Health-related quality of life in 2nd-line endocrine therapy for patients with acquired endocrine-resistantpostmenopausal ER-positive, HER2-negative metastatic breast cancer: the HORSE-BC study

PO133Yuichiro Kikawa1, Kentaro Sakamaki2, Tomomi Fujisawa3, Kazuhiro Araki3,4, Takayuki Iwamoto5, Takafumi Sangai6, Tadahiko Shien5, Shintaro Takao7,
Reiki Nishimura8, Masato Takahashi9, Tatsuya Toyama10, Tomohiko Aihara11, Hirofumi Mukai12, Naruto Taira5
1Department of Breast Surgery, Kobe City Medical Center General Hospital ,2School of Data Science, Yokohama City University , 3Department of Breast Oncology, Gunma Prefectural Cancer Center, 4Department of Breast and Endocrine Surgery, Hyogo College of Medicine,Comprehensive Support
Project For OncologicalResearch of Breast Cancer

5Department of Breast and Endocrine Surgery, Okayama University Hospital, 6Department of Breast and Thyroid Surgery, Chiba University Hospital, 7Department of Breast Surgery, Hyogo Cancer Center, 8Department of Breast Oncology, Kumamoto Shinto General Hospital,
9Department of Breast Surgery, NHO Hokkaido Cancer Center, 10Department of Breast Surgery, Nagoya City University Hospital, 11Breast Center, Aihara Hospital, 12Department of Breast and Medical Oncology, National Cancer Center Hospital East

Table 3. MIDs by Distribution-based method

BackgroundAlpha◼ Maintaining health-related quality of life (HR-QOL) is one of the most important outcomes for metastatic breast cancer (MBC)
patients.
◼ Endocrine therapy (ET) is often chosen as the upfront treatment option instead of chemotherapy for estrogen receptor-positive
patients.
◼ HORSE-BC, a multicenter cohort study (UMIN ID: 000019556), previously demonstrated that 2nd-line ET for MBC patients withacquired endocrine resistance still provided a clinically meaningful benefit (presented by Araki at SABCS 2018).
◼ The HR-QOL in the HORSE-BC was investigated in this study.

Study Objectives◼ To evaluate HR-QOL and the endocrine symptoms found in the endocrine less-sensitive MBC patients during second line ET.
◼ To investigate the minimally important differences (MIDs) of FACT-ES score.
◼ To investigate the correlation between the clinical benefit and HR-QOL.

Methods
Figure 1. Study DesignKey Inclusion Criteria

Registration• ER-positive breast cancer.
• Postmenopausal status.
• Stage IV or progression /recurrence advanced
breast cancer.
• Planned endocrine therapy for advanced
breast cancer.
• ECOG performance status of 0 or 1.
• Previous endocrine therapy with any
endocrine drugs.
• Definition of Endocrine Sensitivity✓ “Low-sensitivity” : recurrence within 5-year
during adjuvant ET, or progression within
9-month of initial ET for MBC.
✓ “Very low-sensitivity” : recurrence within
2-year during adjuvant ET, or progression
within 3-month of initial ET for MBC.
• No previous chemotherapy for advanced
breast cancer.
• Chemotherapy given as peri-operative
adjuvant therapy completed at 6 months
before this study.

2nd-line Endocrine therapy decided by
the attending physician and patient
Primary Endpoint
Clinical Benefit rate
Tumors were assessed by computed tomography or any
imaging methods according to RECIST version 1.1 atbaseline, 3 and 6 months after initiation of secondary
endocrine therapy.

Secondary Endpoints
Safety (CTCAE ver.4.0)
HR-QOL (FACT-G, FACT-B, FACT-ES)

HR-QOL Assessment
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◼

◼
◼
◼

HR-QOL was assessed at baseline, 1 month, and 3 months after initiation of 2nd-line ET using the Japanese version ofthe Functional Assessment of Cancer Therapy (FACT)-General (G), Breast (B) and FACT-Endocrine Symptom (ES).
The FACT-B is a 36-item questionnaire that measures general HR-QOL associated with cancer using 27 items in FACTG [7 for physical well-being (PWB), 7 for social and family well-being (SFWB), 6 for emotional well-being (EWB), and 7for functional well-being (FWB)] and has 9 more items on the breast cancer subscale (BCS) that are more specific towomen with breast cancer.
The ES was designed for use with the FACT-B and comprises 18 items, with a maximum possible score of 72.
The FACT-B Trial Outcome Index (TOI) scores is the sum of scores from PWB, FWB, and BCS. A total of 23 items
contribute to the FACT-B TOI, resulting in a maximum possible score of 92. The FACT-ES TOI is the sum of scores fromPWB, FWB, and ES of which the maximum score is 108. TOI is often used as the main outcome index of HR-QOL.
Each item or question on the FACT-B and ES has response choices ranging from 0 (‘‘not at all’’) to 4 (‘‘very much’’) andthe higher scores indicate a better HR-QOL.

Subjective Significant Questionnaire (SSQ)◼ Six questions corresponding to PWB, SFWB, EWB, FWB, ES, and ES-total score in order to identify the MIDs.
◼ SSQs are the seven grade Likert scale and written as follows:
Since you decided to participate in this study,A) your physical condition is…
B) your social or relationship with your familial people are…
C) your anxious things are….
D) your social activities are…
E) your menopausal symptoms are…..
F) your general health status is….
◼ The choices after each question are as follows:
1, very much better; 2, moderately better; 3, a little better; 4, about the same; 5, a little worse; 6, moderately worse;
7, very much worse

Analyses◼ The means and standard deviations (SDs) of scores for FACT-G, FACT-B and FACT-ES at the time of enrollment and after 1
and 3 months of 2nd-line ET were calculated.
◼ MIDs based on the Distribution Method✓ 1/3 and1/2 SDs were defined as the small and moderate MIDs for the distribution based method (Eton et al., J Clin
Epidemiol, 2004).
✓ The standard error of measurement (SEM) for the HR-QOL scores was calculated across all time points. The SEM isused as the minimal detectable change and was approximately equal to the MID (Wyrwich et al., Med Care, 1999).
✓ The SEM was computed as σx (1-relx)1/2, where σx is the SD of the scale and relx is the reliability (internal consistency)of the scale.
✓ Cronbach alpha coefficients were calculated as the internal consistency of the scale.
◼ MIDs based on the Anchor Method✓ Differences of the change in HR-QOL between categories in six questions of the SSQs (Osoba et al., J Clin Oncol,
1998) were calculated for the anchor based method (Eton et al., J Clin Epidemiol, 2004).
◼ Missing values were systematically deleted and not included in the analyses.

Results
Table 1. Patients characteristics at baseline (n=47)
Value
Employment status at baseline
Age, years
Mean (SD)Median (range)

65.7 (9.0)
66 (41-88)

ECOG PS012
2nd line Endocrine Treatment
Letrozole
Tamoxifen
Tremifene
Fulvestrant

39 (83.0%)
7 (14.9%)
1 (2.1%) Annual household income

Martial Status

Alone
With husband
With children
With parents
OtherNothing
15 (31.9%)
Hypertension 16 (34.0%)
Diabetes
6 (12.8%)
Mellitus
Hyperlipidemia 7 (14.9%)
Other
12 (25.5%)
missing
1 (2.1%)18 (38.3%)
7 (14.9%)
15 (31.9%)
1 (2.1%)4 (8.5%)2 (4.3%)

Table 2. HRQOL scores after 1 month and 3 months of 2nd line ET
Variable
FACT-G total score (range: 0 -108)
FACT-B total score (range: 0 -148)
FACT-B TOI(range: 0 - 96)
FACT-ES total score (range: 0 - 180)
FACT-ES TOI(range: 0 - 128)

13 (27.7%)
20 (42.6%)
12 (25.5%)
4 (8.5%)4 (8.5%)

Comorbidity (multiple answersallowed)

Employment status before
diagnosis of breast cancer
Full time
Part time
Homemaker
Volunteer
Retired
Unemployed

Baseline (n=47)
Mean (SD)75.11 (14.68)
97.71 (16.91)
64.13 (11.64)
138.00 (17.75)
104.43 (12.75)

0.85
0.84
0.90
-FACT-B total score (FACT-G + BCS)
Baseline
1 mo
3 mo
Baseline to 1 moBaseline to 3 mo
Mean

0.85
0.84
0.89
-FACT-B TOI (PWB+FWB+BCS)
Baseline
1 mo
3 mo
Baseline to 1 moBaseline to 3 mo
Mean

0.82
0.83
0.86
-

FACT-ES total score (FACT-G + ES)
Baseline
1 mo
3 mo
Baseline to 1 moBaseline to 3 mo
Mean

0.84
0.85
0.90
-

FACT-ES TOI (PWB+FWB+ES)
Baseline
1 mo
3 mo
Baseline to 1 moBaseline to 3 mo
Mean

0.82
0.85
0.88
-

(*n=44 for FACT-B TOI and ES TOI at 1month)

After 1 month (n=43*)
Mean (SD)74.94 (13.83)
97.81 (15.72)
64.64 (11.28)
136.08 (16.74)
104.68 (13.04)

After 3 months(n=43*)
Mean (SD)74.59 (16.15)
97.36 (18.64)
63.57 (12.80)
137.41 (19.99)
103.63 (14.53)

1/2SD

SEM

4.89
4.61
5.38
3.53
2.57
4.20

7.34
6.92
8.08
5.30
3.88
6.30

5.69
5.53
5.11

5.63
5.24
6.21
3.36
2.68
4.63

8.46
7.86
9.32
5.05
4.02
6.94

6.55
6.29
6.18

3.88
3.76
4.27
1.92
2.37
3.34

5.82
5.64
6.40
2.88
3.55
4.86

4.94
4.65
4.79

5.91
5.58
6.66
3.71
3.23
5.02

8.88
8.37
10.00
5.57
4.85
7.53

7.10
6.48
6.32

4.25
4.35
4.84
2.27
2.91
3.72

6.38
6.52
7.27
3.41
4.37
5.59

5.41
5.05
5.03

5.44

6.34

4.79

6.63

5.16

Table 4a. MID of PWB by Anchor-based method
Change in PWB
Mean SD
Diff
Change in SSQ (A) at 1 month
Improved (n= 9)
1.61 4.83
Stable (n= 29)-0.30 2.59
Declined (n=5 )-4.60 3.65
(Improved↔Stable)
1.91(Stable↔Declined)
4.30

Table 4b. MID of SFWB by Anchor-based method
Change in SFWB
Mean SD
Diff
Change in SSQ (B) at 1 month
Improved (n=8)
7.74 7.11
Stable (n=34)-3.18 9.62
Declined (n=0)
NENE(Improved↔Stable)
10.92(Stable↔Declined)NE

Change in SSQ (A) at 3 months
Improved (n=9)
Stable (n=27)
Declined (n=3)(Improved↔Stable)(Stable↔Declined)

Change in SSQ (B) at 3 months
Improved (n=8)
Stable (n=32)
Declined (n=0)(Improved↔Stable)(Stable↔Declined)

3.11
-0.68
-0.67

3.48
2.51
0.58
3.79
-0.01

5.60
0.22
NE

7.02
7.41
NE
5.38
NE

Table 4c. MID of EWB by Anchor-based method
Change in EWB
Mean SDDiff
Change in SSQ (C) at 1 month
Improved (n=9)
0.89 1.90
Stable (n=29)
0.12 2.33
Declined (n=5)-2.40 4.98
(Improved↔Stable)
0.77(Stable↔Declined)
2.52

Table 4d. MID of FWB by Anchor-based method
Change in FWB
Mean SD
Diff
Change in SSQ (D) at 1 month
Improved (n=2)
3.00 1.41
Stable (n=39)
0.67 3.34
Declined (n=1)-5.00
NE(Improved↔Stable)
2.33(Stable↔Declined)
5.67

Change in SSQ (C) at 3 months
Improved (n=9)
Stable (n=26)
Declined (n=5)(Improved↔Stable)(Stable↔Declined)

Change in SSQ (D) at 3 months
Improved (n=2)
Stable (n=37)
Declined (n=0)(Improved↔Stable)(Stable↔Declined)

0.00
1.35
1.00

3.35
3.19
3.39
-1.35
0.35

3.5
0.24
NE

2.12
3.73
NE
3.26
NE

Table 4e. MID of ES by Anchor-based method
Change in ES
Mean SD
Diff
Change in SSQ (E) at 1 month
Improved (n=2)
3.00 4.24
Stable (n=38)
-0.36
4.6
Declined (n=2)
-2.5
6.36
(Improved↔Stable)
3.36(Stable↔Declined)
2.14

Table 4f. MID of FACT-ES by Anchor-based method
Change in FACT-ES
Mean SD
Diff
Change in SSQ (overall QOL) at 1 month
Improved (n=10)
2.68 10.20
Stable (n=27)-1.88 10.46
Declined (n=4)-9.45 12.16(Improved↔Stable)
4.56(Stable↔Declined)
7.57

Change in SSQ (E) at 3 months
Improved (n=2)
Stable (n=35)
Declined (n=2)(Improved↔Stable)(Stable↔Declined)

1.31
1.19

Change in SSQ (overall QOL) at 3 months
Improved (n=9)-1.05
Stable (n=27)
1.65
Declined (n=2)
1.33(Improved↔Stable)(Stable↔Declined)

2.34
1.66

Change in SSQ (overall QOL) (pooled)
Improved (n=19)
Stable (n=54)
Declined (n=6)(Improved↔Stable)(Stable↔Declined)

Change in SSQ (E) (pooled)
Improved (n=4)
Stable (n=73)
Declined (n=4)(Improved↔Stable)(Stable↔Declined)

1.50
0.19
-1.00

2.12
6.49
4.24

2.25
-0.09
-1.75

9.26
10
4.71
-2.70
0.32

0.91
-0.12
-5.86
1.03
5.74

Figure 2. FACT-ES mean score changes from baseline3

n=22, +2.39
n=20, +1.50

21―Clinical benefit +―Clinical benefit -0-1-2
n=23, -3.75-3Living situation (multipleanswers allowed)

Highest level of education
Compulsoryschool
5 (10.6%)
education
High school
31 (66.0%)
university level
10 (21.3%)
or abovemissing
1 (2.1%)4 (8.5%)10 (21.3%)
15 (31.9%)
1 (2.1%)3 (6.4%)14 (29.8%)

3,000,000 yen
23 (48.9%)
or less
3,000,00010 (21.3%)
5,000,000 yen
5,000,0006 (12.8%)
10,000,000
10,000,000
2 (4.3%)yen or more
missing
6 (12.8%)

1 (2.0%)3 (6.1%)1 (2.1%)39 (83.0%)

Married or with23 (48.9%)
partner
Never Married 5 (10.6%)
Separated or
11 (23.4%)
divorced
Widowed8 (17.0%)

Full time
Part time
Homemaker
Volunteer
Retired
Unemployed

FACT-G total score (PWB+SWB+EWB+FWB)
Baseline
1 mo3 moBaseline to 1 moBaseline to 3 mo
MeanCriterion
1/3SDn=21, -1.79-4-5

baseline

1 month

3 months

Conclusions◼ MIDs of FACT-G and FACT-B from the distribution-based method were almost the same as the previous report (Eton et al., J Clin
Epidemiol, 2004).
◼ MID in FACT-ES scores were inconsistent between the distribution-based method and the anchor-based method in this population.
◼ Regarding the deterioration, a 5-8 point decline may be the MIDs of FACT-ES score from the results of the pooled anchor-based
method and the distribution-based method.
◼ Maintaining HR-QOL within 3 months as determined by FACT-ES may be correlated with a clinical benefit in patients withacquired endocrine-resistant MBC treated with ET.

Acknowledgment
To all of the patients who participated in HORSE-BC and their families​
To the investigators and research coordinators and CSPOR-BC.​
The research fund was provided to CSPOR-BC by AstraZeneca under the study contract. All decisions concerning the planning,implementation and publication of this study were made by the executive committee of this study.​

Yuichiro Kikawa, MD., e-mail: bj.u1ro@gmail.com Clinical trial Registration Information : UMIN (http://www.umin.ac.jp/) Study ID:000019556