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. 2024 Nov 27;19(11):e0313120. doi: 10.1371/journal.pone.0313120

Is tamoxifen good enough for the Asian population in ER+ HER2- post-menopausal women with early breast cancer? A nationwide population-based cohort study

Chuan-Hsun Chang 1,#, Yi-Chan Lee 2,#, Chun-Wen Huang 3, You-Min Lu 4,*
Editor: Pirkko L Härkönen5
PMCID: PMC11602078  PMID: 39602456

Abstract

Background

Numerous clinical trials have compared the efficacy of endocrine therapy in post-menopausal breast cancer patients. This study aims to explore whether there is a difference in recurrence rates between this population using tamoxifen and aromatase inhibitors (AIs) by analyzing real-world data.

Methods

This retrospective cohort study utilized the National Health Insurance (NHI) claims data and the Taiwan Cancer Registry (TCR). We identified 6,050 patients aged over 55 diagnosed with ER-positive, HER2-negative early breast cancer between 2012 and 2016 (4,451 on AIs alone and 1,599 on tamoxifen alone). Recurrence in both groups was assessed until the end of 2020. Hazards were measured based on age of diagnosis, cancer stage, adjuvant chemotherapy, radiation therapy, type of endocrine therapy used, and adherence. Recurrence‑free survival between the AIs and tamoxifen groups was evaluated using the Kaplan-Meier model.

Results

The average age was 65.1 years, with a median follow-up time of 5.7 years and a median duration of endocrine therapy of 4.5 years. The recurrence rate was 2.2%. Using tamoxifen as endocrine therapy reduces the risk of recurrence compared to AIs (adjusted HR: 0.32, p < 0.0001). There was no statistical difference between the two drugs in stage 1 breast cancer. However, in stage 2, the risk of breast cancer recurrence decreased to 0.15 times with the use of tamoxifen compared to AIs (p = 0.0002). Stage 2 cancer, histological grade 3, and non-adherence increased recurrence risk in post-menopausal breast cancer patients.

Conclusion

Based on real-world data analysis, in ER-positive, HER2-negative post-menopausal women with early breast cancer in Taiwan, the use of tamoxifen compared to AIs is associated with a lower risk of recurrence. Improved adherence to medication can break the cycle of recurrence and improve health outcomes.

Introduction

Breast cancer treatment includes surgery, chemotherapy, endocrine therapy, radiation therapy, and targeted therapy. Endocrine therapy is recognized as an effective adjuvant treatment for patients with hormone receptor-positive breast cancer. Endocrine therapy includes two types: tamoxifen and AIs. Tamoxifen can be used in pre-menopausal and post-menopausal patients; however, AIs are only suitable for post-menopausal breast cancer patients. The AIs available include exemestane, anastrozole, and letrozole.

Numerous clinical trials have compared the efficacy of tamoxifen and AIs in post-menopausal breast cancer patients. The ATAC trial [1], which compared the use of 5 years of anastrozole or tamoxifen, found that the anastrozole group had better disease-free survival (HR 0.91; p = 0.04), but there was no difference in overall mortality (HR 0.95; p = 0.4). Another large clinical trial, BIG 1–98 [2], compared the 5- year use of letrozole or tamoxifen and followed patients for a median of 8.1 years. The results showed that the letrozole group had better disease-free survival (HR 0.86, p = 0.007) and overall survival (HR 0.87, p = 0.048) than the tamoxifen group.

Another type of randomized controlled trial was conducted sequentially. Studies such as IES [3], ABCSG 8/ARNO [4], ITA [5], and ARNO 95 [6] administered tamoxifen for 2–3 years followed by AIs. Compared to five years of tamoxifen, these studies showed better disease-free survival. However, in terms of overall survival, only the ARNO 95 study [6] showed a significant improvement (HR 0.53, p = 0.045), while the IES study [3] did not demonstrate a significant difference.

According to the 2019 ESMO Clinical Practice Guidelines [7], AIs and tamoxifen are standard treatments for post-menopausal women. AIs can be used upfront, after 2–3 years of tamoxifen, or as extended adjuvant therapy after 5 years of tamoxifen. The 2023 NICE guideline [8] and the 2019 British Menopause Society consensus statement [9] recommend using AIs as initial treatment for post-menopausal women at medium or high risk of breast cancer recurrence. For women at low risk or those who have contraindications or intolerances to AIs, tamoxifen can be used.

Randomized controlled trials (RCTs) can be used to evaluate the efficacy of drug treatments, meaning the expected effects that drugs can achieve in specific populations meeting their inclusion criteria. However, RCT results may have limited external validity, and their application in clinical practice may be restricted due to factors such as short recruitment periods, small sample sizes, homogeneity of trial participants, and idealized drug usage conditions. In the real-world setting, patients often have different characteristics from those included in clinical trials, such as having multiple comorbidities, requiring multiple medications, having impaired liver or kidney function, or being older. Additionally, in the real world, patients may not adhere to follow-up appointments, and there is no confirmation of medication adherence. Therefore, this study uses real-world data analysis to explore whether there are differences in effectiveness between tamoxifen and AIs in post-menopausal breast cancer patients.

Materials and methods

Study design and data sources

This retrospective cohort study utilizes two databases: the National Health Insurance (NHI) claims data and the Taiwan Cancer Registry (TCR). The NHI program in Taiwan was launched in 1995 and covers healthcare data for over 99% of the country’s 23 million population. Taiwan’s National Health Insurance Research Database (NHIRD) is a population-level data source that requires investigators to conduct on-site analysis at a Health and Welfare Data Center (HWDC) established by Taiwan’s Ministry of Health and Welfare (MOHW). Using encrypted patient IDs, we linked the patients with early stages breast cancer from TCR to the NHI database to obtain their medication records, including outpatient, inpatient, and contracted pharmacy data. The database was de-identified, and we could not identify individual participants during or after data collection. The TCR is a nationwide population-based cancer registry system established by the Ministry of Health and Welfare in 1979. The TCR has maintained a long-form database since 2002 to evaluate cancer care patterns and treatment outcomes, recording cancer staging, detailed treatment information, and recurrence data [10]. This study received review and approval from the Institutional Review Board of Cheng Hsin General Hospital (IRB No. CHGH-IRB 113E-03-2).

Study population

Using the TCR, we identified patients diagnosed with breast cancer for the first time between January 1, 2012, to December 31, 2016, who had cancer stages 1–2. The study period commenced from the initial breast cancer diagnosis date until recurrence, death, or December 31, 2020. We considered the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) to determine breast cancer’s primary site (C50.0-C50.9). Patients with any cancer diagnosis within two years before the confirmation of breast cancer were excluded from the study.

We identified 24,916 patients who had received endocrine therapy for at least one year, and only those who exclusively used tamoxifen or AIs were included in the research. We then included 17,075 individuals who were diagnosed with cancer at stages 1–2. We used an age greater than 55 years as a surrogate indicator for menopause. Therefore, patients diagnosed with cancer at 55 years or younger (9,347 individuals) were excluded from the study. Individuals with breast tumors classified as estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2- negative (HER2-) and those not requiring targeted therapy were less likely to have critically distorted results, excluding 1,631 and 47 individuals, respectively. As a result, 6,050 individuals were considered as the study subjects.

Tamoxifen can be used in pre-and post-menopausal women, while AIs are indicated explicitly for post-menopausal women. The study focused on post-menopausal breast cancer patients to ensure comparability between the two drugs. Unfortunately, the NHI database lacks information on whether patients have stopped menstruating. A meta-analysis [11] that analyzed menarche, menopause, and breast cancer risk included 117 epidemiological studies. The mean age at natural menopause was 49.3 years, and 10% of women (16,144 out of 170,413) reported menopause occurring at age 55 or older. Since 90% of patients undergo menopause before the age of 55, this study uses an age greater than 55 as a proxy indicator for post-menopausal status.

Variables and outcome

Data were collected on the study subjects, including age at initial diagnosis of breast cancer, cancer stage, adjuvant chemotherapy, radiation therapy, histological grade, group classification based on endocrine therapy, duration of follow-up, total duration of medication use, recurrence status, cause of death, interruptions, and adherence. Tumor staging was determined according to the seventh edition of the AJCC Cancer Staging Manual. The stage of breast cancer includes both the pathological and clinical stages. In this study, priority was given to the pathological stage. The clinical stage was used if the pathological stage was indicated as "unclear or not recorded" or unavailable.

The groups for endocrine therapy were classified based on pharmacological classes. Group I included patients who received AIs alone, which included the components anastrozole (ATC code L02BG03), exemestane (ATC code L02BG06), and letrozole (ATC code L02BG04). Group II consisted of patients who received tamoxifen alone (ATC code L02BA01). The prescription history of patients receiving endocrine therapy was examined to determine if interruptions and non-adherence occurred. Any gap period between two consecutive endocrine therapy prescriptions that exceeded 180 days was defined as an "interruption" [12, 13]. The proportion of days covered (PDC) was used as an indicator to assess patient adherence to treatment [14]. PDC was defined as the number of days covered by all medications minus the number of overlapping days, divided by the total number of days between the beginning and end of treatment [15]. Patients with a PDC greater than 80% were considered adherent. In comparison, those with less than 80% were considered non-adherent.

Analysis

Statistical analysis was performed using the SAS 9.4 software package for each cancer stage. Descriptive statistics were used to present the distribution of continuous variables using means. In contrast, percentages were used to illustrate the differences in the distribution of categorical variables between AIs and tamoxifen, with chi-squared tests conducted for comparison.

Inferential statistics were conducted using the Cox proportional hazards model to estimate the crude hazard ratio and 95% confidence interval (CI) for recurrence in breast cancer patients. Subsequently, a multivariable Cox proportional hazards model was employed to incorporate control variables into the analysis, and the adjusted hazard ratio and 95% CI for recurrence associated with AIs and tamoxifen were observed. The significance level for statistical testing was set at p < 0.05.

Breast cancer recurrence‑free survival (RFS) curves were generated using the Kaplan-Meier method to assess cumulative RFS probabilities. The log-rank test was then used to compare the RFS curves and determine whether they had statistically significant differences. Kaplan-Meier curves were plotted to depict the cumulative RFS probabilities of AIs and tamoxifen upon an 8-year follow-up period. Furthermore, the RFS outcomes of AIs and tamoxifen were investigated for each cancer stage. Finally, the log-rank test was employed to compare cumulative RFS probabilities, and if p < 0.05, it indicated a statistically significant difference.

Results

Characteristics of the study cohort

The study population comprised 6,050 individuals with breast cancer incidence for the first time. Among these individuals, 4,451 received treatment with AIs, while 1,599 received tamoxifen, with a 7.0% and 9.7% mortality rate, respectively. The average age of the study cohort was 65.1 ±7.8 years. Post-menopausal breast cancer stage 1–2 cases have increased from 666 in 2012 to 1,736 in 2016. Among patients receiving endocrine therapy, the use of tamoxifen decreased from 461 patients (69.2% of the total) in 2012 to only 253 patients (14.6%) in 2016. In contrast, the proportion of patients using AIs increased annually (Cochran-Armitage trend test, Z = 26.1, p < 0.0001), as shown in Fig 1.

Fig 1. Trends in endocrine therapy use among post-menopausal breast cancer patients from 2012 to 2016.

Fig 1

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Analysis of patients’ breast cancer stages revealed that among those receiving AIs treatment, the most common stage was stage 2 (50.6%); for patients treated with tamoxifen, stage 1 was predominant (65.8%). The median follow-up time is 5.6 years. Most patients (71.6%) were followed up for 4–7 years; 17.1% in the AIs group and 45.3% in the tamoxifen group were followed up for 7–10 years. In this study, 38.7% of patients utilized adjuvant chemotherapy and 48.9% underwent radiation therapy. The prescription duration of endocrine therapy is 3.4 years. Most patients (64.2%) received treatment for 3–5 years, while 21.6% in the AI group and 28.8% in the tamoxifen group received treatment for over five years. Patients receiving tamoxifen had higher rates of treatment interruption (11.6% vs. 8.7%) and non-adherence (14.3% vs. 9.3%) than those receiving AIs. The demographic data of the study cohort are summarized in Table 1.

Table 1. Demographic data of the study cohort.

Total (N = 6,050) AIs alone (n = 4,451; 73.6%) Tamoxifen alone (n = 1,599; 26.4%) P-values
First diagnosis year < .0001
 2012 666 11.0 205 4.6 461 28.8
 2013 971 16.0 629 14.1 342 21.4
 2014 1238 20.5 943 21.2 295 18.4
 2015 1439 23.8 1191 26.8 248 15.5
 2016 1736 28.7 1483 33.3 253 15.8
Breast cancer stage < .0001
 Stage 1 3252 53.8 2200 49.4 1052 65.8
 Stage 2 2798 46.2 2251 50.6 547 34.2
Histological grade < .0001
 Grade 1 1661 27.5 1163 26.1 498 31.1
 Grade 2 3462 57.2 2588 58.1 874 54.7
 Grade 3 722 11.9 571 12.8 151 9.4
 Unknown 205 3.4 129 2.9 76 4.8
Follow-up years (until the end of follow-up or death) < .0001
 <4 years 232 3.8 165 3.7 67 4.2
 4–7 years 4330 71.6 3523 79.2 807 50.5
 7–10 years 1488 24.6 763 17.1 725 45.3
The primary cause of death < .0001
 No death 5582 92.3 4138 93.0 1444 90.3
 Breast cancer 128 2.1 101 2.3 27 1.7
 Non-breast cancer 340 5.6 212 4.8 128 8.0
Years of death after diagnosis < .0001
 No deaths 5582 92.3 4138 93.0 1444 90.3
 <2 years 50 0.8 33 0.7 17 1.1
 2–5 years 270 4.5 197 4.4 73 4.6
 > = 5 years 148 2.4 83 1.9 65 4.1
Adjuvant chemotherapy < .0001
 No 3709 61.3 2549 57.3 1160 72.5
 Yes 2341 38.7 1902 42.7 439 27.5
Radiation therapy < .0001
 No 3092 51.1 2186 49.1 906 56.7
 Yes 2958 48.9 2265 50.9 693 43.3
Prescription duration of endocrine therapy < .0001
 <3 years 741 12.2 493 11.1 248 15.5
 3–5 years 3886 64.2 2996 67.3 890 55.7
 > = 5 years 1423 23.5 962 21.6 461 28.8
Persistence or interruption* 0.0007
 Persistence 5479 90.6 4065 91.3 1414 88.4
 Interruption* 571 9.4 386 8.7 185 11.6
Interruption* (gap number) < .0001
 no gap 5479 90.6 4065 91.3 1414 88.4
 gap = 1 435 7.2 312 7.0 123 7.7
 gap = 2 82 1.4 42 0.9 40 2.5
 gap = 3 32 0.5 19 0.4 13 0.8
 gap>3 22 0.4 13 0.3 9 0.6
Time to the first gap of 180 days 0.0047
 no gap 5479 90.6 4065 91.3 1414 88.4
 <1 year 107 1.8 81 1.8 26 1.6
 1–2 year 122 2.0 78 1.8 44 2.8
 2–3 year 84 1.4 55 1.2 29 1.8
 3–4 year 107 1.8 74 1.7 33 2.1
 > = 4 years 151 2.5 98 2.2 53 3.3
Adherence (PDC**) < .0001
 <0.8 644 10.6 415 9.3 229 14.3
 0.8–0.9 1177 19.5 834 18.7 343 21.5
 > = 0.9 4229 69.9 3202 71.9 1027 64.2
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* Between two consecutive endocrine therapy prescriptions for more than 180 days

** The proportion of days covered

Survival and recurrence‑free survival

By following up until December 31, 2020, the overall survival rate of 6,050 breast cancer patients was 92.3%. Among the 468 deceased patients, approximately 27.4% of deaths were attributed to breast cancer. Analysis of patient death time revealed that the highest number of deaths occurred within 2–5 years after breast cancer diagnosis, accounting for 57.7% (270 individuals). The second-highest number of deaths was observed after 5 years, with 148 individuals (31.6%).

This study included post-menopausal breast cancer patients, among whom the recurrence rate was 2.2% (132 individuals). When stratified by stage, the recurrence rates were 1.3% in stage 1 and 3.3% in stage 2. Regarding different endocrine therapies, the recurrence rate was 2.7% in the AIs group and 0.9% in the tamoxifen group. The highest number of recurrences occurred two years or more after the diagnosis of breast cancer, accounting for 1.3% (81 individuals). The comparison of recurrence rates between the AIs and tamoxifen groups is presented in Table 2.

Table 2. Recurrence between the AIs and tamoxifen groups.

Total (N = 6,050) AIs alone (n = 4,451; 73.6%) Tamoxifen alone (n = 1,599; 26.4%)
N % N % N %
 Recurrence
 No 5918 97.8 4333 97.3 1585 99.1
 Yes 132 2.2 118 2.7 14 0.9
 Breast cancer stage 1
 Non-recurrence 3211 98.7 2169 98.6 1042 99.0
 Recurrence 41 1.3 31 1.4 10 1.0
 Breast cancer stage 2
 Non-recurrence 2707 96.7 2164 96.1 543 99.3
 Recurrence 91 3.3 87 3.9 4 0.7
Years of first recurrence after diagnosis
 Non-recurrence 5918 97.8 4333 97.3 1585 99.1
 <1 year 26 0.4 23 0.5 3 0.2
 1–2 year 25 0.4 22 0.5 3 0.2
 > = 2 year 81 1.3 73 1.6 8 0.5
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For patients with stage 1 breast cancer after menopause, there was no significant difference in the recurrence‑free survival rates between those treated with AIs or tamoxifen (98.6% vs. 99.0%; Log-rank test, p = 0.2313) (Fig 2). However, for patients with stage 2 breast cancer, the recurrence‑free survival rate was higher in the tamoxifen group compared to the AIs group, with a statistically significant difference (96.1% vs. 99.3%; Log-rank test, p = 0.0002) (Fig 3).

Fig 2. The Kaplan-Meier curves depict recurrence-free survival in comparing AIs and tamoxifen for breast cancer stage 1.

Fig 2

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Fig 3. The Kaplan-Meier curves depict recurrence-free survival in comparing AIs and tamoxifen for breast cancer stage 2.

Fig 3

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Recurrence rate and associated factors

In the multivariate analyses, the age of diagnosis increases the risk of breast cancer recurrence by 1.03 times. In different stages of breast cancer, stage 2 increases the risk of recurrence by 2.07 times compared to stage 1 (p = 0.0004). For patients with histological grade 3, the risk of breast cancer recurrence increases by 2.24 times (p = 0.0076). Analyzing the impact of different endocrine therapy, using tamoxifen reduces the risk of recurrence compared to AIs (total adjusted HR: 0.32, p < 0.0001; stage 2 adjusted HR: 0.15, p = 0.0002). Adjuvant chemotherapy shows no statistically significant difference in recurrence. Adherence (PDC > = 0.8) decreases the risk of recurrence (adjusted HR: 0.29, p < 0.0001). Across different stages, recurrence risk rises by 0.50 times in stage 1 and 0.24 times in stage 2. The univariate and multivariable adjusted hazard ratios of covariates for recurrence are summarized in Table 3.

Table 3. Univariate and multivariable adjusted hazard ratios of covariates for recurrence (N = 6,050).

Characteristic Univariate HR P-values Adjusted HR P-values
Age of diagnosis 1.03(1.01–1.05) 0.0016 1.03(1.00–1.05) 0.0307
Breast cancer stage
 Stage 1 1 1
 Stage 2 2.66(1.84–3.84) < .0001 2.07(1.38–3.10) 0.0004
Histological grade
 Grade 1 1 1
 Grade 2 1.78(1.11–2.85) 0.0165 1.50(0.93–2.41) 0.0985
 Grade 3 2.76(1.57–4.88) 0.0005 2.24(1.24–4.06) 0.0076
 Unknown 1.12(0.34–3.74) 0.8540 0.93(0.28–3.13) 0.9078
Endocrine therapy
 AIs alone 1 1
 Tamoxifen alone 0.32(0.18–0.56) < .0001 0.32(0.18–0.57) < .0001
Adherence (PDC* > = 0.8)
 Adherence 0.30(0.21–0.44) < .0001 0.29(0.20–0.42) < .0001
 Non-adherence 1 1
Adjuvant chemotherapy
 No 1 1
 Yes 1.19(0.84–1.67) 0.3337 0.88(0.58–1.33) 0.5314
Radiation therapy
 No 1 1
 Yes 0.74(0.52–1.04) 0.0817 0.86(0.60–1.23) 0.4120
Stage 1
Age of diagnosis 1.03(0.99–1.07) 0.1266 1.04(1.00–1.09) 0.0652
Histological grade
 Grade 1 1 1
 Grade 2 1.99(0.90–4.40) 0.0916 1.95(0.88–4.35) 0.1020
 Grade 3 3.91(1.42–10.78) 0.0084 4.20(1.45–12.16) 0.0081
 Unknown 1.24(0.16–9.92) 0.8392 1.38(0.17–11.11) 0.7602
Endocrine therapy
 AIs alone 1 1
 Tamoxifen alone 0.65(0.32–1.33) 0.2352 0.64(0.31–1.31) 0.2227
Adherence (PDC* > = 0.8)
 Adherence 0.55(0.24–1.23) 0.1432 0.50(0.22–1.14) 0.0993
 Non-adherence 1 1
Adjuvant chemotherapy
 No 1 1
 Yes 1.19(0.60–2.38) 0.6192 1.04(0.49–2.22) 0.9107
Radiation therapy
 No 1 1
 Yes 1.14(0.62–2.12) 0.6689 1.31(0.69–2.49) 0.4144
Stage 2
Age of diagnosis 1.02(1.00–1.05) 0.0525 1.02(0.99–1.05) 0.1585
Histological grade
 Grade 1 1 1
 Grade 2 1.28(0.72–2.31) 0.4037 1.24(0.69–2.24) 0.4754
 Grade 3 1.58(0.79–3.15) 0.1941 1.67(0.82–3.38) 0.1570
 Unknown 0.86(0.20–3.76) 0.8360 0.67(0.15–2.97) 0.5969
Endocrine therapy
 AIs alone 1 1
 Tamoxifen alone 0.19(0.07–0.51) 0.0010 0.15(0.06–0.41) 0.0002
Adherence (PDC* > = 0.8)
 Adherence 0.25(0.16–0.39) < .0001 0.24(0.15–0.37) < .0001
 Non-adherence 1 1
Adjuvant chemotherapy
 No 1 1
 Yes 0.75(0.50–1.13) 0.1722 0.80(0.49–1.31) 0.3789
Radiation therapy
 No 1 1
 Yes 0.66(0.43–1.02) 0.0606 0.72(0.46–1.13) 0.1519
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* The proportion of days covered

Discussion

In Taiwan, the incidence of breast cancer among post-menopausal women has been steadily increasing. This study utilizes real-world data to analyze the effectiveness of tamoxifen and AIs for treating post-menopausal breast cancer. The findings suggest comparable recurrence with both endocrine therapies in stage 1 breast cancer, while tamoxifen shows superiority over AIs in stage 2.

The landscape of endocrine therapy has experienced a significant evolution, marked by a transition from predominantly using tamoxifen before 2013 to a notable preference for AIs. This shift, accompanied by the rising popularity of AIs, introduces a noteworthy aspect of price discrepancy. Analyzing the medication prices covered by the NHI in 2024 reveals that Tamoxifen (Nolvadex®) 10mg, Letrozole (Femara®) 2.5mg, Exemestane (Aromasin®) 25mg, and Anastrozole (Arimidex®) 1mg are priced at NT$4.8, NT$24.6, NT$44.2, and NT$40.0 respectively.

Given the equivalent effectiveness of the inexpensive tamoxifen compared to the costly AIs, unless specific side effects are a concern, choosing the relatively affordable tamoxifen aligns with economic benefits. Furthermore, with the increasing breast cancer screening rate in Taiwan, many cases with early-stage diagnoses are being identified. However, the rising usage of medications primarily recommended for high-risk patients requiring AIs warrants a thoughtful evaluation of their necessity.

This study observed that patients receiving tamoxifen monotherapy exhibited higher rates of non-adherence than those receiving AIs alone (14.3% vs. 9.3%). These findings align with previous studies by Hsieh et al. [13], Hershman et al. [16], and Cavazza et al. [17]. Poor adherence among tamoxifen users may be attributed to the associated side effects. Tamoxifen is known to cause hot flashes and bleeding problems, which can occur early during therapy and lead to treatment discontinuation or withdrawal [18]. Our study revealed that adherence (PDC > = 0.8) is associated with a 0.29-fold recurrence risk. As observed in Pistilli et al.’s study [19], improved adherence among post-menopausal breast cancer patients can reduce recurrence risk. In addition, the 2016 ACS/ASCO Breast Cancer Survivorship Guideline [20] recommends that primary care clinicians counsel patients to adhere to endocrine therapy. We believe that physicians should take an active role in assessing and encouraging adherence to endocrine therapy. It also emphasizes the collaborative and interdisciplinary nature of modern healthcare practices, underscoring the importance of a team-based approach in ensuring the comprehensive care of patients with breast cancer. In this context, physicians play a crucial role not only in prescribing and monitoring endocrine therapy but also in fostering effective communication and cooperation among various healthcare professionals involved in the patient’s care journey.

Many factors can influence whether breast cancer patients experience recurrence. High histological grade and immunohistochemical markers (ER- and PR-negative or HER2-positive) are risk factors for recurrence [21]. This study utilized NHIRD and included adjuvant chemotherapy, radiation therapy and histological grade as covariates to control for interference with recurrence. The HER2-positive breast cancer patients have tumors that grow faster and exhibit a more malignant biological behavior due to the overexpression of the HER2 protein, leading to a higher rate of recurrence compared to other types of breast cancer. Amplification or overexpression of HER2 occurs in approximately 15–30% of breast cancers [22]. The conditions of this study are as follows: Patients newly diagnosed with early-stage breast cancer from 2012 to 2016, aged over 55 at the time of diagnosis, and treated with Tamoxifen or AIs alone for more than one year. Among the population meeting these criteria, there were 1,376 HER2-positive patients with ER-positive status, accounting for 17.8%. To minimize the effect on breast cancer recurrence, this study excludes patients with HER2-positive breast cancer and those who have undergone targeted therapy.

The median follow-up time for endocrine therapy in early breast cancer was 120 months in the ATAC trial [1], 76 months in BIG 1–98 [2], 64 months in ITA [5], and 30 months in MA.17 [23]. In our study, the median follow-up time is 69 months. Most patients (71.6%) were followed up for 4–7 years. Our research team conducted a study [24] using the NHIRD, with enrollment from 2000 to 2005 and follow-up until 2013. In this period, there were only 51 individuals treated with AIs, and 561 individuals treated with tamoxifen. To increase the number of AIs use cases for comparability between the two drugs, enrollment was extended to 2012–2016, resulting in a shorter follow-up period, which is a limitation of this study.

This study utilized the NHI database, which covers nearly the entire population of Taiwan and is highly representative. However, it has the following limitations. Firstly, it can only provide data on insurance-covered treatments, lacking information on patients who obtain medications through out-of-pocket payments. Secondly, due to the higher cost of AIs compared to tamoxifen, the NHI imposes stricter reimbursement criteria for AIs, resulting in patients treated with AIs having a higher disease severity. To mitigate this impact, this study is linked to the TCR database to consider the stage of breast cancer and histological grade. Thirdly, data on the menopausal status of the patients was lacking.

Conclusion

Based on an analysis of real-world data, the use of tamoxifen in ER+ HER2- post-menopausal women with early breast cancer in Taiwan yields a lower risk of recurrence compared to AIs. This finding suggests that tamoxifen can be an effectiveness treatment option for this population.

Furthermore, it is worth noting that improving medication adherence can disrupt the cycle of breast cancer recurrence. Healthcare providers can optimize the therapeutic benefits and improve recurrence‑free survival rates by ensuring patients adhere to their prescribed medication regimen.

Data Availability

The data that support the findings of this study are available from Taiwan's Ministry of Health and Welfare's Health and Welfare Data Center (HWDC). However, due to licensing restrictions, these data are not publicly accessible. Data access is restricted to individuals who register with the HWDC (https://www.apre.mohw.gov.tw/) and are Taiwanese nationals. For inquiries, please contact Mr. Yang at +886-2-85906805 or via email at stsung@mohw.gov.tw. Detailed descriptions of the databases used are provided in the Methods section, and the corresponding codebook is accessible at https://dep.mohw.gov.tw/DOS/lp-2503-113.html. By following the procedures outlined in the Methods section, the findings of this study can be replicated.

Funding Statement

YES. This study was funded by the Cheng Hsin General Hospital (CHGH110-(N)21). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Pirkko L Härkönen

26 Dec 2023

PONE-D-23-23146Is tamoxifen good enough for the Asian Population in post-menopausal breast cancer?

A nationwide population-based cohort studyPLOS ONE

Dear Dr. Lu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The topic of comparing the efficacy of tamoxifen vs aromatase inhibitors in the treatment of breast cancer in postmenopausal women is important and interesting. However, the evaluation process of the manuscript brings up important issues that should be taken into account and corrected before tha manuscript is acceptable. Please consider carefully the concise expert review and revise the manuscript accordingly.Especially, as an obtainable patient and tumor information, data on adjuvant chemotherapy and predictive tumor characteristics (ER and HER2 status, proliferation markers, histological grade) should be presented and discussed in the light of tumor responses. Please also discuss a rather short follow-up time as a weakness of the study. Also, use of invasive-free survival instead of overall survival would be advisable as suggested.

Please submit your revised manuscript by Feb 09 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Pirkko L. Härkönen, M.D., Ph.D.

Academic Editor

PLOS ONE

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"YES

This study was funded by the Cheng Hsin General Hospital (CHGH110-(N)21)."     

Please state what role the funders took in the study.  If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

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This study was funded by the Cheng Hsin General Hospital (CHGH110-(N)21)."

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear authors,

Thank you for you manuscript evaluating outcome by type of endocrine therapy. The authors present data from a large cohort evaluating survival in postmenopausal breast cancer patients by type of endocrine therapy.

Minor comments:

The section on age for postmenopausal status can be shortened.

The number of patients at risk should be listed in the Table of outcome by stage.

Major comments:

The follow-up is short to evaluate the true effect of any endocrine therapy, this should be added to the discussion section. The difference in outcome by type of endocrine therapy is hard to evaluate after less than five years of followup.

Moroever, data on adjuvant chemotherapy should be included as well as data on the tumor´s biological inherence. A minimum is data on oestrogen receptor, HER2-receptor and some proliferation estimation such as Ki67 or histological grade. All these factors greatly influence outcome and it was early anticipated that tumor biology could distinguish breast cancer populations who had greater benefit of adjuvant aromatase inhibitors. This variables should also be discussed in the Discussion. A sentence on Taiwan´s nationel guidelines for adjuvant therapy would also be helpful for the reader.

Consider using invasive recurrence free survival or interval instead of overall survival; these endpoints are more relevant as an endpoint in breast cancer trials/retrospective studies.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Lisa Rydén, professor Lund University

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2024 Nov 27;19(11):e0313120. doi: 10.1371/journal.pone.0313120.r002

Author response to Decision Letter 0

8 Feb 2024

Dear Dr. Härkönen

We have meticulously reviewed and addressed the feedback from the reviewers and the editor. Our responses to each point can be found in the "Response to Reviewers."

Best regards,

You-Min Lu

Attachment

Submitted filename: Response to Reviewers.docx

pone.0313120.s001.docx (27.4KB, docx)

Decision Letter 1

Pirkko L Härkönen

22 Feb 2024

PONE-D-23-23146R1Is tamoxifen good enough for the Asian Population in post-menopausal women with early breast cancer?

A nationwide population-based cohort studyPLOS ONE

Dear Dr. Lu,

Thank you for submitting your revised manuscript to PLOS ONE. Although the presentation of the data and the manuscript generally have improved it does not yet, unfortunately, fully meet PLOS ONE’s publication criteria as it currently stands. Specifically, as pointed out in the first review, the status of the breast tumors classified as ER+,HER- should be certified. However, if it is not possible, the reasons and consequences should be thoroughly discussed and the the uncertainly included should be considered as a limitation in drawing conlusions. Secondly, as the external reviewer pointed out, the "targeted therapy" patients should br excluded from the Tam and AI arms because they may critically distort the results. This revision is mandatory. In addition, please consider adding a life-table with the numbers of patients at risk to the Kaplan-Meier plots.If you are able to complete the data as specified above and in the external reviewer's statement, we invite you to submit a re-revised version of the manuscript.

Please submit your revised manuscript by Apr 07 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Pirkko L. Härkönen, M.D., Ph.D.

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for the updated manuscript.

Major comments.

Data on tumor inherence is still lacking, unfortunately. The population should be restricted to those having an ER+/HER2- tumor. By now the variable "targeted therapy" can be used as a surrogate for HER2-status.

Targeted therapy was delivered to 696 of 7116 patients of which 613 (88%) were found in the AI arm. HER2 status is a strong prognostic factor in ER+ disease and the skewed proportion of patients having targeted therapy, implicated as HER2 positive disease, inbetween the two strata of endocrine therapy can putatively explain the improved outcome by tamoxifen. This is real-world data - not a randomized trial - so all baseline data must evaluated.

The limitation of not being able to select patients by ER+/HER2- status should be elaborated on in the Discussion and I do recommend to exclude all patients having "targeted therapy" as a surrogate for HER2 status.

The Kaplan-Meier plots are to be complemented by a life-table showing numbers at risk.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2024 Nov 27;19(11):e0313120. doi: 10.1371/journal.pone.0313120.r004

Author response to Decision Letter 1

8 Aug 2024

In response to the reviewers' comments, we have taken the following actions to address the concerns raised:

1. Certification of ER+, HER2- Status: We have reapplied for data from the Health and Welfare Data Science Center and obtained detailed information on tumor characteristics. We have now restricted our study population to those with ER-positive and HER2-negative status, as recommended.

2. Exclusion of Targeted Therapy Patients: We have excluded patients who received targeted therapy from our study's Tamoxifen (Tam) and Aromatase Inhibitor (AI) arms to prevent potential distortion of results. This revision has been implemented per the external reviewer's mandatory request.

3. Life-Table Addition: With the suggestion of enhancing our Kaplan-Meier plots, we added a life-table displaying the number of at-risk patients.

Attachment

Submitted filename: Response to Reviewers.docx

pone.0313120.s002.docx (17.9KB, docx)

Decision Letter 2

Pirkko L Härkönen

21 Oct 2024

Is tamoxifen good enough for the Asian Population in ER+ HER2- post-menopausal women with early breast cancer?

A nationwide population-based cohort study

PONE-D-23-23146R2

Dear Dr. You-Min Lu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication The required further analyses have been done properly and discussed and reported appropriately. The manuscript will be formally accepted for publication once it meets all outstanding technical requirements.

The second revision of the manuscript was careful, includes the data and analyses suggested, and appropriate interpretation and and discussion of the results. For my part, I apologize for the unintentional confusion and delay in handling the revised manuscript.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

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Kind regards,

Pirkko L. Härkönen, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Pirkko L Härkönen

18 Nov 2024

PONE-D-23-23146R2

PLOS ONE

Dear Dr. Lu,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

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If we can help with anything else, please email us at customercare@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Pirkko L. Härkönen

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

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    Submitted filename: Response to Reviewers.docx

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    pone.0313120.s002.docx (17.9KB, docx)

    Data Availability Statement

    The data that support the findings of this study are available from Taiwan's Ministry of Health and Welfare's Health and Welfare Data Center (HWDC). However, due to licensing restrictions, these data are not publicly accessible. Data access is restricted to individuals who register with the HWDC (https://www.apre.mohw.gov.tw/) and are Taiwanese nationals. For inquiries, please contact Mr. Yang at +886-2-85906805 or via email at stsung@mohw.gov.tw. Detailed descriptions of the databases used are provided in the Methods section, and the corresponding codebook is accessible at https://dep.mohw.gov.tw/DOS/lp-2503-113.html. By following the procedures outlined in the Methods section, the findings of this study can be replicated.

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