Health-related quality of life and estimation of the minimally important difference in the Functional Assessment of Cancer Therapy-Endocrine Symptom score in postmenopausal ER+/HER2- metastatic breast cancer with low sensitivity to endocrine therapy

Background The HORSE-BC study previously demonstrated that second-line endocrine therapy (ET) for patients with acquired endocrine-resistant metastatic breast cancer (MBC) still provided a clinically meaningful benefit. Herein, we investigated the health-related quality of life (HRQOL) in the HORSE-BC study. Methods Patients with acquired endocrine-resistant MBC who were scheduled for second-line ET were recruited. The HRQOL was assessed at baseline, and 1 and 3 months after second-line ET initiation. To investigate the minimally important difference (MID) in the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES), we evaluated the means and standard deviations for the distribution-based method, and differences in the change in HRQOL for the anchor-based method. We also investigated the association between FACT-ES total scores and clinical benefit. Results Overall, 56 patients were enrolled. Of these, 47 were analyzed. When defined as 1/3 standard deviation estimates based on the distribution method, the calculated MID was 5.9. The MIDs of the FACT-ES total scores based on the anchor method were 7.7 for decline and 4.1 for improvement. The MID decline proportions were 6.1% and 14.7% lower in patients who experienced clinical benefits than in those who did not at 1 and 3 months, respectively. The ratios of MID improvement in patients who experienced clinical benefits were 18.3% and 3.2% higher, respectively; the mean change in the FACT-ES total score from baseline improved in patients who experienced clinical benefits. Conclusions Maintaining the HRQOL as determined by FACT-ES may be associated with clinical benefits in patients with acquired endocrine-resistant MBC treated with ET.

(1) A clinical benefit rate of at least 30% can be expected for the latest endocrine therapeutic medicines for breast cancer with low sensitivity to the primary endocrine therapy.
(2) The effect of the secondary endocrine therapy can be predicted, because responsiveness to previous treatment and the biological characteristics of a given tumor influence the therapeutic effect of the secondary endocrine therapy on breast cancer with low sensitivity to the primary endocrine therapy. 2 Implementation structure of the study This study will be conducted as a research support project of the General Incorporated Association of Comprehensive Support Project for Oncological Research of Breast Cancer (hereinafter referred to as "CSPOR-BC").
An executive committee has been established to implement this study. In addition, a steering committee, study review committee, independent data monitoring committee, and data management committee have been organized by the General Incorporated Association of CSPOR-BC to conduct review of the study protocol, examination and decision of study policies, and management and supervision of the study operation of this research organization. • Reporting of the implementation status of the study to the Steering Committee.
• Matters required for the management and assurance of the quality of the study.
• Evaluation of the quality of facilities participating in the study.
• Support of the Data Center for data management.
• Support of the statisticians for statistical analyses.
• Preparation of reports.
• Other matters important for the smooth and effective implementation of the study. • Development of the budget to implement the program and report of the account settlement to the Foundation.
• Establishment, improvement, and elimination of subcommittees to implement the program, and appointment of subcommittee members.
• Supervision of the activities of the subcommittees.
• Other matters required to implement the objectives of this program. • Appointment of executive committee members of each clinical trial and accompanying study.

CSPOR-BC Study Review Committee
• Supervision of the implementation of clinical trials and accompanying studies.
• Approval of oral presentations and publications related to clinical trials and accompanying studies.
• Matters required for the smooth implementation of clinical trials and accompanying studies of other programs, and coordination among studies. Note 1: The envisioned size of T is the maximum diameter of infiltration of the primary tumor and is holistically determined by visual inspection, palpation, and imaging. When the tumor contains high levels of intraductal components and there is a large difference between the diameter of infiltration obtained by palpation and that obtained by imaging, the result obtained by imaging will be prioritized. When many tumors are present in the mammary gland, the size will be evaluated using the largest T.
Note 2: The chest wall means the rib, intercostal muscle, and serratus anterior muscle, and does not include the pectoral muscle.
Note 3: The location of the primary tumor cannot be confirmed by visual inspection, palpation, and imaging.
Note 4: Cases with abnormal nipple discharge and cases with calcification observed by mammography are not classified as T0, and the determination of these cases will be suspended. These cases will be definitively classified into Tis, T1mic, or others by final pathological diagnosis.
Note 6: Usually the term inflammatory breast cancer is used to describe a condition that shows no mass but diffuse redness, edema, and induration of the skin. Local redness and edema occurring together with detectable growth(s) and progress of mass is not included in this category.   T0  T1  T2  T3  T4   M0   N0  I  IIA  IIB  IIIB   N1  IIA  IIA  IIB  IIIA  IIIB   N2  IIIA  IIIA  IIIA  IIIA  IIIB   N3  IIIC  IIIC  IIIC  IIIC  IIIC   M1  IV  IV  IV  IV  Expression of estrogen receptor α (ERα) is evaluated by an immunohistochemical (IHC) method.
Evaluation will be conducted at each facility, and ER positivity will be determined based on the following criteria in this study.
J-score classification: A tissue area of ER-staining-positive cells of 1% or higher is determined as positive. The Allred score classification is calculated by conversion of the proportion score.
(2) Expression of progesterone receptor (PgR) Expression of progesterone receptor (PgR) is evaluated by an IHC method. Evaluation will be conducted at each facility, and PgR positivity will be determined based on the following criteria in this study.
J-score classification: A tissue area of PgR-staining-positive cells of 1% or higher is determined as positive. The Allred score classification is calculated by conversion of the proportion score.

Response evaluation
The tumor reduction effect will be evaluated in cases that have lesions measurable by RECIST guidelines (version 1.1) to calculate the response rate. The rate of subjects for whom the best overall response is complete response (CR) or partial response (PR), is defined as the response rate 3) .
(1) Definition of measurable lesion Lesions that correspond to at least 1 of the following terms are referred to as "measurable lesions".
1) Lesions other than lymph node lesion (non lymph node lesions) that satisfy at least one of the following criteria: ① The maximum diameter observed by CT using a slice thickness of ≤ 5 mm is ≥ 10 mm.
② The maximum diameter observed by CT using a slice thickness of > 5 mm is at least 2 times thicker than the slice thickness.
④ Cystic metastasis lesions satisfying ① or ② when there are no other measurable non-cystic lesions.
2) Lymph node lesions with a short diameter of ≥ 15 mm observed by CT using a slice thickness of ≤ 5 mm. Lymph node lesions with a short diameter of ≥ 10 mm and < 15 mm are non-measurable lesions, and lymph node lesions with a short diameter of < 10 mm are not lesions.
3) The maximum diameter observed by chest simple radiographic imaging is ≥ 20 mm, and the lesion is surrounded by lung tissue (i.e., the lesion has no contact with the mediastinum or chest wall). 4) Superficial lesions with a maximum diameter of ≥ 10 mm or more that can be photographed in color with a measuring ruler (cutaneous metastasis, etc.).
All lesions that do not satisfy the above terms will be referred to as "non-measurable lesions".
The following lesions, etc. are referred to "non-measurable lesions" regardless of the test methods used and the size of the lesions: • Bone lesions (except for osteolytic lesions with a measurable soft tissue component).
• Lesions with a history of local treatment such as radiotherapy.
• Palpable abdominal tumors and abdominal organ enlargement that cannot be confirmed by imaging.
(2) Selection of target lesion and baseline evaluation Of the measurable lesions observed at the registration of this study (baseline), the top 5 largest lesions in diameter (the long diameter for non-lymph node lesions and the short diameter for lymph node lesions) will be selected as target lesions, with at most 2 lesions selected from each organ. The lesions will be selected with the consideration that the selected lesions should be present in organs with measurable lesions spread evenly as much as possible and should show good reproducibility of measurement on repeated examination (i.e., ease of measurement). The site, testing method, date of test, long diameter of non-lymph node lesions, short diameter of lymph node lesions, and sum of the long and short diameters of the selected target lesions will be recorded in the order of cranial to caudal localization. (

3) Selection of non-target lesions and baseline evaluation
For all lesions that are not selected as target lesions, the site, testing method, and date of test will be recorded as "non-target lesions" regardless of whether the lesions are measurable or not. When a number of similar lesions are observed in the same region of the same organ, such lesions may be recorded as a single non-target lesion.

(4) Determination of tumor reduction effect
Therapeutic response evaluation will be conducted at the discretions of primary physicians because this study is observational in nature. However, exacerbation of the condition may be observed in the early period after the initiation of the treatment because the study is on breast cancer with low sensitivity to endocrine therapy. Response evaluations will be conducted at about 3 and 6 months to ensure the safety of research subjects and avoid missing the optimum timing for determining treatment policy.
Evaluation of target and non-target lesions will be conducted using the same test methods as those used before registration, including the same photographing conditions such as contrast agent and slice thickness to measure the major axis of the target lesion (the short diameter for lymph node) and to record the disappearance of non-target lesions, the presence or absence of progression, and the presence or absence of new lesions. When a sum of diameters of a target lesion becomes at least 20% larger than the smallest sum of diameters measured previously and the absolute value of the sum of diameters increases by at least 5 mm (including the incidence of new lesions).

NE (Not evaluable)
When tests cannot be done for any reason or when a lesion cannot be determined to be any of CR, PR, PD, or SD.
Reduction rate of the longest sum of diameters = (sum of diameters before treatment -sum of diameters at evaluation) / (sum of diameters before treatment) × 100% Increase rate of the longest sum of diameters = (sum of diameters at evaluation -the smallest sum of diameters) / (the smallest sum of diameters) × 100% • Actual measurement values of the diameters of target lesions will be recorded as long as they are measurable (for example, even < 5 mm). However, when the diameter of a target lesion is determined as "non-measurable because it is too small", the diameter of the lesion will be recorded as 0 mm if it is determined that none of the tumor lesion remains, or as 5 mm if it is determined that some tumor lesion remains regardless of the slice thickness used for CT.
• When the reduction rate satisfies the condition for PR and the increase rate satisfies the condition for PD at the same time, the lesion will be considered to be PD.
• When lesions separate from a single lesion during treatment, these lesions will be added to each sum of diameters.
• When > 1 lesion fuses together and their boundaries become identifiable during treatment, the diameter of the fused lesion will be added to the sum of diameters. If the boundaries of the lesions are identifiable, the diameter of each lesion will be added to the sum of diameters even if the lesions share a margin.

Obvious progression
• Cases with non-measurable lesions will be considered to show "obvious progression" when it is determined that the benefits of discontinuing the treatment are greater than those of continuing the treatment because of a notable exacerbation of non-target lesions, even if the target lesions are PR or SD.
• In cases with only non-measurable lesions, for example, when lesion volume is used as a guide, an increase in the volume of non-measurable lesions of 73% will be considered to be "obvious progression".

Incidence of new lesion(s)
• When a lesion that did not exist at baseline is observed after the initiation of treatment, this will be considered a "new lesion". However, it is also necessary to confirm that the "new lesion" is not observed due to a difference in the scan method or imaging modality compared with that used for baseline evaluation or a clinical condition other than a tumor. For example, a cystic lesion occurring in a focus caused by necrosis of liver metastasis will not be considered to be a "new lesion". Lesions that are newly found on examination of regions that were not regarded to be essential for examination at baseline will be considered to be new lesions.When a lesion that existed at baseline disappears and then appears again, such a lesion will be considered to be "PD" if this reappearance occurred after the overall response became CR; however, if other lesions are remaining, the lesion will not be considered to be a "new lesion" or "PD" because of the reappearance alone, but its tumor diameter will be added to the sum of diameters if the lesion is a target lesion. If the lesion is a non-target lesion, it will be considered to be "non-CR/non-PD" unless the lesion corresponds to "obvious progression".
• When a lesion may a new lesion but this cannot be confirmed, the lesion will not immediately be recorded as a new lesion, but imaging examination will be conducted after a clinically appropriate  When there are no non-target lesions at baseline, the overall response will be determined based on the response of the target lesion and incidence of new lesions, and when there are no target lesions at baseline, the overall response will be determined based on the response of non-target lesions and incidence of new lesions in accordance with the criteria specified in the table below.
Determination criteria for time point response (when target lesions are present).
Response of target The best overall response will be considered in the order of CR > PR > SD > PD > NE. The overall evaluation at the best time point from the initiation of treatment through to the initiation of posttreatment will be considered to be the best overall response.
Meanwhile, determination of CR or PR in 4-week periods is not necessary in this study. When an overall response corresponds to the definition given for multiple categories, it will be categorized into the best-fitted category in the order of CR > PR > SD > PD > NE.
SD determination shall satisfy the SD standards after 6 weeks from the start of treatment. When an obvious deleterious change (exacerbation) of the disease is observed before the first effect determination, it will be considered to be PD when no imaging determination is implemented and NE when the determination was not conducted because of discontinuation of treatment due to adverse events or rejection by a subject.

(7) Clinical progression
Progression will be determined in accordance with the following criteria when using a method other than those defined in {3.8 (4) Determination of tumor reduction effect} or when progression in unmeasurable lesions is determined. However, progression will not immediately be determined even when a case corresponds to the following criteria but the judgment of a clinical investigator is prioritized. When image assessment is available, the image assessment will be prioritized. The clinical benefit rate is defined as the rate of patients who are not determined to have experienced disease "progression" for 6 months from the initiation of treatment.
"Patients who are not determined as 'progression' for 6 months" means patients whose time point When the progression is determined based on diagnostic imaging, the date for which progression is recorded will be the day of the examination. In the case of clinical progression, the date of clinical determination will be recorded as the date of progression.
② In survival cases that are not determined to have experienced progression, the most recent day on which no progression is confirmed will be the recorded date for PFS.
③ When the diagnosis of progression is based on diagnostic imaging, the date recorded will be the "examination day" of the diagnostic imaging that provided "certain diagnosis" but not the day of examination where the progression was suspected as "suspicious on image". When the progression is determined clinically but is not based on diagnostic imaging, the date recorded for progression will be the day when the progression was determined.
④ The development of secondary cancer(s), e.g. heterochronic double cancer or heterochronic multiple cancer, will not be considered an event and will not be recorded as such, but will be considered to be PFS until another event is observed.
⑤ When treatment is discontinued due to the characteristics of or rejection by the patient and other treatment is implemented as an after-treatment, such cases will be handled in the same manner as the above for recording events and the endpoint, and will not be recorded at the time of discontinuation of treatment or the date of the initiation of after-treatment.
(3) Overall survival (OS) The period of time from the registration day to the day of death from all causes. The final confirmation day of survival in survival cases will be the recorded date. For cases that are lost to follow-up, the last date when survival of the patient was confirmed before becoming lost to follow-up will be the recorded date.
(4) Time to treatment failure (TTF) A period of time from the registration day to either of the day when progress was determined, the day of death from all causes, or the day of discontinuation of the protocol treatment (whichever is earlier).
① The day of discontinuation of the protocol treatment is the day when the discontinuation will be determined. When the progression is determined based on diagnostic imaging, the date recorded for progression will be the day of the examination. In the case of clinical progression, the date recorded for progression will be the day of clinical determination.
③ When the diagnosis of progression is based on diagnostic imaging, the date recorded for the event will be the examination day when the diagnostic imaging was performed that provided certain diagnosis, but not the day of examination where progression was suspected as "suspicious on image". When the progression is determined clinically but not based on diagnostic imaging, the date recorded for progression will be the day when the progression was determined.
④ When the protocol treatment is continuously implemented and there is no progression, the treatment will be discontinued on the final confirmed day of survival (the final confirmed day of PFS).

(5) Time to chemotherapy (TTC)
The period of time from the registration day to the day of first administration of chemotherapeutic drug ① For cases where mortality occurred before the initiation of chemotherapy, the date of death will be the recorded date.
② For cases that are lost to follow-up and in which implementation of chemotherapy is not confirmable, the last date when survival of the patient was confirmed before becoming lost to follow-up will be the recorded date.
The response rate is the rate of patients whose best overall response {3.8(6) Best overall response} in a target population with measurable lesions is CR or PR as a proportion of all the cases that underwent treatment.  Adverse events that are observed from registration to the discontinuation of the protocol treatment will be evaluated in all treated cases (see "19 Evaluation and reporting of adverse events").
HORSE-BC protocol ver. 1.0 August 12, 2015 4 Objectives and significance of the study 4

.1 Objectives of the study
The objectives of this study are: (1) To evaluate the efficacy and safety of secondary endocrine therapy in general as well as that of specific drugs in estrogen receptor-positive, HER2-negative postmenopausal metastatic breast cancer for which primary endocrine therapy had no favorable clinical effect (low sensitivity to primary endocrine therapy).
(2) To clarify the effect of reactivity to the previous endocrine therapy (the period from the start of postoperative endocrine therapy to recurrence) and the biological characteristics of any given tumor (expression intensity of ER and presence or absence of PgR expression) on the results of the secondary endocrine therapy, and to obtain information to complement Hortobagyi's therapeutic algorithm.

Background inspiring this study
(1) Target disease According to the National Cancer Center, Center for Cancer Control and Information Services, the estimated annual number of Japanese females affected with breast cancer in 2011 was about 72,500, and the rate per 100,000 population was 110.5, showing that the breast was the organ most frequently affected with malignancy in females. The annual number of deaths due to breast cancer in Japan was 13,148 in 2013, which is the 5 th leading cause of mortality following stomach, colorectal, lung, and pancreatic cancers.
The incidence of breast cancer in Japanese females is constantly increasing and ranks closely with colorectal cancer and lung cancer 4) .
About 90% of patients who are diagnosed with breast cancer receive surgical excision of the primary focus; however, the remaining 10% of patients have obvious distant metastasis at the first visit.
The survival rate of breast cancer is good if the tumor is detected early and removed surgically.
It is considered that the presence or absence of micrometastasis, which is clinically undetectable at the initial visit, has a decisive influence on the patient's prognosis. About 60% of patients who received surgery were cured, on the other hand, about 40% experienced a relapse 5) .
The median prognosis for the life expectancy of patients whose breast cancer has developed metastasis and recurrence is 28 months, and achieving a cure of metastatic or recurrent breast cancer is difficult even with current treatment techniques.
(2) Treatment of target population ① Goal of treatment for metastatic breast cancer It is very rare to achieve a complete cure for breast cancer that is already associated with inoperable distant metastasis at the first visit (Stage IV) and recurrent breast cancer caused by distant metastasis; therefore, the major purposes of treatment are alleviation of symptoms, life extension, and maintenance and improvement of quality of life (QoL) in such cases 6,7) .
Metastatic breast cancer is mainly treated by drug therapy. Radiotherapy, surgical therapy, etc. are also used in combination as needed. These treatments are intended to provide alleviation of symptoms and maintenance of daily life. ③ Recent outlooks regarding sensitivity and tolerance to endocrine therapy Recently, several classification models regarding sensitivity and tolerance to endocrine therapies have been proposed as the basis of the clinical course associated with initial endocrine therapy.
The 2nd International Consensus Guidelines for Advanced Breast Cancer (ABC2), which was held as an international consensus conference for recurrent breast cancer, proposed classifications of resistance to endocrine therapies for ER-positive metastatic breast cancer according to the period from the start of initial endocrine therapy to recurrence or progression as below 9) : [Primary endocrine therapy resistant breast cancer] • Cases that showed recurrence within 2 years after the initiation of postoperative adjunct endocrine therapy.
• Cases that showed progression of the disease condition within 6 months after the start of initial endocrine therapy for metastatic breast cancer. • Cases that showed recurrence within 2 years after the initiation of postoperative adjunct endocrine therapy or within 12 months after the completion of the endocrine therapy.
• Cases that showed progression of the disease condition within 6 months after the start of initial endocrine therapy for metastatic breast cancer.
In addition, a classification scheme based on drug sensitivity that categorizes cases that show recurrence within 2 years after the initiation of postoperative adjunct endocrine therapy and cases that show progression within 3 months after the start of initial endocrine therapy as "very low" drug sensitivity, and cases that show recurrence after 2 years from the initiation of postoperative adjunct endocrine therapy as "low" drug sensitivity has also been proposed  Recently, drug treatments for breast cancer that have a mechanism of action different from that of existing drugs became available.
Fulvestrant has no partial agonistic effect on ER such as that observed for tamoxifen, but instead down regulates ER expression in breast cancer cells; therefore, it is classified as a selective estrogen receptor down regulator (SERD) [10][11][12] .
Based on the results of a Phase II comparative study that compared anastrozole and In addition, everolimus is a mammalian target of rapamycin (mTOR) inhibitor. Inhibition of mTOR, which is situated downstream of the PI3K/AKT pathway, a key signaling pathway controlling cell proliferation, reveals a cancer cell proliferation effect, and it was shown that PFS was extended by the combined administration of other endocrine therapies in breast cancer that became endocrine therapy resistant [14][15][16] .
It is expected that a clinically significant treatment effect can be obtained by secondary endocrine therapy, even for cases that have poor responsiveness to primary endocrine therapy, by the use of these drugs. (

3) Study plan
Validation of a randomized controlled study implemented in cases that showed poor responsiveness to the primary endocrine therapy is required to establish the standard treatment for such cases in the future. However, no previous clinical trials have evaluated the efficacy and safety of secondary endocrine therapies in cases that showed poor responsiveness to the primary endocrine therapy. Furthermore, currently there is a wide range of medicines available for use as secondary endocrine therapeutic medicines for breast cancer.
Fundamental information, such as the selection of the target population indicated for treatment with secondary endocrine therapy and the basis underlying the selection of the target population, and the treatment effect expected for the overall secondary endocrine therapy and for each individual medicine are required to plan a comparative clinical trial involving these medicines in the future.
Based on the above background, this observational study was planned.
This study aims to clarify the efficacy and safety of secondary endocrine therapy using endocrine therapeutic medicines in estrogen receptor-positive, HER2-negative postmenopausal metastatic breast cancer for which the primary endocrine therapy had no favorable clinical effect through prospective observation using outcome indices including the clinical benefit rate, progression free survival, overall survival, time to treatment failure, time to chemotherapy, response rate, healthrelated quality of life, and adverse events.
Secondary aims include to categorize the wide variety of endocrine therapeutic medicines that are currently usable in Japan based on their action mechanisms and to evaluate their efficacy and safety.
Cases that showed low sensitivity to previous endocrine therapy are the target population in this study, and it is expected that the response of these cases to secondary endocrine therapy will not

Study hypotheses
To achieve the objectives, the following study hypotheses will be tested in this study.
(1) A clinical benefit rate of at least 30% can be expected for the latest endocrine therapeutic medicines for breast cancer with low sensitivity to the primary endocrine therapy.
(2) The effect of the secondary endocrine therapy can be predicted because responsiveness to previous treatment and the biological characteristics of tumor influence the therapeutic effect of the secondary endocrine therapy on breast cancer with low sensitivity to the primary endocrine therapy. According to our interpretations of the terms "intervention" and "invasion" described in those guidelines, this study corresponds to "non-intervention study involving mild invasiveness", and the study design is regarded as an observational study.
(1) Invasiveness Invasiveness is defined as "To cause injuries or distress to a research subject's body and/or mind by conducting a procedure for investigational purpose, such as puncture, incision, administration of drugs, irradiation and questions related to the subject's mental trauma, etc. Of various types of invasiveness, one causing minor injury and/or distress on the research subject's body and/or mind is called 'minor invasiveness'." in Chapter 1, Part 2 "Glossary" (2) of the guidelines.
The treatment implemented in this study will be conducted as regular clinical practice based on the preferences of medical staff and patients using drugs covered by insurance. Therefore, this study does not correspond to the treatment defined in the "Objectives of the study".
According to the survey plan implemented in this study, evaluation of Quality of life (QoL) by questionnaire will be conducted. Investigation of QoL in medical studies is implemented using scales validated for relevance and reliability, and is generalized as an evaluation approach for medical research. Considerations of the mental or physical burdens to patients are included in the process of the validation of the scales (content validity). Therefore, it is considered that the evaluation of QoL produces no mental damage to the subjects. The amount of time required to complete a QoL evaluation is about 15 minutes each time, and a mild burden is produced due to implementing the evaluation a total of 3 times (at the time of registration and at 1 and 3 months).
Based on the above, it is considered that the burden for the subjects participating in the study is small; therefore, the level of invasion produced for the subjects participating in this study corresponds to "minor invasiveness".
(2) Intervention Intervention is defined as "A practice for investigational purpose to control the presence or absence of factors that can affect a variety of events related to human health (including activities to maintain and promote good health and medical practices such as medication and examinations for prevention, diagnosis, and treatment of the patients), or the degree of such factors. The abovedefined intervention also includes medical techniques beyond usual medical practice that are conducted for investigational purposes." in Chapter 1, Part 2 "Glossary" (3) of the guidelines.
The treatment implemented in this study will be conducted as regular clinical practice based on HORSE-BC protocol ver. 1.0 August 12, 2015 the preferences of medical staff and patients using drugs covered by insurance. Therefore, this study does not correspond to the treatment defined in the "Objectives of the study". A total of 3 imaging evaluations conducted at the time of registration and at 3 and 6 months are specified as investigations in this study. However, these evaluations do not correspond to medical practice exceeding the range of regular medical examination as an evaluation approach of drug therapy for metastatic breast cancer. In addition, evaluation of QoL does not correspond to medical practice.
As mentioned above, this study is a medical research study involving no intervention and is therefore categorized as an observational study.

Case registration
(1) Completion of "Case registration card" Clinical investigators will confirm that study subjects satisfy the inclusion criteria (6.2) and complete all question items of the Case registration card (Appendix B). Then, the cards will be sent to the data center by fax. (2) Confirmation of registration The data center will confirm the eligibility of the study subjects based on the received Case registration cards and will then register the subjects.
① When the description given on the Case registration cards is inadequate, the subject will not be registered.
② The date when a sequence of registration procedures is completed will be used as the registration date, and described in "Confirmation note for case registration" (Appendix C).
The case will not be "registered" at the time of submission of the Case registration card to the data center by fax.
③ Registration of study subjects will not be canceled (i.e., deleted from the database) except when utilization of their data for research is denied. In cases of duplicated registration, the first registration information (earliest registry number) is adopted.
④ When a registration error or duplicated registration is found, a clinical investigator must immediately contact the datacenter.
(3) Sending of "Confirmation note for case registration" The data center sends a "Confirmation note for case registration" via fax to the clinical investigators described in the Case registration card.  Treatment will be selected based on discussion between medical staff and patients in this study (treatment of physician's choice: TPC). In addition, prohibition of concomitant therapy is not specified in this study because this study is an observational study. However, it is recommended to use medical agents with an antitumor effect (chemotherapeutic agent, concomitant use of molecular target drug, and other endocrine therapy) and to combine drug treatment with other treatment (surgery, radiotherapy) as appropriate in accordance with published guidelines 8) .
Furthermore, when these therapies are implemented in combination with the endocrine therapy, the details will be described in the patient's Progress report. Planned treatment shall be clearly indicated on the Case registration card when a subject participates in this study.
Hereinafter, preventive treatments used and evaluated for their efficacy and safety in the study populations are referred to as "protocol treatment". Protocol treatment shall be started within 2 weeks after registration. If treatment cannot be started within 2 weeks, the reasons for the delay are recorded in the "Progress report" (Appendix D  In addition, extensions of the time to significant progression and overall survival were observed in the everolimus + tamoxifen group as compared with the tamoxifen group in a Phase II randomized trial conducted in aromatase inhibitors resistant, locally advanced, or metastatic, postmenopausal breast cancer patients 17) .
Administration of everolimus in combination with an endocrine therapeutic medicine for inoperable or recurrent breast cancer is allowed in Japan. Accordingly, combination use of the endocrine therapeutic medicines listed in 5.3 (2) with everolimus is considered as a therapeutic option in this study. Combination use of everolimus and endocrine therapeutic medicines is considered as a factor that may affect efficacy and adverse events; therefore, this is described as a HORSE-BC protocol ver. 1.0 August 12, 2015 concomitant drug in the Progress report.
(4) Categorization of drug types used for the analysis Currently, the first-line drugs used for postoperative endocrine therapy and primary endocrine therapy for metastatic breast cancer are aromatase inhibitors. It is predicted that most of the cases registered in this study received administration of aromatase inhibitor as a pretreatment. There are a number of aromatase inhibitors that are available for use as secondary therapies. These therapies can be categorized based on their principal mechanism of action as below. Their efficacy and safety will be evaluated using the following categories including the general secondary endocrine therapy in this study. In addition, the subject group categorized into "Others" below will not be subjected to the analysis because the interpretation of the analysis results would be too difficult.
• Cohort with mTORi When the combined use of an endocrine therapeutic medicine and everolimus, which is an mTOR inhibitor, is selected. Cases that used everolimus concomitantly are categorized into this cohort regardless of the type of endocrine therapeutic medicine concomitantly used.

• Others
When the selected therapy cannot be categorized into any of the above cohorts.
(5) Concomitant treatments and medicines, and terms to be described in the Progress report ① Treatment in accordance with guidelines Prohibition of concomitant treatments and medicines associated with participation in this study is not specified, but it is recommended to implement standard treatment in accordance with the published guidelines 8) .
When the following treatments or medicines are concomitantly used with the protocol treatment, which was preliminarily reported after the registration, the reasons for the implementation (the presence or absence of withdrawal due to exacerbation of the disease or adverse events caused by the protocol treatment) must be described in the Progress report.

Survey
(1) Survey items The following survey and examination will be implemented to evaluate the efficacy and safety of the protocol treatment for subjects in this study. Surveys at 6 months after the initiation of protocol treatment and later will not be implemented except for the surveys of aftertreatment and prognosis.
(2) Survey schedule The surveys will be implemented on the schedule shown in the Note 1: Measurement of body weight will be performed only at the time of registration.
Note 2: In principle, image assessment should be implemented by the same technique as that implemented before registration.
Note 3: Evaluation will be implemented within 28 days (within 4 weeks) before registration Note 4: Evaluation within 2 weeks before or after the specified day is recommended.
Note 5: Every year after the end of the protocol treatment.
(3) Survey required before the registration Clinical investigators implement the following survey before registration of the case. The following terms will be evaluated within 28 days (within 4 weeks) before registration.
A) Chest CT, MRI, or chest X-ray (essential) B) Abdominal CT, MRI, or abdominal ultrasound (essential) C) Bone scintigraphy when bone metastasis is clinically suspected * When bone metastasis is suspected by bone scintigraphy, bone radiography, CT or MRI, etc. is conducted to evaluate the lesion. D) Brain CT or MRI when clinically brain metastasis is clinically suspected.
E) Evaluation and recording of lymph node and local skin recurrent focus * Inspection: It is favorable to observe progress using photos with indicators attached.
* Palpation: The size of foci such as superficial lymph nodes and cutaneous metastases are directly measured from outside the body if the size is measurable. It is desirable to evaluate with CT and/or ultrasound when the measurement method is applicable.

④ Survey of adverse events
Adverse events of Grade 3 or higher will be confirmed in accordance with the Common Terminology Criteria for Adverse Events v4.0 Japanese translation JCOG edition, and recorded.
Especially, the presence or absence of the following adverse events, which are common symptoms in breast cancer patients and associated with endocrine therapy, will be confirmed and recorded.
When adverse events of Grade 3 or higher are confirmed for symptoms other than the followings, the symptoms as recorded as "Other adverse events".

• Constipation
• Diarrhea The following questionnaire (scale) will be used to evaluate HRQoL.
It is desirable that evaluation of HRQoL is completed by the date of registration. However, if it is not completed because of a lack of time or other reasons, the questionnaire should be completed by the patient the day before the initiation of the protocol treatment.

(4) Survey plan at 1 month after the initiation of protocol treatment
The following survey will be implemented at 1 month after the initiation day of protocol treatment: ① HRQoL survey (See details for 5.5 Survey of health related quality of life) The following survey will be implemented at 1 month after the initiation of protocol treatment: * It is acceptable to implement the survey within 2 weeks before or after the specified day.

A) FACT (ES and B)
B) Questions about changes to identify minimally important differences

(5) Survey planned at 3 months after the initiation of protocol treatment
The following survey will be implemented at 3 months after the initiation date of protocol treatment: ① Physical findings * It is acceptable to implement the survey within 2 weeks before or after the specified day. * Palpation: The size of foci such as superficial lymph nodes and cutaneous metastases will be directly measured from outside the body if their sizes are measurable. It is desirable to use CT and/or ultrasound for evaluations where applicable.

③ Survey of adverse events
The presence or absence of adverse events of Grade 3 or higher occurring within the past 3 months will be confirmed and recorded.
* It is acceptable to implement the survey within 2 weeks before or after the specified day.
The contents of survey are the same as specified in ④ of 5.4 (3). The survey must be completed before registration. The following survey will be implemented at 6 months after the initiation day of protocol treatment: * However, the survey at 6 months after the initiation is not required when discontinuation of the protocol treatment or progression is reported in the survey at 3 months after the initiation. Move to the survey detailed in (7) for such cases.
① Physical findings * It is acceptable to implement the survey within 2 weeks before or after the specified day. * Palpation: The size of foci such as superficial lymph nodes and cutaneous metastases will be directly measured from outside the body if their sizes are measurable. It is desirable to use CT and/or ultrasound for evaluations where applicable.

③ Survey of adverse events
The presence or absence of adverse events of Grade 3 or higher occurring between the previous survey and the day of the current survey is confirmed and recorded.
* It is acceptable to implement the survey within 2 weeks before or after the specified day.
The contents of survey are the same as specified in ④ of 5.4 (3). The survey must be completed before registration. (3) HRQoL scales The following scales are used (Appendix F).
In addition, a questionnaire survey related to the social background and expectancy of QoL of patients, which may have an impact on subsequent HRQoL scores, will be conducted at the time When there is insufficient time, the survey should be completed before the initiation of the protocol treatment.
Note 2: It is acceptable to implement the survey within 2 weeks before or after the specified day.
HORSE-BC protocol ver. 1.0 August 12, 2015 (5) HRQoL survey for patients who discontinued the protocol treatment Evaluation of HRQoL will be discontinued when the protocol treatment is discontinued due to disease progress, development or exacerbation of complications, or adverse events.
(6) Survey method • ECOG PS will be determined by a clinical investigator at the same time as the QoL survey is conducted using specified survey terms and the results will be described in the Progress report.
• When the patient cannot complete the questionnaire due to an exacerbation of the disease condition of the patient, it is acceptable to implement the survey by reading the questionnaire by the Clinical Research Coordinator (CRC).

(7) Survey of reasons for missing data
When the questionnaire is not sent back for a patient after the scheduled survey period (5.5 (4) ), the data center surveys the reasons for the missing data, including the situation of questionnaire distribution and the health condition of the subject by asking the responsible clinical investigator.
The reasons for missing data are classified as below, and described as profiles of the study subject in the statistical analysis report and publications of the study results (conference presentations and paper publications). All of the subjects registered into this study are subjects of the survey.

Submission of data
The Case registration card for each subject will be submitted by fax, while other case report forms are submitted to the CSPOR data center via an electronic data capture (EDC) system in this study.  The analysis set is defined as below: Total eligible cases: "Total eligible cases" is defined as a group of patients that overlapped and error registrations are removed from patients who registered in accordance with "5.2 Registration of cases".
Total treated cases: "Total treated cases" is defined as a subgroup of patients among the total eligible cases who received scheduled treatment at least once daily. Whether CBR, the primary outcome measures, exceeds 30% will be examined using accurate tests based on binomial distribution and the corresponding 90% confidence interval by cohorts with the entire secondary endocrine therapy. Meanwhile, the analysis set includes all treated cases, and a significance level of 5% is set for 1-sided tests.

② Other analyses
Analysis of the interaction effect of CBR is conducted for responsiveness to the primary endocrine therapy, expression intensity of ER, and presence or absence of PgR expression for all registered cases to examine the significance of effect predictors of the secondary endocrine therapy. The following classification will be used for each factor: A) Responsiveness to the primary endocrine therapy • ER high group: ER positive (J-score classification is 10% or higher)

C) Presence or absence of PgR expression
• PgR negative group: PgR negative (J-score classification is negative) • PgR positive group: PgR positive (J-score classification is 1% or higher) Analyses of secondary outcomes will also conducted on a by-cohort basis. For RR defined by a 2-value endpoint response, an accurate 90% confidence interval based on point estimation and the binomial distribution is calculated. Furthermore, for PFS, OS, TTF, and TTC, which are time-to-event outcomes, a survival curve will be estimated using a Kaplan-Meier method, and 90% confidence intervals of the survival rate at each event will be calculated using Greenwood's formula. The interaction effect will be analyzed for effect predictors in the same manner as that used for the primary outcomes.
Analysis of adverse events will be performed in all treated cases. Incidence rate by types and grade will be calculated for reported adverse events.
③ Analysis of HRQoL FACT-G, Breast, and ES, which are calculated as total scores, will be calculated for the aggregate score and subdomain scores in accordance with a scoring manual to calculate the fundamental statistics at the time of each survey for all subjects.
Furthermore, cases with decreases in scores exceeding the threshold values as compared with scores at the registration will be individually identified and the maintenance rate of QoL will be calculated using MIDs identified by scales as a meaningful threshold value of decrease of QoL score at each measurement point.
Information obtained from questions about changes will be used as subjective anchoring information required for the identification of MID during the endocrine therapy, and differences from the previously established MID will be examined.
Since it is considered that the evaluation and analysis of HRQoL have no influence on the clinical benefit rate, which is the primary outcome measures of this study, analysis will be implemented immediately after the data collection (after the collection of QoL questionnaires at 3 months for the last registered case). The results of the analysis will be published as conference presentations and papers. 6 Subject selection policy 6

.1 Definition of the subject of this study
Although there is no existing consensus about how to define "ER-positive, HER2-negative postmenopausal metastatic breast cancer with low sensitivity to the primary endocrine therapy", a definition is established as below in this study: • Cases that are continuing postoperative adjunct endocrine therapy and experienced recurrence within 5 years after the initiation of the therapy.
• Cases that experienced disease progression within 9 months after the initiation of the primary endocrine therapy for metastatic breast cancer.
These correspond to the "very low" and "low" groups described in Figure 1 in 4.2 (2).
Cases that fit the definition of the above-mentioned clinical course are called "breast cancer with low sensitivity to the primary endocrine therapy" in this study.

Inclusion criteria
Cases that satisfy all of the following conditions are included in this study as subjects.
(1) A patient with estrogen receptor (ER) positive Note 2 postmenopausal Note 3 breast cancer who is histologically diagnosed as breast cancer Note 1 . When the presence or absence of menopause of the subject is unclear, FSH and plasma estradiol levels will be measured to confirm whether these are at the after menopausal level as defined by the criteria of each facility.
(2) Diagnosis of breast cancer corresponds to either of the following. No distinction is made according to the presence or absence of measurable lesions. ② Breast cancer associated with progression or recurrence caused by distant metastasis after initial treatment (after surgery and treatment before or after the surgery) for breast cancer aiming at curing. However, local recurrence for which radical excision is applicable (this represents the chest wall surrounded by the lower edge of the clavicle as the upper limit of surgical site, the costal arch as the lower limit, the midline of the sternum as interior limit, and the anterior edge of the latissimus dorsi muscle as the outer limit) is excluded.
(3) Endocrine therapy for metastatic breast cancer is planned.

(See 3.5 Evaluation of Performance Status (PS))
Note 4: A case determined as PS 2 because of decreased activity due to bone metastasis will be considered as eligible.
(5) Previous endocrine therapy for breast cancer corresponds to either of the following. No distinction is made according to the type of endocrine therapeutic medicines used.
① A case that has continuously received endocrine therapeutic medicines as a postoperative adjunct therapy and in which recurrence occurred within 5 years after the initiation of the endocrine therapy.
② A case that received endocrine therapy as the primary treatment for metastatic breast cancer Note 5 and in which progression of the disease occurred within 9 months after the initiation of the endocrine therapy.
Note 5: A case that received postoperative endocrine therapy for at least 5 years and had metastasis 5 or more years after the initiation of the endocrine therapy will not be included.
In addition, a case that discontinued postoperative endocrine therapy within 5 years for any reason and then had metastasis and recurrence will also not be included.
(6) Previous chemotherapy for breast cancer corresponds to either of the following: ① No previous chemotherapy was administered.
② When chemotherapy was administered as a preoperative or postoperative adjunct therapy, it has been at least 6 months (168 days, 24 weeks) since the final day of administration.
(7) Previous radiotherapy for breast cancer corresponds to the following: ① It has been at least 14 days after the final day of radiotherapy administration. (8) Agreement about the participation in the study will be obtained from the subject him/herself using the consent form (Appendix G).

Exclusion criteria
A case that corresponds to any of the following is excluded from participating in this study as a subject.
(1) HER2-positive breast cancer (See 3.7 Determination of HER2 expression status) (2) A case not indicated for endocrine therapy (3) Any other case that a physician determines to be unsuitable for participation in this study

Scientific rationale and grounds for research hypothesis
The usual current first-line drugs for postmenopausal breast cancer are aromatase inhibitors as a postoperative endocrine therapeutic medicine or as a primary endocrine therapy for metastatic breast cancer. Hence, it is presumed that most of cases registered in this study will have been administered an aromatase inhibitor in their previous treatment. The following reports detail the results of clinical trials related to the use of secondary endocrine therapy after previous treatment with an aromatase inhibitor. [Tamoxifen] • In the TARGET trial, which compared tamoxifen with anastrozole as primary endocrine therapies for metastatic breast cancer, 137 cases received administration of tamoxifen as the secondary endocrine therapy of the anastrozole group, and a CBR of 48.7% was obtained 25) .
• A CBR of 50% was obtained for the use of tamoxifen after anastrozole in a subtrial of the TARGET trial implemented in Switzerland (SAKK 21/95 subtrial).

[Other aromatase inhibitors]
• Nine previous reports examined the therapeutic effect of steroidal exemestane as the secondary treatment after primary treatment with a nonsteroidal aromatase inhibitor (anastrozole or letrozole), and the CBR was 12-55% 27) .

[Fulvestrant]
• In the EFECT trial, which compared steroidal exemestane with a fulvestrant loading dose regimen as secondary treatments after primary treatment with a nonsteroidal aromatase inhibitor (anastrozole or letrozole), the therapeutic effect was equivalent in each group, and the CBRs of fulvestrant and exemestane were 32.2% and 31.5%, respectively 28) . with cancer recurrence under postoperative endocrine therapy, the CBRs of the 250 mg/month and 500 mg/month groups were high (39.6% and 45.6%, respectively) and the 500 mg/month group also showed better overall survival 29,30) .

[mTOR inhibitors: combination use of everolimus and endocrine therapy]
• In the BOLERO-2 trial, which compared exemestane with an mTOR inhibitor (everolimus) + exemestane as secondary treatments after primary treatment with a nonsteroidal aromatase inhibitor (anastrozole or letrozole), superiority of the combination of exemestane + everolimus was indicated, and the CBRs of the exemestane group and the everolimus + exemestane group were 59% and 79.6%, respectively 15,16) .

•
In the TAMRAD trial, which compared tamoxifen with everolimus + tamoxifen, the CBRs of the tamoxifen group and the everolimus + tamoxifen group were 42.1% and 61.1%, respectively; indicating the superiority of the combined use of everolimus + tamoxifen 17) .
As described above, CBRs of about 50% were obtained for several trial therapies tested as secondary treatments used after primary treatment with aromatase inhibitors, although there have been variations between different studies and medicines. Especially, a strong trend towards higher CBR was observed for the combined use of fulvestrant 500 mg and an mTOR inhibitor in a recent clinical study 31) .
This study targets breast cancer with low sensitivity to the primary endocrine therapy, and previous trial results may not always be applicable; therefore, the therapeutic effect of secondary endocrine treatment in this clinical population needs to be evaluated. On the other hand, a clinically acceptable minimum therapeutic effect must be guaranteed.
As a hypothesis to validate one of the study objectives {4.

Procedures to obtain informed consent etc.
Clinical investigators provide information documents approved by the ethical review committee of their host facility to each potential study subject before registration, together with an adequate explanation of what the study will involve for the subjects. After the explanation, sufficient time will be given so that the subjects can raise questions and make a judgment about whether or not to participate. It will be confirmed whether the subjects understood the contents of the study well, then participation in the study will be requested and voluntary agreement will be obtained as a completed and signed consent form.
When agreement to participate in the study is obtained from a subject, the subject will enter the date of the agreement and his/her name and provide their seal or signature on the consent form. In addition, the clinical investigators and research collaborators (when the research collaborators provided supplementary explanation) will enter the date of the explanation and his/her name and seal or signature. Two photocopies of the consent form are created for each subject. One copy of the consent form is provided for the patient and the other copy is filed at the facility. The original copy is filed with the subject's medical records.
The following terms are explained to study subjects when informed consent is obtained: (1) Title of the study and the procedures involved in implementation of the study information. Data of the study subjects obtained in this study will not be used for any other purpose than meeting the objectives of this study. In addition, information that can specify the study subjects will not be used when the study results are published.
(2) Linkable anonymization Identification and inquiry of registered patients is conducted using registry numbers issued at the time of registration (linkable anonymization). Information from which bystanders can directly identify a patient, such as the name, initials, and date of birth of patients, will not be registered into the database of the CSPOR data center. (

3) Timing and method of anonymization
Anonymization is conducted at the CSPOR data center at the registration of cases.
The CSPOR datacenter issues registry numbers for patient identification numbers described in the "Case registration card" and registered facilities. The data center will book the registry numbers issued on a "Confirmation note for case registration", which is sent to the clinical investigators.
Registry numbers will be used for the identification of subjects required for data collection (including QoL questionnaires) and subsequent inquiries. A correspondence table will be securely managed and stored by the CSPOR data center.

Burden and expected risks and benefits for study subjects
Treatment implemented in this study does not exceed the range of regular clinical practice, and the treatment will be conducted based on the preferences of medical staff and patients. Furthermore, the techniques used and the frequency of image assessment implemented to evaluate the therapeutic effect and side effects do not exceed the range of regular clinical practice. Therefore, it is considered that there are no increased risks or benefits for study subjects associated with participation in this study.
QoL evaluation using survey sheets will be conducted in this study. The investigation time for a single survey is ≤ 15 minutes, and the survey will be performed 3 times (at the time of enrollment and at 1 and 3 month after the initiation of the protocol treatment). Therefore, no excessive burden is borne by study subjects, and it is considered that the level of invasion associated with participation in this study is minor.

Storage
Records of the consent given by subjects, test data etc. for the preparation of reports, certificates of approval by the ethical committee, and records prepared in medical institutes are securely stored under the supervision of the principal investigator. However, when the storage methods used for these materials (storage site and person in charge of storage) are specified to be at a collaborating research facility, storage will be conducted in accordance with the same rules as those used for central storage.
Adequate care will be exercised for storage to avoid leakage of personal information.
The duration of information storage is up to 5 years from the discontinuation or completion of the study.

Disposal
When information are disposed of, adequate care will be exercised to avoid leakage of personal information by deleting electronic data and shredding printed documents containing personal information.
13 Contents and methods of report to Chief Executive of research implementing entity 13.1 Contents of report to Chief Executive of research implementing entity Principal investigators in collaborating research institutes will report the following items to the Chief Executive of the research implementing entity.
Meanwhile, when the contents of the report to the Chief Executive of the research implementing entity are specified by the research institute, the report is conducted in accordance with the provision.

Timing and methods of reporting
When the timing and methods of reporting to the Chief Executive of the research implementing entity are specified by the research institute, the report will be conducted in accordance with the provision.
When provision is not provided by the research institute, principal investigators will prepare a "Status report on the study implementation" containing the contents of 13.1 and report to the chief executive of the research implementing entity.
The timing of reporting is as follows: All responsibilities for the planning of the study, implementing institutes/facilities, and approval of the Ethical Review Board, implementation of the study, analysis, interpretation, and publication of the study results, and ensuring transparency of the study are assumed by researchers, and AstraZeneca K.K.
is not involved in such decision-making.
The above will be clearly described at conference presentations and paper publications of the study results.
14. information. Furthermore, the information will be renewed on a timely basis in response to changes in the protocol and development of the study. When the study is completed, the study results will be registered without delay.

Publication of study results
When the study is completed, the study results will be published after taking measures required for the protection of the human rights of study subjects and involved persons or the rights and benefits of researchers etc. and their involved parties without delay. Publication of the study results will be determined by the steering committee based on a proposal by the executive committee of this study.
Publication related to this study will be appropriately conducted based on a preliminary publication plan, which is specified separately. Planned presentation styles are conference presentations and submission of papers to medical journals.

Response to consultation etc. from study subjects and involved persons
The followings are described in a briefing paper as contacts for consultation etc. from study subjects and interested persons.
• Name, affiliation, and contact information of the research representative of this study.
• Name, affiliation, and contact information of principal investigators of research institutes.
• Contact information of consultation services designated by collaborating research institutes, if there are any available.

Informed consent by legally acceptable representative
This study has no legally acceptable representative.

Economic burden and rewards for study subjects
Medical examination of this study will be conducted within the normal range of regular clinical practice.
Accordingly, all medical expenses including medication and examination during participation in the study will be paid as healthcare services provided by health insurance or by the patients participating in the study.
No reward is provided to the study subjects who participate in this study. When adverse events occur, clinical investigators must immediately take the required measures (examinations, treatment of the adverse events, and discontinuation of the treatment etc.) to ensure the safety of the study subjects.

Evaluation of adverse events
The naming of adverse events and their grades is determined based on the Common Terminology Criteria for Adverse Events v4.0 Japanese translation JCOG edition. Adverse events described as side effects in the package insert of each drug are considered to be known adverse events, and those not described are considered to be unknown adverse events.
(1) Evaluation duration of adverse events The evaluation duration of adverse events in this study is from the registration to 30 days after the completion of the protocol treatment specified as the object of evaluation.

Reporting of adverse events
When adverse events carrying an obligation to report corresponding to the below categories occur, a principal investigator reports to the secretariat. In addition, if serious adverse events ("serious" specified in ICH E2A) for which a causal correlation with the study treatment cannot be negated are observed, a report as stipulated by the reporting system of safety information on drugs etc. (1) Adverse events carrying an urgent obligation to report Adverse events corresponding to any of the following must be urgently reported via an "Emergency adverse event report" (Appendix X). These adverse events are defined as "Major adverse events".
① All deaths occurring during the study endocrine therapy.
② Deaths within 30 after the final administration of the study endocrine therapy and all deaths before the initiation of the next treatment.
"30 days" means 30 days counted from the day following a treatment day (the treatment day is defined as Day 0). All deaths occurred during this period are urgently reported regardless of the suspected causation.
However, even deaths occurring in a period other than the above (i.e., more than 30 days after the final administration of the study endocrine therapy and after the initiation of subsequent treatment) must be urgently reported when a correlation with the study endocrine therapy is suspected.
③ Unknown non-hematotoxicity observed before the initiation of the next treatment (2) Adverse events carrying a regular obligation to report Adverse events carrying a regular obligation to report are defined as any adverse events corresponding to Grade 3 or Grade 4 that are not adverse events carrying an urgent obligation to report {19.2 (1)}.
(3) Principal investigators' obligation to report and reporting procedures ① Urgent report When adverse events occur that carry an urgent obligation to report {19.2 (1)}, a clinical investigator must immediately inform the relevant principal investigator. When the principal investigator is not available, the clinical investigator must cover the responsibility of the principal investigator.
When an adverse event subjected to urgent reporting is observed, the event must be orally reported to the secretariat within 24 hours and the principal investigator must complete an "Emergency adverse event report" (Appendix X) (It is also acceptable to use a form provided by the hospital) and submits a fax (03-5298-8536) or E-mail (info@csp.or.jp) to the CSPOR data center within 72 hours after knowing the incidence of the adverse event.
In addition, the principal investigator must prepare a case report (A4 size, free format) describing further information as a separate document and submit a fax to the CSPOR data center within 15 hours after knowing the incidence of the adverse event. ② Regular report Principal investigators should record predefined terms in the "Progress report" (Appendix X) corresponding to the timing of the incidence of the adverse events and submit it to the CSPOR data center at the stipulated normal submission time of the Progress report.

Responsibility of the secretariat
(1) Determination of the necessity of discontinuance of registration and urgent notification to a facility When the secretariat receives a report from a principal investigator, the secretariat must seek the decision of a research representative or his/her proxy regarding the urgency, importance, and degree of impact of the reported contents. The secretariat must then take measures as needed including discontinuation of registration (communication to CSPOR data center and all participating facilities) and urgent communication about terms that must be recognized to participating facilities. Furthermore, the principal investigator is strongly prompted to implement reporting as stipulated by the reporting system of safety information on drugs etc. based on the Pharmaceutical and Medical Device Act.
(2) Report to independent data monitoring committee When the research representative determines that an adverse event reported as an urgent or regular report from a facility corresponds to an "adverse event carrying an obligation to report", the research representative must report it to the independent data monitoring committee in writing within 15 days after knowing the incidence of the adverse event and request review of the accuracy of the opinion of the research representative about the adverse event and any measures taken against the adverse event.

Examination by the independent data monitoring committee
The independent data monitoring committee will review the reported contents and make a recommendation in written form about future responses including handling of cases and the advisability of continuing registration to the research representative. 21 Response to queries regarding the delivery of medical care after the completion of the study Medical care after the completion of the treatment specified in the protocol of this study is not stipulated.
In addition, medical practice implemented in this study will be conducted within the normal range of regular clinical practice; therefore, no response related to the delivery of medical care after the completion of the study will be offered. Clinical investigators provide the best medical treatment aiming at prolonged survival, alleviation of symptoms, and maintenance and improvement of QoL, which are the goals for the treatment of metastatic breast cancer.

Handling of information related to health conditions of study subjects and study results
When information or research results that may influence the will of study subjects to continue participating in the study is obtained during the intervention period, the clinical investigator must immediately provide information documents describing the corresponding information and offer explanations of the following to the study subjects based on these documents:

Corresponding information
 Continuation of the participation in the study is left to their discretion.
The clinical investigator offering the explanation will enter the date of the explanation and his/her name and seal or signature on the information documents and consent form, and the study subject will enter the date they received the information and his/her name and seal or signature. In addition, when a research collaborator offers a complementary explanation, the research collaborator will also enter the date of the explanation and his/her name and seal or signature. A copy of the materials will be provided to the study subjects.
The clinical investigator will confirm with the study subject whether he/she wishes to continue participating in the study, and will enter the date and the subject's answer on the original copy of the information documents and consent form and then file them. The clinical investigator will revise the information documents and consent form and obtain approval from the ethical review board of the facility, as needed.
They must then explain the results to the study subject again using the revised information documents and consent form, and obtain voluntary consent for continuing participation in the study from the study subject in writing. The clinical investigator will enter the date when they gave the explanation and his/her name and seal or signature on the consent form and the study subject will also enter the date of consent and his/her name and seal or signature. A copy of the consent form will be provided to the study subject and the original copy will be filed.

Future utilization of samples and information
When the information obtained from subjects of this study are used for a study conducted for objectives different from this study or when the information are provided for other research institutes in the future, a new protocol will be developed and the study will be implemented under the approval of the ethical review board.

Monitoring
Monitoring will be implemented to confirm whether the study is implemented safely and in accordance with the protocol of the study, and will evaluate whether data are accurately collected.
Monitoring will be conducted as in-house monitoring with case report forms collected by the CSPOR data center using computerized data processing results as reference in cooperation with the executive committee and CSPOR data center. Monitoring through facility visits is not planned.

Audit
Audit is not planned for this study because this study does not correspond to an "intervention study involving high degree of invasiveness" as described in the "Ethical Guidelines for Medical and Health Research Involving Human Subjects" (issued on December 22, 2014).

Approval by Ethical Review Boards
26.1 Approval at the start of participation in the study When facilities start to participate in this study, each facility must submit necessary documents and receive approval from the ethical review board of the facility. When approval is obtained, the facility sends a copy of the certificate of approval to the secretariat. The facility will file the original copy of the certificate of approval, and the secretariat will file a copy of the certificate.

Annual renewal of the approval by the ethical review board
Review and annual renewal of approval for the study protocol and information documents for patients by the ethical review board of each facility will be conducted in accordance with the stipulations of each facility.

Completion, withdrawal, and interruption of the study (1) Completion of the study
The completion of the study is defined as the point when all follow-ups until the completion of the study duration are completed in all facilities. When the study is completed at each facility, principal investigators will submit a study completion report to the Chief Executive of the relevant research implementing entity and the research representative immediately.
(2) Withdrawal and interruption of the study ① The independent data monitoring committee examines the relevancy of continuation of the study, as needed. If at any point the committee determines that the continuation of the study is not appropriate, the committee will make a recommendation of withdrawal or interruption of the study to the research representative.
If the research representative decides to execute withdrawal of the study in accordance with the recommendation, the withdrawal, the reason of the withdrawal, and measures for participants will be communicated to principal investigators as soon as possible.
The principal investigators will report the situation in writing to the Chief Executives of research implementing entities and to the ethical review board of the facility at the same time.
Suitable measures will then be taken for each study participant in accordance with the directions given by the research representative and the ethical review board of the facility.
HORSE-BC protocol ver. 1.0 August 12, 2015 ② When a recommendation or direction of withdrawal is issued by the ethical review board, the research representative and principal investigators must take appropriate measures in accordance with the following: A) When a recommendation or direction to withdraw the study is issued to the research representative by the ethical review board, the research representative must consider the withdrawal of the study. When withdrawal is decided, the withdrawal, the reasons for withdrawal, and measures for participating in the study will be communicated to principal investigators as soon as possible.
The principal investigators must report the situation in writing to the Chief Executives representative who received the report will relay it to the independent data monitoring committee, which will examine the relevancy of the continuation of the study. When withdrawal or interruption of the study is decided based on the recommendation or direction from the ethical review board of the facility, the principal investigators will immediately report it together with the reasons to the Chief Executive of the relevant research implementing entity in writing.
③ Principal investigators must examine the advisability of continuation of the study when the following terms apply: A) When it is determined that recruitment of the planned number of study subjects is difficult because of difficulty in recruiting study subjects.
B) When the objective of the study is achieved before the number of planned study subjects is recruited or before the end of the planned study duration.
C) When the independent data monitoring committee or ethical review board directed a change in the protocol and it is determined that it is difficult to accept this direction.
Note: "The independent data monitoring committee" refers to the independent data monitoring committee of the General Incorporated Association of CSPOR-BC organized by the General Incorporated Association of CSPOR-BC.

Compliance with the protocol
Researchers who conduct this study shall comply with the protocol of the study as long as the safety