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Adjuvant Ovarian Suppression in Premenopausal Breast Cancer

Prudence A. Francis, M.D., Meredith M. Regan, Sc.D., Gini F. Fleming, M.D., István
Láng, M.D., Eva Ciruelos, M.D., Meritxell Bellet, M.D., Hervé R. Bonnefoi, M.D.,
Miguel A. Climent, M.D., Gian Antonio Da Prada, M.D., Harold J. Burstein, M.D.,
Ph.D., Silvana Martino, D.O., Nancy E. Davidson, M.D., Charles E. Geyer, Jr., M.D.,
Barbara A. Walley, M.D., Robert Coleman, M.B., B.S., M.D., Pierre Kerbrat, M.D.,
Stefan Buchholz, M.D., James N. Ingle, M.D., Eric P. Winer, M.D., Manuela
Rabaglio-Poretti, M.D., Rudolf Maibach, Ph.D., Barbara Ruepp, Pharm.D., Anita
Giobbie-Hurder, M.S., Karen N. Price, B.S., Marco Colleoni, M.D., Giuseppe Viale,
M.D., Alan S. Coates, M.D., Aron Goldhirsch, M.D., and Richard D. Gelber, Ph.D.
for the SOFT Investigators and the International Breast Cancer Study Group
N Engl J Med 2015; 372:436-446January 29, 2015DOI: 10.1056/NEJMoa1412379
Adjuvant endocrine therapy with tamoxifen has been recommended for
premenopausal women with hormone-receptor–positive breast cancer (positive
for estrogen receptor, progesterone receptor, or both) during the past 15
years.1,2 The value of therapeutic suppression of ovarian estrogen production in
premenopausal women who receive tamoxifen is uncertain.3 The American
Society of Clinical Oncology endorsed guidelines recommending that ovarian
ablation or suppression (hereafter, ovarian suppression) not be added routinely
to adjuvant therapy in premenopausal women.4 Chemotherapy-induced ovarian
suppression (amenorrhea) is correlated with a reduced risk of relapse5-7 but is
less likely to be achieved in very young women. International consensus
guidelines for breast-cancer management in young women suggested that the
addition of a gonadotropin-releasing hormone (GnRH) agonist to tamoxifen be
discussed on an individualized basis.8
In 2003, the International Breast Cancer Study Group (IBCSG) initiated two
randomized, phase 3 trials, the Suppression of Ovarian Function Trial (SOFT) and
the Tamoxifen and Exemestane Trial (TEXT), involving premenopausal women
with hormone-receptor–positive early breast cancer. SOFT was designed to
determine the value of adding ovarian suppression to tamoxifen and to
determine the role of adjuvant therapy with the aromatase inhibitor exemestane
plus ovarian suppression in premenopausal women. Here we report the results of
the planned primary analysis in SOFT9 comparing adjuvant tamoxifen plus
ovarian suppression with tamoxifen alone after a median follow-up of 67 months.
METHODS
Patients
The trial was designed to evaluate adjuvant endocrine therapy in women who
remained premenopausal after the completion of adjuvant or neoadjuvant
chemotherapy and in premenopausal women for whom adjuvant tamoxifen

operable breast cancer. and intended initial method of ovarian suppression. and tumor that expressed estrogen or progesterone receptors in at least 10% of the cells (see the Supplementary Appendix. if assigned. the interval from randomization to the recurrence of breast cancer at a distant site. and overall survival. The assessments of the patients and the recording of adverse events followed a regular schedule (see the Supplementary Appendix). Study Design Women were randomly assigned to receive oral tamoxifen at a dose of 20 mg daily.org. The ethics committee at each participating center approved the study protocol. or oral exemestane (Aromasin. or distant). Randomization was performed by means of the IBCSG Internet-based system and was stratified according to prior chemotherapy (yes vs. regional. second (nonbreast) invasive cancer. Patients who had not received chemotherapy underwent randomization within 12 weeks after definitive surgery. Patients had to have undergone either a total mastectomy with subsequent optional radiotherapy or breast-conserving surgery with subsequent radiotherapy. available with the full text of this article at NEJM. Pfizer) at a dose of 25 mg daily plus ovarian suppression. or distant) or invasive contralateral breast cancer. or Trelstar Depot [triptorelin pamoate]. Eligibility criteria included documented premenopausal status. or bilateral ovarian irradiation. who vouch for the data and analyses reported and for the fidelity of the study to the protocol. and analysis. regional. the respective manufacturers of exemestane and triptorelin. The primary end point was disease-free survival. tamoxifen plus ovarian suppression. Patients who received chemotherapy before randomization and remained premenopausal were enrolled within 8 months after completing chemotherapy. Debio) at a dose of 3. available at NEJM.75 mg administered by means of intramuscular injection every 28 days. and all the patients provided written informed consent. Either axillary dissection or a sentinel-node biopsy was required. or death without recurrence or second cancer. data collection. Ovarian suppression was achieved by choice of triptorelin (Decapeptyl Depot [triptorelin acetate]. lymph-node status (positive vs. defined as the time from randomization to the first appearance of one of the following: recurrence of invasive breast cancer (local. according to the study protocol. donated the study drugs. neither manufacturer imposed restrictions with respect to the trial data. bilateral oophorectomy. Patients were allowed to receive adjuvant oral endocrine therapy before randomization. Patients receiving triptorelin could subsequently opt to undergo oophorectomy or irradiation. once a premenopausal estradiol level was confirmed by a local laboratory. Treatment was for 5 years from the date of randomization. Secondary end points included the interval without breast cancer. invasive contralateral breast cancer. defined as the time from randomization to the recurrence of invasive breast cancer (local.org). The manuscript was written solely by the authors. no).alone was considered suitable treatment. negative). Ipsen. defined as the time from randomization to death from any cause. The steering . The IBCSG was responsible for the trial design. Pfizer and Ipsen.

respectively. After exclusions. designating the test of the superiority of tamoxifen plus ovarian suppression over tamoxifen alone as the primary analysis for SOFT..9 The design assumed the enrollment of predominantly very young women who remained premenopausal after chemotherapy and would have an expected disease-free survival rate at 5 years of 67% when treated with tamoxifen. Hypothesis tests compared the two groups with the use of log-rank tests. and 53.9 We calculated that with an estimated 186 events of disease recurrence. The median age of the patients was 43 years (Table 1TABLE 1Characteristics of Patients in the Primary Analysis. and Fig. RESULTS Study Population From December 2003 through January 2011. negative). or death in the two treatment groups after a median follow-up of 5 years. Stratified Cox proportional-hazards regression was used to estimate hazard ratios and 95% confidence intervals. and 25%. In prespecified secondary analyses. 1024 to tamoxifen plus ovarian suppression.10 Analyses were performed according to the intention-to-treat principle. Kaplan– Meier estimates of time-to-event end points were calculated. and the comparison of exemestane plus ovarian suppression with tamoxifen plus ovarian suppression was analyzed by means of a combined analysis with the TEXT data. heterogeneity of the treatment effect according to subgroup was investigated by tests of treatment-by-covariate interaction. Statistical Analysis The original statistical analysis plan for SOFT was to assess disease-free survival between the treatment groups with three pairwise comparisons. S1 in the Supplementary Appendix). the study would have at least 80%. and the rate of disease-free survival was higher than expected.05. 2033 women were included in the intention-to-treat population for the primary analysis comparing tamoxifen plus ovarian suppression with tamoxifen alone (Figure 1FIGURE 1Randomization and Primary Analysis Populations. with tamoxifen plus ovarian suppression versus tamoxifen alone. stratified according to prior use of chemotherapy (yes vs. no) and lymph-node status (positive vs. 30%. at a two-sided alpha level of 0. A total of 46. Overall and According to Chemotherapy Cohort. 69%. and 1021 to exemestane plus ovarian suppression. and 52% power to detect reductions in risk of 33. second invasive cancer. on the basis of outcomes for patients younger than 35 years of age in previous trials. The comparison of exemestane plus ovarian suppression with tamoxifen alone became a secondary objective.7% of the patients had not received chemotherapy previously. we randomly assigned 1021 premenopausal women to tamoxifen.5%. and an adjusted hazard ratio for the treatment effect was estimated.3% received chemotherapy before .).committee (which included employees of Pfizer and Ipsen) reviewed the manuscript and made the decision to submit it for publication.9 The enrolled patients were older and had lower-risk characteristics than anticipated. A protocol amendment to the analysis plan was adopted in 2011.

or death.7% (95% CI.2 to 88.). 0. or death.78.6) remained free from breast cancer at 5 years. 0.09) (Figure 3AFIGURE 3Kaplan–Meier Estimates of Freedom from Recurrence of Breast Cancer and Freedom from the Recurrence of Breast Cancer at a Distant Site after a Median Follow-up of 67 Months. 0.0% were second (nonbreast) malignant conditions (Table S3 in the Supplementary Appendix).4% (95% CI.10) (Figure 2AFIGURE 2Primary Analysis Comparisons of Tamoxifen plus Ovarian Suppression (OS) with Tamoxifen Alone.40) (Figure 3B).75.6% (95% confidence interval [CI].4% (95% CI.2% of the first events involved distant sites.5) of those assigned to receive tamoxifen alone (hazard ratio for recurrence.7) among patients assigned to receive tamoxifen plus ovarian suppression.96.9) among those assigned to tamoxifen alone (hazard ratio for recurrence. However. tamoxifen plus ovarian suppression significantly reduced the hazard of recurrence. 84. S2 in the Supplementary Appendix).1 to 90. 0.7% (95% CI.9 to 92. a second invasive cancer. Death was reported in 106 patients (5. 299 patients (14. P=0. 0. and 12. 95.1% . P=0.1%). 95% CI. P=0. 4 patients died without a breast-cancer recurrence or a second invasive cancer.04.18. tamoxifen plus ovarian suppression reduced the hazard of breast-cancer recurrence. 0. with no significant difference between those assigned to tamoxifen plus ovarian suppression and those assigned to tamoxifen alone (hazard ratio for recurrence. 95% CI.9% (95% CI. second invasive cancer.02). A total of 58. as compared with 86. Node-positive disease was present in 34. 0. 95% CI.9% of the patients.0 to 88. Among patients assigned to receive exemestane plus ovarian suppression. The rate of disease-free survival at 5 years was 86.3) of the patients assigned to receive tamoxifen plus ovarian suppression remained free from breast cancer. 82.randomization and remained premenopausal. P=0. Overall survival at 5 years was 96.66 to 1. 95% CI. Planned subgroup analyses did not reveal heterogeneity of treatment effect across most subgroups (Fig. 90.03. P=0. 88.83. 84. According to Treatment Assignment.7%) had recurrent disease or a second invasive cancer or had died.59 to 0.66 to 1. with adjustment for covariates.88. 86.7) among patients assigned to tamoxifen plus ovarian suppression and 95. as compared with tamoxifen alone (hazard ratio.62 to 0.2%).2 to 86.2 to 97. as compared with tamoxifen alone (hazard ratio. 0.).98. as compared with 84. In the multivariable Cox proportional-hazards model. 0. Efficacy At a median follow-up of 67 months.63 to 1. 88. 95% CI.81. At 5 years. Recurrence of breast cancer at a distant site was reported in 185 patients (9. the subgroup of patients with human epidermal growth factor receptor 2–positive tumors appeared to have a greater benefit with tamoxifen plus ovarian suppression than with tamoxifen alone. 0.03) (Table S4 in the Supplementary Appendix). After adjustment for covariates in the multivariable Cox proportional-hazards model.

94.2) among those assigned to tamoxifen alone (hazard ratio for death.5. 0.9% of first events (a second invasive cancer or death) were not related to breast cancer (Table S3 in the Supplementary Appendix). with or without the substitution of alternative endocrine therapy. 87. 2.2%.3) among those assigned to tamoxifen alone (hazard ratio for death. Overall survival at 5 years in the chemotherapy cohort was 94.60 to 1.9 to 89. and 4 years after randomization. 95% CI.6) among those assigned to receive tamoxifen plus ovarian suppression and 78.9% (95% CI. 14.0 to 96. 78. S5 in the Supplementary Appendix).96) (Figure 2B. 85.78.7% (95% CI.9%. 93. More than 90% of the deaths occurred in patients who had received chemotherapy previously. 25.5% (95% CI.7% of the patients. in 16.5% (95% CI. 0.8% among those assigned to tamoxifen plus ovarian suppression.5) remained free from breast cancer at 5 years (Figure 3E).8 to 85.8% of the patients were continuing to receive some or all of the protocol-assigned treatment.2) among patients assigned to tamoxifen plus ovarian suppression. and 83. and 21.5) for those assigned to tamoxifen plus ovarian suppression. 233 of whom were included in the primary analysis.6% among patients assigned to tamoxifen alone. and 87.9% (95% CI.42 to 0. more than 95% remained free from breast cancer at 5 years in each group (Figure 3C). 0.9% at 0. In this very young subgroup. 0. 95% CI. . with few distant recurrences (Figure 3D). 3.64.13) (Figure 2B). Tamoxifen was discontinued early. and Fig.(95% CI.0% (95% CI.3) for those assigned to exemestane plus ovarian suppression. The rates of freedom from distant recurrence at 5 years in this cohort were as follows: 83. Among these women.74. Most recurrences of breast cancer were in patients who remained premenopausal after receiving chemotherapy (Figure 3E).3 to 88.51 to 1.0) for patients assigned to tamoxifen alone. 84. Among patients who did not receive chemotherapy.3%.0 to 81. 92. 82.09. and 32. it was achieved entirely through administration of the GnRH agonist triptorelin in 80. the rate of freedom from breast cancer at 5 years was 82.0% of the patients had received chemotherapy previously. 74. 18.8 to 85.3 to 76. respectively. 57. 0. Rates of nonadherence with ovarian suppression were 5.4% (95% CI. among patients assigned to exemestane plus ovarian suppression. 95% CI. 0. In the chemotherapy cohort. as compared with 90. Treatment and Adverse Events At a median follow-up of 67 months.9 to 93. In this cohort.0%.7% (95% CI. 78. the rate of freedom from breast cancer at 5 years was 67. A total of 350 women younger than 35 years of age participated in the trial. 1.4 to 96.7% of the tamoxifen–ovarian suppression group and 21.02). 74.8% among those assigned to exemestane plus ovarian suppression (Figure 3F). 69. P=0. Among patients assigned to ovarian suppression.7% of the tamoxifen group (Table S5 in the Supplementary Appendix).5) among those assigned to receive tamoxifen alone (hazard ratio for recurrence. Most recurrences of breast cancer at a distant site occurred in the patients who had received chemotherapy previously. 9.

Osteoporosis as defined by a T score of less than −2. Previous trials evaluating ovarian suppression were . we had hypothesized that therapeutic ovarian suppression would provide a benefit similar to that observed with chemotherapy-induced amenorrhea. The first cohort included 949 premenopausal women for whom adjuvant tamoxifen without chemotherapy was considered to be suitable treatment.5-7 Resilience of ovarian function to chemotherapy correlates with younger age. The clinicopathological features that warranted prior chemotherapy use12 and the younger age of the women who remained premenopausal after chemotherapy (median age. hypertension.5% of those assigned to tamoxifen alone.3% of the patients assigned to receive tamoxifen plus ovarian suppression. The findings in this cohort do not currently inform us about the clinical relevance of ovarian suppression because one third of the first events were not related to breast cancer..5-7 The SOFT design for the chemotherapy cohort targeted younger patients by mandating that only women who remained premenopausal or reverted to premenopausal status could be enrolled.7% of those assigned to receive tamoxifen alone (Table 2TABLE 2 Key Targeted Adverse Events Reported during Follow-up.Targeted adverse events of grade 3 or higher were reported in 31. Chemotherapy-induced ovarian suppression is common in older premenopausal women and is associated with improved breast-cancer outcomes. These patients were predominantly older than 40 years of age. as compared with 23. Hot flushes. DISCUSSION The results of SOFT show that.8% of the patients assigned to tamoxifen plus ovarian suppression and in 3. had small. By contrast. With a median of 67 months of follow-up. and glucose intolerance (diabetes) were reported more frequently in the tamoxifen–ovarian suppression group than in the tamoxifen group. as shown by estradiol measurement regardless of menses. 40 years) contributed to the higher risk of recurrence in this cohort than in the cohort that had not received chemotherapy. depression. For women with ovarian estrogen production after chemotherapy. musculoskeletal symptoms.5 was reported in 5. and had excellent outcomes with tamoxifen alone after a median follow-up of 67 months. sweating. and additional recurrences are anticipated with further follow-up. insomnia. According to Treatment Assignment. However. vaginal dryness. the second cohort included 1084 women who remained premenopausal after completing chemotherapy. the number of breast-cancer recurrences observed was large enough to indicate that including ovarian suppression as a component of adjuvant therapy can meaningfully reduce recurrences in this cohort (Figure 3E). decreased libido. the addition of ovarian suppression to adjuvant tamoxifen did not significantly improve disease-free survival. considering the entire population of patients who underwent randomization. node-negative tumors of low to intermediate grade. freedom from recurrence exceeded 95% at 5 years. and Table S6 in the Supplementary Appendix). SOFT investigated ovarian suppression in two distinct patient cohorts.

the comparison of exemestane plus ovarian suppression with tamoxifen plus ovarian suppression. After a protocol amendment. as compared with tamoxifen alone. Adding ovarian suppression to tamoxifen resulted in increased adverse events — most notably.13-15 When SOFT was planned.10 Overall. as compared with tamoxifen alone. breast cancer recurred within 5 years in approximately one third of the patients assigned to receive tamoxifen alone but in one sixth of those assigned to receive exemestane plus ovarian suppression. a second invasive cancer. depression. tamoxifen plus ovarian suppression resulted in a 22% reduction in the relative risk of breast-cancer recurrence.001). in the proportion of patients without recurrent breast cancer at 5 years.17. a second invasive cancer. These observed relative and absolute benefits at 5 years from ovarian suppression plus tamoxifen or ovarian suppression plus exemestane. After adjustment for covariates in the multivariable Cox model.7 percentage points. these trials also lacked a 5-year tamoxifen control group. Intergroup trials.5 percentage points. compare favorably with the practice-changing results of randomized trials of adjuvant aromatase inhibitors versus tamoxifen in postmenopausal women. on the basis of a combined analysis with TEXT. diabetes. In the higher-risk cohort of patients who remained premenopausal after chemotherapy.0 percentage points. in the proportion of patients without recurrent breast cancer at 5 years. Any benefit from ovarian suppression must be weighed against the adverse effects. the absolute improvement was 7. as compared with tamoxifen alone. a second invasive cancer. or death (P=0. it was hypothesized that tamoxifen plus ovarian suppression would reduce the relative risk of breast-cancer recurrence.confounded by the inclusion of women who became permanently postmenopausal from chemotherapy or who had an unknown or negative hormone-receptor status. tamoxifen plus ovarian suppression resulted in an absolute improvement of 2. on the basis of retrospective analyses of data from IBCSG and U. and furthermore.S.13-15 Among the women younger than 35 years of age. and adverse events with possible long-term health implications such as hypertension. showed a 28% reduction in the relative risk of breast-cancer recurrence. as compared with tamoxifen alone. tamoxifen plus ovarian suppression resulted in an absolute improvement of 4. and .16 Patients who receive a diagnosis of hormone-receptor–positive breast cancer when they are younger than 35 years of age are a subgroup considered to be at higher risk for adverse outcomes than are older premenopausal women. as compared with tamoxifen alone. that exemestane plus ovarian suppression would reduce the relative risk by 25%. as compared with tamoxifen alone. or death and a 34% reduction in the relative risk of breast-cancer recurrence in the exemestane–ovarian suppression group (P<0. menopausal symptoms.03) and a 25% reduction in the relative risk of breast-cancer recurrence. as compared with tamoxifen plus ovarian suppression. with exemestane plus ovarian suppression.18 The results observed in this subgroup in SOFT add to the evidence that ovarian suppression plays an important role in younger premenopausal patients. or death by 25%.

the Australia . Melbourne.org. and the overall survival analysis is premature after 5% of patients have died.osteoporosis. Locked Bag 1. Appendix The authors' affiliations are as follows: the Peter MacCallum Cancer Centre..10 The current analysis indicates that in a cohort selected for chemotherapy and persistent premenopausal status. The combined analysis from TEXT and SOFT showed that adjuvant endocrine therapy with ovarian suppression plus exemestane is significantly more effective than ovarian suppression plus tamoxifen. available at NEJM.). musculoskeletal. because SOFT is currently underpowered. with the most striking differences observed among younger patients. Drs.org. A'Beckett St. Melbourne. ovarian suppression plus tamoxifen improves outcomes. 2014. We conclude that adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall population of premenopausal women in this trial.org. and the National Cancer Institute. When exemestane is combined with ovarian suppression. Source Information The authors' affiliations are listed in the Appendix. ovarian suppression in addition to tamoxifen reduced the risk of breast-cancer recurrence. in this higher-risk premenopausal cohort. However. the International Breast Cancer Study Group. Ovarian suppression combined with an aromatase inhibitor further reduced the risk of recurrence. Ipsen. as compared with tamoxifen alone.10 Longer follow-up is required. Supported by Pfizer. Address reprint requests to Dr. This article was published on December 11. VIC (P.F. and bone-density effects are more frequent than with tamoxifen plus ovarian suppression. St Vincent's Hospital. at NEJM. as compared with tamoxifen-based therapy. Francis and Regan contributed equally to this article. Disclosure forms provided by the authors are available with the full text of this article at NEJM. as compared with tamoxifen alone. Australia. Francis at the Peter MacCallum Cancer Centre. adverse sexual. or at ibcsgcc@ibcsg. University of Melbourne. A complete list of investigators in the Suppression of Ovarian Function Trial (SOFT) and the International Breast Cancer Study Group is provided in the Supplementary Appendix.A.org. VIC 8006. in the cohort of women who had a sufficient risk of recurrence to warrant adjuvant chemotherapy and who had premenopausal estradiol levels despite chemotherapy.

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