High Adherence to Adjuvant Endocrine Therapy Improves Outcome in Early Breast Cancer – Results from a Large Real-World Claims Data Analysis in Germany

Abstract

In hormone-receptor positive (HR+) early breast cancer (EBC), adjuvant endocrine therapy (ET) significantly reduces recurrence and mortality. A common means of estimating therapy adherence is to use patient-reported outcome measures. Yet, this method is inaccurate due to social-desirability bias. We therefore aimed to analyze adherence to ET over the first five years of treatment by using claims data from a large health insurance provider in Germany (AOK Baden-Wuerttemberg).
Female patients diagnosed with HR+ EBC who received inpatient treatment and breast cancer surgery between 1 July 2010 and 31 December 2019 were included in the analysis. Adherence to ET was defined as the ratio between the sum of the number of pills from filled prescriptions and the duration of ET in days (from the start of the first prescription after completing surgery and chemotherapy). ET use was observed over five years. Low adherence was defined as a ratio smaller than 0.8 and high adherence as a ratio larger than or equal to 0.8. Distant recurrence-free survival (DRFS) was calculated from the day of the first diagnosis of EBC until onset of distant recurrence. Overall survival (OS) was defined as the period between first diagnosis of EBC until death of any cause.
In total, 16642 patients with EBC were included. Of these patients, 4303 (86%) showed high adherence to ET in the first year after initiating treatment. After five years, high adherence persisted in 68% of patients. Continuous high adherence to ET had a significant impact on DRFS (HR: 0.66; 95% CI: 0.58–0.76, p > 0.0001) and OS (HR 0.52, 95% CI: 0.47–0.57, p < 0.0001).
In conclusion, adherence to ET is an independent risk factor that significantly influences DRFS and OS. Further real-world studies should explore the factors contributing to treatment discontinuation and evaluate prospective strategies to enhance adherence.

 

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Zusammenfassung

Bei Patientinnen mit hormonrezeptorpositivem (HR+) frühem Brustkrebs (EBC) reduziert die adjuvante endokrine Therapie (ET) signifikant das Rezidiv- und Mortalitätsrisiko. Eine gängige Methode zur Messung der Therapieadhärenz ist die direkte Befragung der Patientinnen, die jedoch ungenau sein kann. Daher war das Ziel dieser Studie, die Adhärenz zur ET über die ersten 5 Behandlungsjahre mithilfe von Abrechnungsdaten eines großen deutschen Krankenversicherers (AOK Baden-Württemberg) zu analysieren.
In die Analyse wurden weibliche Patientinnen mit der Diagnose HR+ EBC einbezogen, die zwischen dem 1. Juli 2010 und dem 31. Dezember 2019 eine stationäre Behandlung und eine Brustkrebsoperation erhielten. Die Adhärenz zur ET wurde als das Verhältnis zwischen der Summe der Tablettenanzahl aus eingelösten Rezepten und der Therapiedauer in Tagen definiert (beginnend mit der ersten Verschreibung nach Abschluss der Operation und Chemotherapie). Die Nutzung der ET wurde über 5 Jahre beobachtet. Eine niedrige Adhärenz lag bei einem Verhältnis von weniger als 0,8 vor, während eine hohe Adhärenz einem Verhältnis von 0,8 oder mehr entsprach. Das fernrezidivfreie Überleben (DRFS) wurde vom Tag der Erstdiagnose des EBC bis zum Auftreten eines Fernrezidivs berechnet. Das Gesamtüberleben (OS) wurde als der Zeitraum zwischen der Erstdiagnose und dem Tod jeglicher Ursache definiert.
Insgesamt wurden 16642 Patientinnen mit EBC in die Studie eingeschlossen. Davon zeigten 4303 (86%) im 1. Jahr nach Therapiebeginn eine hohe Adhärenz zur ET. Nach 5 Jahren hielten 68% der Patientinnen eine hohe Adhärenz aufrecht. Eine kontinuierlich hohe Adhärenz zur ET hatte einen signifikanten Einfluss auf das DRFS (HR: 0,66; 95%-KI: 0,58–0,76, p > 0,0001) und das OS (HR 0,52, 95%-KI: 0,47–0,57, p < 0,0001).
Zusammenfassend ist festzuhalten, dass die Adhärenz zur ET ein unabhängiger Risikofaktor ist, der DRFS und OS signifikant beeinflusst. Weitere Real-World-Analysen sollten die Faktoren, die zum Therapieabbruch beitragen, untersuchen und prospektive Strategien zur Verbesserung der Adhärenz evaluieren.

 

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Keywords

adherence - endocrine therapy - breast cancer - outcome

Schlüsselwörter

Adhärenz - endokrine Therapie - Brustkrebs - Behandlungsergebnis

Highlights

• This is the first German claims analysis to show the impact of adherence to endocrine therapy on recurrence and mortality.

• High adherence to endocrine therapy (ET) improves survival in early breast cancer.

• 68% maintained high adherence to ET after five years of treatment.

• Low adherence significantly increased risks of recurrence and mortality.

• Older age and higher comorbidities negatively impacted ET adherence.

Introduction

In women, breast cancer is the most common cancer type and the leading cause for cancer-related deaths in Germany and worldwide [1] [2]. Breast cancer can be divided into different subtypes by the expression of hormone receptors (HR) and the HER2 receptor. Patients with HR+ breast cancer account for approximately 80% of early breast cancer (EBC) cases. In addition to surgical tumorectomy, radiation therapy and, where appropriate, chemotherapy, adjuvant endocrine therapy (ET) is a key instrument in the treatment of HR+ EBC [3]. Large studies could demonstrate that adjuvant ET significantly improves overall survival (OS) and distant recurrence-free survival (DRFS) [4] [5] [6]. To date, the most frequently used adjuvant ET are tamoxifen and the aromatase inhibitors (AI) letrozole, anastrozole, and exemestane [7]. Both tamoxifen and AI can be used in combination with gonadotropin-releasing hormone (GnRH) analogues to suppress ovarian function in premenopausal patients [6]. Yet, adjuvant ET is accompanied by various side effects such as fatigue, joint pain, hot flashes, decreased libido, mood fluctuations, and many more [8]. Hence, several studies have demonstrated that adherence to ET decreases over time [9] [10].

Therapy adherence is defined as “the extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen”, whereas therapy persistence is “the duration of time from initiation to discontinuation of therapy” [11]. According to a report from the Centers for Disease Control and Prevention (CDC), high medication adherence is a public health priority and could reduce the economic and health burdens of many chronic diseases [12]. In contrast, medication nonadherence is associated with worsened clinical outcomes and avoidable health care expenditures, such as implementation of more diagnostic tests, unnecessary therapy escalation, and use of more expensive therapeutics [13] [14] [15]. Thus, different techniques to measure therapy adherence have been developed: subjective (e.g., self-reporting) and objective (e.g., analysis of secondary data) as well as direct (e.g., directly observed medication intake) and indirect (e.g., detection of drug metabolites in body fluids) methods can be distinguished [16]. However, the method used to assess therapy adherence has important implications for the results [17]. The prospective CANTO trial illustrated that patients with HR+ EBC report higher adherence rates in subjective self-reporting than objectively detected rates of ET metabolites in blood serum [18].

Adherence to adjuvant ET has been under investigation in multiple studies. Different factors that influence ET adherence could be identified: older age (> 65 years), younger age (< 45 years), higher comorbidity index, depression, and ET-associated side effects show a detrimental effect on ET adherence, whereas chemotherapy use, prior (non-breast-cancer) medication, and AI treatment have a beneficial effect on ET adherence [10] [19]. Moreover, tamoxifen metabolization by cytochrome P450 2D6 isoforms significantly decreases therapy efficacy in slow metabolizers and increases the occurrence of side effects in ultrarapid metabolizers, thereby negatively influencing therapy adherence [20].

This retrospective, secondary, real-world data analysis on adherence to adjuvant ET is among the largest that have been conducted so far and it is the first analysis with claims data from Germany. The breast cancer disease model has been validated in previous studies [21] [22] [23]. Aim of the present study was to determine adherence to adjuvant ET over the recommended period of five years. Furthermore, we evaluated the impact of adjuvant ET adherence on OS and DRFS and the factors influencing adjuvant ET adherence.

 

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Materials and Methods

This study is a retrospective claims data analysis from AOK Baden-Wuerttemberg, a large statutory health insurance provider in Germany. The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of Tuebingen University (380/2020BO). Data reporting follows the ESMO-GROW guideline [24].

Details of the dataset were reported in an earlier paper, to which we refer for more in-depth information [21]. Briefly, AOK Baden-Wuerttemberg provided a dataset consisting of 97121 patients with a documented breast cancer diagnosis (ICD10 code C50) between 2010 and 2020 (inclusive) and 94849 age-matched control patients in whom the ICD10 code for breast cancer was not used. The same exclusion criteria outlined earlier were applied to select for non-metastatic breast cancer patients who underwent breast cancer surgery [21]. Additionally, patients were matched as previously described, but in this study, a 1 : 2 matching ratio was used [21]. Follow-up data for all patients were available up to 31 December 2020.

Adherence measurement

To investigate adherence to adjuvant ET, all prescriptions with Anatomic Therapeutic Chemical (ATC) codes starting with L02BA (anti-estrogens such as tamoxifen or fulvestrant), L02BG (aromatase inhibitors such as letrozole or anastrozole), or L02AE (gonadotropin-releasing hormone analogues [GnRH analogues] such as goserelin and leuprorelin) were selected. Importantly, if patients had received GnRH analogues without further ET, they were excluded from the analysis as this medication can be used to suppress ovarian function during chemotherapy. Every prescription showed the ATC code, the fill date, the package size, and the specialty of the prescribing physician.

Secondary adherence to adjuvant ET, i.e., whether patients continued to adhere to therapy, was investigated. In line with the Continuous, Multiple Interval Measure of Medication Acquisition (CMA) method, prescriptions were grouped into therapy years and the package sizes of the prescriptions in each therapy year were summed and divided by 365.25 (except for the last therapy year, where the number of days from therapy year’s start to the last prescription was used) [16]. Three groups were defined to describe different patterns of adherence within the first five years of treatment: continuously low adherent were patients with an annual adherence below 0.8 in every therapy year; continuously high adherent were patients with an annual adherence above or equal to 0.8 in every therapy year; and mixed-adherent patients were those with an annual adherence below 0.8 in some years and above or equal to 0.8 in other years. To investigate why patients stopped adjuvant ET, three groups were defined: those that died within a half year of the last prescription (“death”), those that ended insurance (including reaching the date of 31 December 2020) within half a year of last prescription (“censored”), and the others that stopped therapy for no obvious reason that could be extrapolated from the secondary dataset (“stopped”). If patients died or were censored before completing five years of adjuvant ET, albeit having displayed continuous high adherence until death, they were classified as continuously high adherent.

 

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Statistical analysis

Data processing and statistical analysis were performed using R version 4.3.3 and RStudio (version 2024.04.0+735, Posit PBC, Boston, Massachusetts, USA) with the tidyverse packages dplyr 1.1.4, readr 2.1.5, forcats 1.0.0, stringr 1.5.1, ggplot2 3.5.1, tibble 3.2.1, lubridate 1.9.3, tidyr 1.3.1, and purrr 1.0.2. For generating tables, we used packages janitor 2.2.0, gt 0.11.0, and gtsummary 2.0.0. To calculate comorbidities, the R extension package comorbidity 1.1.0 was used. In detail, we used function comorbidity() with parameters map = “charlson_icd10_quan” and assign0 = TRUE followed by function score() with parameters weights = “quan” and assign0 = TRUE. Kaplan-Meier methodology was performed using the packages survival 3.7–0 and ggsurvfit 1.1.0 to estimate OS and DRFS together with the associated 95% confidence intervals (CI). Cox proportional hazards model was used to compute hazard ratios (HR). All p values were nominal and significance level was alpha = 0.05.

 

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Results

The in- and exclusion criteria as well as the included population were described in an earlier publication [21]. In total, 16642 patients with HR+ EBC that underwent breast cancer surgery were subjected to further analysis ([Table 1]). The majority of patients was between 50 and 79 years of age (72%), approximately 9% of the patients received HER2-targeted therapy, and in most patients (78%) the axillary lymph nodes were not involved. Furthermore, 71% of patients received radiation therapy and 32% systemic chemotherapy.

Table 1 Basic patient characteristics.

	n = 16642
Age at breast cancer diagnosis (years)
< 50	2908 (17%)
50ies	3978 (24%)
60ies	4285 (26%)
70ies	3580 (22%)
> 80	1891 (11%)
Urban density level
Rural	4340 (26%)
Suburban	5266 (32%)
Urban	7028 (42%)
Missing	8
Axillary lymph node involvement
No	12950 (78%)
Yes	3692 (22%)
Received HER2-targeted therapy
No	15143 (91%)
Yes	1499 (9%)
Radiation therapy
No	4824 (29%)
Yes	11818 (71%)
Chemotherapy
No	11376 (68%)
Yes	5266 (32%)

 

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Adherence to Adjuvant Endocrine Therapy in Baden-Wuerttemberg

[Fig. 1] shows the annual distribution of ET adherence. The proportion of patients with a high annual adherence (greater or equal to 0.8) was highest in year 1 (86%) but decreased to 82% in year 3 and to 68% in year 5 ([Fig. 1] a). For details, see Supplementary Table S1. [Fig. 1] b displays the reason for discontinuing therapy. The majority of patients discontinued adjuvant ET within the first five years (13142/16642; 79%) mainly because of being censored (6641/16642; 40%). Approximately 33% of all patients stopped ET (5494/16642), especially within the first year (year 1: 1794/16642; 11%) or after five years (year 5: 2181/16642; 13%). The number of patients that stopped treatment in between was relatively constant (year 2: 535/16642, 3%; year 3: 461/16642, 3%; and year 4: 523/16642, 3%). Of all patients, 6% died within the first five years (1007/16642). For further details, see Supplementary Table S2. [Fig. 1] c shows the distribution of the annual adherence rate: 7545/16642 patients (45%) were continuously high adherent; 1808/16642 patients (11%) were continuously low adherent; and 7289/16642 (44%) patients were mixed adherent.

Fig. 1 a Annual adherence to adjuvant endocrine therapy (ET) within the first five years of treatment. The sum of prescribed ET package sizes in each year was divided by 365.25. A ratio ≥ 0.8 was defined as high annual adherence. Annual adherence declined over time: In year 1, 86% of all patients showed a high adherence to adjuvant ET. This rate dropped to 84% in year 2, 80% in year 3, 82% in year 4, and to 68% in year 5. For further details, see Supplementary Table S1. b Reasons for discontinuing therapy. Therapy discontinuation was highest in year 5 and only few patients continued to take adjuvant ET for a longer duration than five years. In the first five years, 40% (6641/16642) of the patients were censored, 6% (1007/16642) died, and 33% (5494/16642) stopped using adjuvant ET. The largest proportion of patients stopped ET in year 1 and year 5. For further details, see Supplementary Table S2. c Continuous high, continuous low, and mixed adherence. In year 1, 14303/16642 patients (86%) showed a high adherence and 2339/16642 patients (14%) showed low adherence to adjuvant ET. Within the first five years of treatment, 7545/16642 patients (45%) were continuously high adherent, 1808/16642 (11%) were continuously low adherent, and 7289/16642 (44%) patients showed a mixed adherence to adjuvant ET.

Effect of patient adherence on distant recurrence-free and overall survival

The outcome parameters DRFS and OS were highly comparable between patients with mixed and continuous high adherence; therefore, these groups were merged in the subsequent analysis and compared to patients with continuous low adherence (for further details, see Supplementary Fig. S1). After a median follow-up of 5.8 years, a total of 1496 DRFS events were observed. Patients with mixed/continuously high adherence to ET had a statistically significant higher DRFS than patients with continuously low adherence (HR 0.66, 95% CI: 0.58–0.76, p > 0.0001, Cox regression), with 10-year DRFS rates of 83%, (mixed/continuously high adherence) versus 79% (continuously low adherence); [Fig. 2] a, Supplementary Table S3). During the observation period 1232 deaths were observed. OS was significantly improved in patients with mixed/continuously high adherence (HR 0.52, 95% CI: 0.47–0.57, p < 0.0001, Cox regression). The 10-year OS rate of patients with mixed/continuously high adherence decreased from 71% to 53% in patients with continuously low adherence ([Fig. 2] b, Supplementary Table S4).

Fig. 2 High adherence to adjuvant endocrine therapy influences distant recurrence-free survival and overall survival. a Distant recurrence-free survival. Kaplan-Meier curves of distant recurrence-free survival for patients with mixed/continuously high adherence to adjuvant endocrine therapy (blue) and continuously low adherence to adjuvant endocrine therapy (red). b Overall survival. Kaplan-Meier curves of overall survival for patients with mixed/continuously high adherence to adjuvant endocrine therapy (blue), continuously low adherence to adjuvant endocrine therapy (red), and the healthy, age-matched control groups for the mixed/continuously high adherence group (violet) and the continuously low adherence group (green).

[Table 2] displays a logistic regression model evaluating factors that influenced therapy adherence. Receiving the prescription for adjuvant ET from a general practitioner (odds ratio: 0.71, 95% CI: 0.59–0.84, p < 0.001) as well as undergoing radiation therapy (odds ratio: 0.21, 95% CI: 0.18–0.40, p < 0.001) were positively associated with mixed/continuously high adherence to adjuvant ET. A higher comorbidity index (odds ratio: −0.03, 95% CI: −0.05–−0.01, p = 0.0007), higher age (odds ratio: −0.02, 95% CI: −0.02–−0.02, p < 0.0001), and receiving the prescription from an oncologist (odds ratio: −0.95, 95% CI: −1.20–−0.64, p < 0.0001) had a negative impact on therapy adherence. HER2 status, axillary lymph node involvement, and having received chemotherapy had no impact on therapy adherence.

Table 2 Factors that influence mixed/continuously high adherence to adjuvant endocrine therapy versus continuously low adherence.

	log(OR)	95% CI	p value
CI = confidence interval; OR = odds ratio
Age (per 10 years)	−0.02	−0.02, −0.02	< 0.001
Estimated HER2 receptor expression
HER2−	–	–
HER2+	0.05	−0.15, 0.26	0.6
Axillary lymph node involvement
No	–	–
Yes	−0.05	−0.19, 0.09	0.5
Medical specialty
Gynecology	–	–
Oncology	−0.95	−1.2, −0.64	< 0.001
General practitioner	0.71	0.59, 0.84	< 0.001
Other	−0.46	−0.95, 0.10	0.087
Missing	−1.7	−2.0, −1.4	< 0.001
Radiation therapy
No	—	—
Yes	0.29	0.18, 0.40	< 0.001
Chemotherapy
No	—	—
Yes	0.12	−0.02, 0.25	0.10
Charlson comorbidity index	−0.03	−0.05, −0.01	0.007

 

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Discussion

This retrospective, secondary, real-world data analysis is the first to demonstrate that high adherence to adjuvant ET significantly improves OS and DRFS. The annual adherence rates for adjuvant ET (year 1: 86%, year 3: 82%, year 5: 68%) were slightly higher than previously reported data from Europe and the United States [19] [25] [26] [27] [28] [29] [30] [31] [32]. Although the first prescription for adjuvant ET is prescribed by gynecologists, our analysis revealed that the continuing prescription of adjuvant ET was predominantly performed by gynecologists (73% for patients under 50 years of age and 67% for patients over 50 years) and general practitioners (20% for patients under 50 and 29% for patients over 50) (Supplementary Table S5). These specialties provide low-threshold access for patients requiring repeat prescriptions and are well-equipped to deliver comprehensive patient care, including complementary medicine, which may enhance side-effect management. Interestingly, patients who received their prescriptions from general practitioners tended to exhibit higher adherence, whereas those who received prescriptions from oncologists showed lower adherence to adjuvant ET.

Adherence to adjuvant ET was measured indirectly and objectively by real-world data from a large health insurance provider in Germany (AOK Baden-Wuerttemberg) using the CMA method [16]. Hence, this analysis closely approximates the true adherence rate to adjuvant ET. Approximately 11% of all patients who filled the first prescription for adjuvant ET were unable to successfully and continuously use their medication in the first year.

Patients showing continuously low adherence to ET had a significantly worse prognosis in terms of DRFS and OS. Interestingly, the outcomes for patients who discontinued adjuvant ET after maintaining high adherence for at least one year were similar to those who maintained high adherence to ET over five years. As a result, these groups were combined for survival analysis. One possible explanation for this observation is that the largest drop in annual adherence occurred between years 4 and 5, with a decline from 82% to 68%. Although a dose-dependent effect of ET on prognosis is plausible, it could not be confirmed with the available dataset.

The 10-year OS rate among patients with high adherence to adjuvant ET aligns with the existing literature, showing 21–24% of breast cancer patients dying from any cause within 10 years [33]. Additionally, our analysis included age-matched controls without a breast cancer diagnosis. The results showed a comparable OS rate between the high-adherence group and its age-matched controls. In contrast, patients with continuously low adherence to adjuvant ET had a significantly worse OS than their age-matched controls. Similar effects of high and low adherence could be observed in patients that did not receive prior chemotherapy (Supplementary Fig. S3, Supplementary Tables S6–S8) and in patients below the age of 50 and receiving concurrent GnRH-analogue (Supplementary Fig. S4, Supplementary Tables S9–S11). While Cox regression analysis revealed an age-related effect on DRFS and OS, the findings underscore a clear adherence-related effect among patients who did not receive adequate adjuvant ET. The 10-year DRFS rate for patients with high adherence (17%) closely aligns with the existing literature, which reports a 10-year DRFS rate of 19–23% as described by the EBCTCG [33].

The World Health Organization (WHO) identifies five categories of factors that contribute to reduced medication adherence: socioeconomic factors, therapy-related factors, patient-related factors, condition-related factors, and health system/health care team-related factors [34]. In our analysis, higher age and a higher comorbidity index were associated with reduced adherence to adjuvant ET. In contrast, receiving radiation therapy and having adjuvant ET prescribed by a general practitioner positively influenced adherence ([Table 2]).

The model we used has several limitations. A key limitation of claims data is the absence of information regarding tumor receptor status. To address this, we used a proxy definition, identifying patients as HR-positive if they filled a prescription for adjuvant ET. This approach, however, prevents us from distinguishing between patients with low (1–9% estrogen receptor positivity) and higher levels of HR positivity. Furthermore, if a patient consistently receives and fills prescriptions for adjuvant ET but does not actually take the medication, adherence to ET may be overestimated. One potential solution to this issue could be to directly detect ET metabolites in body fluids [18]. To address the phenomenon of ‘white coat adherence,’ where patients only take their medication before scheduled tests [35], the use of electronic medication packaging devices has been proposed as an alternative [36]. Another limitation is the lack of data on subjective adherence measurements obtained through patient self-reporting. While subjective measurements often overestimate therapy adherence, they can provide valuable insights into the reasons for discontinuing therapy [17] [18]. Importantly, primary nonadherence to adjuvant ET cannot be analyzed using this dataset. If patients never filled a prescription for adjuvant ET, they could not be identified as HR+. Additionally, all patients included in the analysis were residents of Baden-Wuerttemberg, a state in southwestern Germany. As one of the wealthiest states in the country, Baden-Wuerttemberg’s higher socioeconomic status and the potentially greater self-efficacy of its residents may have influenced the results. Consequently, the comparability of these data to non-Western countries may be limited.

For high-risk, HR+/HER2− early breast cancer, adjuvant CDK 4/6 inhibitors are now a standard treatment in Germany, with approved options including ribociclib and abemaciclib. Patients receive this therapy for either two years (abemaciclib) or three years (ribociclib) in combination with adjuvant endocrine therapy [37] [38] [39] [40]. Evaluating patient adherence to these combination regimens is crucial, and future studies are needed to determine if adherence in a high-risk setting is comparable or superior to the treatment protocol described in this manuscript in Germany.

In conclusion, approximately two-thirds of patients who start ET remain adherent after five years. However, patients with low adherence face an increased risk of distant recurrence and death, highlighting the critical importance of maintaining high treatment adherence. Further real-world studies should explore the factors contributing to treatment discontinuation and evaluate prospective strategies — such as comprehensive care models, complementary medicine, and patient empowerment interventions — to enhance adherence. Additionally, establishing close collaboration between inpatient and outpatient healthcare providers, alongside end-payers, is essential for implementing clinical programs that sustainably improve adherence to adjuvant ET.

 

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Supplementary Material

• Supplementary Fig. S1: A Distant recurrence-free survival. Distant recurrence-free survival stratified after continuously high (blue), continuously low (red), and mixed adherence (green). B Overall survival. Overall survival stratified after continuously high (blue), continuously low (red), and mixed adherence (green) and their corresponding age-matched control groups (violet = control for high; brown = control for low; light blue = control for mixed).

• Supplementary Fig. S2: A Kaplan-Meier curves of distant recurrence-free survival stratified after mixed/continuously high (blue) and continuously low (red) adherence without axillary lymph nodes being involved. B Kaplan-Meier curves of overall survival stratified after mixed/continuously high (blue) and continuously low (red) adherence and their corresponding age-matched control groups (violet = control for mixed/continuously high; green = control for continuously low) for early breast cancer without axillary lymph nodes being involved. C Kaplan-Meier curves of distant recurrence-free survival stratified after mixed/continuously high (blue) and continuously low (red) adherence without axillary lymph nodes being involved. D Kaplan-Meier curves of overall survival stratified after mixed/continuously high (blue), continuously low (red) adherence, and their corresponding age-matched control groups (violet = control for mixed/continuously high; green = control for continuously low) for early breast cancer with axillary lymph nodes being involved.

• Supplementary Fig. S3: A Distant recurrence-free survival for patients not receiving prior chemotherapy. Distant recurrence-free survival stratified after continuously mixed/high (blue), continuously low (red) adherence. B Overall survival for patients not receiving prior chemotherapy. Overall survival stratified after continuously mixed/high (blue) and continuously low (red) adherence and their corresponding age-matched control groups (violet = control for mixed/high; green = control for low).

• Supplementary Fig. S4: A Distant recurrence-free survival for patients under the age of 50 receiving adjuvant ET plus GnRH-analogue. Distant recurrence-free survival stratified after continuously mixed/high (blue), continuously low (red) adherence. B Overall survival for patients under the age of 50 receiving adjuvant ET plus GnRH-analogue. Overall survival stratified after continuously mixed/high (blue) and continuously low (red) adherence and their corresponding age-matched control groups (violet = control for mixed/high; green = control for low).

• Supplementary Table S1: Yearly adjuvant endocrine therapy adherence.

• Supplementary Table S2: Reasons for endocrine therapy cessation stratified after years.

• Supplementary Table S3: Distant recurrence-free survival low vs. high adherence log-rank test.

• Supplementary Table S4: 5- and 10-year overall survival low vs. high adherence log-rank test.

• Supplementary Table S5: Prescribed adjuvant endocrine therapy and the prescribing medical specialty.

• Supplementary Table S6: Patient characteristics of patients not receiving prior chemotherapy.

• Supplementary Table S7: Distant recurrence-free survival low vs. mixed/high adherence log-rank test for patients not receiving prior chemotherapy.

• Supplementary Table S8: Overall survival low vs. mixed/high adherence log-rank test for patients not receiving prior chemotherapy.

• Supplementary Table S9: Patient characteristics of patients under the age of 50 receiving adjuvant ET plus GnRH-analogue.

• Supplementary Table S10: Distant recurrence-free survival low vs. mixed/high adherence log-rank test for patients under the age of 50 receiving adjuvant ET plus GnRH-analogue.

• Supplementary Table S11: Overall survival low vs. mixed/high adherence log-rank test for patients under the age of 50 receiving adjuvant ET plus GnRH-analogue.

 

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Declaration of Generative AI and AI-assisted technologies in the writing process

During the preparation of this work the authors used ChatGPT model 4.0 in order to optimize language, grammar and style. After using this service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

 

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Conflict of Interest

Dominik Dannehl – Honoraria from Gilead, Novartis, Daiichi Sankyo, Onkowissen.TV, Oncologics, AstraZeneca and Pfizer. Lea Volmer – Honoraria from Novartis. Tobias Engler – Honoraria from AstraZeneca, Eli Lilly, Daiichi Sankyo, Gilead, GSK, MDS, Novartis, Pierre Fabre, Pfizer, Roche, Stemline. Andreas Hartkopf – Honoraria from Roche, Novartis, Lilly, MSD, AstraZeneca, Agendia, Seagen, GSK, ExactScience, Riemser, Teva, Onkowissen.TV, Gilead, Menarini Stemline, Pfizer, Amgen, Pierre Fabre, Eisai, Daiichi Sankyo, Thieme, Veracyte, Springer. All remaining authors have no conflict of interest to declare.

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Publication History

Received: 20 July 2025

Accepted after revision: 17 August 2025

Article published online:
10 September 2025