2

Healthcare resource utilization for first line chemotherapy
versus endocrine therapy in patients with advanced
HR-positive/HER2-negative breast cancer in Taiwan

Dwan-Yin Chang ＊ 1, Yi-Chen Juan ＊ 2, Yen-Shen Lu ＊ 1, Jiun-Jen Lynn ＊ 3,
Chih-Ta Chien ＊ 3, Fan-Chen Ku ＊ 3, K Arnold Chan ＊ 1, 2
Corresponding author
K Arnold Chan
Abstract
Objective
The goal of this retrospective database analysis was to describe treatment patterns, compare healthcare
resource utilization, and evaluate frequency of potential treatment-related toxicity among patients with hormone
receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2–) advanced breast
cancer using upfront endocrine therapy or chemotherapy, as well as to assess the effect of choice of systemictreatment on survival outcome in Taiwan.
Methods
Eligible HR+ HER2– advanced breast cancer patients were identified using Taiwan Cancer Registry from2011-2017 and Taiwan National Health Insurance database from 2011-2018 and classified as those who received
first line chemotherapy or endocrine therapy. Comparisons between these two groups were made in terms ofnumber of hospitalization episodes, hospitalization duration, healthcare resource utilization and frequency ofpotential treatment-related toxicity. Survival outcomes were evaluated by Kaplan-Meier method.
Results
There were 2,874 patients with HR+ HER2– advanced breast cancer during the study period, 42% of themreceived first line endocrine therapy and 56% received first line chemotherapy. Mean hospitalization episodes
were higher in the first line chemotherapy group compared to first line endocrine therapy in the first year after
initial breast cancer diagnosis, and the number of hospitalization episodes were similar in the second and thirdyear. Treatment for adverse events likely to be associated with cancer treatment, such as blood transfusion,
emergency department visits, use of granulocyte-stimulating colony factor, anti-inflammatory medication andintravenous antibiotics were more commonly administered in patients who received chemotherapy as initial
therapy. Multiple regression analysis showed that first line chemotherapy as initial therapy was associated withhigher level of healthcare resource utilization in the first year compared to first line endocrine therapy but thedifferences were not statistically significant in the second and third year. Use of chemotherapy or endocrine
therapy were associated with similar survival outcomes over three years.
＊1 National Taiwan University Hospital＊2 Health Data Research Centre, National Taiwan University＊3 Novartis (Taiwan) Co. Ltd.

Healthcare resource utilization for first line chemotherapy versus endocrine therapy inpatients with advanced HR-positive/HER2-negative breast cancer in Taiwan

3

Conclusion
In Taiwan, a higher percentage of patients with HR+ HER2– advanced breast cancer were started on
chemotherapy in the recent decade, more frequent hospitalizations and higher incidence of adverse events wereassociated with the use of chemotherapy, and they had higher healthcare resource utilization than those who wereprescribed endocrine therapy. Data from this analysis can help inform optimal management of advanced breast
cancer.
[Keywords] Taiwan National Health Insurance database, HR+ HER2– advanced breast cancer, chemotherapy,
endocrine therapy, healthcare resource utilization

Introduction
According to the latest GLOBOCAN 2018 statistics, breast cancer was the most common cancer in females
globally as well as in East Asia 1. Modern cancer treatments are expensive; in Taiwan, cancer expenditureaccounted for 10.2% of National Health Insurance (NHI) total expenditure in 2012 2. Throughout the years,
incidence of breast cancer has been increasing steadily, which contributed to the increasing expenditure borne by
the NHI 3. With escalating healthcare expenditure in Taiwan, there is a need to optimize cancer treatment tomaintain long term sustainability of NHI.
Current international treatment guidelines recommend that endocrine-based therapy be the preferred first line
strategy for hormone receptor positive (HR+) human epidermal growth factor receptor 2-negative (HER2–)
advanced breast cancer, while chemotherapy is deferred unless there is visceral crisis or endocrine treatment
resistance 4, 5. However, in real-world practice, first line chemotherapy is still used extensively in Europe andUnited States 6.
To our knowledge there are limited publications on healthcare resource utilization of endocrine therapy andchemotherapy in patients with HR+ HER2– advanced breast cancer in Taiwan to date. In this population-based
study in Taiwan we described treatment patterns for HR+ HER2– advanced breast cancer (de novo stage 4) andcompared healthcare resource utilization, frequency of potential treatment-related toxicity and survival between
those who received upfront chemotherapy or endocrine therapy.

Methods
We carried out a retrospective cohort study utilizing secondary health data in Taiwan.
Data source
Taiwan launched the National Health Insurance program in 1995, which covers up to 99% of the population.
Insurance claims data for ambulatory visits, emergency service, hospital care and drug prescriptions are includedin the NHI data 7. In addition, the Taiwan Cancer Registry was established to collect information on all newly
diagnosed cancer cases from hospitals with 50 or more beds, and it has cancer staging and histology information;
as well as tumor marker data for selected cancer 8. The Department of Statistics at Taiwan Ministry of Health andWelfare maintains a repository of health data for public health research, including the NHI, Taiwan Cancer Registry,
and mortality statistics, which are linkable through the encrypted and unique national identifier for each individual.
This study was approved by the National Taiwan University Hospital Research Ethics Committee (case number
201905085RINA). Individual informed consent was waived because of the use of de-identified data.
Study population
We identified all patients age 20 or older who had a first breast cancer diagnosis (International Classification of

4Asian Pacific Journal of Health Economics and Policy Vol.5 No.1 2022

Diseases, 9th revision, Clinical Modification [ICD-9-CM] code 174-175, or ICD-10-CM code C50.0-C50.9) from2011 through 2017 from Taiwan Cancer Registry and restricted the study population to those who had de novo
stage 4 disease per American Joint Committee on Cancer (AJCC) staging, 7th edition 9. The de novo stage 4 breast
cancer population was further evaluated according to the “Site Specific Factor (SSF)” data field in the Cancer
Registry and cancer treatment information from NHI. From 2011 onward, ER status and HER2 status wererecorded in Taiwan Cancer Registry in the SSF data field for breast cancer patients, and the HR+ HER2– target
population could be defined accordingly. In addition, we utilized drug use information in NHI to exclude patients
whose treatment regimens were not compatible with HR+ HER2– advanced breast cancer. Those who had everreceived trastuzumab, a standard of care for HER2+ subtype and those who received treatment for stage 0, 1, or
2 breast cancer or for local recurrence of breast cancer were excluded.
NHI and national mortality statistics data from 2011 through 2018 were utilized so that all patients would haveat least one year of post-diagnosis follow-up. All patients were followed for up to three years after the breast
cancer diagnosis.
Outcomes of interest
Treatment category was defined by the first systemic treatment after breast cancer diagnosis and further
classified by record of surgery. The hospital level that a patient received the most treatment regimen during thefirst year after initial diagnosis was classified as medical center, regional hospital, or could not be classified. A
patient could receive endocrine therapy (ET) only, chemotherapy (CT) only or both. Those who received
concomitant ET + CT were included in the CT group unless the patient only received low dose oral
cyclophosphamide, who would be categorized under ET as initial therapy. Only surgeries directed at the primarybreast tumor during the first year after initial diagnosis were identified, including but not limited to partial
mastectomy, mastectomy, modified radical mastectomy, and any type of lymph node dissections. Other cancerrelated surgeries, such as central venous port insertion or bone surgery for fracture were not included. As wewere unable to differentiate the type of radiation and to which site it was applied because of the NHI coding
system, radiation therapy to all anatomical sites were identified. We identified all hospitalization episodes andduration of hospital stay. The type of hospital (medical center or regional hospital) that a patient received cancer
treatment was defined according to the one with the most visits during the first year after initial diagnosis. NHI
reimbursement amount for each treatment item (ET, CT, surgery, and radiation therapy) were identified.
We assessed treatment for common toxicities associated with systemic treatment, include nausea/vomiting,mucositis, myelosuppression and serious infections (represented by intravenous antibiotics). Psychiatry visits
and treatment for mental health conditions were also evaluated.
Statistical analysis
Data were presented descriptively with appropriate metrics (proportion, mean and standard deviation [SD], or
median). Comparative analysis was restricted to patients who received ET or CT. Healthcare resource utilization
costs were presented in US Dollar under the assumption of an exchange rate of 1 US dollar to 30 Taiwan dollar.
Multiple linear regression was used to evaluate the effects of treatment modality (ET or CT) on healthcare
resource utilization in each of the three years during follow-up while controlling for patientsʼ age, level of hospital,
breast surgery and radiotherapy during the first year after initial diagnosis. Chi square test was used to compare
proportions of patients who received treatment for adverse outcomes association with breast cancer treatment
between the ET and CT groups. Three-year survival outcomes between the two treatment groups were describedusing Kaplan-Meier method.

Healthcare resource utilization for first line chemotherapy versus endocrine therapy inpatients with advanced HR-positive/HER2-negative breast cancer in Taiwan

5

Results
Baseline characteristics
A total of 2,874 patients were identified from Taiwan Cancer Registry as having incident de novo Stage 4 HR+
HER2– advanced breast cancer from 2011 through 2017 (Figure 1). A majority of them were female (99.5%).
Mean age of patients at initial diagnosis was 57.9 (SD 13.0) (Table 1).

Figure 1. Identification of study subjects

Asian Pacific Journal of Health Economics and Policy Vol.5 No.1 2022

6

Table 1. Baseline demographics of patients diagnosed with de novo Stage 4 HR+ HER2– breast cancer
in Taiwan, 2011-2017
Stage 4 HR+/HER2- Breast Cancer
2,874NGender, n (%)
Male
FemaleAge, mean (SD)Age group, n (%)
20-39
40-49
50-59
60-69
≥ 70

15 (0.5)
2,859 (99.5)
57.9 (13.0)
182 (6.3)
618 (21.5)
851 (29.6)
686 (23.9)
537 (18.7)

Treatment patterns and healthcare resource utilization
More than half (1,627 out of 2,874, 56.6%) of the advanced breast cancer patients received treatment at a
medical center during the year after initial diagnosis and about 40% (1,142 out of 2,874) received treatment at aregional hospital. All but 44 of them had records of treatment after the initial diagnosis and the vast majority ofthem (98%) received systemic treatments. (Table 2) A total of 1,207 patients (42%) received first line ET and
1,610 patients (56%) received first line CT. Among patients whom we classified as receiving CT as initial treatment,
Table 2. Treatment patterns among 2,874 patients with HR+ HER2– advanced breast cancer
Total
n (%)
Total patients

Level of hospital that provided the treatments
Medical Center

Regional Hospital

Other or unclassified

n (%)

n (%)

n (%)

2,874

1,627

1,142

105

1,207 (42.0)

696 (42.8)

460 (40.3)

51 (48.6)

ET without breast surgery

544 (18.9)

336 (20.7)

181 (15.8)

27 (25.7)

ET with breast surgery

169 (5.9)

105 (6.5)

58 (5.1)

6 (5.7)

ET + CT without breast surgery

321 (11.2)

169 (10.4)

141 (12.3)

11 (10.5)

First line ET

ET + CT with surgery
Switch to CT or added CT totreatment regimen in first year†
First line CT

173 (6.0)

86 (5.3)

80 (7.0)

7 (6.7)494 (40.9%)

-

-

-

1,610 (56.0)

904 (55.6)

667 (58.4)

39 (37.1)

CT without breast surgery

590 (20.5)345 (21.2)

227 (19.9)

18 (17.1)

CT with breast surgery

703 (24.5)

391 (24.0)

301 (26.4)

11 (10.5)

CT + ET without breast surgery

238 (8.3)

126 (7.7)

112*

CT + ET with breast surgery
Switched to ET or added ET to theregimen in first year‡
Without systemic treatment

79 (2.7)

42 (2.6)37*317 (19.7%)

-

-

-

57 (2.0)27 (1.7)

15 (1.3)

15 (14.3)

Breast surgery or Radiotherapy

13 (0.5)

6 (0.4)7 (0.6)0 (0.0)No record of treatment
44 (1.5)
21 (1.3)
8 (0.7)15 (14.3)
Percentage is based on total number of patients on first line ET ‡Percentage is based on total number of patients on first line
CT *Cell size of 3 or less in a table could not be individually presented and the table cells were combined
Abbreviations: ET, endocrine therapy; CT, chemotherapy†

Healthcare resource utilization for first line chemotherapy versus endocrine therapy inpatients with advanced HR-positive/HER2-negative breast cancer in Taiwan

7317 patients received CT plus ET combination. Overall, nearly 40% of patients (n=1,124) had received breast
surgery in the first year after diagnosis, 342 patients in the first line ET group and 782 patients in the first line CT
group. During the first year after diagnosis, 494 (40.9%) of patients on initial ET had either switched to CT or had
CT added to the regimen, while 317 (20%) patients on initial CT switched to ER or had ET added to the regimen(Table 2).
Further analysis was restricted to the 2,817 patients who received systemic treatment. The mean number ofhospitalization events were similar across patients who were prescribed first line ET from the first year to thirdyear of diagnosis while patients on first line CT had a higher mean number of hospitalization episodes in the firstyear (5.8 and 6.3 hospitalization episodes, without breast surgery and with breast surgery, respectively) (Table 3).
Except the first year in which there was an apparent difference in number of hospitalization episodes, the numberof hospitalization episodes and length of hospital stay, regardless of underlying cause of hospitalization, weregenerally similar between the ET and CT groups (Table 3).
Median NHI reimbursement amount for treatment among the first line CT group was apparently higher thanthat among the first line ET group. When taking breast surgery into consideration, patients who had received
surgery in addition to either first line CT or ET had larger reimbursement amount in the first year compared tothose who had not. Patients who received surgery seemed to have lower cost in the second and third year, and thetrend was more conspicuous in the group that received first line CT (Table 3).
Table 3. Healthcare resource utilization among 2,817 HR+ HER2- advanced breast cancer patients*
First line ET(N=1,207)
Without breast surgery
With breast surgery(N=865)(N=342)First line CT(N=1,610)
Without breast surgery
With breast surgery(N=828)(N=782)

Mean number of hospitalization episodes (SD)Year 1

3.3 (3.1)

3.6 (3.4)

5.8 (4.6)

6.3 (5.3)

Year 23.1 (3.3)

2.6 (2.3)

3.8 (3.6)

3.7 (3.6)

Year 33.3 (3.7)

3.2 (3.4)

3.7 (3.8)

3.7 (5.2)

Median duration of hospitalization stay (days)
Year 1

19

12

26

16

Year 2

12.5

9

14

13

Year 3

11

14

15

14

Median NHI reimbursement amount associated with treatment, US dollar
Year 1

10,641

14,847

18,11021,084

Year 2

6,995

6,145

10,018

6,463

Year 3
6,238
5,784
9,803
*As a result of cancer deaths and follow-up cut-off at 2018, not all patients had three years of follow-up
Abbreviation: ET, endocrine therapy; CT, chemotherapy; NHI, National Health Insurance

6,103

Multiple linear regression was used to estimate the differences in healthcare utilization costs between ET and
CT while adjusting for patientsʼ age, breast surgery and radiotherapy in the first year, and level of hospital care foreach of the three years after initial breast cancer diagnosis First line CT was associated with a significantly higher
costs in the first year compared to first line ET (p < 0.0001), but the differences were not statistically significant
in the second and third year. Breast surgery in the first year was associated with higher costs in the first year
(p=0.0051) and was associated with lower costs in the second and third year (p < 0.0001 and 0.0002). Older age
at diagnosis was associated with lower costs in general (Table 4).

8Asian Pacific Journal of Health Economics and Policy Vol.5 No.1 2022

Table 4. Multiple linear regression on the effect of systemic treatment modalities for
HR+ HER2– advanced breast cancer on healthcare resource utilization
Estimate (inUS Dollar)

95% confidence interval

p-valueFirst Year
Initial treatment (CT vs. ET)

4,883

4,212

5,554

<0.0001

Age at diagnosis (per year)

-78

-103

-52

<0.0001

Regional hospital vs. Medical center-662-1,296-28

0.0408

Breast surgery vs. no surgery

953

286

1,620

0.0051

Radiotherapy vs. no radiotherapy

7,200

6,545

7,855

<0.0001

Initial treatment (CT vs. ET)

327

-449

1,102

0.4091

Age at diagnosis (per year)

-65

-94

-36

<0.0001

Regional hospital vs. Medical center-299-1,029431

0.4222

Breast surgery vs. no surgery-1,943-2,684-1,201<0.0001

Radiotherapy vs. no radiotherapy

8,897

8,011

9,784

<0.0001

Second Year

Third Year
Initial treatment (CT vs. ET)

683

-440

1805

0.2330Age at diagnosis

-49

-92

-5

0.0274

Regional hospital vs. Medical center

131

-924

1186

0.8080Breast surgery vs. no surgery-2,031
Radiotherapy vs. no radiotherapy
10,160Abbreviation: CT, chemotherapy; ET, endocrine therapy-3,094
8,792-969
11,5280.0002<0.0001

As for management of treatment-related adverse effects, within the first year after initial diagnosis, comparedto those who received first line ET, patients who were prescribed first line CT required more platelet transfusions(7.3% vs 5.6%) or blood transfusions (37.5% vs 30.5%), granulocyte-colony stimulating factor use (46.0% vs
14.1%), antiemetics (96.3% vs 66.3%), intravenous antibiotics (73.4% vs 57.8%), steroid oral paste (28.9% vs
19.0%), and mycostatin oral suspensions (5.9% vs 2.9%). There was also a higher percentage of anti-hepatitis B
virus drugs prescribed in the first line CT group as expected, due to the use being mandated by practice guidelines
in Taiwan for patients undergoing chemotherapy (Table 5).

Healthcare resource utilization for first line chemotherapy versus endocrine therapy inpatients with advanced HR-positive/HER2-negative breast cancer in Taiwan

Table 5. Management of treatment-related toxicities among 2,817 HR+ HER2– advanced
breast cancer within one year after initial diagnosis
ET as initial treatment

CT as initial treatment

N=1,207

N=1,610p-value

CT-related regimen, n (%)
Cardiac ultrasound (pre-CT use)
Antiemetics prophylaxis for CT

379 (31.4)

616 (38.3)

0.0002800 (66.3)

1,551 (96.3)<0.0001

Antiviral agent for hepatitis B (related to CT)

65 (5.4)

182 (11.3)<0.0001

Steroid injection

625 (51.8)

1,504 (93.4)<0.0001

Steroid oral base459 (38.0)

999 (62.0)<0.0001

Steroid oral paste

229 (19.0)

465 (28.9)<0.0001

Non-steroidal anti-inflammatory drug

884 (73.2)

1,304 (81.0)<0.0001

Opioid861 (71.3)

1,203 (74.7)

0.0444Anti-inflammatory medication, n (%)

Pain medications, n (%)

For mental health conditions, n (%)
Outpatient psychiatry visits107 (8.9)

132 (8.2)

0.5300AntidepressantAnxiolytic agent

181 (15.0)

250 (15.5)

0.6979626 (51.9)

996 (61.9)<0.0001

Hypnotics agent

354 (29.3)

576 (35.8)

0.0003

Barbiturates

0 (0.0)0 (0.0)

Short-acting benzodiazepine

111 (9.2)

176 (10.9)

0.1319Intermediate-acting benzodiazepine

169 (14.0)

277 (17.2)

0.0212Long-acting benzodiazepineNon-benzodiazepine hypnotics*

188 (15.6)

303 (18.8)

0.0247

Platelet transfusion

67 (5.6)

118 (7.3)

0.0594

Blood transfusion (with platelet)

368 (30.5)

603 (37.5)

0.0001

Intravenous fluid/nutrition supply

973 (80.6)

1527 (94.8)<0.0001614 (50.9)883 (54.8)

0.0364170 (14.1)

741 (46.0)<0.0001698 (57.8)

1182 (73.4)<0.000136 (3.0)51 (3.2)

0.778735 (2.9)95 (5.9)0.000270.2503

Management of adverse events, n (%)

Emergency room visits
Drugs for adverse events, n (%)
Granulocyte colony-stimulating factor
Intravenous antibiotics (excluding use forsurgical prophylaxis)
Antimycotics
Mycostatin (Oral use)

* Non-benzodiazepine hypnotics include zopiclone, eszopiclone, zaleplon and zolpidem.
Abbreviations: CT, chemotherapy; ET, endocrine therapy

910Asian Pacific Journal of Health Economics and Policy Vol.5 No.1 2022

Survival outcomesThree-year survival outcome among the ER and CT groups are shown in Figure 2, which were generally thesame for either ET or CT as initial therapy with the curve converging from year 2 onwards.

Figure 2. Survival among HR+ HER2- advanced breast cancer patients over three years after initialdiagnosis in Taiwan

Discussion
To the best of our knowledge, this is the first population-based report on first line systemic treatment strategy
for HR+ HER2– stage 4 breast cancer in Taiwan. Its strength is the population-based nature of the data source,
such that we could identify all eligible patients during the study period from Taiwan. More patients received CT(56%) than ET (42%) as the first line therapy. There was a relatively high rate of surgery (39.1%) among thesepatients, which was inconsistent with treatment guidelines. Use of first line CT was generally associated withhigher cost of treatment compared to first line ET, especially in the first year (USD18,110 vs USD10,641). Thesefindings are similar to that reported for treatment costs for advanced breast cancer in US, Canada and Europe 10-13.
Unsurprisingly, the addition of breast surgery to systemic therapy increases the cost in the first year of diagnosis,
however the cost in the subsequent years are lower than those that did not receive surgery. This could be due toHealthcare resource utilization for first line chemotherapy versus endocrine therapy inpatients with advanced HR-positive/HER2-negative breast cancer in Taiwan

11

the different regimens used versus primary chemotherapy protocols which may affect costs, as well as possibly
reduced adverse events.
The three-year survival was similar in either ET first or CT first group, which is consistent with that of a US
study, where first-line CT was not associated with a survival benefit, but had significantly higher costs comparedwith first line ET14. Although the overall percentage of initial CT was high and seemed not adhering to current
treatment guidelines, we observed a trend of increasing utilization of ET first strategy over the years: from 30%
in 2011 to 49% in 2017 (data not shown).
In Taiwan, most CTs are delivered in hospitals, resulting in higher cost, and delivery of CT in out-patient clinics
was not common until recent years. CT is usually associated with more side effects compared to ET, such as
nausea, vomiting and diarrhea, while hot flashes being more common with endocrine therapy 15. Prophylaxis
antiemetics are prescribed as standard of care to prevent chemotherapy-induced nausea and vomiting, as evidenced
by the data. A certain proportion of patients on ET were also prescribed antiemetics which may be attributed tothe use of low potency anti-emetics, such as dopamine agonists, and the fact that 41% of patients had added or
switched to CT within the first year. CT is also associated with increased risk of infections due to myelosuppression 16.
Granulocyte-stimulating colony factors are also usually prescribed alongside CT to treat or to prevent neutropenia 17,
but not indicated for ET of which neutropenia is not a known side effect 18. However, under NHI, use of granulocytestimulating colony factors is only reimbursed for the treatment of neutropenic sepsis or grade 4 neutropenia, notfor prophylaxis. Therefore, the actual cost should be higher as some patients would have paid for granulocytestimulating colony factors out-of-pocket. Consequences of myelosuppression was also reflected by the higher rateof platelet, blood transfusion, and intravenous therapeutic antibiotics for patients on CT.
Generally, a diagnosis of breast cancer is associated with a deterioration of mental well-being with a reported
prevalence of 0-58% 19. The psychosocial stress is especially high for incurable stage 4 disease. Intriguingly, ETs
are well known to be associated with the adverse effects as insomnia and depression 20, 21. In our study, patients on
first-line CT were prescribed with more anxiolytics and hypnotic agents than those on ET, although frequency ofpsychiatric consultation was similar between two groups. These findings suggested that in Taiwan side effects ofchemotherapy resulted in more discomfort than the pharmacologic effect of endocrine therapies and compromised
quality of life, which in turn contributed to a higher level of healthcare expense and burden. Furthermore, themore frequent hospital visits, admission, and intravenous injections accompanying chemotherapy further burdened
the patients.
As a population-based study, we did not exclude men, although the small number of male patients did not allow
us to draw inference from this subgroup. Interestingly, we observed that older patients had lower medical costutilization compared with younger patients. It is probable that older patients may be more frail and treating
physicians tend to apply dose modifications when prescribing chemotherapies and use less combination
chemotherapies; once neutropenia occurs, the treating physician would tend to lengthen the treatment intervalrather than using granulocyte-stimulating colony factors to meet chemotherapy schedules.
As a study based on secondary health data, a limitation of our study was that no additional clinical information
was available for individual patients. The clinical condition of the patients would dictate which therapy wasrecommended, e.g. if a patient was in visceral crisis or had aggressive disease, chemotherapy would therecommended therapy. Usually, it would be assumed that patients who received endocrine therapy do not haveserious disease burden. However, for certain fragile patients, endocrine therapy is the only option regardless of
disease extent due to poor tolerance to chemotherapy.
This study was conducted before cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors use was approved andreimbursable under NHI, as CDK4/6 inhibitors were only approved for reimbursement from October 2019. The
benefit of adding CDK4/6 inhibitors to endocrine therapy has been consistently proven in clinical trials, withribociclib, palbociclib and abemaciclib prolonging progression free survival 22-25 and as well as ribociclib significantly
improving overall survival in advanced breast cancer 26. The impact of CDK4/6 inhibitors is transforming
management of breast cancer, and nowadays, the combination of CDK4/6 inhibitors and endocrine therapy has
become the first line standard of care. Although CDK4/6 inhibitors are generally more expensive, CDK 4/6

12

Asian Pacific Journal of Health Economics and Policy Vol.5 No.1 2022

inhibitors are usually very well tolerated along with the added survival benefits. More studies are required tounderstand the healthcare resource utilization comparison of CDK4/6 inhibitors compared with other therapies.

Conclusion
Our analysis of healthcare costs associated with treating HR+ HER2– advanced breast cancer using data fromthe Taiwan NHI has provided a snapshot on the population-based impact in Taiwan and we showed that healthcare
resource utilization was higher in patients prescribed chemotherapy compared to endocrine therapy, as well as thehigher level of toxicity associated with treatment. Three-year survival analysis showed that mortality outcomes
were similar between first line CT and ET, which is supportive of the current international consensus to consider
ET first. The treatment landscape has changed and the combination of CDK4/6 inhibitors and ET have now
become the standard of care. Findings from this analysis would help inform future healthcare resources planningin management of advanced breast cancer.

Acknowledgements
The authors would like to thank Ms. Yuan-Ting Chang of National Taiwan University and Ms. Ya-Ling Huang of
National Taiwan University Hospital for data development and analysis and Emily Teng of Novartis Malaysia Sdn
Bhd for providing medical editorial assistance with this manuscript.

Funding/Support
This study was co-sponsored by National Taiwan University and Novartis (Taiwan) Co. Ltd.

References
1. Ferlay J, Colombet M, Soerjomataram I, et al. Estimating the global cancer incidence and mortality in 2018:
GLOBOCAN sources and methods. Int J Cancer. 2018;144:1941-53.
2. National Health Insurance Administration. Ministry of Health and Welfare in Taiwan. Claims for the
reimbursement of medical expenses. [updated 11 Feb 2010. Available from:http://www.nhi.gov.tw/Information/newsdetail.aspx?menu=9&menu_id=544&No=1100.]
3. Chu PC, Hwang JS, Wang JD, Chang YY. Estimation of the financial burden to the National Health Insurance
for patients with major cancers in Taiwan. J Formos Med Assoc. 2008;107:54-63.
4. Cardoso F, Senkus E, Costa A, et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast
Cancer (ABC 4). Ann Oncol. 2018;29:1634-57.
5. Partridge AH, Rumble RB, Carey LA, et al. Chemotherapy and targeted therapy for women with humanepidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American Society ofClinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014;32:3307-29.
6. Caldeira R, Scazafave M. Real-World Treatment Patterns for Hormone Receptor-Positive, Human Epidermal
Growth Factor Receptor 2-Negative Advanced Breast Cancer in Europe and the United States. Oncol Ther.
2016;4:189-97.
7. Lin L-Y, Warreng-Gash C, Smeeth L, Chen P-C. Data resource profile: the National Health Insurance Research
Database (NHIRD). Epidemiol Health. 2018;40:e2018062.
8. Chiang CJ, You SL, Chen CJ, Yang YW, Lo WC, Lai MS. Quality assessment and improvement of nationwide
cancer registration system in Taiwan: a review. Jpn J Clin Oncol. 2015;45(3):291-296.
doi:10.1093/jjco/hyu211
9. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, (editors). AJCC cancer staging manual, 7thedition. France: Springer; 2010 [cited 2014 Jun 12] Available from:Healthcare resource utilization for first line chemotherapy versus endocrine therapy inpatients with advanced HR-positive/HER2-negative breast cancer in Taiwan

13

http://www.springer.com/medicine/surgery/book/978-0-387-88440-0.
10. Blumen H, Fitch K, Polkus V. Comparison of Treatment Costs for Breast Cancer, by Tumor Stage and Type ofService. Am Health Drug Benefits. 2016;9:23-32.
11. Broekx S, Den Hond E, Torfs R, et al. The costs of breast cancer prior to and following diagnosis. Eur J HealthEcon. 2011;12:311-7.
12. Jay N, Nuemi G, Gadreau M, Quantin C. A data mining approach for grouping and analyzing trajectories of careusing claim data: the example of breast cancer. BMC Med Inform Decis Mak. 2013;13:130.
13. Mittmann N, Porter JM, Rangrej J, et al. Health system costs for stage-specific breast cancer: a populationbased approach. Curr Oncol. 2014;21:281-93.
14. Burton T, Byfield SD, Smith GL, et al. Clinical and economic outcomes by first-line treatment among womenwith HR+/HER2- metastatic breast cancer in a large US health plan database. Curr Med Res Opin.
2016;32:1417-23.
15. Gupta S, Zhang J, Jerusalem G. The association of chemotherapy versus hormonal therapy and health outcomesamong patients with hormone receptor-positive, HER2-negative metastatic breast cancer: experience fromthe patient perspective. Expert Rev Pharmacoecon Outcomes Res. 2014;14:929-40.
16. Verma R, Foster RE, Horgan K, et al. Lymphocyte depletion and repopulation after chemotherapy for primarybreast cancer. Breast Cancer Res. 2016;18:10.
17. Chan A, Liu Yin JA, Narayan S, Natarajan S. The Use of Prophylactic Granulocyte-colony Stimulating Factor
for Chemotherapy-induced Febrile Neutropenia. European Oncology & Haematology. 2012;08:14.
18. Condorelli R, Vaz-Luis I. Managing side effects in adjuvant endocrine therapy for breast cancer. Expert Rev
Anticancer Ther. 2018;18:1101-12Petrelli, F., Barni, S. Surgery of primary tumors in stage IV breast cancer:
an updated meta-analysis of published studies with meta-regression. Med Oncol. 2021;29:3282–3290.
19. Tsaras K, Papathanasiou IV, Mitsi D, et al. Assessment of Depression and Anxiety in Breast Cancer Patients:
Prevalence and Associated Factors. Asian Pac J Cancer Prev. 2018;19:1661-9.
20. Desai K, Mao JJ, Su I, et al. Prevalence and risk factors for insomnia among breast cancer patients on aromataseinhibitors. Support Care Cancer. 2013;21:43–51
21. Chumsri S, Yu S, Schech A, et al (2016) Aromatase inhibitors for breast cancer prevention. In: Trends in breast
cancer prevention (Russo J, ed) pp 103–111. New York: Springer
22. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced
breast cancer. N Engl J Med. 2016;375:1738-1748.
23. Goetz MP, Toi M, Campone M et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer.
J Clin Oncol. 2017;35:3638-3646.
24. Johnston S, Martin M, Di Leo A, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial
therapy for advanced breast cancer. NPJ Breast Cancer. 2019;5:5.
25. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med.
2016;375:1925-1936.
26. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival (OS) results from the phase III
MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/humanepidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated withendocrine therapy (ET) ± ribociclib (RIB). Ann Oncol. 2021;32(suppl_5): S1283-S1346.