Factors Influencing Patient-Reported Symptom Outcomes in Women with Metastatic Breast Cancer

Factors Influencing Patient-Reported Symptom Outcomes in Women with Metastatic Breast Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Factors Influencing Patient-Reported Symptom Outcomes in Women with Metastatic Breast Cancer Yan Zhan, Shelli Feder, Maryam Lustberg, Q. Margaret Rosenzweig, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7328394/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Feb, 2026 Read the published version in Supportive Care in Cancer → Version 1 posted 7 You are reading this latest preprint version Abstract Background Utilization of targeted agents and immunotherapy led to improved survival in women with metastatic breast cancer (MBC). However, a knowledge gap remains about the side effects and symptom burden associated with these therapies that are not fully described for people living with MBC. We examined patient-reported symptom severity, interference and symptom burden related to MBC cancer treatments and identified correlated sociodemographic and clinical factors. Methods Women with MBC on systemic cancer treatment recruited from oncology clinics and advocacy organizations, completed a survey from February to September 2024. We used the MD Anderson Symptom Inventory (MDASI) Immunotherapy module to describe symptom severity and interference of 20 symptoms and symptom burden. We conducted descriptive statistics and stepwise multiple linear regression to identify sociodemographic and clinical factors correlated with symptom severity, interference, and symptom burden. Results In the sample of 209 participants, the mean age was 50.1 years (SD = 14.11), 76.6% were White. Most were HR+/HER2- subtype, with an average time of 4.35 years since MBC diagnosis. Fatigue, sleep disturbance, forgetfulness, drowsiness, and sadness were the most prevalent symptoms. Participants identified as non-White, have completed more lines of treatments reported higher symptom severity, interference and total symptom burden. However, having dependent children (β = 0.32, 95% CI [0.04, 0.60], P = 0.027) was associated with more severe symptom interference. Conclusion The type and number of treatments, being non-White and caring dependent children were associated with higher symptom burden. Symptom management interventions should be tailored for specific MBC subgroup and to improve overall well-being for MBC population. Metastatic breast cancer MBC Cancer symptoms Symptom burden Systemic therapy Introduction Metastatic breast cancer (MBC) refers to stage IV disease, when cancer has spread beyond the breast to distant organs of the body [ 1 ]. While MBC remains incurable, it is increasingly recognized as a chronic condition due to advances in systemic therapy that has extended survival [ 2 – 4 ]. By 2025, the number of individuals living with MBC is predicted to rise to more than 169,000 in the United States [ 5 ]. Historically, systemic treatments for MBC include hormone (endocrine) therapy and chemotherapy. The combination and sequential use of targeted therapy (e.g., trastuzumab, CDK4/6 inhibitors, and mTOR inhibitors) and immunotherapy (e.g., pembrolizumab, atezolizumab) with chemotherapy and hormone therapy are now integral components of MBC treatment [ 6 , 7 , 1 ]. While these therapies improved survival rates, they are also associated with distinct and often burdensome symptoms, including fatigue, pain, skin rash, diarrhea and neuropathy. Inadequate management of symptoms can impair patients’ physical function and reduce psychosocial well-being and overall quality of life. Earlier studies have documented symptom severity, frequency and distress associated with chemotherapy and hormonal therapy for women with MBC [ 8 – 11 ]. However, there is lack of research that systematically examined the prevalence, severity and interference of symptoms related to contemporary MBC systemic treatment, particularly targeted agents and immunotherapy [ 12 ]. Patient-reported outcomes (PROs) refer to a patient’s subjective experience about their symptoms, physical functioning, social functioning and quality of life [ 13 , 14 ]. The use of standardized, validated PRO measures allows clinicians to conduct comprehensive symptom monitoring and has been associated with improved patient-clinician communication, symptom management, and quality of life in patients with advanced cancers [ 15 , 16 ]. Guidelines recommend integrating patient self-reported symptoms into metastatic cancer survivorship care from the start of treatment to the end-of-life [ 17 , 7 ]. To date, few studies have utilized PROs to describe and compare symptom prevalence, severity, and interference across contemporary cancer treatments in women with MBC receiving systemic treatment. Furthermore, little is known about the factors that influence the symptom experience in this population. To address these gaps, we aimed to expand the current knowledge regarding patients’ subjective symptom experience while receiving systemic therapy regimens commonly used in current MBC clinical practice. The objectives of the current study were to: 1) assess and compare symptom severity, interference and burden of participants receiving different MBC treatments; 2) identify sociodemographic and clinical factors that correlate with symptom severity, interference and overall symptom burden in this population. Methods Study design We used a descriptive, cross-sectional design to obtain survey data from women with MBC in the U.S. The inclusion criteria for participants were: 1) adult women diagnosed with MBC; 2) on systemic cancer treatment (chemotherapy, hormonal therapy, targeted therapy and/or immunotherapy); and 3) able to read and understand English. The survey questionnaire in this study was administered in English. Exclusion criteria included having another cancer diagnosis at the same time and unable to consent. Participants were recruited from a Comprehensive Cancer Center in the Northeastern U.S, a non-profit cancer research organization, and five MBC patient advocacy groups across the country. Using convenience and snowball sampling methods, women who were interested in this study participated voluntarily. Informed consent was obtained from all individual participants. This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Yale University (IRB No: HIC# 2000036269) Data collection Data were collected from February to September in 2024. We distributed recruitment flyers in the infusion center and outpatient clinic of the cancer center, cancer research organization and MBC patient advocates groups. In clinical settings, breast oncologists and a nurse champion identified patients with MBC and referred them to the investigator if they expressed interest in the study. In non-clinical settings, recruitment included emails to members of research organizations and patient advocacy groups and posting the study flyer on organization websites. We used Qualtrics™, an online data collection platform to obtain informed consent, sociodemographic and clinical information and deliver survey questionnaire. To enhance the data quality and the rigor of the data collection, we incorporated the reCAPTCHA, a Completely Automated Public Turing test to Tell Computers and Human Apart owned by Google, on the survey portal to protect the online survey from fraudulent respondents. Prior to the study, we conducted pilot testing of the survey among five women volunteers with MBC to test the readability and acceptability of the questionnaire. The study flyer included a QR code and URL link for participants to access the survey. Individuals first completed screening questions to determine their eligibility. Those who met the criteria signed the electronic informed consent prior to the survey. Participants were able to save answers and return to complete the survey within two weeks from the starting date. We used pop-up notifications for missing answers and allowed one question to be answered each time to reduce missing data. Participants were not provided direct incentives for their participation; however, those who completed the questionnaire and expressed interest were eligible to enter a lottery to win one of four $ 50 gift certificates. The study received 217 responses in total, in which 209 participants completed the questionnaires and were included into the analysis. Variables and Measures Sociodemographic and clinical factors Socioeconomic factors included age, race [ 18 ], ethnicity [ 18 ], educational level (less than high-school, high-school graduate, some college, college, master's degree or above), marital status (married/cohabitating, widowed, divorced/separated, never married), insurance coverage (Medicare, Medicaid, private insurance/marketplace, uninsured/Other), employment status (unemployed, employed-full time, employed part-time, retired), annual household income ( $ 150,000), and religion (Christian, Catholic, Muslim, Judaism, and other/none). Clinical characteristics were tumor characteristics of MBC (Hormone receptor positive or negative, HER-2 positive or negative), current breast cancer treatment(s) (Chemotherapy with/without targeted therapy or immunotherapy, Hormone therapy with/without targeted therapy or immunotherapy, and Targeted therapy only), time on the current treatment(s), method of therapy delivery, time since the first MBC diagnosis, number of treatment line(s) completed, being enrolled in palliative care and clinical trials. Patient-reported symptom outcomes Patient-reported outcomes for symptoms were collected by the MD Anderson Symptom Inventory (MDASI), a validated PRO assessment tool for assessing cancer related symptoms [ 19 ]. We used the MDASI-Immunotherapy EPT [ 20 ] to measure cancer-related and treatment-related symptoms of women with MBC. The MDASI-Immunotherapy EPT includes 13 common symptom items (fatigue, disturbed sleep, pain, drowsiness, poor appetite, nausea, vomiting, shortness of breath, numbness, forgetfulness, dry mouth, distress and sadness) and 7 immunotherapy specific symptoms (diarrhea, abdomen pain, swelling of hands, legs or feet, rash or skin change, headache, night swears, fever or chills). These symptoms were also reported in patients on targeted therapy. Since targeted therapy and immunotherapy have similar side effects in terms of skin reactions (e.g. skin redness, swelling and rash) and gastrointestinal symptoms (e.g. diarrhea, nausea, vomiting, abdominal pain) [ 6 , 21 – 24 ], we used the MDASI-Immunotherapy EPT to capture the shared symptoms for patients treated with either treatment, as well as measure other cancer-related symptoms. The severity of each symptom during the last 24 hours was rated on a 0–10 rating scale, with 0 representing “not present” and 10 representing “as bad as you can imagine”. Symptom interference with daily functions (general activity, mood, work, relations with other people, walking ability and enjoyment of life) was rated from 0 (did not interfere) to 10 (interfered completely). A higher total score indicates a higher symptom severity and interference. The internal consistency of the instrument was excellent, with Cronbach's Alpha score ranging from 0.88 to 0.95. A predetermined cut point of 5 and higher on a 0–10 scale [ 20 , 25 , 26 ] was used to determine moderate to severe symptom and interference in this study. The MDASI defined symptom burden as the combined severity and impact of symptoms on patient daily functioning [ 27 ]. We used the MDASI component scores as outcomes to represent different aspects of symptom burden: 1) overall mean of 20 MDASI- Immunotherapy EPT symptom items; 2) the mean of interference items; 3) the total symptom burden score is the sum of the mean scores for symptom severity and symptom interference. Statistical analysis We used R software (version 4.4.1) for all data analyses. We conducted descriptive analysis for all variables with mean, standard deviation (SD), median, and range for continuous variables, and frequency and percentage for categorical variables. To examine the differences in symptom outcomes, we employed ANOVA and post-hoc tests to compare mean scores of symptom severity, interference, and overall symptom burden across cancer treatment groups. We described the percentage of participants who reported a moderate to severe score for each symptom stratified by cancer treatment and used Chi-square test and the Fisher exact test to examine the difference in moderate-to-severe symptoms by treatment types. Univariate linear regression was conducted to identify sociodemographic and clinical factors associated with each of the three symptom outcomes: symptom severity, symptom interference and symptom burden. Variables with a P ≤ 0.1 in the univariate analyses were retained for inclusion in the multiple linear regression models. We used hierarchical modelling approach to identify sociodemographic and clinical factors associated with symptom outcomes. To develop the initial model (Model 1), we applied “StepAIC ( )” function in R using both forward and backward stepwise selection methods to identify significant sociodemographic predictors according to the Akaike Information Criterion (AIC), an indicator of model goodness-of-fit. The lowest AIC indicates the better model fit. Then clinical variables were added to the model (Model 2). To avoid multi collinearity, we calculated the variance of inflation factor (VIF) for all potential variables and removed those with VIF scores > = 10. The assumptions of linearity, normality and homoscedasticity were checked for the final model. The standardized coefficient estimates of models with 95% confidence interval (CI), adjusted R 2 , and P values were reported. In all models, the two-sided P values < .05 were considered statistically significant. Results Sociodemographic and clinical characteristics of participants The sociodemographic and clinical characteristics of the participants are shown in Table 1 and 2. All participants were female with a mean age of 50.1 years (± 14.1). Most participants identified as White (76.6%), non-Hispanic (85.2%), and married/cohabitating (70.3%). Among the total sample (see Table 2), about 65% were diagnosed as having hormone receptor positive and HER-2 negative (HR+/HER2-) MBC. Treatment with chemotherapy or chemotherapy + targeted or immunotherapy was reported by 37.8% and 44% reported Hormone or hormone+/- targeted or immunotherapy” (n=92). Slightly less than half (42.1%) were on their current treatment(s) less than 1 year and 44% were enrolled in palliative care. The average number of treatment line(s) completed was 2.36 (SD=1.81), with the time since MBC diagnosis ranging from 0-19 years (Mean=4.35, SD=3.97). Symptom burden and prevalence of moderate-to-severe symptoms The mean scores for the 13 core symptoms, 7 immunotherapy symptoms, and 6 symptom interference were 3.85, 2.71 and 4.01 respectively (Table 3). The most common and severe symptoms were fatigue (Mean= 5.76, SD= 2.71), disturbed sleep (Mean= 5.11, SD= 3.11), forgetfulness (Mean= 4.45, SD= 2.95), feeling drowsy (Mean= 4.95, SD= 2.91), and sadness (Mean= 4.48, SD= 3.11). Participants who received chemotherapy or chemotherapy with targeted or immunotherapy reported higher symptom severity scores than those receiving hormone or hormone therapy targeted or immunotherapy and targeted therapy only. More than half of the participants reported moderate to severe fatigue (n=137, 66.8%), disturbed sleep (n=114, 55.6%) and feeling drowsy (n=111, 54.1%). There was a higher incidence of patients with moderate to severe fatigue (74.7%) and disturbed sleep (69.6%) for those receiving chemotherapy or chemotherapy with targeted or immunotherapy treatment (Supplemental Table 1). The chemotherapy-based treatment group also reported the highest level of interference in work (58.2%) and enjoyment of life (53.2%), while patients receiving targeted therapy alone experienced the lowest interference in all functional domains. Patient factors associated with symptom outcomes We conducted multiple linear regression analysis using hierarchical modelling approach to identify sociodemographic and clinical factors that were independently associated symptom severity and interference and symptom burden. The results of univariate analysis were shown in Supplemental Table 2. For symptom severity, private insurance (b = -0.44, 95% CI [-0.75, -0.14], P =0.005), and receiving targeted therapy alone (b = -0.65, 95% CI [-1.00, -0.31], P < 0.001) were significantly associated with lower severity. Higher symptom severity was found in participants who self-identified as non-White (b = 0.46, 95% CI [0.15, 0.78], P = 0.004), and those completed more number of treatment lines (b = 0.16, 95% CI [0.04, 0.29], P =0.011). The result of symptom severity is shown in Table 4. Table 5 shows factors associated with increased symptom interference included Non-White race (b=0.54, 95% CI [0.21, 0.86], P=0.001) and having dependent children (b=0.32, 95% CI [0.04, 0.60], P=0.027). Participants receiving targeted therapy alone (b=-0.49, 95% CI [-0.87, -0.12], P=0.011) and completed a greater number of treatment lines (b=0.18, 95% CI [0.04, 0.32], P=0.010) reported less interference. Similar to symptom severity, high symptom burden was associated with Non-white (b = 0.62, 95% CI [0.31, 0.93], P <0.001) and completed more lines of treatment (b = 0.19, 95% CI [0.06, 0.32], P = 0.004). Private insurance (b = -0.42, 95% CI [-0.73, -0.10], P = 0.010), and receiving targeted therapy (b= -0.61, 95% CI [-0.97, -0.25], P = 0.001) were related to a lower symptom burden (Table 6). Discussion The current study examined the symptom severity, interference and symptom burden among women with MBC and identified sociodemographic and clinical factors that were associated with symptom outcomes. Multivariable regression analyses revealed that receiving targeted therapy alone, completed a greater number of treatment lines and race were significant predictors of all three symptom outcomes. Private insurance converge was associated with symptom severity and symptom burden, but not with symptom interference. Notably, having dependent children was only related to symptom interference. We analyzed three commonly used systemic regimens and identified differences among them in terms of symptom outcomes. Our finding has shown that participants who receiving chemotherapy or chemotherapy combined with targeted or immunotherapy reported higher symptom severity, symptom interference and total symptom burden than those on hormone or hormonal based combination therapy and targeted therapy alone. This finding aligns with current literature indicating that chemotherapy is associated with more severe treatment induced side effects, such as fatigue, pain, nausea [ 28 , 29 ] and psychological distress [ 30 ] than other cancer treatments. In the meantime, we identified high prevalence of fatigue and sleep disturbance, forgetfulness, feeling drowsy, and sadness among study participants, which suggested these symptoms may be co-occurring during cancer treatment trajectory. Further investigation is needed to confirm whether these symptoms form clusters in MBC population receiving systemic cancer treatment. A recent systematic review conducted by So and colleagues (2024) reported fatigue-sleep disturbance cluster and psychological symptom cluster of anxiety, depression, nervousness, sadness and worry in breast cancer [ 31 ]. However, these symptom clusters were associated with traditional chemotherapy and radiotherapy in early-stage breast cancer and there is no study specifically reported symptom clusters related to new treatments among MBC population. Future research is thus warranted to confirm whether these symptoms form clusters in MBC population receiving systemic cancer treatment and investigate pattern of symptom cluster in relation to treatments. For symptom interference, work and mood were the most affected areas of daily functioning. Women who received chemotherapy-based treatment reporting the highest levels of symptom interference, particularly in work-related activities and enjoyment of life. These fundings align with previous research that symptom interference, as measured by the MDASI, was associated with impairment in work productivity and daily activities in women with locally recurrent and MBC [ 32 , 33 ]. In addition, Chapman et al. found that better working quality of life among employed women with MBC was associated with greater cognitive functioning, improved overall health, and lower levels of depression [ 34 ]. Improving symptom management may enhance women with MBC’s ability to return to or remain employment during their treatment, an aspect that in many cases is essential to maintaining financial stability and psychological well-being. However, effective interventions that support the return to work for people with advanced cancer are not known, as this population is frequently excluded from major work rehabilitation clinical trials [ 35 , 36 ]. More number of completed treatment line(s) was identified as a factor contributed to severe symptom outcomes. This finding is expected as the longer time exposure to systemic treatments is associated with increased cumulative toxicity [ 7 ], which contribute to worse symptom outcomes. Similar results were also reported in patients with lung cancer patients and early-stage breast cancer, where more lines of palliative chemotherapy and longer duration of chemotherapy were strongly associated with severe symptom burden in fatigue, pain, worse physical functioning [ 37 ] and more treatment-related toxicities [ 38 ]. To address cumulative toxicity, clinicians should continuously monitor and manage symptoms for women with MBC, as most of them are likely on life-long therapy. Further longitudinal study should describe symptoms over time, and to inform targeted interventions to minimize treatment-induced toxicity and improve health outcomes. In this study, participants who self-identified as Black, Asian, American Indian or Alaska Native, and Native Hawaiian or other pacific Islander reported higher symptom burden compared to those who identified as White. Research evidence has shown that breast cancer patients who identified as Black experienced greater pain and lower physical function throughout cancer trajectory [ 39 ]. Given the small number of minoritized participants in this study, we were unable to directly compare their symptom experience. Future research is warranted to examine the unique symptom experience of minoritized patients receiving targeted and immunotherapy. The relationship between having dependent children and higher symptom interference can be explained by the conflict of coping with advanced cancer while taking responsibility for child-care. This conflict exacerbates the levels of anxiety and depression [ 40 , 41 ], and mood disorders [ 42 ] among parents with advanced cancer, which in turn result in a greater interference of symptoms to daily life and reduced health-related quality of life [ 43 ]. Further research in health policy, supportive care (e.g., financial assistance, child-care and mental health services) and resource allocation is needed to advocate for the well-being of parents with advanced cancer. Strengths and limitations This study contributed to the existing literature by providing an overview of symptom burden in women living with MBC receiving contemporary breast cancer treatments. To the best of our knowledge, this is one of the first studies to use PROs to compare symptoms related to chemotherapy-based and hormone therapy-based regimens with the combinations of targeted therapy and immunotherapy, that reflect MBC treatment in current clinical practice. The use of a web-based survey in collaboration with cancer advocacy organizations represents a strategy to engage this understudied, sub-population of women with breast cancer. Although our participants were predominantly identified as White, we were able to recruit a higher percentage of women who identified as Black and other minorities (23.4%) relative to 11.3% in other MBC studies [ 8 ]. There are several limitations to this study. First, study respondents were women with an above-average education and income, and internet access. This sample may not be representative of all patients with MBC including male, and those affected by adverse social determinants of health, such as neighborhood deprivation, limited access to healthcare, and social isolation [ 44 ]. Second, the cross-sectional design limited our ability to make casual interferences for the associations between salient sociodemographic and clinical factors and symptom outcomes, as well as tracking changes in symptom burden across treatment trajectory. In the future, longitudinal studies should be conducted to examine individual symptom and overall symptom burden across time, as time on treatment was a predictive factor for symptom burden. Third, cancer diagnoses and treatments were self-reported by participants, and we were unable to verify and confirm clinical information. Although we used screening questions prior to the survey to exclude ineligible participants, it is possible that some participants reported inaccurate information regarding their tumor characteristics and treatments. Lastly, we did not collect data about baseline symptoms, previous treatments and comorbidities. Future studies should account for these factors since they also affect cancer outcomes. Implications for clinical practice and research This study has several implications for clinical practice and research. For clinical practice, oncologists and nurses should closely monitor patients who are receiving chemotherapy-based treatment, as they experienced greater symptom burden and interference than those receiving hormonal therapy or targeted therapy. To alleviate symptom burden, pharmaceutical interventions [ 45 ] and non-pharmaceutical interventions, such as cognitive behavioral therapy [ 46 ] can be incorporated into symptom management. In addition, clinicians should also pay attention to patients who are caring for dependent children, without insurance coverage or have completed multiple treatment lines, as those individuals were more likely to experience more severe symptoms. For research, future study is needed to examine symptom clusters related to specific novel therapies for MBC. High prevalent fatigue, sleep disturbances, forgetfulness, drowsiness, and sadness identified in this study, indicating that these symptoms may co-occur in this population. In addition, symptom profile analysis that describes symptom pattens experienced by a group of patients with similar characteristics,[ 47 ] can be used to identify those at higher risk of developing worse symptom burden and poorer health outcomes, such as health-related quality of life. This information may guide the development of more effective symptom management strategies for women with MBC. Conclusions In this cross-sectional study, we assessed the prevalence and severity of individual symptoms related to cancer treatments using validated PRO measures and identified sociodemographic and clinical factors associated with symptom burden among women with MBC. Our findings contribute to the body of evidence by comparing symptom experience across contemporary systemic cancer treatments. Although the symptom burden in our sample was mild to moderate, participants reported supportive care needs related to child-care, and employment during life-prolonging treatment. These findings suggest future interventions should address not only symptom management but also psychosocial and supportive care issues pertinent to specific MBC subgroups to improve overall well-being for MBC population. Abbreviations HRQOL= Health Related Quality of Life PROs= Patient-Reported Symptom Outcomes MBC= Metastatic Breast Cancer Declarations AUTHOR CONTRIBUTIONS All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Yan Zhan. The first draft of the manuscript was written by Yan Zhan and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Disclosures and Acknowledgements This study was funded by the Sigma Tau International Nursing Society Delta Mu Research Award. The authors gratefully acknowledge all the women who participated in this study, Lesley Glenn (CEO/Founder of Project Life), Julia Maués (Co-Founder of GRASP Cancer) for their invaluable support with recruitment, and the breast oncology team at the Yale University Smilow Cancer Center. Conflict of Interest Statement No conflict of interest has been declared by the author(s). References American Cancer Society. (2025, January 22). Treatment of stage IV (advanced) breast cancer . American Cancer Society. https://www.cancer.org/cancer/types/breast-cancer/treatment/treatment-of-breast-cancer-by-stage/treatment-of-stage-iv-advanced-breast-cancer.html Caswell-Jin, J. L., Sun, L. P., Munoz, D., Lu, Y., Li, Y., Huang, H., ... & Plevritis, S. K. (2024). Analysis of breast cancer mortality in the US—1975 to 2019. Jama, 331(3), 233-241. Giaquinto, A. N., Sung, H., Newman, L. A., Freedman, R. A., Smith, R. A., Star, J., ... & Siegel, R. L. (2024). Breast cancer statistics 2024. 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(2013). Quality of life during chemotherapy in lung cancer patients: results across different treatment lines. British journal of cancer, 109(9), 2301-2308. Nyrop, K. A., Deal, A. M., Shachar, S. S., Basch, E., Reeve, B. B., Choi, S. K., ... & Muss, H. B. (2019). Patient‐reported toxicities during chemotherapy regimens in current clinical practice for early breast cancer. The Oncologist, 24(6), 762-771. Abujaradeh, H., O'Brien, J., Mazanec, S. R., Bender, C. M., Schlemmer, I. M., Brufsky, A. M., ... & Rosenzweig, M. (2025). The Effect of Race and Area Deprivation on Symptom profiles over the course of early-stage breast Cancer. Journal of Pain and Symptom Management. Muriel, A. C., Moore, C. W., Baer, L., Park, E. R., Kornblith, A. B., Pirl, W., ... & Rauch, P. K. (2012). Measuring psychosocial distress and parenting concerns among adults with cancer: The Parenting Concerns Questionnaire. Cancer, 118(22), 5671-5678. Park, E. M., Deal, A. M., Check, D. K., Hanson, L. C., Reeder‐Hayes, K. E., Mayer, D. K., ... & Rosenstein, D. L. (2016). Parenting concerns, quality of life, and psychological distress in patients with advanced cancer. Psycho‐Oncology, 25(8), 942-948. Nilsson, M. E., Maciejewski, P. K., Zhang, B., Wright, A. A., Trice, E. D., Muriel, A. C., ... & Prigerson, H. G. (2009). Mental health, treatment preferences, advance care planning, location, and quality of death in advanced cancer patients with dependent children. Cancer, 115(2), 399-409. Park, E. M., Deal, A. M., Yopp, J. M., Edwards, T., Resnick, S. J., Song, M. K., ... & Rosenstein, D. L. (2018). Understanding health‐related quality of life in adult women with metastatic cancer who have dependent children. Cancer, 124(12), 2629-2636. Badger, T. A., Segrin, C., Crane, T. E., Chalasani, P., Arslan, W., Hadeed, M., & Sikorskii, A. (2023). Social determinants of health and symptom burden during cancer treatment. Nursing research, 72(2), 103-113. Palesh, O., Scheiber, C., Kesler, S., Mustian, K., Koopman, C., & Schapira, L. (2018). Management of side effects during and post‐treatment in breast cancer survivors. The breast journal, 24(2), 167-175. Poort, H., Peters, M. E. W. J., Van Der Graaf, W. T. A., Nieuwkerk, P. T., Van de Wouw, A. J., Nijhuis-van Der Sanden, M. W. G., ... & Knoop, H. (2020). Cognitive behavioral therapy or graded exercise therapy compared with usual care for severe fatigue in patients with advanced cancer during treatment: a randomized controlled trial. Annals of Oncology, 31(1), 115-122. Spurk, D., Hirschi, A., Wang, M., Valero, D., & Kauffeld, S. (2020). Latent profile analysis: A review and “how to” guide of its application within vocational behavior research. Journal of vocational behavior, 120, 103445. Tables Tables 1 to 6 are available in the Supplementary Files section Additional Declarations No competing interests reported. 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While MBC remains incurable, it is increasingly recognized as a chronic condition due to advances in systemic therapy that has extended survival [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. By 2025, the number of individuals living with MBC is predicted to rise to more than 169,000 in the United States [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHistorically, systemic treatments for MBC include hormone (endocrine) therapy and chemotherapy. The combination and sequential use of targeted therapy (e.g., trastuzumab, CDK4/6 inhibitors, and mTOR inhibitors) and immunotherapy (e.g., pembrolizumab, atezolizumab) with chemotherapy and hormone therapy are now integral components of MBC treatment [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. While these therapies improved survival rates, they are also associated with distinct and often burdensome symptoms, including fatigue, pain, skin rash, diarrhea and neuropathy. Inadequate management of symptoms can impair patients\u0026rsquo; physical function and reduce psychosocial well-being and overall quality of life. Earlier studies have documented symptom severity, frequency and distress associated with chemotherapy and hormonal therapy for women with MBC [\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, there is lack of research that systematically examined the prevalence, severity and interference of symptoms related to contemporary MBC systemic treatment, particularly targeted agents and immunotherapy [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePatient-reported outcomes (PROs) refer to a patient\u0026rsquo;s subjective experience about their symptoms, physical functioning, social functioning and quality of life [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The use of standardized, validated PRO measures allows clinicians to conduct comprehensive symptom monitoring and has been associated with improved patient-clinician communication, symptom management, and quality of life in patients with advanced cancers [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Guidelines recommend integrating patient self-reported symptoms into metastatic cancer survivorship care from the start of treatment to the end-of-life [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo date, few studies have utilized PROs to describe and compare symptom prevalence, severity, and interference across contemporary cancer treatments in women with MBC receiving systemic treatment. Furthermore, little is known about the factors that influence the symptom experience in this population. To address these gaps, we aimed to expand the current knowledge regarding patients\u0026rsquo; subjective symptom experience while receiving systemic therapy regimens commonly used in current MBC clinical practice. The objectives of the current study were to: 1) assess and compare symptom severity, interference and burden of participants receiving different MBC treatments; 2) identify sociodemographic and clinical factors that correlate with symptom severity, interference and overall symptom burden in this population.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design\u003c/h2\u003e\u003cp\u003eWe used a descriptive, cross-sectional design to obtain survey data from women with MBC in the U.S. The inclusion criteria for participants were: 1) adult women diagnosed with MBC; 2) on systemic cancer treatment (chemotherapy, hormonal therapy, targeted therapy and/or immunotherapy); and 3) able to read and understand English. The survey questionnaire in this study was administered in English. Exclusion criteria included having another cancer diagnosis at the same time and unable to consent. Participants were recruited from a Comprehensive Cancer Center in the Northeastern U.S, a non-profit cancer research organization, and five MBC patient advocacy groups across the country. Using convenience and snowball sampling methods, women who were interested in this study participated voluntarily. Informed consent was obtained from all individual participants. This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Yale University (IRB No: HIC# 2000036269)\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eData were collected from February to September in 2024. We distributed recruitment flyers in the infusion center and outpatient clinic of the cancer center, cancer research organization and MBC patient advocates groups. In clinical settings, breast oncologists and a nurse champion identified patients with MBC and referred them to the investigator if they expressed interest in the study. In non-clinical settings, recruitment included emails to members of research organizations and patient advocacy groups and posting the study flyer on organization websites.\u003c/p\u003e\u003cp\u003e We used Qualtrics\u0026trade;, an online data collection platform to obtain informed consent, sociodemographic and clinical information and deliver survey questionnaire. To enhance the data quality and the rigor of the data collection, we incorporated the reCAPTCHA, a Completely Automated Public Turing test to Tell Computers and Human Apart owned by Google, on the survey portal to protect the online survey from fraudulent respondents. Prior to the study, we conducted pilot testing of the survey among five women volunteers with MBC to test the readability and acceptability of the questionnaire.\u003c/p\u003e\u003cp\u003eThe study flyer included a QR code and URL link for participants to access the survey. Individuals first completed screening questions to determine their eligibility. Those who met the criteria signed the electronic informed consent prior to the survey. Participants were able to save answers and return to complete the survey within two weeks from the starting date. We used pop-up notifications for missing answers and allowed one question to be answered each time to reduce missing data. Participants were not provided direct incentives for their participation; however, those who completed the questionnaire and expressed interest were eligible to enter a lottery to win one of four \u003cspan\u003e$\u003c/span\u003e50 gift certificates. The study received 217 responses in total, in which 209 participants completed the questionnaires and were included into the analysis.\u003c/p\u003e\n\u003ch3\u003eVariables and Measures\u003c/h3\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eSociodemographic and clinical factors\u003c/h2\u003e\u003cp\u003eSocioeconomic factors included age, race [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], ethnicity [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], educational level (less than high-school, high-school graduate, some college, college, master's degree or above), marital status (married/cohabitating, widowed, divorced/separated, never married), insurance coverage (Medicare, Medicaid, private insurance/marketplace, uninsured/Other), employment status (unemployed, employed-full time, employed part-time, retired), annual household income (\u0026lt;\u003cspan\u003e$\u003c/span\u003e50,000, \u003cspan\u003e$\u003c/span\u003e50,000 - \u003cspan\u003e$\u003c/span\u003e100,000, \u003cspan\u003e$\u003c/span\u003e101,000 - \u003cspan\u003e$\u003c/span\u003e150,000, \u0026gt;\u003cspan\u003e$\u003c/span\u003e150,000), and religion (Christian, Catholic, Muslim, Judaism, and other/none).\u003c/p\u003e\u003cp\u003eClinical characteristics were tumor characteristics of MBC (Hormone receptor positive or negative, HER-2 positive or negative), current breast cancer treatment(s) (Chemotherapy with/without targeted therapy or immunotherapy, Hormone therapy with/without targeted therapy or immunotherapy, and Targeted therapy only), time on the current treatment(s), method of therapy delivery, time since the first MBC diagnosis, number of treatment line(s) completed, being enrolled in palliative care and clinical trials.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePatient-reported symptom outcomes\u003c/h3\u003e\n\u003cp\u003ePatient-reported outcomes for symptoms were collected by the MD Anderson Symptom Inventory (MDASI), a validated PRO assessment tool for assessing cancer related symptoms [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. We used the MDASI-Immunotherapy EPT [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] to measure cancer-related and treatment-related symptoms of women with MBC. The MDASI-Immunotherapy EPT includes 13 common symptom items (fatigue, disturbed sleep, pain, drowsiness, poor appetite, nausea, vomiting, shortness of breath, numbness, forgetfulness, dry mouth, distress and sadness) and 7 immunotherapy specific symptoms (diarrhea, abdomen pain, swelling of hands, legs or feet, rash or skin change, headache, night swears, fever or chills). These symptoms were also reported in patients on targeted therapy. Since targeted therapy and immunotherapy have similar side effects in terms of skin reactions (e.g. skin redness, swelling and rash) and gastrointestinal symptoms (e.g. diarrhea, nausea, vomiting, abdominal pain) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], we used the MDASI-Immunotherapy EPT to capture the shared symptoms for patients treated with either treatment, as well as measure other cancer-related symptoms.\u003c/p\u003e\u003cp\u003eThe severity of each symptom during the last 24 hours was rated on a 0\u0026ndash;10 rating scale, with 0 representing \u0026ldquo;not present\u0026rdquo; and 10 representing \u0026ldquo;as bad as you can imagine\u0026rdquo;. Symptom interference with daily functions (general activity, mood, work, relations with other people, walking ability and enjoyment of life) was rated from 0 (did not interfere) to 10 (interfered completely). A higher total score indicates a higher symptom severity and interference. The internal consistency of the instrument was excellent, with Cronbach's Alpha score ranging from 0.88 to 0.95. A predetermined cut point of 5 and higher on a 0\u0026ndash;10 scale [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] was used to determine moderate to severe symptom and interference in this study.\u003c/p\u003e\u003cp\u003eThe MDASI defined symptom burden as the combined severity and impact of symptoms on patient daily functioning [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. We used the MDASI component scores as outcomes to represent different aspects of symptom burden: 1) overall mean of 20 MDASI- Immunotherapy EPT symptom items; 2) the mean of interference items; 3) the total symptom burden score is the sum of the mean scores for symptom severity and symptom interference.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eWe used R software (version 4.4.1) for all data analyses. We conducted descriptive analysis for all variables with mean, standard deviation (SD), median, and range for continuous variables, and frequency and percentage for categorical variables. To examine the differences in symptom outcomes, we employed ANOVA and post-hoc tests to compare mean scores of symptom severity, interference, and overall symptom burden across cancer treatment groups. We described the percentage of participants who reported a moderate to severe score for each symptom stratified by cancer treatment and used Chi-square test and the Fisher exact test to examine the difference in moderate-to-severe symptoms by treatment types.\u003c/p\u003e\u003cp\u003eUnivariate linear regression was conducted to identify sociodemographic and clinical factors associated with each of the three symptom outcomes: symptom severity, symptom interference and symptom burden. Variables with a P\u0026thinsp;\u0026le;\u0026thinsp;0.1 in the univariate analyses were retained for inclusion in the multiple linear regression models. We used hierarchical modelling approach to identify sociodemographic and clinical factors associated with symptom outcomes. To develop the initial model (Model 1), we applied \u0026ldquo;StepAIC ( )\u0026rdquo; function in R using both forward and backward stepwise selection methods to identify significant sociodemographic predictors according to the Akaike Information Criterion (AIC), an indicator of model goodness-of-fit. The lowest AIC indicates the better model fit. Then clinical variables were added to the model (Model 2). To avoid multi collinearity, we calculated the variance of inflation factor (VIF) for all potential variables and removed those with VIF scores\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;10. The assumptions of linearity, normality and homoscedasticity were checked for the final model. The standardized coefficient estimates of models with 95% confidence interval (CI), adjusted R\u003csup\u003e2\u003c/sup\u003e, and P values were reported. In all models, the two-sided P values\u0026thinsp;\u0026lt;\u0026thinsp;.05 were considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eSociodemographic and clinical characteristics of participants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; The sociodemographic and clinical characteristics of the participants are shown in Table 1 and 2. All participants were female with a mean age of 50.1 years (± 14.1). Most participants identified as White (76.6%), non-Hispanic (85.2%), and married/cohabitating (70.3%). Among the total sample (see Table 2), about 65% were diagnosed as having hormone receptor positive and HER-2 negative (HR+/HER2-) MBC. Treatment with chemotherapy or chemotherapy + targeted or immunotherapy was reported by 37.8% and 44% reported Hormone or hormone+/- targeted or immunotherapy” (n=92). Slightly less than half (42.1%) were on their current treatment(s) less than 1 year and 44% were enrolled in palliative care. The average number of treatment line(s) completed was 2.36 (SD=1.81), with the time since MBC diagnosis ranging from 0-19 years (Mean=4.35, SD=3.97). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSymptom burden and prevalence of moderate-to-severe symptoms\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;The mean scores for the 13 core symptoms, 7 immunotherapy symptoms, and 6 symptom interference were 3.85, 2.71 and 4.01 respectively (Table 3). The most common and severe symptoms were fatigue (Mean= 5.76, SD= 2.71), disturbed sleep (Mean= 5.11, SD= 3.11), forgetfulness (Mean= 4.45, SD= 2.95), feeling drowsy (Mean= 4.95, SD= 2.91), and sadness (Mean= 4.48, SD= 3.11). Participants who received chemotherapy or chemotherapy with targeted or immunotherapy reported higher symptom severity scores than those receiving hormone or hormone therapy targeted or immunotherapy and targeted therapy only.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; More than half of the participants reported moderate to severe fatigue (n=137, 66.8%), disturbed sleep (n=114, 55.6%) and feeling drowsy (n=111, 54.1%). There was a higher incidence of patients with moderate to severe fatigue (74.7%) and disturbed sleep (69.6%) for those receiving chemotherapy or chemotherapy with targeted or immunotherapy treatment (Supplemental Table 1). The chemotherapy-based treatment group also reported the highest level of interference in work (58.2%) and enjoyment of life (53.2%), while patients receiving targeted therapy alone experienced the lowest interference in all functional domains.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient factors associated with symptom outcomes\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; We conducted multiple linear regression analysis using hierarchical modelling approach to identify sociodemographic and clinical factors that were independently associated symptom severity and interference and symptom burden. The results of univariate analysis were shown in Supplemental Table 2. For symptom severity, private insurance (b\u0026nbsp;= -0.44, 95% CI [-0.75, -0.14], \u003cem\u003eP\u0026nbsp;\u003c/em\u003e=0.005), and receiving targeted therapy alone (b\u0026nbsp;= -0.65, 95% CI [-1.00, -0.31], \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001) were significantly associated with lower severity. Higher symptom severity was found in participants who self-identified as non-White (b\u0026nbsp;= 0.46, 95% CI [0.15, 0.78], \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.004), and those completed more number of treatment lines (b\u0026nbsp;= 0.16, 95% CI [0.04, 0.29], \u003cem\u003eP\u0026nbsp;\u003c/em\u003e=0.011). The result of symptom severity is shown in Table 4.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Table 5 shows factors associated with increased symptom interference included Non-White race (b=0.54, 95% CI [0.21, 0.86], P=0.001) and having dependent children (b=0.32, 95% CI [0.04, 0.60], P=0.027). Participants receiving targeted therapy alone (b=-0.49, 95% CI [-0.87, -0.12], P=0.011) and completed a greater number of treatment lines (b=0.18, 95% CI [0.04, 0.32], P=0.010) reported less interference.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Similar to symptom severity, high symptom burden was associated with Non-white (b\u0026nbsp;= 0.62, 95% CI [0.31, 0.93], \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001) and completed more lines of treatment (b\u0026nbsp;= 0.19, 95% CI [0.06, 0.32], \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.004). Private insurance (b\u0026nbsp;= -0.42, 95% CI [-0.73, -0.10], \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.010), and receiving targeted therapy (b= -0.61, 95% CI [-0.97, -0.25], \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.001) were related to a lower symptom burden (Table 6).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe current study examined the symptom severity, interference and symptom burden among women with MBC and identified sociodemographic and clinical factors that were associated with symptom outcomes. Multivariable regression analyses revealed that receiving targeted therapy alone, completed a greater number of treatment lines and race were significant predictors of all three symptom outcomes. Private insurance converge was associated with symptom severity and symptom burden, but not with symptom interference. Notably, having dependent children was only related to symptom interference.\u003c/p\u003e\u003cp\u003eWe analyzed three commonly used systemic regimens and identified differences among them in terms of symptom outcomes. Our finding has shown that participants who receiving chemotherapy or chemotherapy combined with targeted or immunotherapy reported higher symptom severity, symptom interference and total symptom burden than those on hormone or hormonal based combination therapy and targeted therapy alone. This finding aligns with current literature indicating that chemotherapy is associated with more severe treatment induced side effects, such as fatigue, pain, nausea [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] and psychological distress [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] than other cancer treatments. In the meantime, we identified high prevalence of fatigue and sleep disturbance, forgetfulness, feeling drowsy, and sadness among study participants, which suggested these symptoms may be co-occurring during cancer treatment trajectory. Further investigation is needed to confirm whether these symptoms form clusters in MBC population receiving systemic cancer treatment. A recent systematic review conducted by So and colleagues (2024) reported fatigue-sleep disturbance cluster and psychological symptom cluster of anxiety, depression, nervousness, sadness and worry in breast cancer [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. However, these symptom clusters were associated with traditional chemotherapy and radiotherapy in early-stage breast cancer and there is no study specifically reported symptom clusters related to new treatments among MBC population. Future research is thus warranted to confirm whether these symptoms form clusters in MBC population receiving systemic cancer treatment and investigate pattern of symptom cluster in relation to treatments.\u003c/p\u003e\u003cp\u003eFor symptom interference, work and mood were the most affected areas of daily functioning. Women who received chemotherapy-based treatment reporting the highest levels of symptom interference, particularly in work-related activities and enjoyment of life. These fundings align with previous research that symptom interference, as measured by the MDASI, was associated with impairment in work productivity and daily activities in women with locally recurrent and MBC [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In addition, Chapman et al. found that better working quality of life among employed women with MBC was associated with greater cognitive functioning, improved overall health, and lower levels of depression [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Improving symptom management may enhance women with MBC\u0026rsquo;s ability to return to or remain employment during their treatment, an aspect that in many cases is essential to maintaining financial stability and psychological well-being. However, effective interventions that support the return to work for people with advanced cancer are not known, as this population is frequently excluded from major work rehabilitation clinical trials [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMore number of completed treatment line(s) was identified as a factor contributed to severe symptom outcomes. This finding is expected as the longer time exposure to systemic treatments is associated with increased cumulative toxicity [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], which contribute to worse symptom outcomes. Similar results were also reported in patients with lung cancer patients and early-stage breast cancer, where more lines of palliative chemotherapy and longer duration of chemotherapy were strongly associated with severe symptom burden in fatigue, pain, worse physical functioning [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] and more treatment-related toxicities [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. To address cumulative toxicity, clinicians should continuously monitor and manage symptoms for women with MBC, as most of them are likely on life-long therapy. Further longitudinal study should describe symptoms over time, and to inform targeted interventions to minimize treatment-induced toxicity and improve health outcomes.\u003c/p\u003e\u003cp\u003eIn this study, participants who self-identified as Black, Asian, American Indian or Alaska Native, and Native Hawaiian or other pacific Islander reported higher symptom burden compared to those who identified as White. Research evidence has shown that breast cancer patients who identified as Black experienced greater pain and lower physical function throughout cancer trajectory [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Given the small number of minoritized participants in this study, we were unable to directly compare their symptom experience. Future research is warranted to examine the unique symptom experience of minoritized patients receiving targeted and immunotherapy. The relationship between having dependent children and higher symptom interference can be explained by the conflict of coping with advanced cancer while taking responsibility for child-care. This conflict exacerbates the levels of anxiety and depression [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], and mood disorders [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] among parents with advanced cancer, which in turn result in a greater interference of symptoms to daily life and reduced health-related quality of life [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Further research in health policy, supportive care (e.g., financial assistance, child-care and mental health services) and resource allocation is needed to advocate for the well-being of parents with advanced cancer.\u003c/p\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eStrengths and limitations\u003c/h2\u003e\u003cp\u003eThis study contributed to the existing literature by providing an overview of symptom burden in women living with MBC receiving contemporary breast cancer treatments. To the best of our knowledge, this is one of the first studies to use PROs to compare symptoms related to chemotherapy-based and hormone therapy-based regimens with the combinations of targeted therapy and immunotherapy, that reflect MBC treatment in current clinical practice. The use of a web-based survey in collaboration with cancer advocacy organizations represents a strategy to engage this understudied, sub-population of women with breast cancer. Although our participants were predominantly identified as White, we were able to recruit a higher percentage of women who identified as Black and other minorities (23.4%) relative to 11.3% in other MBC studies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThere are several limitations to this study. First, study respondents were women with an above-average education and income, and internet access. This sample may not be representative of all patients with MBC including male, and those affected by adverse social determinants of health, such as neighborhood deprivation, limited access to healthcare, and social isolation [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Second, the cross-sectional design limited our ability to make casual interferences for the associations between salient sociodemographic and clinical factors and symptom outcomes, as well as tracking changes in symptom burden across treatment trajectory. In the future, longitudinal studies should be conducted to examine individual symptom and overall symptom burden across time, as time on treatment was a predictive factor for symptom burden. Third, cancer diagnoses and treatments were self-reported by participants, and we were unable to verify and confirm clinical information. Although we used screening questions prior to the survey to exclude ineligible participants, it is possible that some participants reported inaccurate information regarding their tumor characteristics and treatments. Lastly, we did not collect data about baseline symptoms, previous treatments and comorbidities. Future studies should account for these factors since they also affect cancer outcomes.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eImplications for clinical practice and research\u003c/h2\u003e\u003cp\u003eThis study has several implications for clinical practice and research. For clinical practice, oncologists and nurses should closely monitor patients who are receiving chemotherapy-based treatment, as they experienced greater symptom burden and interference than those receiving hormonal therapy or targeted therapy. To alleviate symptom burden, pharmaceutical interventions [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e] and non-pharmaceutical interventions, such as cognitive behavioral therapy [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e] can be incorporated into symptom management. In addition, clinicians should also pay attention to patients who are caring for dependent children, without insurance coverage or have completed multiple treatment lines, as those individuals were more likely to experience more severe symptoms.\u003c/p\u003e\u003cp\u003eFor research, future study is needed to examine symptom clusters related to specific novel therapies for MBC. High prevalent fatigue, sleep disturbances, forgetfulness, drowsiness, and sadness identified in this study, indicating that these symptoms may co-occur in this population. In addition, symptom profile analysis that describes symptom pattens experienced by a group of patients with similar characteristics,[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e] can be used to identify those at higher risk of developing worse symptom burden and poorer health outcomes, such as health-related quality of life. This information may guide the development of more effective symptom management strategies for women with MBC.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this cross-sectional study, we assessed the prevalence and severity of individual symptoms related to cancer treatments using validated PRO measures and identified sociodemographic and clinical factors associated with symptom burden among women with MBC. Our findings contribute to the body of evidence by comparing symptom experience across contemporary systemic cancer treatments. Although the symptom burden in our sample was mild to moderate, participants reported supportive care needs related to child-care, and employment during life-prolonging treatment. These findings suggest future interventions should address not only symptom management but also psychosocial and supportive care issues pertinent to specific MBC subgroups to improve overall well-being for MBC population.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eHRQOL= Health Related Quality of Life\u003c/p\u003e\n\u003cp\u003ePROs= Patient-Reported Symptom Outcomes\u003c/p\u003e\n\u003cp\u003eMBC= Metastatic Breast Cancer\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Yan Zhan. The first draft of the manuscript was written by Yan Zhan and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosures and Acknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by the Sigma Tau International Nursing Society Delta Mu Research Award. The authors gratefully acknowledge all the women who participated in this study, Lesley Glenn (CEO/Founder of Project Life), Julia Maués (Co-Founder of GRASP Cancer) for their invaluable support with recruitment, and the breast oncology team at the Yale University Smilow Cancer Center.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo conflict of interest has been declared by the author(s).\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAmerican Cancer Society. (2025, January 22). \u003cem\u003eTreatment of stage IV (advanced) breast cancer\u003c/em\u003e. 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Journal of vocational behavior, 120, 103445.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 6 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Metastatic breast cancer, MBC, Cancer symptoms, Symptom burden, Systemic therapy","lastPublishedDoi":"10.21203/rs.3.rs-7328394/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7328394/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eUtilization of targeted agents and immunotherapy led to improved survival in women with metastatic breast cancer (MBC). However, a knowledge gap remains about the side effects and symptom burden associated with these therapies that are not fully described for people living with MBC. We examined patient-reported symptom severity, interference and symptom burden related to MBC cancer treatments and identified correlated sociodemographic and clinical factors.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWomen with MBC on systemic cancer treatment recruited from oncology clinics and advocacy organizations, completed a survey from February to September 2024. We used the MD Anderson Symptom Inventory (MDASI) Immunotherapy module to describe symptom severity and interference of 20 symptoms and symptom burden. We conducted descriptive statistics and stepwise multiple linear regression to identify sociodemographic and clinical factors correlated with symptom severity, interference, and symptom burden.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eIn the sample of 209 participants, the mean age was 50.1 years (SD\u0026thinsp;=\u0026thinsp;14.11), 76.6% were White. Most were HR+/HER2- subtype, with an average time of 4.35 years since MBC diagnosis. Fatigue, sleep disturbance, forgetfulness, drowsiness, and sadness were the most prevalent symptoms. Participants identified as non-White, have completed more lines of treatments reported higher symptom severity, interference and total symptom burden. However, having dependent children (β\u0026thinsp;=\u0026thinsp;0.32, 95% CI [0.04, 0.60], P\u0026thinsp;=\u0026thinsp;0.027) was associated with more severe symptom interference.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThe type and number of treatments, being non-White and caring dependent children were associated with higher symptom burden. Symptom management interventions should be tailored for specific MBC subgroup and to improve overall well-being for MBC population.\u003c/p\u003e","manuscriptTitle":"Factors Influencing Patient-Reported Symptom Outcomes in Women with Metastatic Breast Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-09 04:34:41","doi":"10.21203/rs.3.rs-7328394/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-18T23:43:18+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-16T17:51:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"26177120270703741189978545492633183802","date":"2025-12-12T19:44:11+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-27T12:13:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-27T12:12:13+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-13T12:36:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"Supportive Care in Cancer","date":"2025-08-08T14:42:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c01a190a-3ded-4c4b-821b-07feff032142","owner":[],"postedDate":"October 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-02T16:16:02+00:00","versionOfRecord":{"articleIdentity":"rs-7328394","link":"https://doi.org/10.1007/s00520-026-10489-1","journal":{"identity":"supportive-care-in-cancer","isVorOnly":false,"title":"Supportive Care in Cancer"},"publishedOn":"2026-02-24 15:57:57","publishedOnDateReadable":"February 24th, 2026"},"versionCreatedAt":"2025-10-09 04:34:41","video":"","vorDoi":"10.1007/s00520-026-10489-1","vorDoiUrl":"https://doi.org/10.1007/s00520-026-10489-1","workflowStages":[]},"version":"v1","identity":"rs-7328394","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7328394","identity":"rs-7328394","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}