P4-13-09 Sequential 2nd Line Endocrine Therapies Is Still Effective Strategy for Endocrine Less Sensitive
Postmenopausal ER+ and HER2- Advanced Breast Cancer Patients
Kazuhiro Araki1, Tomomi Fujisawa2, Kentaro Sakamaki3, Yuichiro Kikawa4, Takayuki Iwamoto5, Takafumi Sangai6, Tadahiko Shien5, Shintaro Takao7, Reiki Nishimura8, Masato Takahashi9, Tomohiko Aihara10, Hirofumi Mukai11, Naruto Taira 5
1. Hyogo College of Medicine, 2. Gunma Prefectural Cancer Center, 3. The University of Tokyo, 4. Kobe City Medical Center General Hospital, 5. Okayama University Hospital, 6. Chiba University Hospital, 7. Hyogo Cancer Center, 8. Kumamoto Shinto General Hospital, 9. Hokkaido Cancer Center, 10. Aihara Hospital, 11. National Cancer Center Hospital East.

RESULTSBACKGROUND
 Several classification models for sensitivity and resistance to endocrine
therapies have been proposed for the clinical course associated with initialendocrine therapy.
 Although endocrine therapy remains a foundation of treatment for hormone
receptor-positive advanced breast cancer in the era of current moleculartargeted drug, it has been unclear how to choose sequential strategy during theclinical course in terms of endocrine responsiveness.

OBJECTIVES Endpoint: To evaluate the efficacy and safety of secondary endocrine therapy
among estrogen receptor (ER)-positive, and human epidermal growth receptor(HER) 2-negative postmenopausal metastatic breast cancer patients who had(very) low sensitivity to initial endocrine therapy.

METHODS
Study Design and Patientsdetermines to be unsuitable for A multicenter observational cohort
participation in this study.
study (HormOnal therapy ResiStant 4. Statistical Hypothesis
Estrogen receptor-positive Breast
5. To achieve the primary objective,cancer Cohort: HORSE-BC) was
clinical benefit rates (CBR: defined as
performed for 2nd-line treatment ofpatients (pts) who achieved CR or PR
physician and patient preference.
or SD for 24 weeks) were expectedMajor Inclusion Criteria
50%, the null hypothesis that a CBR
1. ER-positive breast cancer.
is 30 % was tested at one-sided alpha2. Postmenopausal status.
of 5%.
3. Stage IV or progression /recurrence 6. 90% confidence intervals (CIs) wereadvanced breast cancer.
calculated in relation with hypothesis
4. Planned endocrine therapy fortests.
advanced breast cancer.
Efficacy and Safety Measures
5. ECOG performance status of 0 or 1. 1. Tumors were assessed by computed
6. Previous endocrine therapy with any
tomography or any imaging methods
endocrine drugs.
according to RECIST version 1.1 at
7. Definition of Endocrine Sensitivity
baseline, 3 and 6 months after
a. “Low-sensitivity” : recurrence within
initiation of secondary endocrine
5-year during adjuvant ET, ortherapy.
progression within 9-month of initial 2. Adverse events were graded for
ET for ABC.
severity according to the Nationalb. “Very low-sensitivity” : recurrence
Cancer Institute Common Terminology
within 2-year during adjuvant ET, or
Criteria version 4.0.
progression within 3-month of initial 3. Medical treatment and examination of
ET for ABC.
subjects in this study is conducted
8. No previous chemotherapy forwithin the normal range of regularadvanced breast cancer.
clinical practice. Therefore, the risk of
9. Chemotherapy given as peri-operative
adverse events in subjects who
adjuvant therapy completed at 6participate in this study is similar tomonths before this study.
that in regular clinical practice. ForMajor Exclusion Criteria
this reason, information about
1. HER2-positive breast cancer.
adverse events of Grade 2 or milder is
2. Endocrine therapy must be
not collected in this study.
inappropriate.
3. Any patients that a physician
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Table 1. Characteristics of the Patients
Characteristic
February 2016 to January
Registered patients2017
Eligible patients
Ineligible patients

Number(%)

56

10049787.5
12.5
Median(range)
66 (41-88)
23.4(16.4-31.9)
（%）
100
20.4
16.3
63.3
83.7
14.3
2.0
4.1
18.4
22.5
14.3
8.2
14.3
16.3
2.0
89.8
10.2
49.0
51.0
69.4
30.6
75.5
24.5
85.7
14.3
51.0
49.0
63.3
36.7

Mean (SD）Age (years)

65.8 (8.9)

Body Mass Index (kg/sqm)

23.9 (3.7)

Hormone-receptor status
ER-positive
PgR-positivePS

TNM staging

Histological type
Metastatic site
Liver
LungLocal
Bone
Lymph node

≧10%0%
1-9%≧10%012Ⅰ
ⅡAⅡB
ⅢA
ⅢBⅢCⅣ
Unknown
IDC
ILC
VisceralNon-visceral
NoYes
NoYes
NoYes
NoYes
NoYes

Number49
10831417129117478144524253415371242725243118

Table 2. Adjuvant and First-Line Endocrine Therapy

Table 3. Choice of 2nd Line Endocrine Treatment after registration
Number49（%）
100

Letrozole

12.0

Tamoxifen

3

6.1

Toremifene

24.1

Fulvestrant
Exemestane + Everolimus
Additional use of bone-modifying agents

40381.6
6.1

10No

4081.60

Yes

918.4

No3469.4

Preference of 2nd line endocrine therapy
Total number of patients

Bisphosphonate
Denosumab

20

Mean (SD)

Duration of recurrence after operation (months) 32.2 (16.2)
Duration of recurrence after adjuvant 30.3 (14.4)
chemotherapy (months)
N
Adjuvant endocrine
Anastrozole
17
therapy
2
Exemestane
20
Letrozole
3
Tamoxifen
Mean (SD)
Duration of 1st line endocrine Tx (months)
1st line endocrine
therapy

Anastrozole
Letrozole
Tamoxifen

5.7 (2.8)
N
26
1

5

n=49

n=40

n=39

n=10

n=32

n=17

n=24-5-10Yes

15

30.6-15-20

Table 4. Reasons for Preference of Secondary Endocrine Therapy
Reasons forchoice

AllN (%)

Therapeutic
45 90effects
Side effects 14 28Costs
2 4Others
2 4N(%)

N(%)

N(%)

N(%)

N(%)

Table 5. Treatment-Emergent Adverse Events (≧Grade 3)

36

87.8

3

100

3

100

2

100

1

100

1322

31.7
4.9
4.9

______1__33.3______________Fulvestrant(n=3)

Letrozole(n=1)

Figure 1. Prespecified Subgroup Analysis of Clinical Benefit Rates%8070p=0.009

n=25Clinical response rate (CRR) were evaluated as asecondary endpoints.
The overall CRR was 8.16%, n=49, 90% CI: 4.1117.7, fulvestrant subgroup: n=40, 8.2 %, 90% CI; 4.117.7; PgR+: n=39, 7.69%, 90% CI: 3.58-18.7; PgR:n=10, 10%, 90% CI; 3.7-39.4; low sensitive group:
n=32, 6.25%, 90% CI; 2.6-18.4; very low sensitivity
group: n=17, 11.8%, 90% CI: 5.0-32.6; visceralmetastases: n=24, 8.3%, 90%CI; 3.4-23.1; nonvisceral metastases: n=25, 8%, 90% CI; 3.4-23.1.
Bar graph indicates point estimation, solid line
indicates 90% confidence interval. Abbreviation: CI,confidence interval; PgR, progesterone receptor; +,positive; -, negative; n, number of patients; %,percentage.

Fulvestrant EVE + EXE Tamoxifen Toremifene Letrozole

p=0.063

p=0.0016

p=0.617p=0.1326

p=0.003

p=0.072

p=0.0175

60

Everolimus +Exemestane(n=2)

Grade 3
Increased AST

Grade 3
Increased total bilirubin
Case 1

Grade 3
Depression

Grade 4
Depression

Grade 3
Fatigue
Case 4

Grade 3
Increased γ-glutamyl transpeptidase
Case 6

Grade 3
Insomnia

Case 20
Grade 3
Interstitial pneumonia

Grade 3
Appetite loss

Grade 3
Fatigue

Grade 3
Fatigue

Case 46

Grade 3
Oral mucositis
Case 47

5040

DISCUSSION and CONCLUSIONS

3020
100-10Median(range)
31.7(3.5-64.9)
29.6(5.3-58.9)
（%）
34.7
4.1
40.8
6.1
Median(range)
5 (2.3-10.8)
（%）
4.1
12.2
2.0%

15-20

CharacteristicFigure 2. Prespecified Subgroup Analysis of Clinical Response Rates

n=49

n=40n=39n=10n=32n=17n=24n=258 The null hypothesis that a clinical benefit rate (CBR) of at least 30% can beexpected (Red dots line).
 The overall CBR was 47.9% (90% CI: 34.6-57.6, p=0.009), and CBR was
similar across following subgroups (PgR+: n=39, 51.3%, 90% CI: 39.6-65.2,p=0.0016; very low sensitive group: n=17, 58.8%, 90% CI: 42.0-78.8,p=0.003; non-visceral metastases: n=25, 40%, 90% CI; 34.1-65.9, p=0.0175).
However, there were not statistically significant CBR in PgR- (n=10, 20.0%,90% CI; 8.73-50.7, p=0.617), fulvestrant subgroup (n=40, 40.0 %, 90% CI;
29.2-54.2, p=0.063), low sensitive group (n=32, 37.5%, 90% CI; 26.0-53.6,p=0.1326), and visceral metastases (n=24, 48%, 90%CI; 28.2-60.3 p=0.072).
 Bar graph indicates point estimation, solid line indicates 90% confidence
interval. Abbreviation: CI, confidence interval; PgR, progesterone receptor; +,positive; -, negative; n, number of patients; %, percentage.

 Since CBR was better than we expected, in the era of shared decision making, second line endocrine therapy that was chose based on
patients preference could be an optimal strategy.
 Our subgroup analysis indicated that PgR-positive, very low sensitivity, and non-visceral metastasis might have a clinical benefit from2nd line endocrine therapy.
 Although both PgR-positive and non-visceral metastasis could be a possible explanation factors, it was still unknow that “very lowsensitive group” has better CBR than that of “low sensitive group”. Since small sample size and/or multiple comparisons problem might
effect our results, further larger study or real world cohort big data should be expected to explore the predictive marker of second line
endocrine therapy.

ACKNOWLEDGEMENTS•••

The authors would like to thank the patients enrolled in this study, and their families.
This study was supported by research funding for Investigator Initiated-Sponsored Research (IISR) of the Externally Sponsored Research
Program of AstraZeneca K.K., which was provided to the Comprehensive Support Project for Oncological Research of Breast Cancer(CSPOR-BC). The researchers assume all responsibilities for the planning of the study, including communicating among
institutes/facilities, obtaining ethical approval, implementing the study, analyzing and interpreting the data, publishing the results, andensuring transparency.
K.A. was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number JP16K10485.

Printed by Iwamoto T., et al. Acta Med. Okayama, 2018, 72, 369

REFERENCES
 Taira et al., J Clin Trials 2016, 6:2