Original Article
`
`Health-Related Quality of Life of Patients With Advanced
`Breast Cancer Treated With Everolimus Plus Exemestane
`Versus Placebo Plus Exemestane in the Phase 3, Randomized,
`Controlled, BOLERO-2 Trial
`
`Howard A. Burris, III, MD1; Fabienne Lebrun, MD2; Hope S. Rugo, MD3; J. Thaddeus Beck, MD4; Martine Piccart, MD, PhD2;
`Patrick Neven, MD, PhD5; Jose Baselga, MD, PhD6; Katarina Petrakova, PhD7; Gabriel N. Hortobagyi, MD8;
`Anna Komorowski, MD9; Edmond Chouinard, MD10; Robyn Young, MD11; Michael Gnant, MD12; Kathleen I. Pritchard, MD13;
`Lee Bennett, MS14; Jean-Francois Ricci, PhD15; Hounayda Bauly, PhD16; Tetiana Taran, MD17;
`Tarek Sahmoud, MD, PhD17; and Shinzaburo Noguchi, MD18
`
`BACKGROUND: The randomized, controlled BOLERO-2 (Breast Cancer Trials of Oral Everolimus) trial demonstrated significantly
`improved progression-free survival with the use of everolimus plus exemestane (EVEþ EXE) versus placebo plus exemestane
`(PBO þ EXE) in patients with advanced breast cancer who developed disease progression after treatment with nonsteroidal aroma-
`tase inhibitors. This analysis investigated the treatment effects on health-related quality of life (HRQOL). METHODS: Using the
`European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) question-
`naire, HRQOL was assessed at baseline and every 6 weeks thereafter until disease progression and/or treatment discontinuation. The
`30 items in 15 subscales of the QLQ-C30 include global health status wherein higher scores (range, 0-100) indicate better HRQOL.
`This analysis included a protocol-specified time to definitive deterioration (TDD) analysis at a 5% decrease in HRQOL versus baseline,
`with no subsequent increase above this threshold. The authors report additional sensitivity analyses using 10-point minimal important
`difference decreases in the global health status score versus baseline. Treatment arms were compared using the stratified log-rank
`test and Cox proportional hazards model adjusted for trial stratum (visceral metastases, previous hormone sensitivity), age, sex, race,
`baseline global health status score and Eastern Cooperative Oncology Group performance status, prognostic risk factors, and treat-
`ment history. RESULTS: Baseline global health status scores were found to be similar between treatment groups (64.7 vs 65.3). The
`median TDD in HRQOL was 8.3 months with EVEþ EXE versus 5.8 months with PBO þ EXE (hazard ratio, 0.74; P¼.0084). At the 10-
`point minimal important difference, the median TDD with EVEþ EXE was 11.7 months versus 8.4 months with PBO þ EXE (hazard ratio,
`0.80; P¼.1017). CONCLUSIONS: In patients with advanced breast cancer who develop disease progression after treatment with non-
`steroidal aromatase inhibitors, EVEþ EXE was associated with a longer TDD in global HRQOL versus PBOþ EXE. Cancer
`2013;119:1908–15. VC 2013 American Cancer Society.
`
`KEYWORDS: advanced breast cancer, everolimus, exemestane, health-related quality of life, hormone receptor-positive.
`
`INTRODUCTION
`Everolimus (EVE) is a mammalian target of rapamycin inhibitor with direct anticancer effects. In preclinical and clinical
`studies, EVE demonstrated that mammalian target of rapamycin inhibition can enhance the efficacy of endocrine therapy,
`including exemestane (EXE).1-3 The phase 3 BOLERO-2 (Breast Cancer Trials of Oral Everolimus) trial was designed to
`evaluate the efficacy and safety of EVEþ EXE versus placebo (PBO)þ EXE in postmenopausal women with hormone
`
`Corresponding author: Howard A. Burris, III, MD, Sarah Cannon Research Institute, 3322 West End Ave, Suite 900, Nashville, TN 37203; Fax: (615) 340-1576;
`howard.burris@scresearch.net
`
`1Drug Development Program, Sarah Cannon Research Institute, Nashville, Tennessee; 2Department of Medicine, Institute Jules Bordet, University Libre Brussels,
`Brussels, Belgium; 3Division of Hematology and Oncology, University of California at San Francisco Helen Diller Family Comprehensive Cancer Center, San Fran-
`cisco, California; 4Highlands Oncology Group, Fayetteville, Arkansas; 5Department of Gynecologic Oncology, Multidisciplinary Breast Centre, University Hospitals
`Leuven, Leuven, Belgium; 6Solid Tumor Breast Department, Memorial Sloan-Kettering Cancer Center, New York, New York; 7Department of Medical Oncology, Ma-
`saryk Memorial Cancer Institute, Brno, Czech Republic; 8Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston,
`Texas; 9Hematology Oncology Associates of Rockland, Nyack, New York; 10Department of Medical Oncology, Cambridge Memorial Hospital, Cambridge, Ontario,
`Canada; 11Breast Cancer Center of Excellence, The Center for Cancer and Blood Disorders, Fort Worth, Texas; 12Department of Surgery, Comprehensive Cancer
`Center, Medical University of Vienna, Vienna, Austria; 13Department of Oncology, Sunnybrook Odette Cancer Centre and the University of Toronto, Toronto, On-
`tario, Canada; 14RTI Health Solutions, Research Triangle Park, North Carolina; 15Wellmera AG, Basel, Switzerland; 16Novartis Pharma AG, Basel, Switzerland; 17Novar-
`tis Pharmaceuticals Corporation, East Hanover, New Jersey; 18Department of Breast and Endocrine Surgery, Osaka University, Osaka, Japan
`
`We thank Marithea Goberville, PhD, ProEd Communications, Inc, for medical editorial assistance with this article.
`
`Previously presented in abstract form as Beck JT, Rugo HS, Burris HA, et al. BOLERO-2: health-related quality of life in metastatic breast cancer patients treated
`with everolimus and exemestane versus exemestane. Presented at the 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago, IL
`[abstract]. J Clin Oncol. 2012;30(suppl). Abstract 539.
`
`DOI: 10.1002/cncr.28010, Received: October 30, 2012; Revised: December 5, 2012; Accepted: December 26, 2012, Published online February 15, 2013 in Wiley
`Online Library (wileyonlinelibrary.com)
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`receptor-positive advanced breast cancer who developed
`disease progression after treatment with nonsteroidal
`aromatase inhibitors (NSAIs; letrozole or anastrozole).4
`Data from an interim analysis at 7 months of follow-up
`demonstrated that EVEþ EXE significantly improved
`the primary endpoint of progression-free survival (PFS)
`versus PBOþ EXE (hazard ratio [HR], 0.43; P < .001)
`based on local investigator assessment.4 Median durations
`of PFS were 6.9 months and 2.8 months, respectively.
`The PFS benefit was confirmed at 12.5 months and 18
`months of median follow-up.5,6 Adverse events were con-
`sistent with the safety profile of EVE.6 The findings from
`this trial supported the recent approval in the United
`States and Europe of EVEþ EXE for the treatment of
`postmenopausal women with hormone receptor-positive
`advanced breast cancer who developed disease progression
`while receiving treatment with NSAIs.7,8
`Treatment-related toxicities combined with often
`painful and debilitating metastases resulting from disease
`progression can erode health-related quality of
`life
`(HRQOL).9-12 Therefore, in addition to clinical benefit,
`providing palliation and maximizing HRQOL remain the
`key goals of treating patients with advanced breast can-
`cer.13 Studies of HRQOL can aid in treatment selection
`and provide information regarding the impact of disease
`progression on patients’ lives.14,15 Furthermore, evalua-
`tion of HRQOL concerns such as fatigue, pain, and anxi-
`ety, as well as the impact of disease on physical and social
`functioning, can augment the overall risk:benefit analysis,
`and HRQOL is now regarded as an important outcome
`in clinical cancer trials.14,16,17 These outcomes are espe-
`cially important in patients with hormone receptor-posi-
`tive advanced breast cancer, in whom endocrine therapy
`options after disease progression with NSAI treatment
`(eg, fulvestrant and EXE) might provide limited therapeu-
`tic benefit, but have relatively low toxicity.18 In the BO-
`LERO-2 trial, time to HRQOL deterioration was a
`secondary objective because it was essential to determine
`the impact of EVEþ EXE versus PBOþ EXE on
`HRQOL. In the current study, we report the results of
`that HRQOL analysis.
`
`MATERIALS AND METHODS
`Patients and Study Design
`The study design for BOLERO-2 has been described
`previously.4 The population comprised postmenopausal
`women with hormone receptor-positive, human epider-
`mal growth factor receptor-2 (HER2)–negative, meta-
`static or locally advanced breast cancer who developed
`
`QOL in Advanced Breast Cancer/Burris et al
`
`disease progression despite prior treatment with anastro-
`zole or letrozole. All patients provided informed consent.
`In this multicenter, double-blind,
`randomized,
`placebo-controlled trial, all patients received EXE (at a
`dose of 25 mg/day) and were randomized 2:1 to treatment
`with EVE (at a dose of 10 mg/day) or matching PBO.4
`Randomization was stratified by the presence of visceral
`metastasis (yes vs no) and sensitivity to prior hormonal
`therapy (yes vs no).4 Treatment continued until disease
`progression, the development of unacceptable toxicity, or
`withdrawal of patient consent.
`The primary endpoint was PFS, as assessed by inves-
`tigators. Overall survival, overall response rate, clinical
`benefit rate, time to deterioration of Eastern Cooperative
`Oncology Group (ECOG) performance status, safety,
`and HRQOL were secondary endpoints. This analysis
`includes HRQOL outcomes; the results of all other end-
`points have been reported previously.5,6
`
`HRQOL Assessment
`HRQOL was evaluated at baseline and every 6 weeks
`thereafter until disease progression and/or discontinua-
`tion using version 3.0 of the European Organisation for
`Research and Treatment of Cancer Quality of Life Ques-
`tionnaire-Core 30 (EORTC QLQ-C30). All question-
`naires were completed at the study center before disease
`assessment. The questionnaire consists of 30 items
`arranged in 15 subscales, including a global health status/
`QOL scale; higher scores for this scale (range, 0-100) indi-
`cate better HRQOL.19
`
`Statistical Analysis
`All HRQOL analyses were performed on the full analysis
`set (N¼ 724). Partially completed questionnaires were
`included if the data were sufficient to calculate the global
`health status/QOL domain subscale score. A deterioration
`event was defined as a 5% decrease in HRQOL relative to
`baseline. Protocol-specified time to definitive deteriora-
`tion (TDD) in the global health status score was defined
`as a 5% HRQOL decrease relative to baseline, with no
`subsequent
`increase above this
`threshold. The ‘‘5%
`decrease in HRQOL from baseline’’ criterion was selected
`based on previously established thresholds for minimal
`important differences (MID) in QOL from the perspec-
`tive of the patient.20 This criterion for TDD was less strin-
`gent than previously published MID values for global
`health status.21-23 Generally established and accepted
`MID values for global health status range from 5 to 10
`points. Therefore, a sensitivity analysis was performed to
`assess the larger, 10-point MID decrease in global health
`status score compared with baseline; this criterion has been
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`TABLE 1. ECOG Performance Status
`EVEþEXE, % (n ¼ 485)
`PBOþEXE, % (n ¼ 239)
`
`Score
`
`0
`1
`2
`
`60
`36
`2
`
`59
`35
`3
`
`Abbreviations: ECOG, Eastern Cooperative Oncology Group; EVE, everoli-
`mus; EXE, exemestane; PBO, placebo.
`Reprinted with permission from Baselga J, Campone M, Piccart M, et al.
`Everolimus in postmenopausal hormone-receptor-positive advanced breast
`cancer. N Engl J Med. 2012;366:520-529. Copyright VC 2011 Massachusetts
`Medical Society. Reprinted with permission from the Massachusetts Medi-
`cal Society.4
`
`validated for EORTC QLQ-C30 in other studies.21-23
`TDD in global health status for each of the definitions was
`calculated using Kaplan-Meier estimates and was described
`using medians and 95% confidence intervals (95% CIs).
`TDD was compared between the treatment groups using a
`stratified log-rank test (strata were based on the presence of
`visceral metastases and sensitivity to hormonal therapy)
`with a 2-sided type I error rate of 0.05, and a multivariate
`Cox proportional hazards model adjusted for trial strata
`(the presence of visceral metastases and sensitivity to hor-
`mone therapy), age, sex, race, baseline score and ECOG
`performance status, prognostic risk factors, and treatment
`history. If a definitive deterioration event was observed after
`missing assessments, the event was backdated to the first of
`the missing assessments before the deterioration (ie, calcu-
`lated as the last available assessment before the definitive
`deterioration plus 8 weeks). No other adjustments were
`made for missing data. Patients who had no definitive dete-
`rioration events were censored at the time of the last avail-
`able assessment. All analyses were conducted using SAS
`statistical software for Windows (version 9.2; SAS Institute
`Inc, Cary, NC).
`
`RESULTS
`Patient Characteristics and Disposition
`Between June 2009 and January 2011, 724 women across
`189 centers in 24 countries were randomized to study
`treatments (485 in the EVEþ EXE arm and 239 in the
`PBOþ EXE arm).4 The treatment arms were well bal-
`anced for patient and disease characteristics, including
`ECOG performance status score.4 Notably, the majority
`of patients in both the EVEþ EXE and PBOþ EXE
`treatment arms had an ECOG performance status score
`of 0 (60% vs 59%, respectively) (Table 1).
`At a median follow-up of 18 months, 91 patients
`continued to receive study treatment: 81 (17%) in the
`EVEþ EXE arm and 10 (4%) in the PBOþ EXE arm.6
`
`The median duration of treatment exposure was 23.9
`weeks
`for EVE and 29.5 weeks
`for EXE in the
`EVEþ EXE arm and 13.4 weeks for PBO and 14.1 weeks
`for EXE in the PBOþ EXE arm. Most patients in the
`EVEþ EXE and PBOþ EXE treatment arms discontin-
`ued treatment because of disease progression (62% vs
`89%, respectively). Other reasons for discontinuation
`included adverse events (10% vs 3%, respectively) and
`consent withdrawal (9% vs 3%, respectively).
`
`Efficacy and Safety
`Data from a preplanned analysis at a median follow-up
`of 18 months demonstrated that EVEþ EXE more
`than doubled PFS versus PBOþ EXE.6 However,
`EVEþ EXE was associated with a higher incidence of
`adverse events than PBOþ EXE, with the most com-
`mon grade 3 or 4 adverse events (graded using the NCI
`CTCAE version 3.0) being stomatitis, hyperglycemia,
`and fatigue.6
`
`Questionnaire Completion Rates
`At baseline, questionnaires were completed by 455
`patients (93.8%) in the EVEþ EXE arm and 224 patients
`(93.7%) in the PBOþ EXE arm. Data are presented
`through 48 weeks only, given a substantial decrease in
`subsequent data availability in both treatment arms.
`Questionnaire compliance was > 80% through week 48
`and was not found to be markedly different between the
`treatment arms (Fig. 1a). Questionnaire completion rates
`decreased from baseline to week 48 (Fig. 1b), mainly
`because of disease progression and subsequent removal
`from the study. Compared with baseline, completion rates
`from weeks 12 through 48 were higher in the EVEþ EXE
`arm versus the PBOþ EXE arm (Fig. 1b).
`
`TDD in Global Health Status
`Baseline global health status scores were similar between
`the EVEþ EXE and PBOþ EXE arms (64.7 vs 65.3,
`respectively; difference, 0.7 [95% CI, 4.3 to 3.0]).
`At a median follow-up of 18 months, the cumula-
`tive percentages of patients with a definitive deteriora-
`tion in global health status treated with EVEþ EXE
`versus PBOþ EXE were comparable for both TDD def-
`initions (Table 2). At a 5% change from baseline, 49%
`of patients in the EVEþ EXE arm versus 44% of
`patients in the PBOþ EXE arm had a definitive deterio-
`ration event, and death occurred in 3% of patients in
`each treatment arm. At a 10-point MID, definitive dete-
`rioration rates were 39% in the EVEþ EXE arm versus
`30% in the PBOþ EXE arm, and death rates were 3%
`and 5%, respectively.
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`QOL in Advanced Breast Cancer/Burris et al
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`Figure 2. Time to definitive deterioration (TDD) for European
`Organisation for Research and Treatment of Cancer Quality
`of Life Questionnaire-Core 30 (EORTC QLQ-C30) global
`health status is shown, indicating a 5% change from baseline.
`HR indicates hazard ratio; 95% CI, 95% confidence interval;
`EVE, everolimus; EXE, exemestane; PBO, placebo; QOL,
`quality of life.
`
`Figure 1. The European Organisation for Research and Treat-
`ment of Cancer Quality of Life Questionnaire-Core 30
`(EORTC QLQ-C30) global health status questionnaire results
`for (a) compliance and (b) completion rates at baseline and
`follow-up visits are shown. (a) Percentage compliance rates
`were calculated based on the number of on-study patients in
`each treatment arm at every visit. (b) Percentage completion
`rates were calculated based on the intent-to-treat population
`in each treatment arm. EVE indicates everolimus; EXE,
`exemestane; PBO, placebo.
`
`At 5% change from baseline, EVEþ EXE was associ-
`ated with longer TDD in global health status versus
`PBOþ EXE. The median TDD was 8.3 months (95% CI,
`7.0 months-9.7 months) in the EVEþ EXE arm versus
`5.8 months (95% CI, 4.2 months-7.2 months) in the
`PBOþ EXE arm (Fig. 2). This translated into a 26%
`reduction in the risk of definitive deterioration with
`EVEþ EXE (HR, 0.74; 95% CI, 0.58-0.95 [P¼ .0084 by
`the log-rank test]). Using the 10-point MID, the median
`TDD remained longer in the EVEþ EXE arm versus the
`PBOþ EXE arm (11.7 months [95% CI, 9.7 months-
`13.3 months] vs 8.4 months [95% CI, 6.6 months-12.5
`months], respectively) (HR, 0.8; 95% CI, 0.61-1.06
`[P¼ .1017 by the log-rank test]) (Fig. 3). The P value for
`TDD using a 5% change from baseline was found to be
`more significant than the P value for TDD using a 10-
`point MID (.0084 vs .1017, respectively), although the
`magnitudes of effect in terms of HR and difference in
`
`Figure 3. Time to definitive deterioration (TDD) for European
`Organisation for Research and Treatment of Cancer Quality
`of Life Questionnaire-Core 30 (EORTC QLQ-C30) global
`health status is shown, with a minimal important difference of
`10. HR indicates hazard ratio; 95% CI, 95% confidence inter-
`val; EVE, everolimus; EXE, exemestane; PBO, placebo; QOL,
`quality of life.
`
`TDD were similar. This may be because of the number of
`patients for whom censoring was greater based on the 10-
`point MID criteria for TDD.
`Regardless of the definition used (a 5% change from
`baseline or a 10-point MID), no statistically significant
`differences were observed with regard to the TDD of
`global health status for the majority of the prospectively
`defined patient-related and disease-related variables
`(Fig. 4); 1 exception was baseline ECOG performance sta-
`tus: in the overall trial, patients with a baseline ECOG
`performance status of 1 or 2 were found to have an
`increased risk of deterioration in global health status ver-
`sus patients with a baseline performance status of 0.
`In addition, TDD of global health status was ana-
`lyzed for subsets defined by baseline ECOG performance
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`Original Article
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`Figure 4. Risk of definitive deterioration in European Organisation for Research and Treatment of Cancer Quality of Life Ques-
`tionnaire-Core 30 (EORTC QLQ-C30) global health status (GHS) by subgroups is shown, based on a 5% change from baseline
`and a 10-point minimal important difference (MID). Only patients with a valid baseline score were included, and only extended
`model data were reported. The hazard ratios (HRs) represent multiplicative increases in the risk of definitive deterioration per 1-
`unit increase in age or GHS. EVE, everolimus; EXE, exemestane; PBO, placebo; mets, metastases; ECOG PS, Eastern Cooperative
`Oncology Group performance status; PgR, progesterone receptor; 95% CI, 95% confidence interval.
`
`status (0 vs 1-2) and age (< 65 years vs  65 years).
`Kaplan-Meier estimates indicated a longer median TDD
`for EVEþ EXE versus PBOþ EXE by both definitions in
`patients with an ECOG performance status of 1 or 2 (5%
`change from baseline: 8.2 months vs 4.1 months
`[P¼ .0076]; 10-point MID: 9.7 months vs 6.0 months
`[P¼ .0342]) and in patients aged < 65 years (5% change
`from baseline: 9.6 months vs 5.6 months [P¼ .0130]; 10-
`
`point MID: 12.5 months vs 9.7 months [P¼ .0353]).
`Cox proportional hazards models adjusted for study strata
`(the presence of visceral metastases and sensitivity to
`hormone therapy) also demonstrated a longer median
`TDD for EVEþ EXE versus PBOþ EXE in patients
`with an ECOG performance status of 1 or 2 (5% change
`from baseline: HR, 0.58 [95% CI, 0.41-0.84]; 10-point
`MID: HR, 0.61 [95% CI, 0.41-0.91]) and in those aged
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`TABLE 2. Definitive Deterioration in EORTC QLQ-C30 Global Health Status
`
`Characteristic
`
`Definition of Definitive Deterioration
`
`5% Change From Baseline
`EVEþEXE (n ¼ 485)
`PBOþEXE (n ¼ 239)
`
`MID¼10
`EVEþEXE (n ¼ 485)
`PBOþEXE (n ¼ 239)
`
`Deterioration event, no. (%)
`Definitive deterioration
`Death
`Censored, no. (%)
`Median TDD (95% CI), mo
`P
`
`254 (52)
`240 (49)
`14 (3)
`231 (48)
`8.3 (7.0-9.7)
`.0084
`
`113 (47)
`105 (44)
`8 (3)
`126 (53)
`5.8 (4.2-7.2)
`
`202 (42)
`188 (39)
`14 (3)
`283 (58)
`11.7 (9.7-13.3)
`.1017
`
`84 (35)
`71 (30)
`13 (5)
`155 (65)
`8.4 (6.6-12.5)
`
`Abbreviations: 95% CI, 95% confidence interval; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Question-
`naire-Core 30; EVE, everolimus; EXE, exemestane; MID, minimal important difference; PBO, placebo; TDD, time to definitive deterioration.
`
`< 65 years (5% change from baseline: HR, 0.70 [95% CI,
`0.52-0.93]; 10-point MID: HR, 0.70 [95% CI, 0.50-
`0.98]). No differences in the median TDD were observed
`between treatment groups by either analysis method in
`patients with an ECOG performance status of 0 or those
`aged  65 years.
`
`DISCUSSION
`The current study assessed the effects of treatment with
`EVEþ EXE versus PBOþ EXE on patients’ HRQOL
`using the EORTC QLQ-C30, which is one of the most
`common and well-developed/validated instruments for
`measuring HRQOL in oncology trials.15,24 The EORTC
`QLQ-C30 global health status scores were analyzed based
`on 2 definitions of TDD: a protocol-specified 5% change
`from baseline and a MID of a 10-point change from base-
`line that was found to be relevant in other cancer popula-
`tions.21 With the 5% change from baseline, the TDD of
`global health status was found to be prolonged in patients
`who received EVEþ EXE versus
`those
`receiving
`PBOþ EXE (8.3 months vs 5.8 months, respectively;
`P¼ .0084). Using the 10-point MID assessment, the dif-
`in TDD between the EVEþ EXE and
`ference
`PBOþ EXE arms (11.7 months vs 8.4 months, respec-
`tively; P¼ .1017) was of a magnitude similar to that
`observed with the 5% TDD analysis, with more profound
`benefits noted in patients with a baseline ECOG perform-
`ance status of 1 or 2 and those aged < 65 years. Unad-
`justed cumulative definitive deterioration event rates were
`slightly higher in the EVEþ EXE treatment arm versus
`the PBOþ EXE arm, although the TDD of global health
`status was longer with EVEþ EXE. This is likely because
`of the earlier occurrence of disease progression in patients
`treated with PBOþ EXE compared with those receiving
`EVEþ EXE, and the resultant
`longer
`follow-up of
`patients in the EVEþ EXE arm. Together, these results
`indicate that, at a minimum, adding EVE to EXE does
`
`not have a deleterious effect on HRQOL versus the use of
`PBOþ EXE in patients with hormone receptor-positive
`advanced breast cancer who develop disease progression
`after initial treatment with NSAIs.
`The improvement in the TDD of global health
`status with EVEþ EXE was demonstrated despite a
`higher incidence of grade 3 or 4 toxicities and discontinu-
`ations because of adverse events reported in this treatment
`arm.6 Therefore, it is possible that other factors, such as
`clinical benefit, may have contributed to this longer TDD
`noted in global health status in the EVEþ EXE arm. In
`the BOLERO-2 trial, at a median follow-up of 18
`months, EVEþ EXE more than doubled the median
`PFS6 and resulted in higher clinical benefit rates com-
`pared with PBOþ EXE.5 Furthermore,
`lower overall
`mortality rates were reported in the EVEþ EXE treat-
`ment arm versus the PBOþ EXE arm; this difference
`was not
`statistically significant and mature survival
`data were still awaited at the time of last follow-up.6
`In addition, at a median follow-up of 18 months, the
`EVEþ EXE treatment arm was associated with much
`lower discontinuation rates because of disease progres-
`sion (62% vs 89%), and a greater percentage of
`patients in this arm were still receiving treatment at
`the time of last follow-up (17% vs 4%).6 Protocol-
`defined adverse event management strategies may also
`have helped limit HRQOL deterioration.25 In contrast
`to these
`findings,
`although second-line
`endocrine
`therapies such as EXE and fulvestrant have not been
`associated with worsening HRQOL,
`to the best of
`our knowledge they have provided only limited clini-
`cal efficacy in the advanced breast cancer setting after
`NSAI therapy. These observations suggest that signifi-
`cantly improved clinical efficacy outcomes may have
`positively impacted HRQOL in the EVEþEXE arm
`despite higher incidence of grade 3 or 4 toxicities
`observed with EVEþEXE.
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`Original Article
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`As with most HRQOL studies, a limitation of the
`current study is the number of missing questionnaires.
`Although compliance with questionnaire completion was
`high (> 80%) in both treatment arms, data availability
`decreased over time because of study discontinuations
`subsequent to progressive disease (because HRQOL was
`not assessed after disease progression). Patients who did
`not meet definitive deterioration criteria before disease
`progression were censored. Given that a greater percent-
`age of patients developed disease progression earlier in the
`PBOþ EXE arm compared with the EVEþ EXE arm,
`and that HRQOL typically deteriorates after disease pro-
`gression,26 this analysis is likely conservative in terms of
`the benefit of EVEþ EXE.
`Although effective treatments for breast cancer are
`expected to maintain or improve the patient’s HRQOL, as
`has been demonstrated with EVEþ EXE in the current
`study, mixed effects on HRQOL have been observed in the
`setting of advanced breast cancer.27 Some studies investigat-
`ing combined targeted therapies (eg, lapatinib plus trastuzu-
`mab vs lapatinib alone) reported small, nonsignificant
`HRQOL benefits,28 but these effects are inconsistent. In
`other studies, adverse events attributable to breast cancer
`treatment (such as the TEX [epirubicin, paclitaxel, and
`capecitabine]
`regimen) had a detrimental
`impact on
`HRQOL.29 Symptom clusters such as pain, fatigue, insom-
`nia, and mood disturbances are prevalent in patients after
`cancer treatment, particularly chemotherapy and radiother-
`apy, and can adversely affect QOL and functional status.30
`In addition, decreases in QOL may also be exacerbated by
`the route of administration of chemotherapy,31 as well as
`the dose intensity of the regimen.32 Time-to-progression or
`PFS benefits observed with the addition of targeted agents
`to chemotherapy and/or endocrine therapy (eg, capecitabine
`or letrozole plus lapatinib vs either treatment alone) gener-
`ally have neutral effects at best on QOL,14,33 most likely
`because the delay in disease progression is offset by an
`increased burden of adverse events. Given that HRQOL
`might also be prognostic in women with metastatic breast
`cancer,34,35 it is essential to take into account the potential
`negative effects of treatment on HRQOL, and the HRQOL
`data from BOLERO-2 are reassuring in this context.
`In the BOLERO-2 trial, postmenopausal women
`with hormone receptor-positive advanced breast cancer
`who developed disease progression after initial treatment
`with NSAI and then received the all-oral combination of
`EVEþ EXE experienced a longer TDD in their global
`HRQOL than those in the PBOþ EXE treatment arm.
`This was particularly evident in younger patients and
`those with a reduced ECOG performance status at base-
`
`line. Together with significant improvements in clinical
`efficacy outcomes, these HRQOL findings provide added
`support for the benefit of EVEþ EXE in this patient
`population.
`
`FUNDING SUPPORT
`Financial support for medical editorial assistance was
`provided by Novartis Pharmaceuticals Corporation.
`
`CONFLICT OF INTEREST DISCLOSURES
`Dr. Baselga has acted as a consultant for Novartis. Dr. Bauly is
`an employee of Novartis. Mr. Bennett has been employed by
`Novartis as a contracted analyst while an employee of RTI
`Health Solutions. Dr. Chouinard has received research support
`and advisory board honoraria from Novartis. Dr. Gnant has
`acted as a consultant for Novartis and Merrion and as a member
`of the advisory board for Novartis, AstraZeneca, GlaxoSmith-
`Kline, and Amgen and has
`received research funding from
`Roche, Sanofi-Aventis, GlaxoSmithKline, Novartis, and AstraZe-
`neca. Dr. Hortobagyi is a member of the BOLERO-2 steering
`committee and has received research support, honoraria, and
`reimbursements from Novartis. Dr. Noguchi has received grant
`support
`from AstraZeneca, Bristol-Myers Squibb, Chugai,
`GlaxoSmithKline, Novartis, Pfizer, Sanofi-Aventis, and Takeda
`and honoraria from AstraZeneca, Chugai, GlaxoSmithKline,
`Novartis, Pfizer, Sanofi-Aventis, and Takeda. Dr. Piccart has
`received support from Novartis. Dr. Pritchard has acted as a
`consultant for Sanofi-Aventis, AstraZeneca, Roche, Pfizer, Ortho
`Biotech, YM Biosciences, Amgen, GlaxoSmithKline, and Novar-
`tis; has received research funding (directly or indirectly) from
`the National Cancer Institute of Canada Clinical Trials Group
`and contracted with AstraZeneca, YM Biosciences, Bristol-Myers
`Squibb, Sanofi-Aventis, Amgen, Ortho Biotech, Pfizer, Glaxo-
`SmithKline, and Novartis; and received honoraria from Sanofi-
`Aventis, AstraZeneca, Pfizer, Roche, GlaxoSmithKline, Amgen,
`and Novartis. She has also provided paid expert testimony for
`Sanofi-Aventis and AstraZeneca and been a member of the advi-
`sory boards of Sanofi-Aventis, AstraZeneca, Ortho Biotech,
`Roche, Pfizer, Novartis, GlaxoSmithKline, Amgen, and Bayer
`Schering Pharma. Dr. Ricci has acted as a consultant for Novar-
`tis. Dr. Rugo has received research support
`from Novartis,
`Pfizer, and Merck. Drs. Sahmoud and Taran are employees of
`Novartis. Dr. Young has acted as a member of the Speakers’ Bu-
`reau for Celgene and Bristol-Myers Squibb.
`
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