third limitation is that chemotherapy was given concurrently with tamoxifen. This may have lessened the efficacy of chemotherapy (13), but it is highly unlikely to have masked an effect of ovarian ablation or suppression.
Finally, 11% of patients did not receive ovarian ablation as allocated. The most common reason was patient refusal after randomization, illustrating the difficulties of performing trials of ovarian ablation. Noncompliance of this magnitude may result in a slight underestimation of the effect but would be unlikely to lead to a gross distortion of the results.
Several studies, like the ABC (OAS) Trial, have investigated the combination of other systemic therapies with ovarian ablation or suppression, whether tamoxifen or chemotherapy (14–17), or both (18,19). In the 2005 publication of the EBCTCG overview (9), ovarian ablation or suppression results were not presented according to concurrent tamoxifen use, but it is known that most of the ovarian ablation or suppression trials did not use tamoxifen. The Zoladex in Premenopausal Patients Trial (15) randomly assigned 2710 women (with no exclusion based on ER status) to goserelin for 2 years, tamoxifen for 2 years, and combined treatment or no further treatment in a 2 x 2 factorial design. Randomized treatment was given in addition to standard therapy following surgery, which could include radiotherapy and/or chemotherapy. In that study, 51% tumors were known to be ER+. Goserelin treatment was associated with a statistically significant improvement in both event-free survival (HR = 0.80, 95% CI = 0.70 to 0.92) and overall survival (HR = 0.82, 95% CI = 0.67 to 0.99) (15). Although no statistically significant heterogeneity was observed, the effect of goserelin was greatest in patients with ER+ tumors who had not received chemotherapy (HR = 0.68, 95% CI = 0.51 to 0.90). The US Breast Intergroup Study 0142 (14) randomly assigned 345 women with ER+ tumors (target accrual 1684) to LH-RH agonist against a background of 5 years tamoxifen in node-negative premenopausal women not prescribed chemotherapy. All the patients were known to have ER+ tumors. No benefit was observed for disease-free (HR = 0.88, 95% CI = 0.48 to 1.61) or overall survival (HR = 0.65, 95% CI = 0.23 to 1.84), but the limited number of events precluded definitive interpretation of the results.
Other studies have examined the combination of chemotherapy and ovarian ablation or suppression. The International Breast Cancer Study Group (IBCSG) Trial VIII (17) randomly assigned 1063 pre- /perimenopausal patients with node-negative disease to goserelin for 2 years (six cycles of CMF or six cycles of CMF followed by goserelin). In that study (17), 68% of patients were known to have ER+ tumors. In ER+ patients, there was no additional benefit of adding goserelin to adjuvant chemotherapy (relative risk = 0.80, 95% CI = 0.54 to 1.19). Two further studies (16,18) did not find a benefit of adding ovarian ablation or suppression to chemotherapy. Kaufmann et al. (18) found no benefit for goserelin following chemotherapy in 776 patients (HR = 0.92, 95% CI = 0.70 to 1.21). Although 60% of patients in this study had ER– tumors, subgroup analysis provided no evidence of benefit in patients with ER+ tumors. Arriagada et al. (16) also found no benefit of ovarian ablation or suppression in total or in subgroups based on ER status or in women who experienced amenorrhea following chemotherapy. However, a subgroup analysis of the IBCSG Trial VIII found that younger women (
39 years) had a statistically significant benefit of combined treatment (CMF followed by goserelin) (HR = 0.34, 95% CI = 0.14 to 0.87) versus CMF alone (17). This patient population is least likely to develop chemotherapy-induced ovarian failure.
Only one published study has randomly assigned all three potential adjuvant treatments. The INT-0101 study (19) enrolled 1504 node-positive premenopausal women with ER+ breast cancer to compare six cycles of oral combination chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) versus CAF plus goserelin (CAFZ), versus CAFZ plus 5 years tamoxifen (CAFZT). After a median follow-up of 9.6 years, 9-year disease-free survival was 57% for CAF, 60% for CAFZ, and 68% for CAFZT, and 9-year overall survival rates were 70%, 73%, and 76%, respectively (19). Hypothesis-generating subgroup analyses suggest that women younger than 40 years of age at trial entry, those with premenopausal estradiol levels after chemotherapy, and those who retained menses after chemotherapy benefited the most from the addition of goserelin. A limitation to this trial is the lack of a cyclophosamide, doxorubicin, fluorouracil, and tamoxifen arm.
The ABC (OAS) Trial adds new data to the limited data available on the effects of combining long-term tamoxifen, chemotherapy, and ovarian ablation or suppression. The results suggest that ovarian ablation or suppression does not add to the benefits of prolonged tamoxifen in premenopausal women who are prescribed chemotherapy. However, we cannot rule out the possibility that a subgroup of premenopausal patients with ER+ tumors who did not receive chemotherapy or who did not become amenorrheic with chemotherapy, benefited from the addition of ovarian ablation or suppression. This question could not be tested in the ABC (OAS) Trial, but it will be addressed in the Suppression of Ovarian Function Trial coordinated by the IBCSG (20). This trial will randomly assign patients with ER+ tumors who are still premenopausal following chemotherapy to tamoxifen alone, tamoxifen plus LH-RH agonists, or exemestane plus LH-RH agonists and should provide definitive results to inform future practice on the use of ovarian ablation or suppression in patients with hormone-sensitive early breast cancer.
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NOTES |
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The ABC Trials Collaborative Group includes the following:
ABC Trials Management Group—Institute of Cancer Research, Sutton, Surrey, UK (J. M. Bliss, L. Johnson, D. Lawrence, J. Peto, D. Price, J. Yarnold [chair]); Velindre Hospital, Cardiff, Wales, UK (P. Barrett-Lee); University Hospital of North Staffordshire, Stoke-on Trent, Staffs, UK (A. M. Brunt); Cookridge Hospital, Leeds, West Yorkshire, UK (D. Dodwell); University of Cambridge NHS Foundation Hospital Trust, Cambridge, Cambridgeshire, UK (H. Earl); University of Birmingham Hospitals NHS Foundation Trust, Birmingham, West Midlands, UK (I. Fernando); ISD Cancer Clinical Trials, Edinburgh, Scotland (L. Foster); Western Infirmary, Glasgow, Scotland (W. D. George); Norfolk and Norwich University Hospital, Norwich, Norfolk, UK (A. M. Harnett); St James' University Hospital, Leeds, West Yorkshire, UK (T. Perren); University of Birmingham, Birmingham, West Midlands, UK (C. Poole); Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India (V. Raina); Southend Hospital, Southend, Essex, UK (A. Robinson).
Collaborating groups and staff—ICR-CTSU: L. Lloyd, D. Price, G. Sumo, M. Warren-Perry; ISD Cancer Clinical Trials Team: A. Gould, M. Mclinden, P. Stroner, J. Watson, J. Young; Cancer Research UK Clinical Trials Unit, University of Birmingham: S. Bowden, C. Jevons, L. Lynch, J. Mair, K. Milligan, A. Parkinson, L. Payne, S Siviter; Clinical Trials Research Unit, University of Leeds: G. Eddison, L. Graham, S. Leigh, J. Kitcheman, S. Stubbs; Ministry of Health Clinical Trials & Epidemiology Research Unit, Singapore: B.-C. Tai, N. Mustapa, J. Seldrup.
UK hospitals (accrual), chief and coinvestigators—Aberdeen RI (47): K. W. Ah-See, J. D. Bissett, O. Eremin, W. Groundwater, S. Heys, A. Hutcheon, J. A. Jibril; Addenbrooke's NHS Trust (60): R. E. Bleehen, A. Daley, M. Williams, C. Wilson; Airedale General Hospital, Keighley (27): I. Hutchinson, A. Nejim; Alexandra Hospital, Redditch, UK (2): C. Irwin, A. Stockdale; Beatson Oncology Centre (306): J. D. Bissett, P. Canney, J. Cassidy, T. Cooke, D. Dodds, D. Dunlop, J. Evans, W. D. George, T. Habeshaw, A. M. Harnett, R. Jones, H. Josef, L. Junor, S. Kaye, C. McArdle, N. O'Rourke, R. Rampling, D. Ritchie, G. Robertson, J. Russell, D. C. Smith, M. Soukop, S. Stallard, P. Stanton, C. Twelves, P. Vasey, J. Wallace, H. Yosef; Birmingham Heartlands Hospital (15): I. Fernando; Bradford RI (24): C. Bradley, D. Parker; Bristol RI (62): V. Barley, J. A. Bullimore, S. J. Falk, S. Goodman, J. Graham, C. Price, E. Whipp; Charing Cross Hospital, London (2): S. Stewart; Cheltenham General Hospital, Gloucestershire Oncology Centre (15): K. Benstead, S. Elyan, R. Owen; Christie Hospital, Manchester (28): A. Howell, B. Magee, A. Stewart, A. Clayton; City Hospital, Birmingham (21): H. Earl, I. Fernando, D. Spooner; Cookridge Hospital, Leeds (52): H. Close, D. Dodwell, F. Roberts, D. Sebag-Montefiore, Taylor; Cumberland Infirmary, Carlisle (26): P. Dyson; Derbyshire RI (82): A. Benghiat, D. Guthrie, D. Otim-Oyet, G. Thomas; Essex County Hospital, Colchester (1): W. Pratt; Glan Clwyd Hospital, Rhyl (2): J. Bishop, S. W. Gollin; Goodhope Hospital, Birmingham (23): I. Fernando, A. Goodman, M. Hallisey, D. Kerr, C. Poole, D. Spooner; Hammersmith Hospital, London (3): H. Thomas; Huddersfield Royal Infirmary (24): R. Sainsbury; Ipswich Hospital (7): J. LeVay; James Cook University Hospital (13): P. D. J. Hardman, A. Rathmell; Kent Oncology Centre, Maidstone (14): N. Mithal, F. McKinna, M. O'Brien, D. Pickering, M. Snee; King Edward VII Hospital, Midhurst (3): S. Whitaker; Leicester RI (2): F. Madden; Leighton Hospital, Crewe (23): P. Burt; Little Aston BUPA Hospital, Sutton Coldfield (1): A. D. Chetiyawardana; Manor Hospital, Walsall (56): I. Fernando; Middlesex/UC Hospital, London (18): M. Gaze, P. Ostler, M. Spittle; Mount Vernon Hospital, Northwood (5): J. Maher, A. Makris; N. Staffordshire RI (165): F. A. Adab, A. M. Brunt, J. E. Scoble; Nevill Hall Hospital, Abergavenny (1): I. C. M. Patterson; Newcastle General Hospital (52): J. M. Bozzino, P. Dawes, H. Lucraft, U. Mallick, D. Ritchie, W. B. Taylor; Ninewells Hospital, Dundee (117): J. A. Dewar, P. Preece, A. Thompson, Wood; Norfolk and Norwich University Hospital (3): A. Bulman; Northampton General Hospital (1): C. MacMillan; Northwick Park, Harrow (32): M. Burke; Nottingham City Hospital (12): E. Bessell, J. Carmichael, D. Morgan; Oldchurch Hospital, Romford (39): M. Quigley; Peterborough District Hospital (8): K. McAdam, C. Wilson; Pinderfields General Hospital, Wakefield (12): D. Sebag-Montefiore; Pontefract General Infirmary (5): F. Roberts; Poole Hospital Trust (2): N. Cowley; Princess Royal Hospital, Hull (3): A. Chaturvedi; Priory Hospital, Birmingham (3): C. Poole; Queen Alexandra Hospital, Portsmouth (34): D. Dubois, P. Golding; Queen Elizabeth Hospital, Birmingham (20): A. Chettiyawarana, H. Earl, I. Fernando, A. Goodman, A. Mould, C. Poole, D. Rea, D. Spooner; Queen Elizabeth Hospital, King's Lynn (2): M. Daly; Queens Hospital, Burton-on-Trent (33): Bucknell, Cheti, I. Fernando; Raigmore Hospital, Inverness (78): D. Whillis; Royal Berkshire Hospital, Reading (66): J. Barrett, C. Charlton; Royal Halifax Infirmary (8); Royal Lancaster Infirmary (10): M. McIllmurray; Royal London Hospital (21): C. Gallagher, G. Mair, B. Mantell; Royal Marsden/Mayday Hospital (48): J. Yarnold; Royal South Hants Hospital, Southampton (8): C.R. Hamilton, P. Simmonds, C. Williams; Royal Sussex County Hospital (36): D. Bloomfield, G.P. Deutsch, S. Murrell, M. Wilkins; Royal United Hospital, Bath (15): H. Newman, G. Rees; Sandwell District General Hospital, W. Bromwich (31): Auckland, I. Fernando, D. Spooner, A. Stockdale; Scunthorpe General Hospital (11): T. Sreenivasan; Selly Oak Hospital, Birmingham (43): H. Earl, I. Fernando, A. Goodman, T. Latief, C. Poole, D. Rea, D. Spooner; Singleton Hospital, Swansea (25): T. Joannides; Southend Hospital (179): A. Lamont, A. Robinson, C. Trask; St Bartholomew's Hospital, London (17): C. Gallagher; St. George's Hospital, Tooting (13): J. Mansi; St. James University Hospital, Leeds (28): T. Perren; Taunton & Somerset Hospital (4): J.A. Bullimore, J. Graham; Velindre Hospital, Cardiff (81): P. Barrett-Lee, C. Burnet, C. Gaffney, M. Mason, T. Maughan, O. Tilsley; West Suffolk Hospital, Bury St. Edmunds (2): A. Thompson; Western General Hospital, Edinburgh (119): D. Cameron, U. Chetty, I. Kunkler, R. Leonard, O'Neil; Weston Park Hospital, Sheffield (21): A. Champion, R. Coleman, Ramakrishnan; Weston Super Mare General Hospital (8): A.E. Brewster, C.G.A. Price; Worcester RI (8) S. Goodman; Yeovil District Hospital, Yeovil (3): S. Goodman.
International hospitals (accrual), chief and coinvestigators—All India Institute of Medical Sciences, New Delhi, India (509): Deo, V. Raina, G. Rath, A. Sharma, Shukla; Assiut University Hospital, Assiut, Egypt (94): S. Eid, M. Faris; Aswan Cancer Institute, Aswan, Egypt (21): M. Abdeen, A. Bishara; Sir Paul Boffa Hospital, Floriana, Malta (75): S. Brincat, V. Muscat; Christchurch Hospital, Christchurch, New Zealand (15): Atkinson, Colls, Fitzharris, B. Robinson; Dunedin Hospital, Dunedin, New Zealand (13): Jefferson, D. Perez; Gujarat Cancer & Research Institute, Ahmedabad, India (104): P. Shah; King Abdulaziz Hospital, Jeddah, Saudi Arabia (60): Abdullah, A. Alradi, Kotega; Regional Cancer Centre, Hyderabad, India (25): S. Rao; National Cancer Institute, Colombo, Sri Lanka (153): K. Weerasekara; National Cancer Institute, University of Tehran, Iran (110): K. Dehshiri, P. Haddad, F. Amouzgar-Hashemi; National Cancer Institute, Karachi, Pakistan (24): I. Malik; Regional Cancer Centre, Trivandrum, India (43): B. Rajan; Shahid Beheshti University of Medical Sciences and Jorjiani Hospital, Tehran, Iran (149): S. H. Mortazavi, B. Shahrad, M.Shahidi; Singapore General Hospital, Singapore (24): G.-S. Hong, E.-H. Ng; Tata Memorial Hospital, Mumbai, India (41): R. Gopal, R. Nair.
Supported by grants from Cancer Research UK and the Medical Research Council, which played no role in the study design, analysis or interpretation of the data, writing of the manuscript, or the decision to submit the manuscript for publication. This trial was performed under the auspices of the National Cancer Research Institute (Breast Studies Group).
We thank Cancer Research UK and the Medical Research Council for financial support for the trial; the trial investigators, nurses, data managers, and other support staff in participating hospitals; and most importantly the patients participating in the trial.
We would like to dedicate this paper to the memory of Dr Kumar Weerasekera, National Cancer Institute, Colombo, Sri Lanka, who was a dedicated oncologist to his patients, community, and staff. He was held in the highest regard by colleagues and friends throughout the world for the work that he carried out in often very difficult and demanding circumstances.
Funding to pay the Open Access publication charges for this article were provided by Cancer Research UK.
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Manuscript received June 15, 2006; revised January 24, 2007; accepted February 21, 2007.
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J Natl Cancer Inst 2007 99: 1344-1345.
J Natl Cancer Inst 2007 99: 494-495.
J Natl Cancer Inst 2007 99: 493.
J Natl Cancer Inst 2007 99: 493.
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