Adjuvant Tamoxifen Plus Ovarian Function Suppression Versus Tamoxifen Alone in Premenopausal Women With Early Breast Cancer: Patient-Reported Outcomes in the Suppression of Ovarian Function Trial

Abstract

Purpose

The Suppression of Ovarian Function trial showed improved disease control for tamoxifen plus ovarian function suppression (OFS) compared with tamoxifen alone for the cohort of premenopausal patients who received prior chemotherapy. We present the patient-reported outcomes.

Patients and Methods

The quality-of-life (QoL) analysis includes 1,722 of 2,045 premenopausal patients with hormone receptor–positive breast cancer randomly assigned to receive adjuvant treatment with 5 years of tamoxifen plus OFS or tamoxifen alone. Chemotherapy use before enrollment was optional. Patients completed a QoL form consisting of global and symptom indicators at baseline, every 6 months for 24 months, and annually during years 3 to 6. Differences in the change of QoL from baseline between the two treatments were tested at 6, 24, and 60 months with mixed models for repeated measures with and without chemotherapy and overall.

Results

Patients on tamoxifen plus OFS were more affected than patients on tamoxifen alone by hot flushes at 6 and 24 months, by loss of sexual interest and sleep disturbance at 6 months, and by vaginal dryness up to 60 months. Without prior chemotherapy, patients on tamoxifen alone reported more vaginal discharge over the 5 years than patients on tamoxifen plus OFS. Symptom-specific treatment differences at 6 months were less pronounced in patients with prior chemotherapy. Changes in global QoL indicators from baseline were small and similar between treatments over the whole treatment period.

Conclusion

Overall, OFS added to tamoxifen resulted in worse endocrine symptoms and sexual functioning during the first 2 years of treatment, with variable magnitudes of treatment differences. Short-term differences in symptom-specific QoL, treatment burden, and coping effort between treatment groups were less pronounced for patients with prior chemotherapy, the cohort that benefited most from OFS in terms of disease control.

INTRODUCTION

Clinical results from the recently published Tamoxifen and Exemestane Trial (TEXT) and Suppression of Ovarian Function Trial (SOFT) provide new treatment options for premenopausal women with endocrine-responsive early breast cancer.^1,2 In SOFT, adding ovarian function suppression (OFS) to tamoxifen did not significantly improve disease-free survival versus tamoxifen alone in the overall population.² However, the addition of OFS improved disease outcomes in women at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal thereafter.

When determining the most appropriate adjuvant endocrine therapy with the individual patient, adverse effect profiles are a concern, and patient-reported outcomes provide valuable complementary information.^3,4 With respect to exemestane versus tamoxifen in patients who received OFS, there were no differential effects on global quality of life (QoL), yet there were distinct effects on the burden of endocrine symptoms.⁵

The effect of OFS on patient-reported outcomes in patients who received adjuvant tamoxifen was investigated in the Zoladex in Premenopausal Patients (ZIPP)^6,7 and the Eastern Cooperative Oncology Group E-3193⁸ trials. Results indicate a greater detrimental effect on menopausal symptoms and sexual activity during treatment with OFS compared with tamoxifen alone.^6-8 In E-3193, overall QoL was worse when OFS was added to tamoxifen compared with tamoxifen alone at 3 years, with subsequent lessening of differences.⁸

For many women, chemotherapy is likely to be part of their adjuvant therapy. The effect of chemotherapy on the perception of endocrine symptoms is poorly understood. In the ZIPP trial, the type of endocrine therapy had different effects on patient-reported symptoms only in patients who did not receive chemotherapy.⁶

In parallel to the efficacy analysis of SOFT,² we investigated patients’ experiences of individual symptoms and QoL when adding OFS to tamoxifen, also considering the influence of prior chemotherapy use. If adjuvant treatment includes OFS, current recommendations favor an aromatase inhibitor over tamoxifen.⁹ Therefore, we also present QoL results for exemestane plus OFS compared with tamoxifen alone.

PATIENTS AND METHODS

Study Design and Participants

SOFT was designed to evaluate adjuvant endocrine therapy in women who remained premenopausal after completion of (neo)adjuvant chemotherapy and in premenopausal women for whom adjuvant tamoxifen alone was considered suitable treatment (for details, see Data Supplement). SOFT eligibility criteria have been described elsewhere.^2,10 Patients who did not receive chemotherapy were randomly assigned within 12 weeks of definitive surgery. Patients who received chemotherapy were randomly assigned within 8 months after completing chemotherapy, once a premenopausal estradiol level was confirmed. The ethics committee of each participating center approved the study protocol, and all patients gave written informed consent.

Treatment

Eligible women were randomly assigned 1:1:1 to receive oral tamoxifen (20 mg once per day), tamoxifen plus OFS, or oral exemestane (25 mg once per day) plus OFS for 5 years from the date of random assignment. OFS was achieved using triptorelin at a dose of 3.75 mg by intramuscular injection every 28 days, bilateral oophorectomy, or bilateral ovarian irradiation. Random assignment was stratified by chemotherapy use (yes/no), lymph node status (positive/negative), and intended initial method of OFS, if assigned. Patients may have received oral endocrine therapy before random assignment. Protocol-assigned endocrine therapy was to cease 5 years from random assignment.

QoL Assessment

Patients completed the International Breast Cancer Study Group QoL Core Form¹¹ and a trial-specific module at baseline, every 6 months for 2 years, then annually for years 3 through 6. The forms were to be completed at the clinic, before diagnostic procedures (exception: baseline) and before treatment was given and regardless of disease status. Eligibility exceptions were cognitive or physical impairment that interfered with the QoL assessment and inability to read any of the languages available on the core form. The core form includes global indicators for physical well-being,¹² mood,¹³ coping effort,¹⁴ subjective health estimation,¹⁵ and five indicators specific to symptoms and adverse effects.¹⁶ The module consisted of 12 endocrine symptom indicators, one global indicator for treatment burden,¹⁷ and a question regarding sexual activity during the past 6 months (yes/no). The selection of endocrine symptoms was based on the findings of two breast cancer prevention trials^18,19 and a symptom checklist^20-22 (see Data Supplement). All indicators were in linear analog self-assessment format¹⁶ and transformed to range from 0 to 100, with higher numbers reflecting a better condition. For all indicators, a clinically significant change was conservatively defined as at least ± 8 points.²³

Prospectively Defined Hypotheses

Primary.

Primary hypotheses were as follows: (1) Patients receiving tamoxifen plus OFS will report more hot flushes compared with those receiving tamoxifen alone. (2) Patients receiving tamoxifen plus OFS will report a higher loss of sexual interest compared with those receiving tamoxifen alone. (3) There will be a differential effect on specific menopausal symptoms (ie, more vaginal discharge in patients receiving tamoxifen only, and more vaginal dryness, sleep disturbance, and bothersome weight gain in patients receiving tamoxifen plus OFS).

Secondary.

Secondary hypotheses were as follows: (1) There will be no difference in global QoL indicators (mood, physical well-being, or coping effort) in patients receiving tamoxifen plus OFS compared with those receiving tamoxifen alone, but patients receiving tamoxifen plus OFS will report higher treatment burden than those receiving tamoxifen alone. (2) Patients who report worse menopausal symptoms during the first 6 months on endocrine therapy will also report delayed adaptation in global domains (coping effort, mood, and physical well-being).

Statistical Analysis

From the intent-to-treat (ITT) efficacy analysis population, patients were excluded from the QoL analysis for the following reasons: a QoL eligibility exemption; participating centers with poor overall QoL submission compliance (< 60% of QoL assessments; Data Supplement); or no QoL data submitted (Fig 1).

Fig 1.

CONSORT flowchart to identify the intent-to-treat (ITT) quality-of-life population (N = 3,066). OFS, ovarian function suppression; QoL, quality of life; SOFT, Suppression of Ovarian Function Trial.

For each QoL indicator, changes from baseline to each time point were calculated (time point minus baseline scores) and summarized in figures descriptively as means with 95% CIs. Mixed-effects linear modeling for repeated measures analyzed the effects of treatment on changes from baseline in QoL indicators. Models included chemotherapy cohort, treatment assignment (tamoxifen v tamoxifen plus OFS), time point (seven time points, categorical), and the two- and three-way interactions, without regard for statistical significance of the interaction parameters. Models were adjusted for the following baseline covariates: age, race/ethnicity, body mass index, menstruation status, family history of breast or ovarian cancer, nodal status, tumor size, tumor grade, and human epidermal growth factor receptor 2 status. An unstructured covariance was used. For hypothesis testing, within each cohort and overall, model contrasts estimated mean differences between treatment groups, 95% CIs, and Wald P values for testing the treatment differences versus zero at short (month 6), intermediate (month 24), and long term (month 60).

For secondary hypothesis 2, the model added a covariate of more versus less severe menopausal symptoms during the first 6 months of therapy, which was created by categorizing the change in hot flushes at the median. The mean difference between the two severity groups in QoL change from baseline to 6, 12, 18, and 24 months was estimated and tested.

Hypothesis tests were two-sided, consistent with the protocol. The reported P values were not adjusted for testing of multiple QoL indicators over time to look for consistency of the signal among comparable QoL indicators. As supplementary analyses of the effect of exemestane plus OFS on symptom burden and QoL relative to tamoxifen alone, changes in all indicators from baseline over time were summarized descriptively without formal comparison.

RESULTS

Patient and Disease Characteristics

Of the 3,066 premenopausal women enrolled onto SOFT between December 2003 and January 2011, 2,045 were randomly assigned to tamoxifen or to tamoxifen plus OFS, with 2,033 patients in the ITT efficacy population. After exclusions, 1,722 patients remained in the ITT QoL population for the primary analysis comparing tamoxifen plus OFS versus tamoxifen alone (Fig 1). Median follow-up was 5.6 years (interquartile range, 4.4 to 6.8 years); 63 patients (3.7%) died within 60 months.

The median age at random assignment was 43 years. Node-positive disease was present in 36% of patients, and 55% of patients received prior chemotherapy. Overall, 27% of patients also received prior oral endocrine therapy for an average duration of 16 weeks (interquartile range, 8 to 22 weeks). Among patients who received prior chemotherapy, 45% received endocrine therapy before random assignment. Patient and disease characteristics at random assignment were balanced across treatment groups. Patients in the chemotherapy cohort had higher risk disease characteristics (greater proportions had node-positive disease, human epidermal growth factor receptor 2–positive disease, and tumor size > 2 cm) and were younger (Table 1; Data Supplement). Patient, disease, and treatment characteristics were generally balanced between the ITT QoL population and excluded patients (Data Supplement), although excluded patients had lower rates of physician-reported symptoms at random assignment (data not shown).

Table 1.

Patient Characteristics Overall and According to Chemotherapy Cohort and Treatment Assignment

Characteristic	No Chemotherapy				Prior Chemotherapy				Overall (n = 1,722)
	T (n = 385)		T+OFS (n = 387)		T (n = 476)		T+OFS (n = 474)
	No.	%	No.	%	No.	%	No.	%	No.	%
Age, years
< 35	3	0.8	5	1.3	93	19.5	104	21.9	205	11.9
35 to < 40	28	7.3	26	6.7	137	28.8	125	26.4	316	18.4
40 to < 45	113	29.4	116	30.0	156	32.8	151	31.9	536	31.1
45 to < 50	178	46.2	169	43.7	74	15.5	80	16.9	501	29.1
≥ 50	63	16.4	71	18.3	16	3.4	14	3.0	164	9.5
Median	46		46		40		40		43
IQR	43-48		43-49		36-44		35-44		38-47
Nodal status
Negative	348	90.4	352	91.0	206	43.3	202	42.6	1,108	64.3
Positive	37	9.6	35	9.0	270	56.7	272	57.4	614	35.7
Tumor size > 2 cm	46	11.9	64	16.5	221	46.4	220	46.4	551	32.0
HER2 positive	20	5.2	16	4.1	89	18.7	92	19.4	217	12.6
Time from final surgery to random assignment, months
Median	1.8		1.9		8.2		8.1		3.6
IQR	1.2-2.4		1.3-2.5		5.8-10.7		6.0-10.1		1.8-8.5
Endocrine therapy before random assignment*	24	6.2	20	5.2	224	47.1	202	42.6	470	27.3

NOTE. Characteristics were well balanced according to treatment assignment. A more complete summary of characteristics is provided in the Data Supplement.

Abbreviations: HER2, human epidermal growth factor receptor 2; IQR, interquartile range; OFS, ovarian function suppression; T, tamoxifen.

^*Oral endocrine therapy before random assignment was allowed while premenopausal status was established or re-established. In the no chemotherapy cohort, average duration was 5 weeks (IQR, 3 to 7 weeks) for patients assigned to T and 5 weeks (IQR, 2 to 7 weeks) for patients assigned to T+OFS; in the prior chemotherapy cohort, average duration was 17 weeks (IQR, 10 to 24 weeks) for patients assigned to T and 16 weeks (IQR, 10 to 23 weeks) for patients assigned to T+OFS.

The overall QoL form submission rate (QoL ITT population) was 84% between baseline and 60 months but declined over time, with rates of 89% at 6 months, 83% at 24 months, and 74% at 60 months. Submission rates were similar between the randomly assigned treatment groups and chemotherapy cohorts.

Changes in QoL Symptom and Global Indicators Over Time

Vasomotor symptoms showed the greatest early worsening from baseline, as shown for hot flushes by treatment and chemotherapy cohort (Figs 2A and 2B). Thereafter, hot flushes improved continuously in patients receiving tamoxifen plus OFS but without reaching baseline scores, whereas scores worsened slightly in patients receiving tamoxifen. Patients reported a continuous decline in sexual interest over the whole treatment period, with a clinically meaningful decrease observed between months 6 and 60 (range, −8 to −11) in patients on tamoxifen plus OFS, and after 36 months (−9 at month 36 and −9 at month 60) in patients on tamoxifen (Figs 2C and 2D). Changes in gynecologic symptoms were smaller than for vasomotor symptoms and marginally clinically meaningful (Fig 3). Only for vaginal dryness did patients in both arms report a clinically meaningful worsening at 24 and 60 months. Both treatment groups reported a clinically meaningful worsening over time regarding bone and joint pains and being troubled by weight gain. Changes in other symptoms (ie, headaches, being irritable, feeling dizzy, appetite, feeling sick, tiredness) and global QoL indicators for physical well-being, mood, and health perception were small over time and similar in each treatment group (Figs 3 and 4).

Fig 2.

(A) Scores for hot flushes (mean with 95% CIs; higher score indicates better condition) from baseline to 60 months according to treatment assignment and chemotherapy cohort. (B) Change in hot flush scores from baseline to 6, 24, and 60 months according to chemotherapy cohort. (C) Scores for loss of sexual interest (mean with 95% CIs; higher score indicates better condition) from baseline to 60 months according to chemotherapy cohort. (D) Change in scores for loss of sexual interest from baseline to 6, 24, and 60 months according to chemotherapy cohort. The vertical line at ± 8 indicates the minimal clinically meaningful change in quality-of-life (QoL) scores. Chemo, chemotherapy; OFS, ovarian function suppression; T, tamoxifen

Fig 3.

Change in quality-of-life (QoL) symptom indicator scores from baseline to 6, 24, and 60 months, according to treatment assignment, overall across chemotherapy cohorts. The vertical line at ± 8 indicates the minimal clinically meaningful change in QoL scores. OFS, ovarian function suppression.

Fig 4.

Change in quality-of-life (QoL) global indicator scores from baseline to 6, 24, and 60 months, according to treatment assignment, overall across chemotherapy cohorts. The vertical line at ± 8 indicates the minimal clinically meaningful change in QoL scores. OFS, ovarian function suppression.

Treatment Comparisons

Baseline QoL scores were similar between treatment arms (Table 2). Treatment comparisons are presented in Figs 2 to 4 and Table A1, online only. Treatment differences for changes in hot flushes (primary hypothesis 1) and sweats from baseline were substantial at 6 and 24 months, with women receiving tamoxifen plus OFS significantly more affected than those receiving tamoxifen alone. These differences were not present at 60 months.

Table 2.

Baseline Quality-of-Life Scores According to Chemotherapy Cohort and Treatment Assignment

Symptom/Global Indicator	No Chemotherapy				Prior Chemotherapy
	T		T+OFS		T		T+OFS
	Mean Score	SD	Mean Score	SD	Mean Score	SD	Mean Score	SD
Vasomotor
Hot flushes	88.7	20.4	91.2	16.9	71.7	29.9	70.7	33.2
Sweats (including night sweats)	84.9	19.9	87.4	19.1	74.4	27.5	73.5	30.0
Sexual symptoms
Loss of sexual interest	78.5	26.7	78.7	27.0	68.6	30.2	65.4	31.1
Difficulties in becoming aroused	85.3	20.3	83.4	23.0	72.9	27.7	70.3	27.8
Gynecologic symptoms
Vaginal discharge	88.0	17.5	87.1	17.8	77.7	24.5	79.7	22.4
Vaginal dryness	89.7	18.0	92.0	15.4	80.2	25.9	79.8	25.2
Vaginal itching/irritation	91.1	17.3	92.1	14.8	86.2	21.5	85.5	22.7
Musculoskeletal/neurologic pain
Bone or joint pain	83.2	23.1	83.3	23.3	76.1	26.6	74.5	28.4
Headaches	82.1	23.5	82.6	22.4	83.0	21.4	82.2	23.2
GI symptoms
Appetite	80.1	22.2	81.8	21.5	80.5	21.5	80.8	20.5
Feeling sick (nausea/vomiting)	91.5	16.3	93.7	13.3	91.0	17.5	91.1	17.1
Constitutional/psychological symptoms
Sleep disturbance	71.2	27.1	70.7	27.4	67.2	29.4	67.2	29.0
Tiredness	58.4	29.3	60.2	26.3	58.4	25.9	53.4	26.1
Troubled by weight gain	84.9	24.2	84.0	24.7	70.3	30.9	68.5	32.1
Being irritable	74.2	25.2	75.3	23.1	71.8	24.9	71.5	24.5
Feeling dizzy	89.6	17.4	91.1	15.8	86.6	20.3	86.9	19.3
Global indicators
Physical well-being	75.0	23.3	77.6	20.8	77.1	22.1	76.8	20.9
Mood	71.6	23.8	72.2	22.5	75.2	21.8	73.8	23.0
Coping effort	66.9	27.0	69.8	24.9	67.7	26.2	69.2	25.7
Treatment burden	77.3	24.9	78.9	22.6	70.4	25.2	71.5	24.4
Health perception	72.9	21.1	72.8	20.9	70.8	21.9	72.3	21.1

NOTE. All indicators range from 0 to 100, with higher scores indicating a better condition.

Abbreviations: OFS, ovarian function suppression; SD, standard deviation; T, tamoxifen.

The decline in sexual interest was significantly greater in patients receiving tamoxifen plus OFS at 6 months but not at 24 and 60 months (primary hypothesis 2). At baseline, 73% and 75% of the patients receiving tamoxifen plus OFS and tamoxifen alone, respectively, reported being sexually active. These proportions remained quite stable at 6, 24, and 60 months in both groups (tamoxifen plus OFS: 76%, 75%, and 69%, respectively; tamoxifen: 81%, 79%, and 74%, respectively). If sexually active, patients receiving tamoxifen plus OFS experienced significantly greater changes in difficulty becoming aroused than patients receiving tamoxifen alone at 6 and 24 months.

Patients receiving tamoxifen plus OFS experienced a significantly greater exacerbation in vaginal dryness over the whole treatment period (primary hypothesis 3), whereas patients on tamoxifen alone experienced a significantly greater increase in vaginal discharge and vaginal itching/irritation in the short and intermediate term.

Patients receiving tamoxifen plus OFS experienced significantly more sleep disturbance at 6 months (primary hypothesis 3) than those receiving tamoxifen alone, but not at the later time points. Bone and joint pain was reported significantly more often in patients receiving tamoxifen compared with those receiving tamoxifen plus OFS at 60 months. No significant differences between the treatments groups were observed for all other symptoms.

Patients receiving tamoxifen plus OFS had slightly less improvement in coping effort and were more burdened by treatment at 6 and 24 months than those receiving tamoxifen alone (secondary hypothesis 1).

Changes over time in symptom burden and QoL for patients receiving exemestane plus OFS relative to the other two groups were summarized descriptively without formal comparison (Appendix Fig A1, online only). In patients receiving exemestane plus OFS, hot flushes and sweats worsened to a greater extent than those receiving tamoxifen alone, but to a lesser extent than those receiving tamoxifen plus OFS, at short and intermediate terms. Among the three treatment groups, patients receiving exemestane plus OFS were most affected by sexual dysfunction and vaginal dryness but least affected by vaginal discharge over the whole treatment period. Patients receiving exemestane plus OFS reported a greater worsening in bone and joint pains compared with the other two treatment groups. Changes in global QoL were similar in all three groups, with slightly greater treatment burden for exemestane plus OFS in the short term.

Adaptation

Overall, patients with more severe hot flushes compared with those with less severe hot flushes during the first 6 months had less improvement in coping scores at this time point (Δ = −4, P = .0029) but not thereafter (secondary hypothesis 2). Among patients without prior chemotherapy, patients who had more severe hot flushes at 6 months also experienced a slightly greater decline in physical well-being at this time point compared with the group with less severe hot flushes(Δ = −6, P = .0045). No consistent difference in change of mood was observed between the two severity groups (data not shown).

Impact of Chemotherapy

Patients receiving prior chemotherapy were randomly assigned, on average, 8 months from final surgery, which was substantially later than those who did not receive chemotherapy (Table 1). Patients receiving prior chemotherapy reported lower baseline scores for vasomotor, gynecologic, and sexual symptoms; for bone and joint pain; and for being troubled by weight gain compared with the no chemotherapy cohort (Table 2). Thus, changes over time in these symptoms were smaller in this cohort compared with the cohort without chemotherapy, as shown for hot flushes (Figs 2A and 2B). Baseline scores for the other symptoms and global indicators were similar between the two chemotherapy cohorts (Table 2).

At short term, the magnitude of treatment differences between tamoxifen plus OFS and tamoxifen alone varied among the two chemotherapy cohorts (Fig 5). In the cohort with prior chemotherapy, treatment differences were less pronounced for hot flushes (Δ = −26), sweats (Δ = −19), loss of sexual interest (Δ = −6), difficulties becoming aroused (Δ = −4), and sleep disturbance (Δ = −6) in contrast to the cohort without chemotherapy (hot flushes, Δ = −32; sweats, Δ = −27; loss of sexual interest, Δ = −9; difficulties becoming aroused, Δ = −8; sleep disturbance, Δ = −15). Furthermore, treatment differences were not statistically or clinically significant in the chemotherapy cohort for vaginal discharge (Δ = 1), vaginal itching/irritation (Δ = 1), bone/joint pain (Δ = 2), coping (Δ = −2), and treatment burden (Δ = −3) in contrast to the cohort without prior chemotherapy (vaginal discharge, Δ = 7; vaginal itching/irritation, Δ = 6; bone/joint pain, Δ = −6; coping effort, Δ = −7; treatment burden, Δ = −12; each P < .01). Similarly, treatment differences between exemestane plus OFS and tamoxifen alone were less pronounced in the cohort with prior chemotherapy (Appendix Figs A2A and A2B, online only). No such pattern of treatment differences between the chemotherapy cohorts was observed at the intermediate- or long-term time points (Appendix Figs A2A and A2B).

Fig 5.

Change in quality-of-life (QoL) symptom and global indicator scores from baseline to 6 months according to chemotherapy cohorts (side by side). The vertical line at ± 8 indicates the minimal clinically meaningful change in QoL scores. The baseline scores for each indicator are summarized according to cohort and treatment in Table 2. OFS, ovarian function suppression.

DISCUSSION

In SOFT, patients reported considerable changes in key endocrine symptoms, with patients receiving tamoxifen plus OFS showing more detrimental effects than those receiving tamoxifen alone. Changes in global QoL domains were small with differences between the randomly assigned treatments being marginally clinical meaningful for treatment burden. Coping effort decreased slightly over time in both groups and may reflect patient adaptation.

Overall, these results correspond with our hypotheses and confirm previous findings.^6-8 In contrast to the E-3193 trial,⁸ we found that treatment differences for most endocrine symptoms diminished after 2 years and were no longer clinically meaningful at 5 years. At this time point, the average age was 48 years, and more women may have reached menopause. The differing proportions of patients who had OFS achieved by luteinizing hormone-releasing hormone analog (36% in E-3193; 81% in SOFT throughout treatment) and the absence of chemotherapy in E-3193 may explain the more pronounced treatment differences observed in E-3193 compared with SOFT. A subgroup analysis in E-3193 indicated slightly better patient-reported outcomes for these patients compared with those with surgically induced menopause.⁸ Direct comparison between the SOFT and the E-3193 patient-reported outcomes is complicated by the use of a summary score and the lack of consideration of clinically significant treatment differences for menopausal symptoms and sexual activity in E-3193. SOFT showed that the magnitudes of differences between treatments varied for individual symptoms, with vasomotor and sexual symptoms experienced as most burdensome, especially for patients on tamoxifen plus OFS. For gynecologic symptoms, changes over time and differences between treatments, even if statistically significant, were marginally clinically meaningful. However, 19% of patients in the total sample stopped tamoxifen, and 21% of patients discontinued triptorelin early.² A substantial minority of patients are expected to suffer from burdensome symptoms.²⁴ Women’s judgment of gains in survival that make endocrine treatment worthwhile varies considerably, and larger benefits are required to make it worthwhile compared with chemotherapy.^25,26 Our results provide a detailed picture of patients’ perception of individual symptoms over time and can facilitate the discussion of specific adverse effects between physicians and patients.

If the combination of OFS with an aromatase inhibitor is recommended⁹ for women at higher risk of recurrence, the benefit of exemestane plus OFS has to be balanced particularly with the detrimental effects of sexual problems, vaginal dryness, and bone and joint pains. On the basis of descriptive results, these symptoms were expressed substantially more often by patients receiving exemestane plus OFS compared with those receiving tamoxifen alone. Sexual problems are a serious concern considering that they persisted over the whole treatment period in all three treatment groups. Survivorship studies show that sexual dysfunction even continues beyond the treatment phase²⁷ and that younger women have higher rates of sexual dysfunction than expected in healthy women.²⁸

We observed a clinically relevant short-term impact of chemotherapy. The cohort with prior chemotherapy had worse baseline scores for responsive symptoms, possibly caused by chemotherapy and reflecting that half of these patients received tamoxifen before enrollment. Contrary to our expectation, chemotherapy did not exacerbate adverse effects. Differences between treatments in short-term symptom changes (eg, hot flushes, sleep disturbance, bone/joint pains), treatment burden, and coping effort were less pronounced or even statistically and clinically insignificant in patients who received prior chemotherapy. This confirms earlier findings that differential effects of endocrine treatments are seen primarily among patients who have not received chemotherapy.⁶

One limitation of our study is that 7% of participating centers were excluded for the QoL evaluation as a result of poor form submission rates, despite a pragmatic measurement approach based on linear analog self-assessment indicators as used in previous International Breast Cancer Study Group trials. Longitudinal QoL assessment in more than 500 centers worldwide is a challenge. Submission rates decreased over time, but overall, they were balanced between the randomly assigned treatments. Sensitivity analysis confirmed that results were robust to the analysis approach for missing data. Specific clinically relevant domains such as depression and sexual and cognitive functioning could not be addressed in detail but will be investigated in a subset of patients from SOFT and TEXT.

In conclusion, our results confirm the detrimental effect of adding OFS to tamoxifen on endocrine symptom burden. Compared with previous studies, we showed that the cumulative burden of OFS varied for individual symptoms. The effect of OFS on impaired symptom-specific QoL, treatment burden, and coping effort during the first 2 years of treatment was less pronounced for patients who received prior chemotherapy, the cohort that benefited most from OFS in terms of disease control.

Appendix

Suppression of Ovarian Function Trial Investigators and the International Breast Cancer Study Group Participants

Steering Committee: P.A. Francis (Chair, SOFT Co-Chair), G.F. Fleming (Suppression of Ovarian Function Trial [SOFT] Co-Chair), M.M. Regan (Trial Statistician), R. Torrisi, L. Blacher, H. Bonnefoi, E. Ciruelos, A.S. Coates, M. Colleoni, N. Dif, R.D. Gelber, A. Goldhirsch, T. Goulioti, T. Heckman-Scolese, A. Hiltbrunner, R. Kammler, R. Maibach, O. Ortmann, O. Pagani, E.A. Perez, K.N. Price, M. Rabaglio, B. Ruepp, K. Tryfonidis, K. Scott, H. Shaw, G. Viale, G. von Minckwitz, B.A. Walley, D. Zardavas, L. Cisar (Pfizer), E. Chetaille (Ipsen)

International Breast Cancer Study Group (IBCSG) Scientific Committee: A. Goldhirsch, A.S. Coates, M. Colleoni (Co-Chairs)

IBCSG Foundation Council: R. Stahl (President), S. Aebi, A.S. Coates, M. Colleoni, R.D. Gelber, A. Goldhirsch, M. Green, P. Karlsson, I. Kössler, I. Láng

IBCSG Coordinating Center, Bern, Switzerland: A. Hiltbrunner (Director), R. Kammler, R. Maibach, M. Rabaglio, S. Roux, B. Ruepp, P. Sicher

IBCSG Statistical Center, Dana-Farber Cancer Institute, Boston, MA: R.D. Gelber (Director), M.M. Regan (Group Statistician), J. Aldridge, M. Bonetti, Y. Feng, A. Giobbie-Hurder, K. Gray, H. Huang, W. Luo, K.N. Price, L. Zickl

IBCSG Data Management Center, Frontier Science and Technology Research Foundation, Amherst, NY: L. Blacher (Director), K. Scott (DM Section Head), M. Blackwell, A. Cesario, A. Dickinson, K. Donahue, M. Greco, P. Gonzalez, T. Heckman-Scolese, R. Hecker, R. Hinkle, M. Kalera, K. Lupejkis, A. Mora de Karausch, V. Palermo, H. Shaw, J. Swick-Jemison

IBCSG Central Pathology Office, European Institute of Oncology, Division of Pathology, Milan, Italy: G. Viale, D. Lepanto, O. Pala

IBCSG Quality of Life Office, Bern, Switzerland: J. Bernhard, K. Ribi

US National Cancer Institute (NCI): J. Abrams, J.A. Zujewski

US NCI Clinical Trials Support Unit (CTSU)/Westat: M. Hering, M. Greene, A. Nelson, M. Balois-Ouellette, S. Riordan

Almac: W. Mahon, E. Whitney, J. Bryant

CTSU Regulatory Office: R. Catalano, D. Marinucci, B. Niewood, R. Lambersky

Alliance (Cancer and Leukemia Group B) Pathology Coordinating Office, Ohio State University, Columbus, OH: W. Frankel, S. Jewell

Dana-Farber Cancer Institute, Boston, MA (US Food and Drug Administration Investigational New Drug): E.P. Winer, J. Savoie

Pfizer Study Support: B. Campanelli, J.A. Graham, B. Klingele

Ipsen Study Support: E. Chetaille, J. Amauri Soares, C. Descot, S. Hemont-Dacosta, F. Bismuth, P. Chevreau, H. Bibas

Participating Centers and Principal Investigators

Centers with accrual of more than one patient included in quality-of-life analysis.

IBCSG

Australia and New Zealand Breast Cancer Trials Group (ANZBCTG), Australia; Prof. John Forbes, Dianne Lindsay, Lauren Boyes.

Austin Health, Heidelberg, Victoria; J. Stewart

Ballarat Oncology and Haematology Services, Wendouree, Victoria; G. Kannourakis

Border Medical Oncology, Wodonga, Victoria; C. Underhill

Calvary Mater Newcastle, Waratah, New South Wales; A. van der Westhuizen

Canberra Hospital, The, Garran, Australian Capital Territory; A. Davis

Coffs Harbor Health Campus, Coffs Harbor, New South Wales; K. Briscoe

Concord Repatriation General Hospital, Concord, New South Wales; P. Beale

Launceston General Hospital, Launceston, Tasmania; S. Gauden

Liverpool Hospital, Liverpool, New South Wales; E. Moylan

Macarthur Cancer Therapy Centre, Campbelltown, New South Wales; S. Della-Fiorentina

Manning Rural Referral Hospital, Taree, New South Wales; E. Livshin

Maroondah Hospital, Ringwood East, Victoria; J. Chirgwin

Mater Hospital, The, North Sydney, New South Wales; F. Boyle

Monash Medical Centre, East Bentleigh, Victoria; M. White

Mount Hospital, Perth, Western Australia; A. Chan

Nambour Hospital, Nambour, Queensland; G. Hawson

Peter MacCallum Cancer Center, East Melbourne, Victoria; P.A. Francis

Riverina Cancer Care Centre, Wagga Wagga, New South Wales; J. Hill

Royal Adelaide Hospital, Adelaide, South Australia; P.G. Gill

Royal Brisbane and Women's Hospital, Herston, Queensland; M. Nottage

Royal Hobart Hospital, Hobart, Tasmania; D. Boadle

Royal Prince Alfred Hospital, Camperdown, New South Wales; J. Beith

St Andrews Toowoomba Hospital, Toowoomba, Queensland; P. Vasey

St John of God Hospital, Bunbury, Western Australia; M. Buck

St John of God Hospital, Subiaco, Western Australia; S. Ng

St Vincent’s Hospital, Fitzroy, Victoria; R. Snyder

St Vincent's Hospital, Darlinghurst, New South Wales; R. Epstein

Tweed Hospital, The, Tweed Heads, New South Wales; E. Abdi

Victorian Breast and Oncology Care, Melbourne, Victoria; M. Chipman

ANZBCTG, New Zealand.

Auckland City Hospital, Auckland; V.J. Harvey

Christchurch Hospital, Christchurch; B. Fitzharris

Waikato Hospital, Hamilton; I. Campbell

Brazil.

Hospital de Clinicas de Porto Alegre, Porto Alegre; J. Villanova Biazús

Grupo Oncológico Corporativo Chileno de Investigación (GOCCHI), Chile; A. Corvalan, B. Muller.

Instituto Nacional del Cancer, Santiago; R. Torres

Hospital San Juan de Dios, Santiago; S. Torres

Hospital San Borja Arriaran, Santiago; J. Letzkus

Hospital Clinico de la Universidad de Chile, Santiago; O. Barajas

Hospital Dr Sotero Del Rio, Santiago; H. Rojas

Centro De Patologia Mamaria, Santiago; M.E. Bravo

Hospital Base de Valdivia, Valdivia; B. Cardemil

Instituto De Radiomedicina, Vitacura; R. Baeza

India.

Tata Memorial Hospital, Mumbai; V. Parmar

Italy.

Centro di Riferimento Oncologico, Aviano; D. Crivellari

Azienda Sanitaria di Bolzano, Bolzano; C. Graiff

Ospedali Riuniti di Bergamo, Bergamo; C. Tondini

Ospedale degli Infermi, Biella; M. Clerico

Unita Operativa de Medicina Oncologica, Ospedale Ramazzini, Carpi; A. Fabrizio

Oncologia Medica Fano Italy, Fano; R. Mattioli

Ospedale Civile di Lecco, Lecco; M. Visini

Fondazione Salvatore Maugeri, Pavia; L. Pavesi

Ospedale di Circolo e Fondazione Macchi, Varese; G. Pinotti

Dipartimento di Oncologia, Azienda Ospedaliero-Universitaria di Udine, Udine; F. Puglisi

South Africa.

Sandton Oncology Centre, Johannesburg; D. Vorobiof

Sweden.

Sahlgrenska University Hospital, Gothenburg; P. Karlsson

Central Hospital Karlstad, Karlstad; B. Loden

Karolinska University Hospital, Stockholm; J. Bergh

Lund University Hospital, Lund; P. Malmström

Skaraborg Hospital Skovde, Skovde; A. Nissborg

Southern Elfsborg Hospital Boras, Boras; P. Karlsson

Swiss Association for Clinical Cancer Research (SAKK), Switzerland.

Centre Hospitalier Universitaire Vaudois, Lausanne; K. Zaman

Inselspital, Berne; M. Rabaglio

Kantonsspital St Gallen, St Gallen; T. Ruhstaller

Rätisches Kantonos/Regionalspital, Chur; R. von Moos

Kantonsspital Basel, Basel; C. Rochlitz

Onkologiezentrum Thun-Berner Oberland, Thun; D. Rauch

Oncocare Engeried, Bern; K. Buser

Zürich Frauenklinik, Zurich; N. Gabriel

Brust-Zentrum Zurich, Zurich; C. Rageth

Kantonsspital Aarau (AG), Aarau; A. Schoenenberger

Tumor Zentrum Hirslanden Klinik, Aarau; R. Popescu

Kantonsspital Baden, Baden; C. Caspar

Tumor und Brustzentrum Zetup St Gallen, St Gallen; H.J. Senn

SOLTI, Spain; E. Ciruelos

Hospital Clinic i Provincial de Barcelona, Barcelona; M. Muñoz

Hospital Universitari Vall D’Hebron, Barcelona; M. Bellet

Hospital Universitario 12 de Octubre, Madrid; E. Ciruelos

Centro Oncologico MD Anderson, Madrid; A. González Martín

Hospital Son Llatzer, Palma de Mallorca; J.G. Catalán

Clinica Univ. De Navarra, Pamplona; J.M. Aramendia

Hospital Son Dureta (Palma de Mallorca), Palma de Mallorca; J. Rifà

Hospital Santiago De Compostela, Santiago de Compostela; R. López

H.U. Arnau de Vilanova, Lleida; A. Llombart

Hospital Universitario Virgen Macarena, Sevilla; J.A. Virizuela

Hospital Clinico Universitario de Valencia, Valencia; A. Lluch

Hospital Sant Joan de Reus, Reus; M. Melé

Hospital Reina Sofia De Cordoba, Cordoba; J.R. de la Haba

Hospital Dr Negrin, Las Palmas de Gran Canari; Negrin; U. Bohn

Hospital Sant Pau i Santa Tecla, Tecla; C. Pérez Segura

Central and East European Oncology Group; J. Jassem

Poland.

Medical University of Gdansk, Gdansk, Poland; J. Jassem

Serbia.

Institute of Oncology and Radiology of Serbia, Belgrade, Serbia; Z. Neskovic-Konstantinovic

European Organisation for Research and Treatment of Cancer; N. Dif, J. Bogaerts, K. Tryfonidis

Belgium.

ZNA Middelheim, Antwerpen; A. Vandebroek

Cliniques Universitaires St-Luc UCL, Brussels; M. Berliere

U.Z. Gasthuisberg, Leuven; P. Neven

Centre Hospitalier Universitarie Sart Tilman, Liège; G. Jerusalem

Hopital De Jolimont, Haine St Paul; C. Mitine

Clinique Sainte Elisabeth, Namur; P. Vuylsteke

Algemeen Ziekenhuis Sint-Augustinus, Wilrijk; L. Dirix

France.

Centre Henri Becquerel, Rouen; C. Moldovan

Institut Claudius Regaud, Toulouse; B. de Lafontan

Institut Jean Godinot, Reims; C. Jouannaud

Centre Leon Berard, Lyon; T. Bachelot

Centre Georges Francois-Leclerc, Dijon; I. Desmoulins

Centre Rene Huguenin, Saint-Cloud; E. Brain

Institut Curie, Paris; J.Y. Pierga

Centre Eugene Marquis, Rennes; P. Kerbrat

Centre Hospitalier Régional Universitaire de Limoges, Limoges; N. Tubiana-Mathieu

Clinique Mutualiste de l’Estuaire, Saint-Nazaire; V. Delecroix

Clinique De L'alliance, Tours; A. Fignon

Israel.

Rambam Medical Center, Haifa; G. Fried

Netherlands.

Onze Lieve Vrouwe Gasthuis, Amsterdam; O. Leeksma

Portugal.

Centro de Lisboa, Lisboa; A. Moreira

Turkey.

Marmara University Hospital, Istanbul; F. Dane

German Breast Group; S. Buchholz, K. ReiβMüller, S. Loibl, G. Von Minckwitz

Praxis Dr Tessen, Goslar; H.W. Tessen

Universitätsfrauenklinik Erlangen, Erlangen; M.W. Beckmann

Klinikum Mittelbaden/Stadtklinik Baden-Baden, Baden-Baden; A. Hahn

Dr. Horst Schmidt Kliniken, Wiesbaden; F. Lorenz-Salehi

St. Vincentius Kliniken, Karlsruhe; O. Tomé

Caritas-Krankenhaus St Josef, Regensburg; S. Buchholz

Krankenhaus der Barmherzigen Brüder, Regensburg; H. Stauder

All Ireland Cooperative Oncology Research Group

Beaumont Hospital, Dublin; L. Grogan

Mater Misericordiae Hospital, Dublin; J. McCaffrey

Mater Private Hospital, Dublin; J. McCaffrey

University College Hospital Galway, Galway; M. Keane

South Infirmary-Victoria University Hospital, Cork; S. O’Reilly

Adelaide, Meath and National Children’s Hospital, Dublin; J. Walshe

Institute of Cancer Research–Clinical Trials and Statistics Unit on Behalf of the National Cancer Research Institute Breast Clinical Studies Group, United Kingdom; R. Coleman, J. Bliss, A. Gillman, N. Atkins

South Tyneside District Hospital, South Shields, Tyne & Wear; G. Mazdai

Weston Park Hospital, Sheffield, South Yorkshire; R. Coleman

Mount Vernon Hospital, Northwood, Middlesex; A. Makris

Luton & Dunstable Hospital, Luton; A. Makris

Clatterbridge Centre for Oncology, Wirral; S. O’Reilly

Great Western Hospital, Swindon; D. Cole

New Cross Hospital, Wolverhampton; M Churn

Aberdeen Royal Infirmary, Aberdeen; R. Todd

Royal Marsden Hospital–Fulham, London; I.E. Smith

Royal Marsden Hospital–Sutton, Surrey; I.E. Smith

York Hospital, York; J. Joji

St James Univ Hospital, Leeds; T. Perren

Harrogate District Hospital, Harrogate; J. Joji

Stepping Hill Hospital, Stockport; A. Chittalia

Russells Hall Hospital, Dudley; P. Ramachanara

North American Breast Cancer Group

American College of Surgeons Oncology Group (ACOSOG, now part of Alliance for Clinical Trials in Oncology)

Cancer and Leukemia Group B (CALGB, now part of Alliance for Clinical Trials in Oncology)

Eastern Cooperative Oncology Group (now part of ECOG-ACRIN Cancer Research Group); N. Davidson, V. Stearns, R.M. O’Regan, S. Gluck

National Cancer Institute of Canada Clinical Trials Group (NCIC CTG); K.I. Pritchard, T. Whelan, K. Gelmon, M. Webster

National Surgical Adjuvant Breast and Bowel Project (NSABP, now part of NRG Oncology)

North Central Cancer Treatment Group (NCCTG, now part of Alliance for Clinical Trials in Oncology); J.N. Ingle

Radiation Therapy Oncology Group (RTOG, now part of NRG Oncology)

Southwest Oncology Group; G.N. Hortobagyi, S. Martino, J.R. Gralow, A.F. Scott

North American Participating Centers

Canada.

Doctor H. Bliss Murphy Cancer Center, St John's, Newfoundland; J.S. McCarthy

BC Cancer Agency (BCCA)-Vancouver Cancer Center, Vancouver, British Columbia; H. Kennecke

Centre Hospitalier de l'Université de Montréal–Hotel Dieu du Montreal, Montreal, Quebec; A. Robidoux

Hôpital Du Sacre-Coeur de Montreal, Montreal, Quebec; J.A. Roy

Hôpital Charles LeMoyne, Greenfield Park, Quebec; C. Prady

Cancer Centre of Southeastern Ontario at Kingston General Hospital, Kingston, Ontario; V. Kumar

Ottawa Hospital Research Institute, Ottawa, Ontario; S.F. Dent

Thunder Bay Regional Health Science Centre, Thunder Bay, Ontario; D. Vergidis

Health Sciences North, Sudbury, Ontario; P.G. Lopez

Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, Ontario; R.G. Tozer

Odette Cancer Centre, Toronto, Ontario; K.I. Pritchard

London Regional Cancer Center, London, Ontario; K.R. Potvin

Cancercare Manitoba, Winnipeg, Manitoba; D. Grenier

Cross Cancer Institute, Edmonton, Alberta; K.S. Tonkin

Tom Baker Cancer Center, Calgary, Alberta; B.A. Walley (Chair), M. Webster (Primary Investigator)

BCCA Cancer Center for the Southern Interior, Kelowna, British Columbia; S. Ellard

BCCA-Fraser Valley Cancer Center, Surrey, British Columbia; G. K. Pansegrau

Allan Blair Cancer Centre, Regina, Saskatchewan; M. Salim

United States of America.

Providence Alaska Medical Center, Anchorage, AK; J.E. Anderson

University of California at Los Angeles (UCLA), Los Angeles, CA; P.A. Ganz

University of Southern California, Los Angeles, CA; C.A. Russel

Scripps Clinic–La Jolla, La Jolla, CA; J.F. Kroener

University of California San Diego Moores Cancer Center, San Diego, CA; B.A. Parker

John Muir Medical Center, Concord, CA; J.T. Ganey

Kaiser Permanente–Fremont, Fremont, CA; L. Fehrenbacher

Alta Bates Hospital, Berkeley, CA; D.H. Irwin

Kaiser Permanente Santa Teresa (San Jose), Vallejo, CA; L. Fehrenbacher

Mercy General Hospital, Carmichael, CA; M. Javeed

Kaiser Permanente-San Francisco, Vallejo, CA; L. Fehrenbacher

Santa Rosa Memorial Hospital, Santa Rosa, CA; I.C. Anderson

Stanford University Medical Center, Stanford, CA; I.L. Wapnir

Kaiser Permanente, San Diego, CA; J.A. Polikoff

Glendale Memorial Hospital and Health Center, Glendale, CA; G. Al-Jazayrly

Penrose-Saint Francis Healthcare, Colorado Springs, CO; E.R. Pajon

Front Range Cancer Specialists, Fort Collins, CO; D. Medgyesy

Longmont United Hospital, Longmont, CO; E.R. Pajon

The Shaw Regional Cancer Center, Aurora, CO; A.D. Elias

Greenwich Hospital, Greenwich, CT; B.J. Drucker

Norwalk Hospital, Norwalk, CT; R.C. Frank

Eastern Connecticut Hematology and Oncology Associates, Norwich, CT; K. Jagathambal

Northwest Connecticut Oncology–Hematology Associates, Torrington, CT; D.S. Brandt

Georgetown University Hospital, Washington, DC; C. Isaacs

Washington Hospital Center, Washington, DC; A. Aggarwal

Sibley Memorial Hospital, Washington, DC; F. Barr

Christiana Healthcare Services–Christian Hospital, Newark, DE; D.D. Biggs

Mount Sinai Medical Center Community Clinical Oncology Program (CCOP), Miami Beach, FL; M.A. Schwartz

Holy Cross Hospital, Fort Lauderdale, FL; R.C. Lilenbaum

Sarasota Memorial Hospital, Sarasota, FL

Dekalb Medical Center, Atlanta, GA; T.E. Seay

Emory University, Atlanta, GA; R.M. O’Regan

Memorial Health University Medical Center, Savannah, GA; H.C. Lebos

Atlanta Regional CCOP, Atlanta, GA; T.E. Seay

Augusta Oncology Associates, Augusta, GA; M.R. Keaton

Mercy Medical Center–North Iowa, Mason City, IA; W.W. Bate

Medical Associates Clinic, Professional Corporation, Dubuque, IA; C. Holm

Loyola University Medical Center, Maywood, IL; K.S. Albain

University of Chicago, Chicago, IL; H.L. Kindler

St Anthony Medical Center, Rockford, IL; R.E. Nora

Decatur Memorial Hospital, Decatur, IL; J.L. Wade

Memorial Medical Center, Springfield, IL; J.L. Wade

Ingalls Memorial Hospital, Harvey, IL; M.F. Kozloff

Carle Cancer Center CCOP, Urbana, IL; K.M. Rowland

Community Regional Cancer Care North, Indianapolis, IN; R. Walling

Indiana University Medical Center, Indianapolis, IN; K.D. Miller

Fort Wayne Medical Oncology/Hematology Incorporated, Fort Wayne, IN; S.R. Nattam

Northern Indiana Consortium, South Bend, IN; R.H. Ansari

Via Christi Regional Medical Center, Wichita, KS; S.R. Dakhil

Louisiana State University, Shreveport, LA; G.M. Mills

Tufts Medical Center, Boston, MA; J.K. Erban

Massachusetts General Hospital, Boston, MA; H.J. Burstein

Dana-Farber Cancer Institute, Boston, MA; H.J. Burstein

Beth Israel Deaconess Medical Center, Boston, MA; H.J. Burstein

North Shore Cancer Center, Salem, MA; K.J. Krag

Suburban Hospital, Bethesda, MD; C.B. Hendricks

Johns Hopkins University, Baltimore, MD; A.C. Wolff

Anne Arundel Medical Center, Annapolis, MD; S.P. Watkins

Kaiser Permanente–Shady Grove Medical Center, Rockville, MD; L.C. Hwang

Eastern Maine Medical Center, Bangor, ME; H.M. Segal

Mercy Hospital, Portland, ME; R.C. Inhorn

William Beaumont Hospital, Royal Oak, MI; D. Zakalik

University of Michigan Medical Center, Ann Arbor, MI; A.F. Schott

Mid-Michigan Medical Center, Midland, MI; M.R. Hurtubise

Regions Hospital, Minneapolis, MN; D.J. Schneider

United Hospital, St Paul, MN; P.J. Flynn

Duluth Clinic, Duluth, MN; R.J. Dalton

Mayo Clinic, Rochester, MN; J.N. Ingle

Saint Francis Regional Medical Center, Shakopee, MN; D.J. Schneider

Washington University School of Medicine, St Louis, MO; M.J. Naughton

Saint John's Regional Health Center, Springfield, MO; J.W. Goodwin

Missouri Baptist Medical Center, Saint Louis, MO; A.P. Lyss

Montana Cancer Consortium CCOP, Billings, MT; B.T. Marchello

University of North Carolina, Chapel Hill, NC; T.C. Shea

Mission Hospitals, Asheville, NC; M.J. Messino

Forsyth Memorial Hospital, Winston-Salem, NC; J.O. Hopkins

Northeast Medical Center, Concord, NC; J.G. Wall

Hope, A Women's Cancer Center, Asheville, NC; D.J. Hertzel

Altru Hospital, Grand Forks, ND; T. Dentchev

Elliot Hospital, Manchester, NH; D. Weckstein

Dartmouth Hitchcock Medical Center, Lebanon, NH; P.A. Kaufman

Saint Barnabas Medical Center, Livingston, NJ; R.A. Michaelson

Cooper Hospital University Medical Center, Newark, NJ; D.D. Biggs

Cancer Institute of New Jersey, New Brunswick, NJ; D.L. Toppmeyer

Cancer Institute of New Jersey at Hamilton, Trenton, NJ; D.L. Toppmeyer

University of Nevada at Reno Washoe Medical Center, Reno, NV

Saint Vincent's Hospital and Medical Center of New York, New York, NY; P. Klein

Memorial Sloan-Kettering Cancer Center, New York, NY; C.A. Hudis

Weill Medical College of Cornell University, New York, NY; J. Leonard

Staten Island University Hospital, Staten Island, NY; M. Odaimi

Albert Einstein College/Medicine, Bronx, NY; C.M. Pellegrino

Montefiore Medical Center, Bronx, NY; C.M. Pellegrino

North Shore University Hospital, Manhasset, NY; D.R. Budman

Brookdale Hospital Medical Center, Brooklyn, NY; M.R. Kalavar

Roswell Park Cancer Institute, Buffalo, NY; E.G. Levine

Ohio State University Hospital, Columbus, OH; C.D. Bloomfield

Cleveland Clinic Foundation, Cleveland, OH; G.T. Budd

Case Western Reserve University, Cleveland, OH; P. Silverman

Fairview Hospital, Cleveland, OH; G.T. Budd

Aultman Hospital, Canton, OH; J.A. Schmotzer

Samaritan North Health Center, Dayton, OH; H.M. Gross

Lima Memorial Hospital, Toledo, OH; P.L. Schaefer

Cleveland Clinic Wooster Specialty Center, Wooster, OH; G.T. Budd

Kaiser Permanente, Portland, OR; N.R. Tirumali

Allegheny Cancer Center Network, Pittsburgh, PA; N. Wolmark

University of Pittsburgh, Pittsburgh, PA; A.M. Brufsky

Lancaster General Hospital, Lancaster, PA; R.J. Gottlieb

Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA; S.M. Domchek

Fox Chase Cancer Center, Philadelphia, PA; L.J. Goldstein

Chester County Hospital, West Chester, PA; W.E. Luginbuhl

St Mary Regional Cancer Center, Langhorne, PA; R.E. Reilly

Abington Memorial Hospital, Abington, PA; W.G. Andrews

Scranton Hematology Oncology, Scranton, PA; M. Hyzinski

Rhode Island Hospital, Providence, RI; W.M. Sikov

Women's and Infants Hospital, Providence, RI; D.S. Dizon

Sioux Valley Clinic–Oncology, Sioux Falls, SD; M.A. Mazurczak

Erlanger Medical Center, Chattanooga, TN; L.L. Schlabach

Jones Clinic, Germantown, TN; B.A. Mullins

Presbyterian Hospital of Dallas, Dallas, TX; J.F. Strauss

The University of Texas MD Anderson Cancer Center, Houston, TX; M.C. Green

Baylor College of Medicine, Houston, TX; R.M. Elledge

Doctor's Hospital of Laredo, Laredo, TX; G.W. Unzeitig

University of Vermont, Burlington, VT; S. Burdette-Radoux

Swedish Hospital Medical Center, Seattle, WA; S.E. Rivkin

Southwest Washington Medical Center, Vancouver, WA; K.S. Lanier

University of Wisconsin, Madison, WI; J.A. Stewart

Saint Vincent Hospital, Green Bay, WI; T.J. Saphner

Midelfort Clinic, Eau Claire, WI; G.S. Nambudiri

Green Bay Oncology LTD at Saint Mary's Hospital, Green Bay, WI; T.J. Saphner

Marshall University Medical Center, Huntington, WV; M.R.B. Tria Tirona

Fig A1.

Change of symptom and global quality-of-life (QoL) indicator scores from baseline to 6, 24, and 60 months, according to treatment assignment, for the three treatment assignments in the Suppression of Ovarian Function Trial, overall across chemotherapy cohorts. The vertical line at ± 8 indicates the minimal clinically meaningful change in QoL scores. E, exemestane; OFS, ovarian function suppression; T, tamoxifen.

Fig A2.

(A) Change of symptom and global quality-of-life (QoL) indicator scores from baseline to 6, 24, and 60 months, according to treatment assignment, for the three treatment assignments in the no prior chemotherapy cohort in the Suppression of Ovarian Function Trial (SOFT) trial. (B) Change of symptom and global QoL indicator scores from baseline to 6, 24, and 60 months, according to treatment assignment, for the three treatment assignments in the prior chemotherapy cohort in SOFT trial. The vertical line at ± 8 indicates the minimal clinically meaningful change in QoL scores. E, exemestane; OFS, ovarian function suppression; T, tamoxifen.

Table A1.

Differences between treatment groups in changes of symptom and global indicators from baseline

Quality of Life/symptom indicator	Estimated Difference between Treatment Groups (T+OFS minus T)
	6 months				24 months				60 months
	Mean	95% LCL	95% UCL	P-value	Mean	95% LCL	95% UCL	P-value	Mean	95% LCL	95% UCL	P-value
Symptom indicators
Hot flushes	−29	−33	−26	<.0001	−15	−19	−11	<.0001	−4	−9	0	.057
Sweats (incl. night sweats	−23	−26	−19	<.0001	−9	−13	−6	<.0001	−3	−7	1	.12
Vaginal discharge	4	1	7	.0027	3	1	6	.017	1	−2	4	.50
Vaginal dryness	−5	−8	−2	.00055	−6	−9	−3	.00038	−6	−10	−2	.0030
Vaginal itching/irritation	4	1	6	.0053	3	0	6	.044	−1	−4	2	.61
Loss of sexual interest	−8	−11	−4	<.0001	−3	−7	0	.056	−3	−7	1	.16
Difficulties in becoming aroused	−6	−10	−3	.00016	−4	−8	−0	.029	0	−4	5	.88
Bone or joint pain	−2	−5	1	.19	−1	−4	2	.55	5	1	9	.0081
Headaches	−1	−4	1	.26	1	−2	3	.65	−1	−5	2	.42
Appetite	−1	−3	2	.65	−0	−3	2	.92	−1	−4	2	.55
Feeling sick (nausea/vomiting)	−0	−3	2	.74	−0	−3	2	.70	−0	−3	2	.84
Sleep disturbance	−11	−14	−8	<.0001	−2	−5	1	.17	−0	−4	4	.91
Tiredness	1	−2	4	.58	0	−3	3	.89	4	0	8	.028
Troubled by weight gain	−3	−6	0	.066	−4	−7	−0	.033	−0	−4	4	.90
Being irritable	0	−2	3	.86	−1	−4	2	.54	−1	−4	3	.67
Feeling dizzy	−1	−3	2	.56	−0	−2	2	.89	0	−3	3	.97
Global indicators
Physical well-being	−2	−4	1	.17	−1	−4	1	.40	2	−1	6	.17
Mood	−1	−3	2	.69	−0	−3	3	.90	2	−1	5	.29
Coping effort	−4	−7	−2	.00073	−3	−6	−1	.015	−2	−5	2	.31
Treatment burden	−8	−10	−5	<.0001	−4	−7	−1	.0057	−1	−4	3	.72
Health perception	−2	−5	−0	.024	−1	−3	2	.54	1	−1	4	.32

NOTE. Mean < 0 indicates T+OFS had greater worsening than T alone. Mean differences between treatment groups, 95% CIs and Wald P values were estimated with mixed-models contrasts for testing the differences versus zero at short- (6 months), intermediate- (24 months) and long-term (60 months). Some zeroes appear as (-0) because of rounding.

Abbreviations: LCL, lower confidence limit; OFS, ovarian function suppression; T, tamoxifen; UCL, upper confidence limit.

AUTHOR CONTRIBUTIONS

Conception and design: Karin Ribi, Jürg Bernhard, Prudence A. Francis, Harold J. Burstein, Marco Colleoni, Alan S. Coates, Aron Goldhirsch, Richard D. Gelber, Gini F. Fleming

Administrative support: Karen N. Price

Provision of study materials or patients: Prudence A. Francis, Harold J. Burstein, Eva Ciruelos, Meritxell Bellet, Lorenzo Pavesi, Ana Lluch, Marilena Visini, Vani Parmar, Carlo Tondini, Pierre Kerbrat, Antonia Perelló, Patrick Neven, Roberto Torres, Davide Lombardi, Fabio Puglisi, Per Karlsson, Thomas Ruhstaller, Gini F. Fleming

Collection and assembly of data: Prudence A. Francis, Harold J. Burstein, Eva Ciruelos, Meritxell Bellet, Lorenzo Pavesi, Ana Lluch, Marilena Visini, Vani Parmar, Carlo Tondini, Pierre Kerbrat, Antonia Perelló, Patrick Neven, Roberto Torres, Davide Lombardi, Fabio Puglisi, Per Karlsson, Thomas Ruhstaller, Meredith M. Regan, Gini F. Fleming

Data analysis and interpretation: Karin Ribi, Weixiu Luo, Jürg Bernhard, Alan S. Coates, Karen N. Price, Richard D. Gelber, Meredith M. Regan

Manuscript writing: All authors

Final approval of manuscript: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Adjuvant Tamoxifen Plus Ovarian Function Suppression Versus Tamoxifen Alone in Premenopausal Women With Early Breast Cancer: Patient-Reported Outcomes in the Suppression of Ovarian Function Trial

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.

Karin Ribi

No relationship to disclose

Weixiu Luo

No relationship to disclose

Jürg Bernhard

No relationship to disclose

Prudence A. Francis

Travel, Accommodations, Expenses: Roche

Other Relationship: Pfizer

Harold J. Burstein

No relationship to disclose

Eva Ciruelos

No relationship to disclose

Meritxell Bellet

Honoraria: AstraZeneca

Consulting or Advisory Role: AstraZeneca

Lorenzo Pavesi

No relationship to disclose

Ana Lluch

Consulting or Advisory Role: Novartis, Roche, Pfizer

Marilena Visini

No relationship to disclose

Vani Parmar

No relationship to disclose

Carlo Tondini

No relationship to disclose

Pierre Kerbrat

No relationship to disclose

Antonia Perelló

No relationship to disclose

Patrick Neven

No relationship to disclose

Roberto Torres

Research Funding: Roche, GlaxoSmithKline

Travel, Accommodations, Expenses: Sanofi

Davide Lombardi

No relationship to disclose

Fabio Puglisi

No relationship to disclose

Per Karlsson

No relationship to disclose

Thomas Ruhstaller

Consulting or Advisory Role: Roche, AstraZeneca

Marco Colleoni

Honoraria: Novartis

Consulting or Advisory Role: Boehringer Ingelheim, Taiho Pharmaceutical, AbbVie, AstraZeneca, Pierre Fabre, Pfizer

Alan S. Coates

No relationship to disclose

Aron Goldhirsch

No relationship to disclose

Karen N. Price

No relationship to disclose

Richard D. Gelber

Research Funding: AstraZeneca (Inst), GlaxoSmithKline (Inst), Novartis (Inst), Roche (Inst), Celgene (Inst), Merck (Inst), Pfizer (Inst)

Meredith M. Regan

Research Funding: Veridex (Inst), OncoGenex (Inst), Pfizer (Inst), Ipsen (Inst), Novartis (Inst), Merck (Inst), Ferring (Inst), Celgene (Inst), AstraZeneca (Inst)

Gini F. Fleming

Research Funding: Corcept Therapeutics (Inst)

Other Relationship: Aeterna Zentaris