Symptom burden and symptom clusters in patients with breast cancer undergoing endocrine therapy: a cross‐sectional survey

Introduction

Breast cancer (BC) remains one of the most common cancers among women worldwide. In 2022, it led to 2.3 million new diagnoses and 666,000 fatalities globally [ 1 ]. It is estimated that the estrogen receptor (ER) is expressed in 70–84% of BC, and the progesterone receptor (PR) is expressed in 75% of ER-positive BCs [ 2 ]. Five years of tamoxifen treatment have been found to markedly reduce recurrence rates within the first 10 years and reduce mortality by approximately one-third over 15 years [ 3 ]. Compared to tamoxifen, 5 years of treatment with an aromatase inhibitor (AI) reduced the 10-year BC mortality by approximately 15%, representing a 40% reduction relative to no endocrine therapy (ET) [ 4 ]. According to the NCCN guidelines, adjuvant endocrine therapy is recommended for a duration of 5 to 10 years [ 5 ].

Although long-term ET offers survival advantages, it also results in prolonged estrogen deprivation, leading to a range of symptoms and quality of life (QoL) challenges. Ganz et al. found that within the first 12 months of ET, patients experienced an increase in symptom severity, particularly with musculoskeletal issues, hot flashes, cognitive disturbances, and bladder problems [ 6 ]. While addressing individual symptoms remains crucial, investigating symptom clusters offers a more comprehensive understanding of patient experiences, enables targeted interventions, and ultimately enhances QoL and treatment outcomes. A symptom cluster is defined as a set of two or more related symptoms that occur together, simultaneously, and consistently, possibly linked by common biological pathways [ 7 , 8 ]. Although the mechanisms underlying the symptom clusters are not completely understood, emerging evidence suggests that they arise from complex interactions between biological pathways and psychological factors [ 9 , 10 ]. Treatments for one symptom may also “cross over” and reduce the severity of other symptoms included in the cluster [ 11 ].

A previous study examined symptom clusters in BC patients undergoing ET. Li and colleagues used four different outcome measures to assess symptom clusters over the first 18 months of AI treatment, identifying four stable symptom clusters (i.e., musculoskeletal, vasomotor, urinary, sexual) and three relatively stable symptom clusters (i.e., psychological, neurocognitive, weight) [ 12 ]. Agnew et al. identified two distinct symptom clusters in BC patients undergoing ET, namely, one associated with a high symptom burden and the other with a low symptom burden. Patients in the high-symptom cluster exhibited significantly higher rates of non-adherence to ET [ 13 ]. ET non-adherence has been associated with increased mortality risk in patients with BC [ 14 ].

Some studies have investigated how symptom clusters can affect the QoL among BC patients. For instance, Tao et al. [ 15 ] found that a symptom cluster including cancer-related fatigue (CRF), sleep disturbances, and psychological distress had a detrimental impact on the QoL of these patients. Similarly, Tometich et al. [ 16 ] observed that older BC survivors who experienced elevated psychoneurological symptoms reported a decreased BC-specific QoL. These observations highlight the critical role of managing symptom clusters to enhance the QoL of BC patients.

Many cancer patients combine treatment with the use of complementary and alternative medicine (CAM), including TCM, to alleviate distressing symptoms. Recent studies indicate a high prevalence of CAM usage among BC patients [ 17 , 18 ], potentially enhancing their treatment experiences [ 19 ]. Compared with symptomatic treatment drugs such as analgesics, TCM offers a holistic approach, targeting multiple aspects to manage symptom clusters and enhance the quality of life for patients.

We currently lack detailed information on symptom clusters in patients with BC who are undergoing ET and actively seek TCM treatment. Furthermore, the specific symptom clusters that significantly impact their QoL remain unclear. This study was designed to conduct an in-depth analysis of symptom clusters, specifically those comprising symptoms of moderate to severe intensity, among BC patients who actively pursue TCM treatment while undergoing ET, with particular emphasis on identifying those clusters that most significantly compromise the QoL. The findings are intended to provide a foundation for clinicians to enhance integrative TCM care for patients during their ET, ultimately aiming to improve their QoL and generating evidence-based guidance for TCM clinical practice. This integrative approach targets both symptom management and holistic care for patients with BC.

Methods

Study design

This cross-sectional observational study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was obtained from the Ethics Committee of Guang’anmen Hospital, China Academy of Chinese Medical Sciences (approval no. 2023-134-KY) on April 1, 2023. Written informed consent was provided by all participants.

Participants

Recruitment was conducted from April 2023 and February 2024. The study participants were recruited from the outpatient clinic and inpatient ward of the Oncology Department at Guang’anmen Hospital, China Academy of Chinese Medical Sciences.

Eligible participants included those with a pathological diagnosis of BC who were at least 18 years old, actively undergoing any stage of ET, and seeking Chinese herbal medicine treatment. Exclusion criteria for the study were an inability to comprehend the study’s goals, refusal to participate in the research, or a current diagnosis of a severe psychiatric disorder.

Outcomes

The participants were requested to fill out a demographic questionnaire that gathered information on variables such as age, height, weight, level of education, marital status, place of living, job status, and financial burden. Additionally, the physician reviewed the patient’s medical history and completed a questionnaire on disease characteristics. This questionnaire detailed the pathological type, tumor stage, duration of ET, ET regimens, and any previous treatments.

To effectively evaluate the symptomatology of the patients and identify their symptom clusters, we employed the M.D. Anderson Symptom Inventory–Traditional Chinese Medicine (MDASI-TCM) [ 20 ] to assess the general symptoms. Concurrently, we crafted a clinical symptom questionnaire to probe into the specific symptoms experienced by BC patients undergoing ET. The development process was as follows: (1) We reviewed items from the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES) [ 21 ], European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QoL)-BR23 [ 22 ], and Breast Cancer Prevention Trial Symptom Checklist (BCPT-SCL) [ 23 ], from which 14 symptom items were selected to create a BC symptom questionnaire. (2) We examined the occurrence of these 14 symptoms in 30 patients, finding that each symptom had an incidence rate of 20% or higher. (3) After discussions within the research team, it was agreed to retain all 14 symptom items in the BC symptom questionnaire (supplementary material).

The MDASI-TCM includes 20 symptom items. Patients rate the severity of these symptoms over the past 24 h using a numerical scale from 0 to 10, with 0 meaning “not present” and 10 representing “as bad as you can imagine.” Similarly, the BC symptom questionnaire includes 14 items, with the severity of each BC-specific symptom during the past 24 h assessed on the same 0 to 10 numerical rating scale.

For measuring patients’ QoL, a single-item QoL scale was used to record scores for the past 7 days.

Sample size

In our study, we conducted a two-stage approach to determine the sample size, with both stages designed to ensure sufficient statistical power—first for the stability of factor analysis and second for detecting symptom prevalence. Factor analysis served as our primary method for identifying symptom clusters. To achieve adequate statistical power for factor stability, we adopted the widely recommended 5–10 times rule for sample size calculation relative to scale items [ 24 ]. Given that our study involved 40 items across all assessment scales, a minimum of 200 participants (5 × 40 items) was required to meet the to meet the statistical power threshold for robust factor analysis.

During the mid-point of our survey ( n = 76), we conducted a second phase sample size calculation to refine our initial estimate. The sample size was determined using the population rate and its confidence interval. At the mid-point of our survey, the prevalence of moderate to severe symptoms ( p ) was approximately 31.6%. The sample size was calculated using PASS 15 software to accommodate an allowable error of 0.2 p and to achieve a 95% confidence level, resulting in a minimum required sample size of 208 participants.

These dual calculation methods confirmed that 208 participants would provide adequate statistical power for both stable factor solutions and statistically precise prevalence estimates.

Statistical analysis

SPSS 29.0 statistical software was used for data analysis. Descriptive statistics were utilized to describe the demographic and clinical characteristics of the participants. Fisher’s exact test was employed for the analysis of categorical data. Hypothesis testing was performed bilaterally with a significance threshold set at P < 0.05. Exploratory factor analysis (EFA) was implemented to identify clusters of symptoms. Only symptoms rated as moderate to severe (severe ≥ 4) by more than 15% of patients were included in the EFA to ensure sufficient variability and covariation. The Kaiser-Meyer-Olkin (KMO) test and Bartlett’s test of sphericity were used to determine the data’s appropriateness for EFA. Factor loadings of 0.5 or higher were deemed significant. Cronbach’s alpha was calculated to assess the internal consistency of the factors. Confirmatory factor analysis (CFA) was conducted to confirm the symptom clusters identified by EFA. Factors were named based on the dominant symptoms within each cluster. Multivariate linear regression was applied to determine which symptom cluster significantly influenced the QoL as an independent factor. The threshold for statistical significance was maintained at P < 0.05.

Results

Demographic and clinical characteristics

The study surveyed a total of 214 participants. Among these, 126 patients (59%) were premenopausal, while 88 patients (41%) were postmenopausal. The median duration of ET among the participants was 10 months, with an interquartile range (IQR) of 4 to 21 months. The majority of the patients exhibited an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, accounting for 98% of the cohort. Demographic and disease-related characteristics of the study population are summarized in Table 1 .

Symptoms and symptom interference

The study identified the five most common symptoms as follows: difficulty remembering ( n = 178, 83%), sleep disturbance ( n = 170, 79%), fatigue ( n = 164, 77%), sweating ( n = 151, 71%), and joint stiffness ( n = 150, 70%). A total of 88% of participants reported experiencing at least one moderate to severe symptom. The five most frequently reported moderate to severe symptoms were sleep disturbance ( n = 122, 57%), difficulty remembering ( n = 105, 49%), sweating ( n = 90, 42%), fatigue ( n = 89, 42%), and distress ( n = 84, 39%). The severity scores for these symptoms were highest for sleep disturbance (4.1 ± 3.1), followed by difficulty remembering (3.7 ± 2.8), fatigue (3.2 ± 2.6), sweating (3.2 ± 3.0), and distress (3.0 ± 2.8). These details are summarized in Table 2 , which presents both the severity and prevalence of symptoms.

The range of symptom interference incidences was from 38% to 67%, with 47% of patients reporting at least one moderate to severe interference with daily activities as measured by the MDASI. The severity and prevalence of symptom interference are detailed in Table 3 .

Symptoms and symptom interference in premenopausal and postmenopausal patients with BC

Among premenopausal patients, the five most prevalent moderate to severe symptoms were sleep disturbance ( n = 70, 56%), sweating ( n = 64, 51%), difficulty remembering ( n = 59, 47%), hot flashes ( n = 58, 46%), and sadness ( n = 54, 43%). The severest symptoms among this group included sleep disturbance (4.2 ± 3.0), sweating (3.7 ± 3.1), difficulty remembering (3.7 ± 2.8), hot flashes (3.6 ± 3.0), and distress (3.3 ± 2.8).

For postmenopausal patients, the top five moderate to severe symptoms were sleep disturbance ( n = 52, 63%), difficulty remembering ( n = 46, 52%), fatigue ( n = 41, 47%), joint stiffness ( n = 34, 39%), and a decrease in sexual interest or activity ( n = 31, 35%). The most severe symptoms reported included disturbed sleep (4.1 ± 3.1), difficulty remembering (3.8 ± 2.7), fatigue (3.4 ± 2.9), joint stiffness (3.2 ± 2.8), and dry mouth (3.0 ± 2.8), as described in Table 4 .

Regarding symptom interference, among premenopausal patients, the incidence ranged from 36% to 76%, with 44% reporting moderate to severe MDASI symptom interference. Among postmenopausal patients, the incidence ranged from 31% to 55%, with 50% reporting moderate to severe interference (see Table 5 ).

Sweating, hot flashes, sadness, heat in the palms or soles of the feet, and abnormal vaginal discharge were significantly worse in premenopausal patients than in postmenopausal patients (all P < 0.05). Conversely, postmenopausal patients experienced worse dry mouth compared to their premenopausal counterparts ( P < 0.05). Additionally, premenopausal patients reported a higher prevalence of moderate to severe symptoms such as sweating, hot flashes, sadness, vaginal dryness, and heat in the palms or soles of the feet ( P < 0.05). In terms of symptom interference, premenopausal patients experienced more significant disruptions in work and mood compared to postmenopausal patients ( P < 0.05).

Symptom clusters

A total of 25 symptoms were subjected to EFA. The Kaiser-Meyer-Olkin (KMO) test and Bartlett’s test of sphericity verified the suitability of the data for EFA (KMO = 0.868, approximate chi-square = 2105.767, P < 0.001), resulting in seven identified factors with a cumulative variance contribution rate of 63.6%.

Factor 1, termed the distress-sleep disturbance symptom cluster, encompassed five symptoms. Factor 2, designated as the breast-sexual symptom cluster, comprised four symptoms. Factor 3, identified as the fatigue-related symptom cluster, included four symptoms. Factor 4, termed the hot flashes-sweating symptom cluster, included three symptoms. Factor 5, termed the pain-joint stiffness symptom cluster, consisted of three symptoms. Factor 6, which did not form a symptom cluster, included only the symptom of feeling cold, with a factor loading greater than 0.5. Factor 7 was called the constipation-bitter taste symptom cluster, involving two symptoms. Hair loss, shortness of breath, and racing heartbeat did not achieve factor loadings above 0.5; hence, they did not group into any cluster (Table 6 ).

Following the six-factor classification identified by EFA, CFA was performed to verify the factor structure. The CFA results indicated that the EFA-derived model demonstrated acceptable-to-good fit ( χ 2 /df = 2.254, RMSEA = 0.077, 90% CI 0.067 to 0.087, CFI = 0.861, TLI = 0.832, IFI = 0.864). While the CFI and TLI approached the threshold of 0.90, the RMSEA value suggested reasonable approximation error.

Associations of symptom clusters with QoL

The average QoL score of 214 patients with BC undergoing ET was 7.3 ± 1.8. Statistical analysis revealed a statistically significant inverse correlation between all identified symptom clusters and the QoL scores, although the strength of the correlations was relatively weak (all r < 0.4) as shown in Table S3 . To identify the independent predictors of QoL, average scores of symptom clusters were subjected to a stepwise multiple linear regression analysis. The analysis highlighted two significant predictors: the distress-sleep disturbance symptom cluster ( B = −0.258, 95% CI −0.383 to −0.133, P < 0.001) and the hot flashes-sweating symptom cluster ( B = −0.128, 95% CI −0.243 to −0.013, P = 0.029), detailed in Table 7 . After adjusting for age, employment status, menstrual phase, and ET regimen, the distress-sleep disturbance symptom cluster was found to have a particularly adverse impact on QoL ( B = −0.183, 95% CI −0.339 to −0.028, P = 0.021), as indicated in Table 8 .

Discussion

Symptom burden of patients with BC undergoing endocrine therapy

To our knowledge, this study represents the first examination of symptom burden and symptom clusters among BC patients undergoing ET who are also receiving TCM care. We observed that premenopausal women exhibited a higher burden of symptoms including sweating, hot flashes, sadness, heat in the palms or soles of the feet, abnormal vaginal discharge, and vaginal dryness. Interestingly prior studies suggest that premenopausal women with BC tend to experience a greater prevalence of menopausal symptoms compared to their postmenopausal counterparts, which could be attributed to the earlier and more sudden progression of estrogen deprivation caused by ET [ 25 , 26 ]. The significant decrease in endogenous estrogen levels in the bloodstream may adversely affect vasomotor, psychological, physical, and sexual functions [ 27 ].

The differences in symptom profiles between the menopausal subgroups may be further explained by the use of distinct ET regimens. Premenopausal women who received OFS plus tamoxifen reported a higher frequency of vasomotor symptoms (e.g., hot flashes, sweating), sexual dysfunction (e.g., decreased libido, vaginal dryness), and psychological or musculoskeletal complaints (e.g., insomnia, depression, joint pain) compared to those who received tamoxifen alone [ 28 ]. Notably, the combination of OFS with exemestane was associated with more severe vasomotor symptoms than experienced with the OFS plus tamoxifen regimen, underscoring how therapeutic intensity can modulate symptoms [ 29 ]. In contrast, postmenopausal patients in the ATAC trial experienced different patterns; specifically, while tamoxifen users reported higher rates of hot flashes (40.9% vs. 35.7%), AI recipients (anastrozole) showed intensified musculoskeletal symptoms [ 30 ].

Symptom clusters

Our research delineated six distinct symptom clusters: distress-sleep disturbance, breast-sexual, fatigue-related, hot flashes-sweating, pain-joint stiffness, and constipation-bitter taste. Previous studies have identified different clusters, such as five symptom clusters (systemic, pain and emotional, sexual, vaginal, and vasomotor) in patients with BC during ET [ 31 ]. Unlike prior research, our study specifically focused on the severity of moderate to severe symptoms, selecting those with an incidence rate of ≥ 15% for analysis. This approach emphasizes the identification of more clinically significant symptom clusters, which could enhance guidance in clinical practice.

The distress-sleep disturbance symptom cluster, which includes distress, sleep disturbance, impaired concentration, sadness, and difficulty remembering, has a complex mechanism. It has been established that poor sleep can impact cognitive function and depression symptoms through various pathways, including oxidative stress, dopamine function, the hypothalamic-pituitary-adrenal (HPA) axis, and inflammation [ 32 – 34 ]. A previous study indicated that symptom clusters like fatigue-sleep disturbance and psychological symptom clusters, which encompass anxiety, depression, nervousness, irritability, sadness, and worry, are often the most prevalent among BC patients [ 35 ]. Liou et al. [ 36 ] observed that postmenopausal BC patients treated with AIs commonly experience insomnia and cognitive dysfunction, which tend to worsen together, with the perceived cognitive dysfunction increasing as the severity of insomnia escalates.

The breast-sexual symptom cluster comprises four symptoms: breast skin sensitivity, decrease in sexual interest or activity, breast tenderness, and vaginal dryness. Breast tenderness and sensitivity may result from surgery or radiotherapy and can continue during ET. Previous research has shown that breast skin sensitivity remains during ET, occurring in 15–25% of patients [ 37 ]. ET may result in reduced hormone levels, potentially leading to sexual dysfunction. Baumgart et al. [ 38 ] reported that among patients treated with AIs, 74% experienced insufficient lubrication, and 50% reported low sexual interest. Additionally, Gan et al. [ 39 ] observed that 81% of young BC patients undergoing ET reported sexual dysfunction. Thus, considering the cultural backdrop and social norms in China, where sexuality is often viewed as a private matter by both patients and healthcare providers, it is crucial to offer sexual health guidance that is both accessible and sensitive to the needs and comfort levels of all parties involved.

The fatigue-related symptom cluster includes four symptoms: drowsiness, fatigue, lack of appetite, and dry mouth. Fatigue is a prevalent issue among patients undergoing active cancer treatment and during survivorship. It is estimated that during ET, 60% of BC patients have experienced or are experiencing CRF [ 40 ]. There is an increasing recognition of the potential biological mechanisms underlying CRF, such as peripheral immune activation, inflammation dysfunction, dysregulation of the HPA axis, autonomic nervous system dysfunction, and skeletal muscle and mitochondrial dysfunction [ 41 – 43 ]. We hypothesized that fatigue is intricately linked with drowsiness, while a lack of appetite may lead to inadequate nutrient intake and exacerbate fatigue. However, the inclusion of dry mouth in the fatigue-related symptom cluster is not fully understood, indicating the need for further research in this area.

The hot flashes-sweating symptom cluster, which comprises hot flashes, heat in the palms or soles of the feet, and sweating, is commonly reported among BC patients undergoing ET. Moreover, prior studies indicate that up to 95% of premenopausal and 30% of postmenopausal patients treated with ET for early-stage BC experience hot flashes and/or night sweats, with 49% of them citing these symptoms as particularly troublesome [ 26 , 44 ]. The reduction in hormone levels may alter the hypothalamic thermoregulatory set-point, disrupt serotonin receptor balance, and trigger vasomotor responses such as heat sensation and sweating [ 45 ]. BC survivors often face more severe hot flashes and sweating than women going through natural menopause, as anti-cancer treatments can lead to sudden, premature menopause. While hormone therapy can effectively alleviate these symptoms, it must be used cautiously in HR-positive BC patients. Further research is necessary to develop and enhance evidence-based integrative TCM care for ET-treated BC survivors.

The pain-joint stiffness symptom cluster, which includes pain and numbness, pain, and joint stiffness, is commonly experienced by BC patients undergoing ET, with over 46% of patients reporting such symptoms [ 26 ]. Estrogen plays a crucial role in chondrogenesis and interacts with various cellular factors. Its depletion during ET can prompt the release of proinflammatory cytokines, leading to joint pain and swelling [ 46 ]. Additionally, AIs can activate joint fibroblasts and immune cells, further contributing to inflammation and joint stiffness [ 46 ]. Persistent pain and numbness might also stem from chemotherapy-induced peripheral nerve damage, which can continue to affect patients even during ET [ 47 ].

Previous studies have seldom addressed the constipation-bitter taste symptom cluster. More investigations are required to assess its prevalence and consistency among BC patients treated with ET.

According to TCM theory, symptom clusters have specific underlying mechanisms. For instance, the hot flashes-sweating symptom cluster is often linked to Yin deficiency, which can be alleviated using herbs known to nourish Yin. Additionally, acupuncture can help balance the body’s yin-yang, potentially easing symptoms like hot flashes and sweating [ 48 ].

Effects of symptom clusters on QoL

In our study, six symptom clusters were identified that negatively influence QoL, with the distress-sleep disturbance and hot flashes-sweating symptom clusters being particularly detrimental. Controlling for variables such as age, employment status, menstrual phase, and ET regimen, the distress-sleep disturbance cluster was found to have a significantly adverse effect on QoL. However, considering that these clusters are among the most frequently reported and most challenging for patients, clinicians are advised to focus more on managing the distress-sleep disturbance and hot flashes-sweating clusters [ 26 , 35 , 44 ]. Thus, developing targeted integrative TCM care to address these symptom clusters could significantly improve the QoL for BC patients.

Limitations

Firstly, our study participants were recruited from a single tertiary hospital in Beijing, China. Consequently, the sample may not fully represent the broader population of BC patients undergoing ET across China, limiting the generalizability of our findings to all patient demographics. Secondly, the cross-sectional design of this study included patients on various ET regimens and at different disease stages, which could affect the stability of the symptom clusters identified. Furthermore, the identification of symptom clusters was influenced by the varied methodologies used. Future research could benefit from adopting a longitudinal design and increasing the sample size. Thirdly, this study relied on a single-item QoL scale to assess quality of life over the previous 7 days. This method may not adequately capture the complex impacts that symptom clusters have on different dimensions of QoL. Future studies should consider using more comprehensive QoL instruments, such as the EQ-5D or the FACT-G, to better evaluate how symptom clusters influence various aspects of QoL.

Conclusions

This study demonstrated that BC patients undergoing ET who also receive TCM experience multiple symptoms grouped into six clusters: distress-sleep disturbance, breast-sexual, fatigue-related, hot flashes-sweating, pain-joint stiffness, and constipation-bitter taste. These symptom clusters are inversely associated with QoL. Interestingly, the distress-sleep disturbance and hot flashes-sweating clusters emerged as independent predictors of QoL. These findings underscore the potential for developing targeted integrative TCM approaches to manage symptom clusters in BC patients. Future studies should employ longitudinal designs with larger sample sizes to verify the consistency of these symptom clusters over time. This would not only provide a deeper understanding of how these symptoms evolve and interact with treatments but also verify the stability and consistency of these clusters. This approach could significantly enhance the precision of TCM interventions, optimizing them to adapt to the shifting symptom profiles and improving the supportive care for BC patients undergoing ET.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 32.1 KB)

Abbreviations

Aromatase inhibitors

Breast cancer

Breast Cancer Prevention Trial Symptom Checklist

Cancer-related fatigue

Complementary and alternative medicine

Eastern Cooperative Oncology Group

Endocrine therapy

Estrogen receptor

Endocrine therapy

Functional Assessment of Cancer Therapy-Endocrine Subscale

Hormone receptor

Interquartile range

Kaiser-Meyer-Olkin

M.D. Anderson Symptom Inventory–Traditional Chinese Medicine

Ovarian function suppression

Progesterone receptor

Quality of life

European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-BR23

Selective estrogen receptor modulators

Traditional Chinese medicine

Author contribution

Baojin Han: Writing – original draft, Methodology, Formal analysis, Data curation. Simeng Ren: Writing – review & editing, Data curation. Jiayue Jin: Writing – review & editing, Investigation. Hongkun Xu: Writing – review & editing, Investigation. Jingqi Yang: Writing – review & editing, Investigation. Wenzheng Zhang: Writing – review & editing, Investigation. Tingting Lu: Formal analysis, Data curation. Hongsheng Lin: Project administration, Conceptualization. Jie Liu: Project administration, Funding acquisition, Conceptualization, review & editing. All authors had full access to all the data in the study, and the corresponding author had final responsibility for the decision to submit for publication. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding

This study was financially supported by the Traditional Chinese Medicine Regulatory Science Research Project of the China Academy of Chinese Medical Sciences (No. ZYJGKX202404), the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0520800, 2024ZD0520801), Scientific and Technological Innovation Project of the China Academy of Chinese Medical Sciences (no. CI2021A05502) and the High-Level Chinese Medical Hospital Promotion Project (no. HLCMHPP2023019).

Data availability

Data is provided within the manuscript or supplementary information files.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Guang’anmen Hospital, China Academy of Chinese Medical Sciences (approval number 2023-134-KY) in accordance with the Declaration of Helsinki. Written informed consent was obtained from all individual patients included in the study.

Consent for publication

Not applicable

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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

No AI tools/services were used during the preparation of this work.

Contributor Information

Hongsheng Lin, Email: drlinhongsheng@163.com.

Jie Liu, Email: dr.liujie@163.com.

References

1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 74:1–35

2. Hou Y, Peng Y, Li Z (2022) Update on prognostic and predictive biomarkers of breast cancer. Semin Diagn Pathol. 39(5):322–332

3. Early Breast Cancer Trialists' Collaborative G, Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, McGale P, Pan HC, Taylor C, Wang YC, Dowsett M, Ingle J, Peto R (2011) Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 378(9793):771-84

4. Early Breast Cancer Trialists' Collaborative G (2015) Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 386(10001):1341-1352

5. NCCN (2024) NCCN clinical practice guidelines in oncology. Breast Cancer. Version 6. PA: National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf . Accessed 6 Dec 2024

6. Ganz PA, Petersen L, Bower JE, Crespi CM (2016) Impact of adjuvant endocrine therapy on quality of life and symptoms: observational data over 12 months from the mind-body study. J Clin Oncol. 34(8):816–24

7. Miaskowski C, Barsevick A, Berger A, Casagrande R, Grady PA, Jacobsen P, Kutner J, Patrick D, Zimmerman L, Xiao C, Matocha M, Marden S (2017) Advancing symptom science through symptom cluster research: expert panel proceedings and recommendations. J Natl Cancer Inst. 109(4):djw253

8. Cleeland CS, Bennett GJ, Dantzer R, Dougherty PM, Dunn AJ, Meyers CA, Miller AH, Payne R, Reuben JM, Wang XS, Lee BN (2003) Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms. Cancer. 97(11):2919–25

9. Ji YB, Bo CL, Xue XJ, Weng EM, Gao GC, Dai BB, Ding KW, Xu CP (2017) Association of inflammatory cytokines with the symptom cluster of pain, fatigue, depression, and sleep disturbance in Chinese patients with cancer. J Pain Symptom Manage. 54(6):843–852

10. Miaskowski C, Barsevick A, Berger A, Casagrande R, Grady PA, Jacobsen P, Kutner J, Patrick D, Zimmerman L, Xiao C, Matocha M, Marden S (2017) Advancing symptom science through symptom cluster research: expert panel proceedings and recommendations. J Natl Cancer Inst. 109(4):djw253

11. Reich RR, Lengacher CA, Alinat CB, Kip KE, Paterson C, Ramesar S, Han HS, Ismail-Khan R, Johnson-Mallard V, Moscoso M, Budhrani-Shani P, Shivers S, Cox CE, Goodman M, Park J (2017) Mindfulness-based stress reduction in post-treatment breast cancer patients: immediate and sustained effects across multiple symptom clusters. J Pain Symptom Manage. 53(1):85–95

12. Li H, Sereika SM, Marsland AL, Conley YP, Bender CM (2020) Symptom clusters in women with breast cancer during the first 18 months of adjuvant therapy. J Pain Symptom Manage. 59(2):233–241

13. Agnew S, Crawford M, MacPherson I, Shiramizu V, Fleming L (2024) The impact of symptom clusters on endocrine therapy adherence in patients with breast cancer. Breast. 75:103731

14. Reeder-Hayes KE, Troester MA, Wheeler SB (2021) Adherence to endocrine therapy and racial outcome disparities in breast cancer. Oncologist. 26(11):910–915

15. Tao L, Lv J, Zhong T, Zeng X, Han M, Fu L, Chen H (2024) Effects of sleep disturbance, cancer-related fatigue, and psychological distress on breast cancer patients’ quality of life: a prospective longitudinal observational study. Sci Rep. 14(1):8632

16. Tometich DB, Small BJ, Carroll JE, Zhai W, Luta G, Zhou X, Kobayashi LC, Ahles T, Saykin AJ, Clapp JD, Jim HSL, Jacobsen PB, Hurria A, Graham D, McDonald BC, Denduluri N, Extermann M, Isaacs C, Dilawari A, Root J, Rini C, Mandelblatt JS, Thinking, Living with Cancer S (2019) Pretreatment psychoneurological symptoms and their association with longitudinal cognitive function and quality of life in older breast cancer survivors. J Pain Symptom Manage. 57(3):596-606

17. Sarvary A, Sarvary A (2019) Use of complementary and alternative medicine among breast cancer patients in Hungary: a descriptive study. Complement Ther Clin Pract. 35:195–200

18. Fremd C, Hack CC, Schneeweiss A, Rauch G, Wallwiener D, Brucker SY, Taran FA, Hartkopf A, Overkamp F, Tesch H, Fehm T, Hadji P, Janni W, Luftner D, Lux MP, Muller V, Ettl J, Belleville E, Sohn C, Schuetz F, Beckmann MM, Fasching PA, Wallwiener M (2017) Use of complementary and integrative medicine among German breast cancer patients: predictors and implications for patient care within the PRAEGNANT study network. Arch Gynecol Obstet. 295(5):1239–1245

19. Wang R, Wang Y, Fang L, Xie Y, Yang S, Liu S, Fang Y, Zhang Y (2024) Efficacy and safety of traditional Chinese medicine in the treatment of menopause-like syndrome for breast cancer survivors: a systematic review and meta-analysis. BMC Cancer. 24(1):42

20. Wang XS, Wang Y, Guo H, Mendoza TR, Hao XS, Cleeland CS (2004) Chinese version of the M.D. Anderson Symptom Inventory: validation and application of symptom measurement in cancer patients. Cancer. 101(8):1890–901

21. Fallowfield LJ, Leaity SK, Howell A, Benson S, Cella D (1999) Assessment of quality of life in women undergoing hormonal therapy for breast cancer: validation of an endocrine symptom subscale for the FACT-B. Breast Cancer Res Treat. 55(2):189–99

22. Sprangers MA, Groenvold M, Arraras JI, Franklin J, te Velde A, Muller M, Franzini L, Williams A, de Haes HC, Hopwood P, Cull A, Aaronson NK (1996) The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field study. J Clin Oncol. 14(10):2756–2768

23. Stanton AL, Bernaards CA, Ganz PA (2005) The BCPT symptom scales: a measure of physical symptoms for women diagnosed with or at risk for breast cancer. J Natl Cancer Inst. 97(6):448–56

24. Carpenter S (2018) Ten steps in scale development and reporting: a guide for researchers. Commun Methods Measures. 12(1):25–44

25. Balazard F, Bertaut A, Bordet E, Mulard S, Blanc J, Briot N, Paux G, Dhaini Merimeche A, Rigal O, Coutant C, Fournier M, Jouannaud C, Soulie P, Lerebours F, Cottu PH, Tredan O, Vanlemmens L, Levy C, Mouret-Reynier MA, Campone M, Brady KJS, Sasane M, Rice M, Coulouvrat C, Martin AL, Jacquet A, Vaz-Luis I, Herold C, Pistilli B (2023) Adjuvant endocrine therapy uptake, toxicity, quality of life, and prediction of early discontinuation. J Natl Cancer Inst. 115(9):1099–1108

26. Cucciniello L, Garufi G, Di Rienzo R, Martinelli C, Pavone G, Giuliano M, Arpino G, Montemurro F, Del Mastro L, De Laurentiis M, Puglisi F (2023) Estrogen deprivation effects of endocrine therapy in breast cancer patients: incidence, management and outcome. Cancer Treat Rev. 120:102624

27. Lei YY, Yeo W (2021) The risk of menopausal symptoms in premenopausal breast cancer patients and current pharmacological prevention strategies. Expert Opin Drug Saf. 20(10):1163–1175

28. Francis PA, Regan MM, Fleming GF, Lang I, Ciruelos E, Bellet M, Bonnefoi HR, Climent MA, Da Prada GA, Burstein HJ, Martino S, Davidson NE, Geyer CE, Jr., Walley BA, Coleman R, Kerbrat P, Buchholz S, Ingle JN, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Colleoni M, Viale G, Coates AS, Goldhirsch A, Gelber RD, Investigators S, International Breast Cancer Study G (2015) Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 372(5):436–46

29. Bernhard J, Luo W, Ribi K, Colleoni M, Burstein HJ, Tondini C, Pinotti G, Spazzapan S, Ruhstaller T, Puglisi F, Pavesi L, Parmar V, Regan MM, Pagani O, Fleming GF, Francis PA, Price KN, Coates AS, Gelber RD, Goldhirsch A, Walley BA (2015) Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials. Lancet Oncol. 16(7):848–58

30. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS, Group AT (2005) Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet. 365(9453):60–2

31. Jing F, Zhu Z, Qiu J, Tang L, Xu L, Xing W, Hu Y (2023) Symptom clusters and quality of life in patients with breast cancer receiving endocrine therapy in China. Semin Oncol Nurs. 39(4):151443

32. Liu X, Xia X, Hu F, Hao Q, Hou L, Sun X, Zhang G, Yue J, Dong B (2022) The mediation role of sleep quality in the relationship between cognitive decline and depression. BMC Geriatr. 22(1):178

33. Lancel M, Boersma GJ, Kamphuis J (2021) Insomnia disorder and its reciprocal relation with psychopathology. Curr Opin Psychol. 41:34–39

34. George MA, Lustberg MB, Orchard TS (2020) Psychoneurological symptom cluster in breast cancer: the role of inflammation and diet. Breast Cancer Res Treat. 184(1):1–9

35. So WKW, Law BMH, Ng MSN, He X, Chan DNS, Chan CWH, McCarthy AL (2021) Symptom clusters experienced by breast cancer patients at various treatment stages: a systematic review. Cancer Med. 10(8):2531–2565

36. Liou KT, Ahles TA, Garland SN, Li QS, Bao T, Li Y, Root JC, Mao JJ (2019) The relationship between insomnia and cognitive impairment in breast cancer survivors. JNCI Cancer Spectr. 3(3):41

37. Wheeler SB, Spencer J, Pinheiro LC, Murphy CC, Earp JA, Carey L, Olshan A, Tse CK, Bell ME, Weinberger M, Reeder-Hayes KE (2019) Endocrine therapy nonadherence and discontinuation in Black and White women. J Natl Cancer Inst. 111(5):498–508

38. Baumgart J, Nilsson K, Evers AS, Kallak TK, Poromaa IS (2013) Sexual dysfunction in women on adjuvant endocrine therapy after breast cancer. Menopause. 20(2):162–8

39. Gan L, Miao YM, Dong XJ, Zhang QR, Ren Q, Zhang N (2023) Investigation on sexual function in young breast cancer patients during endocrine therapy: a latent class analysis. Front Med (Lausanne). 10:1218369

40. Huang X, Zhang Q, Kang X, Song Y, Zhao W (2010) Factors associated with cancer-related fatigue in breast cancer patients undergoing endocrine therapy in an urban setting: a cross-sectional study. BMC Cancer. 10:453

41. Bower JE (2014) Cancer-related fatigue–mechanisms, risk factors, and treatments. Nat Rev Clin Oncol. 11(10):597–609

42. Yang S, Chu S, Gao Y, Ai Q, Liu Y, Li X, Chen N (2019) A narrative review of cancer-related fatigue (CRF) and its possible pathogenesis. Cells. 8(7):738

43. Garcia-Gonzalez D, Medino-Munoz J, Romero-Elias M, Garcia-Foncillas J, Ruiz-Casado A (2023) Biological mechanisms of cancer-related fatigue in breast cancer survivors after treatment: a scoping review. J Cancer Surviv. Online ahead of print

44. Cole KM, Clemons M, Alzahrani M, Liu M, Larocque G, MacDonald F, Hutton B, Piper A, Fernandes R, Pond GR, Vandermeer L, Emam KE, McGee SF (2022) Vasomotor symptoms in early breast cancer-a “real world” exploration of the patient experience. Support Care Cancer. 30(5):4437–4446

45. Stearns V, Ullmer L, Lopez JF, Smith Y, Isaacs C, Hayes D (2002) Hot flushes. Lancet. 360(9348):1851–61

46. Hyder T, Marino CC, Ahmad S, Nasrazadani A, Brufsky AM (2021) Aromatase inhibitor-associated musculoskeletal syndrome: understanding mechanisms and management. Front Endocrinol (Lausanne). 12:713700

47. Beckwee D, Leysen L, Meuwis K, Adriaenssens N (2017) Prevalence of aromatase inhibitor-induced arthralgia in breast cancer: a systematic review and meta-analysis. Support Care Cancer. 25(5):1673–1686

48. Lu W, Giobbie-Hurder A, Tanasijevic A, Kassis SB, Park SH, Jeong YJ, Shin IH, Yao C, Jung HJ, Zhu Z, Bao C, Bao T, Yang E, Bierer BE, Ligibel JA (2024) Acupuncture for hot flashes in hormone receptor-positive breast cancer: a pooled analysis of individual patient data from parallel randomized trials. Cancer. 130(18):3219–3228

Associated Data

Supplementary Materials

Supplementary file1 (DOCX 32.1 KB)

Data Availability Statement

Data is provided within the manuscript or supplementary information files.