# Side effects and adherence trajectories of adjuvant endocrine therapy in breast cancer patients: results from the VICAN2 study

Eqbal Radwan, Victoria Memoli, Lorène Seguin, Julien Mancini, Anne-Déborah Bouhnik

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Eqbal Radwan, Victoria Memoli, Lorène Seguin, Julien Mancini, Anne-Déborah Bouhnik. Side effects and adherence trajectories of adjuvant endocrine therapy in breast cancer patients: results from the VICAN2 study. Breast Cancer Research and Treatment, 2025, 215 (1), pp.30. 10.1007/s10549-025-07840-1 . inserm-05441929

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# Side effects and adherence trajectories of adjuvant endocrine therapy in breast cancer patients: results from the VICAN2 study

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# Side effects and adherence trajectories of adjuvant endocrine therapy in breast cancer patients: results from the VICAN2 study

Eqbal Radwan<fnref n="1" />, Victoria Memoli<fnref n="1" />, Lorène Seguin<fnref n="2" />, Julien Mancini<fnref n="1" />,<fnref n="3" />*, Anne-Déborah Bouhnik<fnref n="1" />

<footnote n="1">¹Aix-Marseille Univ, Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, Équipe Calipso labélisée Ligue 2024, ISSPAM, Marseille, France.</footnote>

<footnote n="2">²Aix-Marseille Univ, Institut Paoli-Calmettes, Département d'Oncologie Médicale, Marseille, France.</footnote>

<footnote n="3">³Aix-Marseille Univ, Assistance Publique - Hôpitaux de Marseille, Hôpital Sainte Marguerite, BioSTIC, Biostatistique et Technologies de l'Information et de la Communication, Marseille, France.</footnote>

<footnote>*corresponding author: Julien Mancini; email: julien.mancini@univ-amu.fr</footnote>

<footnote>Prof. Julien Mancini, MD, PhD</footnote>

<footnote>UMR1252 SESSTIM (Aix-Marseille Univ)</footnote>

<footnote>Calipso research team: Fight against Inequities in Cancer Prevention and Care</footnote>

<footnote>Institut Paoli-Calmettes</footnote>

<footnote n="232">232 Bd Ste Marguerite, BP 156</footnote>

<footnote n="13273">13273 Marseille Cedex 9, FRANCE</footnote>

<footnote>E-mail: julien.mancini@univ-amu.fr</footnote>

<footnote>Telephone: +33 4 91 22 35 02</footnote>
**Abstract**

**Purpose:** Adjuvant endocrine therapy (AET) lowers breast cancer recurrence risk and improves overall survival. However, some women have suboptimal adherence, mainly due to difficulties coping with side effects. We identified different long-term AET adherence trajectories and investigated associated side effects.

**Methods:** We used multisource data from the French national VICAN2 study, which interviewed women two years after breast cancer diagnosis. We measured AET adherence using the monthly proportion of days covered (PDC) over 41 months (median) after enrolment in VICAN2. Group-Based Trajectory Modelling (GBTM) helped identify adherence trajectory groups.

**Results:** The 637 women included were categorized into three trajectories: continuous optimal adherence (70.6%), late non-adherence (19.8%), and near-simultaneous discontinuation (9.6%). The most common side effects were hot flashes (78.2%) and joint pain (74.4%). Living alone, always or regularly feeling sad or blue, not receiving chemotherapy, and switching AET were all associated with increased odds of belonging to the near-simultaneous discontinuation group. Younger age (44-54 years), low household income, no contact with a social worker, not receiving chemotherapy, being first prescribed aromatase inhibitors for AET, always experiencing hot flashes, and occasionally experiencing joint pain were all associated with increased odds of belonging to the late non-adherence group.

**Conclusion:** This study provides valuable insight into the dynamics of AET adherence patterns and related side effects. Identifying women who experience hot flashes and joint pain two years after diagnosis may strongly predict future non-adherence. Managing these side effects could foster long-term adherence and optimise health outcomes.

**Keywords:** Adjuvant endocrine therapy (AET), VICAN2 study, breast cancer, side effects, Group-based trajectory modelling (GBTM).
**Introduction**

Breast cancer mortality rates have greatly declined in the past two decades; today, patients living with this disease constitute the largest group of cancer survivors [1]. Approximately 70% of breast cancers are hormone receptor-positive; one of the main treatments for this typology is estrogen deprivation, also known as Adjuvant Endocrine Therapy (AET). Tamoxifen and aromatase inhibitors are the most widely used AET medications [2]. Patients with breast cancer are recommended to take AET on a daily basis for at least five years, as it increases overall survival and reduces the risk of recurrence [3]. Despite these advantages, AET is associated with distressing acute side effects that can impair social functioning and lower quality of life, and result in poor treatment adherence and discontinuation [4,5]. Hot flashes and joint pain are two commonly reported vasomotor side effects [3,6], which also have a psychological impact [7,8]. This underlines the importance of effective control of these side effects and of providing tailored mental health care.

Adherence to AET is a crucial factor for achieving optimal health outcomes. However, among other factors, difficulties coping with treatment side effects can lead to poor adherence and/or discontinuation and psychosocial challenges [5]. A meta-analysis found that 31.3% of women discontinue aromatase inhibitors, while 47.1% did not persist with prescribed tamoxifen for the recommended five years [9]. Psychological and emotional challenges further exacerbate adherence problems. Patients with mental health disorders have poor adherence and high rates of discontinuation [5], particularly when there is limited communication with healthcare providers on how to manage side effects [10].

Evidence on long-term AET adherence two years after diagnosis is very limited [11]. Most studies use a single summary measure to estimate adherence, such as the percentage of non-persistent women or the proportion of days covered (PDC), to classify patients as either adherent or not [11-13]. However, these binary classifications can sometimes conceal unique adherence behaviours. Group-based trajectory modelling (GBTM) addresses this issue by analysing adherence over the long term. It identifies and tracks diverse adherence trajectories; the results of GBTM can inform the design of different experimental targeted interventions and allow researchers to examine the impact of each intervention on health outcomes for a specific trajectory [14].

Although previous studies identified side effects and examined adherence in the context of AET, none specifically examined which side effects are associated with different adherence trajectories. Furthermore, of the few studies to date using GBTM to assess AET adherence, all focused on specific time frames, such as the first year following the treatment initiation [15] or the whole recommended five-year period [16,17]. Accordingly, the present study aimed to: (1) identify AET adherence trajectories two years after breast cancer diagnosis until the end of the five-year minimum recommended treatment period; (2) investigate AET-related side effects and other factors associated with belonging to each of these trajectories.

**Methods**

**Study design**

We performed a cohort analysis using data from the French nationwide VICAN2 study (La Vié 2 ans après un diagnostic de CANcer), which focused on patients two years after diagnosis [19]. The methodology used in VICAN2 is described in detail elsewhere [18,19]. It used two data sources: (1) the SNIIR-AM (Système national d'information inter-régimes de l'Assurance maladie) national medico-administrative database, which contains detailed information about France's health insurance expenditure schemes, including prescribed drugs and hospital discharge records, and (2) telephone interviews conducted two years after diagnosis.

The VICAN2 telephone interviews were administered by trained professional interviewers from a national survey research institute using Computer-Assisted Telephone Interviews (CATI) and a standardized questionnaire. Each interview had an average time of 40 minutes. The survey collected a wide range of patient-reported information, including sociodemographic characteristics (e.g., marital and family status, household income, employment), psychosocial factors (e.g., feelings of sadness or blue, social support, contact with a social worker), treatment-related experiences, perceived sequelae of cancer, fatigue, pain, quality of life, health behaviors (e.g., tobacco and alcohol use), daily life and social participation, and side effects related to treatment. Simultaneously, clinical and medical information regarding cancer location and treatments was obtained through a paper questionnaire completed by the physician who had initiated the patient's cancer treatment.

**Study sample**
All adult individuals residing in metropolitan France affiliated with one of the country's three major health insurance schemes, and diagnosed with a first cancer at one of 12 tumour sites (including breast cancer) between 1 January 2010 and 30 June 2010, were eligible for inclusion in VICAN 2. A stratified random sample of 16,429 people (including 4,017 women with breast cancer) was selected from the 60,490 individuals with cancer (all types, including 18,572 women with breast cancer). Of these, 4,349 patients were eligible and agreed to participate (including 1,350 women with breast cancer) (Figure 1). The response rate of women with breast cancer to VICAN2 was 41.4% [18].

Patients older than 82 years were excluded for practical reasons. As the main objective of the VICAN survey was investigating barriers to and drivers of return to work, patients younger than 52 years at diagnosis were deliberately oversampled. Accordingly, two age strata were defined (18–52 and 53–82 years at diagnosis) with equal allocation. This oversampling strategy explains the relatively young mean age of our sample (50 years) [18].

**Inclusion criteria for the present analysis**

For the present analysis, we included women covered by the *Caisse Nationale de l'Assurance Maladie des Travailleurs Salariés* (CNAMTS) – which is France's main national health insurance scheme and covers 87% of the population – during the follow-up period, who were registered in the Long Duration Disease (ALD) patient file with breast cancer, as identified by the International Classification of Diseases 10th edition (ICD-10) codes C50XX [20], and for whom AET was dispensed under Anatomical Therapeutic Chemical (ATC) codes L02BA01, L02BG03, L02BG04, and L02BG06 at least once in the first 12 months following breast cancer diagnosis. Patients registered in the ALD file benefit from 100% free-of-charge care management and a special care protocol.

**Exclusion criteria for the present analysis**

Women not covered by CNAMTS over the follow-up period, those who had a second cancer (ICD-10 CXX) or metastasis (ICD-10 C77-C79) between diagnosis and the end of the first month following AET initiation, and those who had used AET in the 12 months before diagnosis, were all excluded from the present analysis. Women who stopped taking AET between the end of the first month of treatment and the moment the VICAN2 survey was conducted (i.e., at two years post-diagnosis) were also excluded. Although women with metastatic disease may receive AET, they were not included in the present analysis because in this case, the therapy is used to treat active cancer, which could lead to potentially different adherence issues.
<figure><img src="image_2.png" /><figcaption>**Figure 1.** Procedure for sampling and inclusion of VICAN 2's participants. AET: Adjuvant Endocrine Therapy; ALD: Long Duration Disease; ATC: Anatomical Therapeutic Chemical Classification System; CNAMTS: *Caisse Nationale de l'Assurance Maladie des Travailleurs Salariés*; ICD-10: International Classification of Diseases, 10th edition.</figcaption></figure>
# Study variables

## AET Adherence

We measured AET adherence using monthly PDC, which we computed by dividing the number of days a woman had a supply of AET by 30. This calculation was based on the actual days of supply recorded in the SNIIR-AM database, which contained all refill dates for prescriptions. The PDC accounted for all days with AET availability, including periods of overlapping supply when both the refill and remaining supply were available. To address overlapping prescriptions, the supply periods were adjusted so that the new supply period began the day after the last day covered by the previous refill. The numerator represented the total number of days covered by AET prescriptions each month, while the denominator was fixed at 30 days. AET adherence was computed each month as a continuous measure ranging from 0 (no medication taken) to 1 (optimal adherence over the month). Women were followed for five years (i.e. the minimum required duration of AET) or until a censoring event occurred (metastasis, second cancer, or death). Using these data, we created a supply diary for each patient, starting from the index date (i.e., first AET registration) until the end of the AET (i.e., five years after initiation). For the present analysis, we considered AET adherence over the period starting from the month after the VICAN2 survey took place (i.e., at two years post-treatment initiation) until the end of AET (Figure 2).

<figure><img src="image_3.png" /><figcaption>Figure 2. Study timeline: side effect detection and adherence trajectory periods.</figcaption></figure>

## Side effects

The VICAN2 questionnaire included questions about side effects and perceived breast cancer sequelae. Participants were asked whether they had experienced the following side effects in the previous week: hot flashes, excessive sweating, heavy legs, joint pain, and aching muscles. These items were self-reported and derived from a symptom-specific checklist developed for the VICAN survey.

## Other variables

Data on sociodemographic and healthcare-related variables were collected through telephone interviews; these variables included age at diagnosis, marital status, household income at the time of the VICAN2 survey, family status, contact with a social worker since diagnosis, feelings of being sad and blue, and whether the patient had chemotherapy and/or radiotherapy. Other variables were obtained from the SNIIRAM database, including the first type of AET received (i.e., tamoxifen or aromatase inhibitors), whether the patient had switched AET, and the use of anxiolytics.

## Statistical analysis
## Group-based trajectory modelling (GBTM)

We performed GBTM to identify AET adherence trajectories using a censored normal model [21,22]. AET adherence for each participant was assessed using the continuous monthly PDC, which was computed starting from the month following the VICAN2 interview until the end of the 5-year AET period, with data censored at the onset of a second cancer, metastasis, or death. The probability of membership in a given AET adherence trajectories was calculated based on the monthly PDC, and each woman was classified into the trajectory group she had the highest membership probability. To determine the number and order of trajectories we initially fitted multiple models sequentially to identify the appropriate number of trajectories. We subsequently made visual inspections and assessed the shapes of the different trajectories by considering constant, linear, quadratic, and cubic functional forms.

Since interpreting or utilizing more than six adherence trajectory groups would have been challenging in terms of ensuring clear interpretation of the results, we estimated multiple models with various numbers of trajectories. We used second-order and third-order polynomials to represent the probability of adherence for each woman within each trajectory. After comparing the estimated adherence trajectories, we concluded that the third-order model provided the best fit. To determine the optimal number of adherence trajectories, we utilized the Bayesian Information Criterion (BIC) and the Bayes Factor (B10). A higher BIC value indicates a better model fit, while a value of two times the log Bayes Factor [2 logBF] indicated that a model comprising more trajectories than another model would be preferable [23].

We verified the fit of the selected model using the following criteria: (1) the average posterior probability of assignment (APPA), with an acceptable threshold set at an APPA > 0.7; (2) an Odds of Correct Classification (OCC) of 5 or greater; and (3) a difference between the estimated probability of group membership and the proportion assigned to that group close to 0. The GBTM was performed using Stata 14 software with the traj command.

## Factors associated with trajectories

Categorical variables were summarized as frequencies and proportions. The chi-squared test was used to determine significant differences between AET adherence trajectories with respect to categorical variables. Multinomial logistic regression was used to identify factors associated with specific trajectories in comparison to the reference group (i.e., the most adherent trajectory). We estimated 95% confidence intervals (CIs) and odds ratios (ORs) for the univariate and multivariate models. Variables with a p-value < 0.10 in the univariate analysis were included in the multivariate analysis model using a stepwise procedure. Only variables with a p-value < 0.05 were retained in the final model. Data were analysed using SPSS v.27.

## Results

### Description of the study population

The present analysis included 637 eligible women; mean age at the time of breast cancer diagnosis was 50.3 (SD = 10.9) years, and 45.4% of the sample were aged 44-54 years at the time of the VICAN 2 survey (Table 1). Moreover, at the time of the survey, 68.0% were married or cohabiting, 73.3% had moderate to high household income, and 49.1% had at least one dependent child. Most of the participants (80.2%) reported no contact with a social worker after their diagnosis. More than half (57.8%) reported that their doctor provided them with a document outlining their personalized care program and treatment schedule during the diagnostic consultation. Additionally, 57.4% reported regularly feeling sad and blue in the previous four weeks and 42.9% had taken anxiolytics since diagnosis.

The results also showed that 56.7% of the sample had chemotherapy, and 91.8% radiotherapy. With regard to the first prescribed AET, 64.8% had been prescribed tamoxifen. Additionally, 59.8% switched their AET type during treatment. Before the VICAN2 survey, the median time on AET was 19 months (IQR: 17-22).

### GBTM Models

We identified AET adherence trajectory models ranging from 2 to 7 trajectories (supplementary file 1). Based on the criteria mentioned above, the three-group model was determined to be the most suitable for our sample
(Figure 3). We named the three identified trajectories as follows: (1) Near-simultaneous discontinuation (n=61; 9.6%): this trajectory comprised a majority of women who had stopped AET in the first six months after the VICAN2 survey started; (2) Continuous optimal adherence (n=450; 70.6%): this trajectory comprised a majority of women who adhered to AET for more than 95% of the time; (3) Late non-adherence (n=126: 19.8%): this trajectory comprised a majority of women who initially were moderately to optimally adherent but who gradually became less adherent six months after the VICAN2 survey. AET adherence among women across the three trajectories ranged from 0% to 100%, measured over a median period of 41 months (IQR: 38-44) from the start of the VICAN2 survey until the end of the 5-year AET (Figure 2).

<figure><img src="image_4.png" /><figcaption>Figure 3. Three-group based AET adherence trajectory model at two years post-diagnosis (the VICAN2 survey, n = 637).</figcaption></figure>

## Characteristics of AET adherence trajectory groups

Women who lived alone (45.9%, p = 0.032), those whose first AET prescription was tamoxifen (70.5%, p = 0.004), and those who switched AET (72.1%, p = 0.016) were more prevalent in the near-simultaneous discontinuation trajectory than to the two other trajectory groups (Table 1). The continuous optimal adherence group had the highest proportions of women who were married (70.4%, p = 0.032), who had moderate or high income (76.2%, p = 0.036), and were initially treated with chemotherapy (60.7%, p = 0.002). The late non-adherence group had the highest proportion of women who reported no contact with a social worker after diagnosis (88.1%, p = 0.041), who had a low household income (34.1%, p = 0.036), who were first prescribed aromatase inhibitors (47.6%, p = 0.004), and who did not switch AET (49.5%, p = 0.016).

**Table 1.** Patients’ sociodemographic and healthcare-related variables according to their AET adherence trajectories; the VICAN2 survey, n=637.
<table><thead><tr><th rowspan="3">Variables</th><th colspan="2">Trajectory 1</th><th colspan="2">Trajectory 3</th><th rowspan="3">Total</th><th rowspan="3">p-value</th></tr><tr><th>Near-<br>simultaneous<br>discontinuation</th><th>Continuous<br>Optimal<br>Adherence</th><th>Late non-<br>adherence</th><th></th></tr><tr><th>n(%)</th><th>n(%)</th><th>n(%)</th><th>n(%)</th></tr></thead><tbody><tr><td></td><td>61(9.6%)</td><td>450(70.6%)</td><td>126(19.8%)</td><td>637(100.0%)</td><td></td><td></td></tr><tr><td>Age at diagnosis (years)</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; 44</td><td>21(34.4%)</td><td>126(28.0%)</td><td>24(19.0%)</td><td>171(26.8%)</td><td rowspan="4">0.222</td></tr><tr><td>44-54</td><td>25(41.0%)</td><td>202(44.9%)</td><td>62(49.2%)</td><td>289(45.4%)</td></tr><tr><td>55-65</td><td>6(9.8%)</td><td>71(15.8%)</td><td>25(19.8%)</td><td>102(16.0%)</td></tr><tr><td>&gt; 65</td><td>9(14.8%)</td><td>51(11.3%)</td><td>15(11.9%)</td><td>75(11.8%)</td></tr><tr><td>Marital status at the time of the VICAN2 survey</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Married or cohabitation</td><td>33(54.1%)</td><td>317(70.4%)</td><td>83(65.9%)</td><td>433(68.0%)</td><td rowspan="2">0.032</td></tr><tr><td>Single, divorced, separated, or widowed</td><td>28(45.9%)</td><td>133(29.6%)</td><td>43(34.1%)</td><td>204(32.0%)</td></tr><tr><td>Household income per consumption unit at the time of the VICAN 2 survey</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Low income</td><td>20(32.8%)</td><td>107(23.8%)</td><td>43(34.1%)</td><td>170(26.7%)</td><td rowspan="2">0.036</td></tr><tr><td>Moderate to high income</td><td>41(67.2%)</td><td>343(76.2%)</td><td>83(65.9%)</td><td>467(73.3%)</td></tr><tr><td>Family status at the time of the VICAN 2 survey</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No children</td><td>11(18.0%)</td><td>57(12.7%)</td><td>13(10.3%)</td><td>81(12.7%)</td><td rowspan="3">0.115</td></tr><tr><td>At least one dependent child</td><td>30(49.2%)</td><td>230(51.1%)</td><td>53(42.1%)</td><td>313(49.1%)</td></tr><tr><td>No dependent children</td><td>20(32.8%)</td><td>163(36.2%)</td><td>60(47.6%)</td><td>243(38.1%)</td></tr><tr><td>Following your illness, did you have any contact with a social worker?</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>15(24.6%)</td><td>95(21.1%)</td><td>15(11.9%)</td><td>125(19.6%)</td><td rowspan="2">0.041</td></tr><tr><td>No</td><td>46(75.4%)</td><td>354(78.7%)</td><td>111(88.1%)</td><td>511(80.2%)</td></tr><tr><td>During the past four weeks, have there been times when you felt sad and blue?</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Often/Always</td><td>42(68.9%)</td><td>258(57.5%)</td><td>65(51.6%)</td><td>365(57.4%)</td><td rowspan="2">0.082</td></tr><tr><td>Never/Rarely</td><td>19(31.1%)</td><td>191(42.5%)</td><td>61(48.4%)</td><td>271(42.6%)</td></tr><tr><td>Initially treated with chemotherapy</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>24(39.3%)</td><td>274(60.9%)</td><td>63(50.0%)</td><td>361(56.7%)</td><td rowspan="2">0.002</td></tr><tr><td>No</td><td>37(60.7%)</td><td>176(39.1%)</td><td>63(50.0%)</td><td>276(43.3%)</td></tr><tr><td>Initially treated with radiotherapy</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>55(90.2%)</td><td>416(92.4%)</td><td>114(90.5%)</td><td>585(91.8%)</td><td>0.684</td></tr></tbody></table>
<table><thead><tr><th rowspan="3">Variables</th><th colspan="2">Trajectory 1</th><th colspan="2">Trajectory 3</th><th rowspan="3">Total</th><th rowspan="3">p-value</th></tr><tr><th>Near- simultaneous discontinuation</th><th>Continuous Optimal Adherence</th><th>Late non- adherence</th><th></th></tr><tr><th>n(%)</th><th>n(%)</th><th>n(%)</th><th>n(%)</th></tr></thead><tbody><tr><td></td><td>61(9.6%)</td><td>450(70.6%)</td><td>126(19.8%)</td><td>637(100.0%)</td><td></td></tr><tr><td>No</td><td>6(9.8%)</td><td>34(7.6%)</td><td>12(9.5%)</td><td>52(8.2%)</td><td></td></tr><tr><td colspan="7">Type of AET first prescribed</td></tr><tr><td>Tamoxifen</td><td>43(70.5%)</td><td>304(67.6%)</td><td>66(52.4%)</td><td>413(64.8%)</td><td rowspan="2">0.004</td></tr><tr><td>Aromatase inhibitors</td><td>18(29.5%)</td><td>146(32.4%)</td><td>60(47.6%)</td><td>224(35.2%)</td></tr><tr><td colspan="7">Switched AET during the whole study period</td></tr><tr><td>Yes</td><td>44(72.1%)</td><td>273(60.7%)</td><td>64(50.8%)</td><td>381(59.8%)</td><td rowspan="2">0.016</td></tr><tr><td>No</td><td>17(27.9%)</td><td>177(39.3%)</td><td>62(49.2%)</td><td>256(40.2%)</td></tr><tr><td colspan="7">Used Anxiolytics</td></tr><tr><td>Before diagnosis</td><td>19(31.1%)</td><td>123(27.3%)</td><td>33(26.2%)</td><td>175(27.5%)</td><td rowspan="3">0.254</td></tr><tr><td>After diagnosis</td><td>18(29.5%)</td><td>198(44.0%)</td><td>57(45.2%)</td><td>273(42.9%)</td></tr><tr><td>Never</td><td>24(39.3%)</td><td>129(28.7%)</td><td>36(28.6%)</td><td>189(29.7%)</td></tr></tbody></table>

## Side effects of AET according to trajectory

Among the five side effects assessed, hot flashes (78.2%) and joint pain (74.4%) were the two most commonly reported (followed by excessive sweating (65.1%), heavy legs (63.8%), and muscle aches (62.9%)) (Table 2). The late non-adherence group had the highest percentage of women who had always experienced hot flashes (40.5%, p = 0.001) and who had always (26.2%) or often (26.2%) experienced excessive sweating (p = 0.025).

<table><caption>Table 2. Patients self-reported side effects of AET - the VICAN2 survey, n=637.</caption><thead><tr><th rowspan="3">Variables</th><th colspan="2">Trajectory 1</th><th colspan="2">Trajectory 3</th><th rowspan="3">Total</th><th rowspan="3">p-value</th></tr><tr><th>Near- simultaneous discontinuation</th><th>Continuous Optimal Adherence</th><th>Late non-adherence</th><th></th></tr><tr><th>n(%)</th><th>n(%)</th><th>n(%)</th><th>n(%)</th></tr></thead><tbody><tr><td></td><td>61(9.6%)</td><td>450(70.6%)</td><td>126(19.8%)</td><td>637(100.0%)</td><td></td></tr><tr><td colspan="7">In the past 7 days, have you experienced the following symptom: hot flashes?</td></tr><tr><td>Always</td><td>15(24.6%)</td><td>150(33.3%)</td><td>51(40.5%)</td><td>216(33.9%)</td><td rowspan="4">0.001</td></tr><tr><td>Often</td><td>9(14.8%)</td><td>124(27.6%)</td><td>35(27.8%)</td><td>168(26.4%)</td></tr><tr><td>Occasionally</td><td>11(18.0%)</td><td>81(18.0%)</td><td>22(17.5%)</td><td>114(17.9%)</td></tr><tr><td>Never</td><td>26(42.6%)</td><td>95(21.1%)</td><td>18(14.3%)</td><td>139(21.8%)</td></tr><tr><td colspan="7">In the past 7 days, have you experienced the following symptom: excessive sweating?</td></tr><tr><td>Always</td><td>13(21.3%)</td><td>98(21.8%)</td><td>33(26.2%)</td><td>144(22.6%)</td><td rowspan="2">0.025</td></tr><tr><td>Often</td><td>5(8.2%)</td><td>104(23.2%)</td><td>33(26.2%)</td><td>142(22.3%)</td></tr></tbody></table>
<table><thead><tr><th rowspan="3">Variables</th><th colspan="2">Trajectory 1</th><th colspan="2">Trajectory 2</th><th rowspan="3">Total</th><th rowspan="3">p-value</th></tr><tr><th colspan="2">Near-simultaneous discontinuation</th><th colspan="2">Continuous Optimal Adherence</th></tr><tr><th>n(%)</th><th>n(%)</th><th>n(%)</th><th>n(%)</th></tr></thead><tbody><tr><td></td><td>61(9.6%)</td><td>450(70.6%)</td><td>126(19.8%)</td><td>637(100.0%)</td><td></td><td></td></tr><tr><td>Occasionally</td><td>11(18.0%)</td><td>93(20.7%)</td><td>24(19.0%)</td><td>128(20.1%)</td><td></td><td></td></tr><tr><td>Never</td><td>32(52.5%)</td><td>154(34.3%)</td><td>36(28.6%)</td><td>222(34.9%)</td><td></td><td></td></tr><tr><td colspan="7">In the past 7 days, have you experienced the following symptom: heavy legs?</td></tr><tr><td>Always</td><td>14(23.0%)</td><td>62(13.8%)</td><td>17(13.5%)</td><td>93(14.6%)</td><td rowspan="4">0.440</td><td></td></tr><tr><td>Often</td><td>11(18.0%)</td><td>123(27.4%)</td><td>38(30.2%)</td><td>172(27.0%)</td></tr><tr><td>Occasionally</td><td>15(24.6%)</td><td>99(22.0%)</td><td>27(21.4%)</td><td>141(22.2%)</td></tr><tr><td>Never</td><td>21(34.4%)</td><td>165(36.7%)</td><td>44(34.9%)</td><td>230(36.2%)</td></tr><tr><td colspan="7">In the past 7 days, have you experienced the following symptom: joint pain?</td></tr><tr><td>Always</td><td>16(26.2%)</td><td>112(24.9%)</td><td>36(28.6%)</td><td>164(25.8%)</td><td rowspan="4">0.270</td><td></td></tr><tr><td>Often</td><td>16(26.2%)</td><td>145(32.3%)</td><td>41(32.5%)</td><td>202(31.8%)</td></tr><tr><td>Occasionally</td><td>10(16.4%)</td><td>70(15.6%)</td><td>27(21.4%)</td><td>107(16.8%)</td></tr><tr><td>Never</td><td>19(31.1%)</td><td>122(27.2%)</td><td>22(17.5%)</td><td>163(25.6%)</td></tr><tr><td colspan="7">In the past 7 days, have you experienced the following symptom: muscle aches?</td></tr><tr><td>Always</td><td>5(8.2%)</td><td>60(13.4%)</td><td>19(15.1%)</td><td>84(13.2%)</td><td rowspan="4">0.483</td><td></td></tr><tr><td>Often</td><td>14(23.0%)</td><td>121(26.9%)</td><td>34(27.0%)</td><td>169(26.6%)</td></tr><tr><td>Occasionally</td><td>12(19.7%)</td><td>109(24.3%)</td><td>26(20.6%)</td><td>147(23.1%)</td></tr><tr><td>Never</td><td>30(49.2%)</td><td>159(35.4%)</td><td>47(37.3%)</td><td>236(37.1%)</td></tr></tbody></table>

## Factors associated with trajectory groups

Living alone (aOR = 2.02), always or often feeling sad or blue (aOR = 2.03), not having received chemotherapy (aOR = 2.58), and switching AET (aOR = 2.54) were all associated with increased odds of belonging to the near-simultaneous discontinuation trajectory group (Table 3). In contrast, women who took anxiolytics since diagnosis (aOR = 0.43) and those who always (aOR = 0.35) or often (aOR = 0.23) experienced hot flashes were less likely to belong to this group.

Several factors were associated with increased odds of belonging to the late non-adherence trajectory group. These included younger age (44-54 years, aOR = 2.18), low household income (aOR = 1.87), no contact with a social worker (aOR = 1.89), not receiving chemotherapy (aOR = 1.69), being first prescribed aromatase inhibitors for AET (aOR = 3.56), always experiencing hot flashes (aOR = 2.00), and occasionally experiencing joint pain (aOR = 1.99).

**Table 3.** Association between sociodemographic and healthcare-related characteristics and AET adherence trajectories; the VICAN2 survey, n=637.
<table><thead><tr><th rowspan="3"></th><th colspan="4">Univariate analysis</th><th colspan="4">Multivariate analysis</th></tr><tr><th colspan="2">Trajectory 1: Near-simultaneous discontinuation (n = 61) vs. Trajectory 2: Continuous Optimal Adherence (n = 450)</th><th colspan="2">Trajectory 3: late non-adherence (n = 126) vs. Trajectory 2: Continuous Optimal Adherence (n = 450)</th><th colspan="2">Trajectory 1: Near-simultaneous discontinuation (n = 61) vs. Trajectory 2: Continuous Optimal Adherence (n = 450)</th><th colspan="2">Trajectory 3: late non-adherence (n = 126) vs. Trajectory 2: Continuous Optimal Adherence (n = 450)</th></tr><tr><th>OR (95% CI)</th><th>P</th><th>OR (95% CI)</th><th>P</th><th>aOR (95% CI)</th><th>P</th><th>aOR (95% CI)</th><th>P</th></tr></thead><tbody><tr><td colspan="9"><strong>Age at diagnosis (years)</strong></td></tr><tr><td>&lt; 44</td><td>1.97(0.76-5.11)</td><td>0.162</td><td>0.54(0.28-1.01)</td><td>0.056</td><td>2.53(0.55-11.59)</td><td>0.229</td><td>2.06(0.79-5.36)</td><td>0.135</td></tr><tr><td>44-54</td><td>1.46(0.57-3.71)</td><td>0.422</td><td>0.87(0.50-1.49)</td><td>0.616</td><td>1.65(0.39-6.92)</td><td>0.488</td><td><strong>2.18(1.00-4.75)</strong></td><td><strong>0.049</strong></td></tr><tr><td>&gt; 65</td><td>2.08(0.69-6.23)</td><td>0.187</td><td>0.83(0.40-1.74)</td><td>0.631</td><td>1.49(0.47-4.72)</td><td>0.495</td><td>0.77(0.36-1.67)</td><td>0.523</td></tr><tr><td>55-65</td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td></tr><tr><td colspan="9"><strong>Marital status at the time of the survey</strong></td></tr><tr><td>Single, divorced, separated, or widowed</td><td><strong>2.02(1.17-3.48)</strong></td><td><strong>0.011</strong></td><td>1.23(0.81-1.88)</td><td>0.325</td><td><strong>2.02(1.11-3.68)</strong></td><td><strong>0.020</strong></td><td>1.11(0.71-1.75)</td><td>0.627</td></tr><tr><td>Married or cohabiting</td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td></tr><tr><td colspan="9"><strong>Household income per consumption unit at the time of the survey</strong></td></tr><tr><td>Low income</td><td>1.56(0.87-2.78)</td><td>0.129</td><td><strong>1.66(1.08-2.54)</strong></td><td><strong>0.020</strong></td><td>1.19(0.62-2.25)</td><td>0.594</td><td><strong>1.87(1.18-2.98)</strong></td><td><strong>0.008</strong></td></tr><tr><td>Moderate to high income</td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td></tr><tr><td colspan="9"><strong>Following your illness, did you have any contact with a social worker?</strong></td></tr><tr><td>No</td><td>0.82(0.44-1.53)</td><td>0.541</td><td><strong>1.98(1.10-3.56)</strong></td><td><strong>0.021</strong></td><td>0.66(0.32-1.36)</td><td>0.265</td><td><strong>1.89(1.00-3.56)</strong></td><td><strong>0.047</strong></td></tr><tr><td>Yes</td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td></tr><tr><td colspan="9"><strong>During the past 4 weeks, have there been times when you felt sad and blue?</strong></td></tr><tr><td>Always to often</td><td>1.63(0.92-2.90)</td><td>0.092</td><td>0.78(0.53-1.17)</td><td>0.241</td><td><strong>2.03(1.06-3.88)</strong></td><td><strong>0.031</strong></td><td>0.67(0.43-1.04)</td><td>0.079</td></tr><tr><td>Rarely to never</td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td></tr><tr><td colspan="9"><strong>Initially treated with chemotherapy</strong></td></tr><tr><td>No</td><td><strong>2.40(1.38-4.14)</strong></td><td><strong>0.002</strong></td><td><strong>1.55(1.04-2.31)</strong></td><td><strong>0.029</strong></td><td><strong>2.58(1.35-4.92)</strong></td><td><strong>0.004</strong></td><td><strong>1.69(1.08-2.66)</strong></td><td><strong>0.021</strong></td></tr><tr><td>Yes</td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td></tr><tr><td colspan="9"><strong>The type of first AET prescribed</strong></td></tr><tr><td>Aromatase inhibitors</td><td>0.87(0.48-1.56)</td><td>0.645</td><td><strong>1.89(1.26-2.82)</strong></td><td><strong>0.002</strong></td><td>1.80(0.48-6.68)</td><td>0.379</td><td><strong>3.56(1.48-8.52)</strong></td><td><strong>0.004</strong></td></tr><tr><td>Tamoxifen</td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td></tr><tr><td colspan="9"><strong>Switched AET during the study period</strong></td></tr><tr><td>Yes</td><td><strong>1.67(0.92-3.03)</strong></td><td><strong>0.086</strong></td><td><strong>0.66(0.45-0.99)</strong></td><td><strong>0.048</strong></td><td><strong>2.54(1.05-6.16)</strong></td><td><strong>0.038</strong></td><td>1.15(0.60-2.19)</td><td>0.671</td></tr><tr><td>No</td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td></tr><tr><td colspan="9"><strong>Used Anxiolytics</strong></td></tr><tr><td>Before diagnosis</td><td>0.83(0.43-1.59)</td><td>0.575</td><td>0.96(0.56-1.63)</td><td>0.885</td><td>0.66(0.31-1.37)</td><td>0.268</td><td>1.11(0.62-1.98)</td><td>0.724</td></tr><tr><td>Since diagnosis</td><td><strong>0.48(0.25-0.93)</strong></td><td><strong>0.031</strong></td><td>1.03(0.64-1.65)</td><td>0.897</td><td><strong>0.43(0.21-0.88)</strong></td><td><strong>0.021</strong></td><td>1.07(0.64-1.80)</td><td>0.778</td></tr></tbody></table>
<table><tbody><tr><td>Never</td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td></tr><tr><td colspan="9">In the past 7 days, have you experienced the following symptom: hot flashes?</td></tr><tr><td>Always</td><td><strong>0.36(0.18-0.72)</strong></td><td><strong>0.004</strong></td><td><strong>1.79(0.98-3.25)</strong></td><td><strong>0.054</strong></td><td><strong>0.35(0.16-0.80)</strong></td><td><strong>0.013</strong></td><td><strong>2.00(1.02-3.93)</strong></td><td><strong>0.042</strong></td></tr><tr><td>Often</td><td><strong>0.26(0.11-0.59)</strong></td><td><strong>0.001</strong></td><td>1.49(0.79-2.79)</td><td>0.214</td><td><strong>0.23(0.09-0.56)</strong></td><td><strong>0.001</strong></td><td>1.62(0.82-3.19)</td><td>0.160</td></tr><tr><td>Occasionally</td><td>0.49(0.23-1.06)</td><td>0.072</td><td>1.43(0.71-2.85)</td><td>0.306</td><td>0.45(0.19-1.03)</td><td>0.060</td><td>1.38(0.67-2.87)</td><td>0.375</td></tr><tr><td>Never</td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td></tr><tr><td colspan="9">In the past 7 days, have you experienced the following symptom: excessive sweating?</td></tr><tr><td>Always</td><td>0.63(0.31-1.27)</td><td>0.204</td><td>1.44(0.84-2.46)</td><td>0.182</td><td></td><td></td><td></td><td></td></tr><tr><td>Often</td><td><strong>0.23(0.08-0.61)</strong></td><td><strong>0.003</strong></td><td>1.35(0.79-2.31)</td><td>0.262</td><td></td><td></td><td></td><td></td></tr><tr><td>Occasionally</td><td>0.56(0.27-1.18)</td><td>0.131</td><td>1.10(0.62-1.96)</td><td>0.737</td><td></td><td></td><td></td><td></td></tr><tr><td>Never</td><td>Ref.</td><td></td><td>Ref.</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="9">In the past 7 days, have you experienced the following symptom: heavy legs?</td></tr><tr><td>Always</td><td>1.77(0.84-3.70)</td><td>0.127</td><td>1.02(0.54-1.93)</td><td>0.931</td><td></td><td></td><td></td><td></td></tr><tr><td>Often</td><td>0.70(0.32-1.51)</td><td>0.367</td><td>1.15(0.70-1.89)</td><td>0.558</td><td></td><td></td><td></td><td></td></tr><tr><td>Occasionally</td><td>1.19(0.58-2.41)</td><td>0.629</td><td>1.02(0.59-1.75)</td><td>0.935</td><td></td><td></td><td></td><td></td></tr><tr><td>Never</td><td>Ref.</td><td></td><td>Ref.</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="9">In the past 7 days, have you experienced the following symptom: joint pain?</td></tr><tr><td>Always</td><td>0.91(0.45-1.87)</td><td>0.812</td><td>1.78(0.98-3.21)</td><td>0.054</td><td>1.22(0.53-2.81)</td><td>0.630</td><td>1.26(0.65-2.44)</td><td>0.491</td></tr><tr><td>Often</td><td>0.70(0.34-1.43)</td><td>0.340</td><td>1.56(0.88-2.77)</td><td>0.123</td><td>0.87(0.40-1.89)</td><td>0.737</td><td>1.44(0.78-2.65)</td><td>0.235</td></tr><tr><td>Occasionally</td><td>0.91(0.40-2.08)</td><td>0.837</td><td><strong>2.13(1.13-4.03)</strong></td><td><strong>0.019</strong></td><td>1.10(0.45-2.70)</td><td>0.830</td><td><strong>1.99(1.02-3.88)</strong></td><td><strong>0.042</strong></td></tr><tr><td>Never</td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td></td><td>Ref.</td><td>Ref.</td></tr><tr><td colspan="9">In the past 7 days, have you experienced the following symptom: muscle aches?</td></tr><tr><td>Always</td><td>0.44(0.16-1.19)</td><td>0.106</td><td>1.07(0.58-1.97)</td><td>0.825</td><td></td><td></td><td></td><td></td></tr><tr><td>Often</td><td>0.61(0.31-1.20)</td><td>0.157</td><td>0.95(0.57-1.56)</td><td>0.843</td><td></td><td></td><td></td><td></td></tr><tr><td>Occasionally</td><td>0.58(0.28-1.19)</td><td>0.138</td><td>0.80(0.47-1.38)</td><td>0.434</td><td></td><td></td><td></td><td></td></tr><tr><td>Never</td><td>Ref.</td><td></td><td>Ref.</td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

Bold characters indicate a p-value <0.05.

Discussion

This study is the first to examine the association between AET side effects reported two years after breast cancer diagnosis and different AET adherence trajectories. We identified three trajectories, which we named near-simultaneous discontinuation, continuous optimal adherence, and late non-adherence. Most of the sample (70.6%) belonged to the continuous optimal adherence group, which is consistent with findings from previous studies [16,17]. Nevertheless, the fact that 29.4% of our cohort belonged to the other two adherence trajectories, suggests
that non-adherence to AET is a concern in this population; this too reflects previous findings [16,17,24,25]. In addition, recent studies [5,16,26] have pointed out that adherence to AET is dynamic and complex; specifically, it can fluctuate over time, as our cohort demonstrated with the late non-adherence trajectory (19.8%).

Women aged 44–54 years in our sample were less adherent compared to those aged 55–65 years. This result is consistent with several studies [5,6,12,17,25,27,28] which found that younger age was correlated with poor AET adherence. The relatively young mean age of our sample (50 years) reflects the design of the VICAN survey, which oversampled patients younger than 52 years at diagnosis in order to enable analyses of return-to-work outcomes [18]. Therefore, our sample, though younger than the typical population-based samples of breast cancer, provides insight into this high-risk cohort. Younger women usually experience more stressful life profiles such as fertility concerns [29], greater quality of life disturbance with greater impact on emotional well-being and disease-related concerns [30], and competitive responsibilities such as work and childcare [31], all of which are more common in this age group and contribute to lower adherence. Therefore, our findings are especially reflective of younger working-age women prescribed AET, an age group shown to be at increased risk of non-adherence [5,6].

Moreover, women who lived alone in our study were more likely to belong to the near-simultaneous discontinuation adherence trajectory, again reflecting previous work [25,32-34]. In the literature, married women have higher AET adherence rates as they regularly seek medical care and often receive emotional and practical support from their spouses [35,36]. Moreover, marriage has a protective role against psychosocial problems [36], as married women with breast cancer receive greater social and physical support [37], which reduces psychological distress [38]. Our study showed that women from low-income households had increased odds of belonging to the late non-adherence trajectory, which reflects previous research [12,33,39,40]. Other studies found that this population tends to have lower adherence rates due to inadequate financial resources, competing life responsibilities, limited access to medical care, and a lack of health insurance [40,41]. Social workers provide emotional and social support, and discuss the challenges women face (e.g., side effects) [42,43], all of which can encourage adherence. In our study, women who reported no contact with a social worker after breast cancer diagnosis were more likely to belong to the late non-adherence trajectory, suggesting that a lack of support from social workers may contribute to non-adherence.

Our results revealed that women who regularly felt sad or blue were more likely to belong to the near-simultaneous discontinuation trajectory. Positive emotional states have a considerable impact on adherence to AET [44]. This is evidenced by results from other studies where women who did not feel sad or blue had increased odds of continuous optimal adherence [45,46]. In our study, women who took anxiolytics after diagnosis were less likely to belong to the near-simultaneous discontinuation group, suggesting that this population used anxiolytics to manage psychological disorders [47] and that anxiolytics play a positive role in AET adherence. Anxiolytics are primarily used for severe anxiety or anxiety caused by acute stress [48], which is highly common after cancer diagnosis [49]. Women are at a high risk of experiencing severe anxiety after diagnosis, which decreases their quality of life [50,51].

Women who did not have chemotherapy were more likely to belong to the near-simultaneous discontinuation and late non-adherence adherence trajectories. Having chemotherapy before starting AET has been positively correlated with AET adherence [13]. Chemotherapy may reflect an advanced stage of breast cancer, which has also been associated with better adherence. Women who do not have chemotherapy are at a higher risk of non-adherence [16,17,24,52-54], potentially due to low awareness of the associated risks. In our study, women who were first prescribed aromatase inhibitors were more likely to belong to the late non-adherence group. This result may be explained by their tendency to modify their adherence and skip some AET doses because they could not tolerate the side effects [55]. Furthermore, women who switched AET during therapy were more likely to discontinue AET, suggesting that it is difficult to manage new side effects after switching AET [17,56-58].

Our results revealed that women who experienced hot flashes were more likely to belong to the late non-adherence group. Hot flashes are among the most common and severe side effects associated with AET [8], and their persistence over the long term can impair overall quality of life, leading to poor adherence and discontinuation [59]. While hot flashes are more often associated with tamoxifen, persistent and severe hot flashes—albeit less frequent—in women prescribed aromatase inhibitors can influence their adherence. Negative experiences related to disease treatment are considered to be main determinants of adherence to medication [60]. Side effects may also be indicators of treatment effectiveness [59]. In one clinical trial, women experiencing hot flashes had a lower risk of cancer recurrence, suggesting that the symptoms could be predictive of treatment efficacy [61].

Finally, in our study, women who occasionally experienced joint pain were more likely to belong to the late non-adherence group, reflecting previous studies [53,62,63]. In one study of women with breast cancer, the prevalence
of joint pain was higher in those taking aromatase inhibitors than those taking tamoxifen [53]. The side effect that most causes low adherence is joint pain [62], because it leads to decreased physical function; specifically, it negatively impacts daily functioning and reduces overall quality of life. A previous study found that 22% of women stopped taking aromatase inhibitors because of toxicity including joint pain [64].

## Practical implication

Based on the identification of distinct trajectories of adherence to AET and their predictors, the main practical contribution of the present study is the essential need for a targeted, intensive, and sustained support strategy for women with breast cancer undergoing AET. Practitioners should prioritize comprehensive management of hot flashes and joint pain, particularly the first two years of treatment, because these are strong predictors of subsequent non-adherence. In addition, healthcare systems and responsible authorities must integrate enhanced psychosocial and financial support, especially for high-risk patients such as younger women who live alone, have low income, have switched AET, have had no contact with a social worker, and suffer from sadness or the blues, to overcome the challenges leading to non-adherence and optimize long-term treatment outcomes.

## Strengths and limitations

The major strength of our study is that we used GBTM to identify AET adherence in combination with data from a large nationwide survey. GBTM comprehensively classified patients according to their adherence trajectories during the whole study period. In terms of limitations, first, our adherence calculations were based on AET dispensing dates, which means that we hypothesized that all patients took their treatments as prescribed; this potentially led to an overestimation of adherence. Second, the low response rate of eligible patients may have introduced selection bias if the characteristics of those who agreed to participate in VICAN2 differed from non-respondents, for example, in terms of motivation and health status. Such differences could have influenced adherence behaviours. Third, data on certain variables associated with AET adherence were not available for our analysis (e.g. tumour stage, tumour size, ethnicity differences, attitudes towards treatment). Finally, our results on the side effects of AET were based on self-reported information. Accordingly, patients with varying levels of literacy may have understood and recognized side effects to different degrees, which may have affected our results.

## Conclusion

This study identified three distinct AET adherence trajectories with most women belonging to the continuous optimal adherence trajectory, while a non-negligible proportion belonged to the near-simultaneous discontinuation and late non-adherence trajectory. The main factors associated with belonging to the three adherence trajectories were not having chemotherapy, the type of AET first prescribed, switching AET during therapy, the use of anxiolytics, and experiencing hot flashes and joint pain. Side effects reported two years after diagnosis could be important indicators in predicting later non-adherence to AET. Effective management of these side effects is therefore essential to foster long-term adherence and optimize health outcomes.

## Abbreviations

AET: Adjuvant Endocrine Therapy

AIs: Aromatase Inhibitor

GBTM: Group-based trajectory modelling

VICAN2: *Vie deux ans après un diagnostic de CANcer*

PDC: Proportion of Days Covered

## Authors' contributions

ER: methodology, data curation, formal analysis, writing of original draft, writing – reviewing & editing. VM: methodology, formal analysis, writing – reviewing & editing. JM: Investigation, conceptualization, supervision, writing – reviewing & editing. ADB: Investigation, data curation, formal analysis, supervision, writing – reviewing & editing. All authors have read and agreed to publish this version of the manuscript.

## Funding

This study was supported by the French National Institute of Cancer (INCa) (No. 05-2011). ER was supported by Campus France (“France Excellence” Scholarship for PhD degree 141628W).

## Data availability

Data that support the findings of this study are available from the corresponding author upon reasonable request.
**Declarations**

**Ethical approval and consent to participate**

The study was conducted in accordance with the principles of the Declaration of Helsinki. It received approval from the Institute of Public Health (C11-63), the Advisory Committee on Information Processing in Material Research in the Field of Health (11-143), and the French Data Protection Agency (911290). The study does not contain personal information and has no commercial interests. All participants provided written informed consent prior to participation. Additionally, the manuscript does not include any characteristics that could be used to identify the participants.

**Competing interests**

The authors declare no competing interests.

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