Long-term efficacy of Mindfulness Based Stress Reduction on Depression and Anxiety, Symptoms and Distress, Health Status, Coping Capacity and Immune Response in Breast Cancer Survivors: A longitudinal Randomized Controlled Trial

Long-term efficacy of Mindfulness Based Stress Reduction on Depression and Anxiety, Symptoms and Distress, Health Status, Coping Capacity and Immune Response in Breast Cancer Survivors: A longitudinal Randomized Controlled Trial | 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 Long-term efficacy of Mindfulness Based Stress Reduction on Depression and Anxiety, Symptoms and Distress, Health Status, Coping Capacity and Immune Response in Breast Cancer Survivors: A longitudinal Randomized Controlled Trial Elisabeth Kenne Sarenmalm, Salmir Nasic, Anna-Lena Emanuelsson Loft, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7518570/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose This 5-year longitudinal randomized controlled trial explored the long-term efficacy of a MBSR intervention for psychological and biological response in breast cancer survivors. Methods A total of 166 women were randomly assigned into one of 3 groups: MBSR, Active controls and non-MBSR. Data were collected at baseline, 3-months, 6-months and 1-year follow-up, thereafter yearly up to 5-year. The participants completed the Hospital Anxiety and Depression Scale, the Memorial Symptom Assessment Scale, SF-36, and Sense of Coherence. Blood samples were collected and analyzed for NK cells activity, lymphocytes and cytokine concentrations. Results The MBSR intervention demonstrated a strong effect in reducing depression (3-months: 0.015;d Cohen =0.5; 1-year: 0.013;d Cohen =0.5), anxiety (1-year: 0.023;d Cohen =0.4), and a strong effect in psychological symptoms (3-months: 0.019;d Cohen =0.4; 1-year: 0.005;d Cohen =0.6), global distress (3-months: 0.013;d Cohen =0.5; 1-year: 0.002;d Cohen =0.6), and total symptom burden (1-year: 0.046;d Cohen =0.4), a very strong effect on mental health (3-months: <0.001;d Cohen =0.7; 6-months: 0.008;d Cohen =0.5; 1-year: <0.001;d Cohen =0.8), vitality (1-year:0.007;d Cohen =0.5), and general health perceptions (1-year: 0.031;d Cohen =0.4). Coping capacity strongly over improved time (3-months: 0.028;d Cohen =0.4; 6-months: 0.044;d Cohen =0.4; 1-year: 0.006;d Cohen =0.6). A significant increase in NK-cell activity as well as for total number of lymphocytes was seen in all study groups with time. A moderate difference in CD3-16 + 56 + NKx10e9/l (3-months: 0.041;d Cohen =0.4), a moderate difference for cytokines IL-6 (6-months: 0.049;d Cohen =0.4) and IL-8 (1-year: 0.039;d Cohen =0.4) were seen. Conclusions This RTC showed long-term efficacy in reducing depression, anxiety, psychological symptoms, global distress and total symptom burden, improved coping capacity and health status up to 1-year post-intervention. MBSR also seemed to have some beneficial efficacy on immune status. Longitudinal Randomized Controlled Trial Mindfulness Based Stress Reduction Depression Anxiety Symptoms Distress Sense of Coherence Immune Status Introduction Breast cancer survivors are in high risk for developing depression and anxiety [ 1 ]. Results from previous meta-analyses exposed that the prevalence of mood disorder among breast cancer survivors was up to 32.2% and 41.9%, respectively [ 2 , 3 ], with an increased risk of depression and anxiety, severe symptoms and distress, persisting up to least 10 years after diagnosis [ 4 ]. Depression and anxiety are associated with reduced Natural Killer (NK) cell activity, which may compromise immune function [ 5 ]. Distress, which often accompanies mood disorder, has been linked to reduced NK cell activity and dysregulated cytokine production [ 6 ]. Research also suggests a significant link between mood disorder and inflammation, with particular attention to pro-inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-8 (IL-8). Multiple studies have reported elevated IL-6 levels in patients with depression, suggesting that IL-6 plays a role in the inflammatory processes associated with depression [ 7 ]. Research have found that IL-8 levels are associated with psychological conditions, suggesting that IL-6 and IL-8 might play an important role in the pathogenesis of psychological disorder [ 8 ]. Furthermore, research suggests that IL-8 may help reduce the risk of depression and higher levels of IL-8 have been linked to fewer symptoms of depression [ 9 ]. These studies highlight the need for early identification of individuals at risk as well as the need of psychological interventions to help improve long-term mood disorder. Mindfulness-Based Stress Reduction (MBSR) is a structured program to help participants develop mindfulness skills and reduce stress. MBSR focuses on directing attention to the unfolding experience moment-by-moment without judgement, with a high degree of acceptance and openness to reduce stress and promote well-being and quality of life [ 10 , 11 ]. The use of MBSR in oncology has received increasing attention during the last decades [ 12 , 13 ], indicating that MBSR are highly beneficial for reducing symptoms and stress in the short-term [ 14 ]. Previous randomized clinical trials (RTC) demonstrate short-time effects, but long-term effects are unknown. More relevant information on the efficacy of MBSR over time is needed [ 15 ]. Here we present the results of a 5-year longitudinal RCT, to determine the efficacy of MBSR for psychological and biological responses, over time, in breast cancer survivors. The primary aim was to evaluate the long-term effectiveness of MBSR in reducing depression and anxiety in breast cancer survivors. The secondary aims were to assess symptom experience, health status, coping capacity, and immune function. Methods Women with breast cancer were consecutively enrolled to participate after completing of adjuvant chemotherapy and/or radiation therapy, with or without endocrine therapy. Exclusion criteria included severe illness, ongoing major depression, ongoing Trastuzumab therapy, or who had previously used mindfulness-based interventions or other mind-body programs. The design and some of the short-time results have been described elsewhere [ 16 , 17 ]. The trial was designed in accordance with Consort recommendation [ 18 – 20 ]. A three-armed design was chosen, with the intention to minimize a potential placebo effect in the active intervention group and a “frustrebo response” [ 21 ] in controls. Study design and randomization. In this longitudinal, 5-year follow-up RTC, participants were randomly assigned into one of following groups: 1) MBSR (8 weeks self-instructing MBSR-program + instructor and weekly group-sessions), 2) Active controls (8 weeks self-instructing MBSR program) or 3) non-MBSR (no intervention). Randomization was computerized and conducted in blocks of 9, 12, and 15, randomly varied. The sample size was calculated based on breast cancer patient's mood disorder. A one-unit change on the Hospital Anxiety and Depression scale (HAD)-subscales was regarded as clinically relevant. To achieve a statistical power of 80%, the detection of such a difference would require 50 participants per group (a total of 150 participants). A p -value = < 0.05 was considered as statistically significant results. Recruitment and data collection. Eligible patients gained oral and written information by research nurses at the first follow-up appointment for patients receiving hormonal therapy or at the last treatment for patients undergoing chemotherapy. After providing written consent, participants were first invited to a baseline health check-up appointment. MBSR intervention. Participants allocated to MBSR, attended an 8-week standardized, group-based program, led by a certified MBSR-instructor once a week for an average of 2 h with homework assignments consisting of 20 min sessions, 6 days/week. Participants were provided with information material, a CD with meditation exercises, and a diary to report the time allotted to mindfulness training. Active controls received an 8-week self-instructing training program, as well as the same information material, a CD, and a diary. All participants, including the non-MBSR group, received standard care for breast cancer according to the national and local guidelines. Measurements Demographic and clinical data were collected through chart review and interviews. Patient self-reported outcomes and biomarkers were collected at health checks at baseline and follow-ups. The same procedures, at similar time points, were conducted for those in the non-MBSR group. Depression and anxiety were evaluated using the Hospital Anxiety and Depression scale (HAD). The HAD is a 14-item questionnaire consisting of two subscales: depression and anxiety. Subscale scores range from 0 to 21; scores for each subscale are defined as: 0–7 (normal), 8–10 (possible cases), and 11–21 (cases of psychological morbidity) [ 22 , 23 ]. The HADS has been extensively validated for use in cancer patients across various settings [ 24 ]. Symptom experiences were assessed using the Memorial Symptom Assessment Scale (MSAS). The MSAS questionnaire [ 25 ] consists of 32 symptoms and two global indicators: Total Symptom Burden Scale (TMSAS) and the Global Symptom Distress Index (GDI). The MSAS is highly validated for multidimensional assessment of symptom experience in cancer populations [ 26 ] including the Swedish version of the MSAS [ 27 ]. Health status was measured by using the 36-item Short Form Health Survey (SF-36) [ 28 ]. SF-36 consists of eight scaled scores: vitality, physical functioning, bodily pain, general health perceptions, physical, emotional and social role functioning, and mental health. Each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. Validity measurements of the SF-36 are consistently good [ 29 , 30 ]. Coping capacity was evaluated using The Sense of Coherence scale (SOC) [ 31 , 32 ]. SOC consists of a 7-point Likert scale evaluating perceived comprehensibility, manageability and meaningfulness. Higher scores representing a stronger sense of coherence. The validity of the SOC scale has been demonstrated in cancer populations and in various settings [ 33 ]. NK-cell activity was analyzed using a Flow-cytometric Assay of Natural Killer cell Immune response in Activated whole blood (FANKIA), a modified version of a previously published method using flow cytometry and stained K562 cells as target cells [ 34 ]. Whole blood was mixed with a defined number of target cells transfected with the gene for green fluorescent protein [ 35 ]. The lytic activity was defined as the reduction in the number of target cells after mixing with the blood, expressed in percentage of target cells. Lymphocytes distribution in peripheral blood was measured by flow cytometry using a FACSCanto II flow cytometer and the FACSDiva software. The absolute number of blood lymphocytes was determined with Trucount reference beads using the method recommended by the manufacturer. The following subpopulations reported here were CD3 + , CD3 + 4 + and CD3 + 8 + T cells, CD19 + B cells, and CD3-16 + 56 + NK cells. The results for each subpopulation were expressed as the percentage of lymphocytes and as the number of cells × 10 9 /l. Antibodies to the antigens above. Trucount beads, the FACSCanto II flow cytometer and the FACSDiva software were all from BD Biosciences, Mountain View, CA. Cytokines concentrations were determined in sera using commercial high sensitivity IL-6 and IL-8 ELISA kits (R&D Systems, Inc., Abingdon, UK) according to the instructions from the manufacturer. Statistical Methods Descriptive statistics were used to summarize socio-demographic and clinical characteristics. For categorical variables frequencies and/or percentages were presented and for psychometric variables median with quartiles were presented. As most of the variables we explored were of ordinal data type and most of the continuous variables deal with skewed distributions deviating from normal-distribution, we used nonparametric tests (Wilcoxon's test for comparison within groups and Mann-Whitney's test for comparison between groups). To quantify effect size Cohen’s d was calculated [ 36 ]. For comparisons of change over time between the groups the non-MBSR was used as reference group. IBM SPSS Statistics for Windows, Version 28.0 (Armonk, NY, USA) was used for all statistical analyses. Results In this RTC, 177 breast cancer patients were randomly assigned to one of three groups: MBSR, Active controls and non-MBSR. There were 11 dropouts after randomization: two participants were excluded as they did not complete the intervention, two participants withdraw their participation due to breast cancer disease progression, and seven participants did not visit first follow-up (MBSR=4; Active controls=5; non-MBSR=2). A total of 166 participants completed the baseline and first follow-up assessment (MBSR: n=62; Active controls: n=52; non-MBSR: n=52). Post-intervention data were missing for one active control. Partaking participants were at 3-months (n=166); 1 year (n=149); 2-year (n=140), 3-year (n=130), 4-year (n=123), and 116 participants remained at 5-year follow-up. There were 50 dropouts during the study period. Seven participants deceased, and 43 participants dropped out due to a new breast cancer (n=3), breast cancer recurrence (n=13), other cancer disease (n=2), other severe illness (n=11), or other reasons (n=14). During the trial, 15 participants were diagnosed with advanced metastatic breast cancer but remained in this RTC, including all 8 follow-ups. Participants ranged from 34 to 80 years (mean=57.2; SD=10.2). However, there were differences in clinical characteristics regarding tumor size and type of breast cancer (Table 1). Insert Table 1 Depression significantly decreased within MBSR at 6-month follow-up ( p -value=0.012), and Active controls ( p -value=0.001). There was a significant difference between groups at 3-month follow-up ( p -value=0.015; d Cohen =0.5), and 1-year follow-up ( p -value=0.013; d Cohen =0.5) showing remaining improvements regarding depression in MBSR. Anxiety significantly increased within non-MBSR at 1-year follow-up ( p- value=0.026). There was a significant difference between groups at 1-year follow-up ( p -value=0.023; d Cohen =0.4) indicating anxiety improvements in MBSR, but an anxiety deterioration in non-MBSR (Table 2). Physical symptoms significantly decreased within MBSR at 6-month follow ( p -value=0.014). At 1-year follow-up physical symptoms ( p -value=0.032), and Active controls ( p -value=0.045). Psychological symptoms significantly decreased within MBSR at 1-year follow-up ( p -value=0.002). There was a significant difference between MBSR and non-MBSR at 3-month follow-up ( p -value=0.019; d Cohen =0.4), and 1-year follow-up ( p -value=0.005; d Cohen =0.6), demonstrating psychological symptom improvements in MBSR, but a psychological symptom deterioration in non-MBSR. Global distress significantly decreased within MBSR at 6-months follow-up ( p -value=0.034), 1-year follow-up ( p -value=0.031) but increased in non-MBSR ( p -value=0.028). There was a significant difference between MBSR and non-MBSR at 3-month follow-up ( p -value=0.013; d Cohen =0.5), and 1-year follow-up ( p -value=0.002; d Cohen =0.6) proving global distress improvement in MBSR, but global distress deterioration in non-MBSR. Total symptom burden significantly decreased within MBSR at 6-month follow-up ( p -value=0.022), and 1-year follow-up ( p -value=0.003). There was a significant difference between MBSR and non-MBSR at 1-year follow-up ( p- value=0.046; d Cohen =0.4) illustrating total symptom burden improvement in MBSR, but total symptom burden deterioration in non-MBSR, Table 3. Vitality significantly increased within MBSR at 6-months follow-up MBSR ( p -value=<0.001) and in Active controls ( p -value=0.017), 1-year follow-up: MBSR ( p -value=<0.001), and Active controls ( p -value=0.011). There was a significant difference in change between MBSR and non-MBSR at 1-year follow-up ( p -value=0.007; d Cohen= 0.5), indicating improvements in all groups, and significantly vitality in MBSR. Physical functioning. Within MBSR physical functioning significantly increased ( p -value=<0.001) but decreased in non-MBSR ( p -value=0.015) at 6-month follow-up and increased in MBSR ( p -value=<0.001) but decreased in non-MBSR ( p -value=0.021) at 1-year follow-up. General health perceptions significantly increased within MBSR ( p -value=0.029), and Active controls ( p -value=0.048) at 1-year follow-up. There was a significant difference between MBSR and non-MBSR 1-year follow-up ( p- value=0.031; d Cohen= 0.4), showing general health perceptions improvement in MBSR, but deterioration in non-MBSR. Physical role functioning significantly increased within MBSR ( p -value=0.002), Active controls ( p -value=<0.001) and non-MBSR ( p -value=<0.001) at 6-month follow-up. At 1-year follow-up physical role functioning increased within MBSR ( p -value=<0.001), Active controls ( p -value=<0.001) and in non-MBSR ( p -value=<0.001). Physical role functioning increased within Active controls ( p -value=0.005), and non-MBSR ( p -value=<0.001) at 5-year post-intervention. Emotional role functioning significantly increased within MBSR ( p -value=0.004), increased in Active controls ( p -value=0.038), and increased in non-MBSR ( p -value=0.003) at 6-month follow-up; increased in MBSR ( p -value=0.048) at 1-year follow-up; and increased in non-MBSR ( p -value=0.026) at 5-year post-intervention. Social functioning increased within MBSR ( p -value=<0.001), Active controls ( p -value=0.032), and non-MBSR ( p -value=0.031) at 6-month follow-up. At 1-year follow-up social functioning increased within MBSR ( p- value=0.007), and Active controls (p -value=0.008). Social functioning increased in non-MBSR ( p -value=0.005) at 5-year follow-up. Mental health increased within MBSR at 6-month follow-up ( p -value=<0.001), and 1-year follow-up ( p -value=<0.001); and at 5-year postintervention ( p -value=0.038). There was a significant difference between MBSR and non-MBSR ( p -value=<0.001; d Cohen= 0.662) at 3-month follow-up; and at 6-month follow-up ( p- value=<0.008; d Cohen= 0.5); as well as at 1-year post-intervention ( p -value=<0.001; d Cohen= 0.8) demonstrating mental health improvements in MBSR, but deterioration in non-MBSR. There was a significant difference between Active controls and non-MBSR at 3-month follow-up, showing improvements in Active controls but unchanged levels in non-MBSR ( p -value=0.038; d Cohen= 0.4) (Table 4). Sense of coherence significantly decreased within non-MBSR at 1-year follow-up ( p -value=0.031). There was a significant difference between MBSR and non-MBSR at 3-month follow-up ( p- value=0.028; d Cohen =0.4); 6-month follow-up ( p -value 0.044; d Cohen =0.4), and 1-year follow-up ( p -value= 0.006; d Cohen =0.6), demonstrating SOC improvements in MBSR, but deterioration in non-MBSR (Table 5). NK-cells activity significantly inclined within MBSR ( p -value=0.003), Active controls ( p -value=0.001), and non-MBSR ( p -value=0.003) at 5 years follow-up. Lymphocytes x10e9/l inclined within Active controls at 6-month follow-up ( p- value=0.003). At 1-year follow-up Lymphocytesx10e9/l inclined in MBSR ( p- value=0.008), Active controls ( p- value=0.008), and non-MBSR ( p- value=<0.001). Lymphocytesx10e9/l inclined in MBSR ( p- value=0.004), Active controls ( p- value=<0.001), and in non-MBSR ( p- value=0.012) at 5-years follow-up. CD3T% declined within MBSR ( p- value=<0.001), in Active controls ( p- value=0.009), and in non-MBSR ( p- value=<0.001) at 6-month follow-up. At 1-year follow-up CD3T% declined within MBSR ( p- value=<0.001), Active controls ( p- value=0.005), and non-MBSR ( p- value=<0.001). CD3T% declined in MBSR ( p- value=0.017), non-MBSR ( p- value=<0.001) at 5-years follow-up. There was a significant difference between Active controls and non-MBSR at 1-year follow-up ( p -value=0.040; (d Cohen =0.4)), indicating that CD3 T% declined more in non-MBSR compared to Active controls. CD3Tx10e9/l declined within Active controls at 6-months follow-up ( p- value=0.039). At 1-year follow-up CD3Tx10e9/l inclined in non-MBSR ( p- value=0.020). CD3Tx10e9/l inclined within Active controls ( p- value=0.001) and non-MBSR ( p- value=0.037) at 5-years follow-up. CD3+4+Th% declined within non-MBSR ( p- value=<0.001) at 6-month follow-up. At 1-year follow-up CD3+4+Th% declined in MBSR ( p- value=0.008), and non-MBSR ( p- value=<0.001). CD3+4+Th% declined within non-MBSR ( p- value=0.046) at 5-years follow-up. There was a significant difference between Active controls and non-MBSR ( p- value=0.035; d Cohen =0.4), indicating a larger decline of CD3+4+Th% in non-MBSR than in Active controls at 1-year follow-up, compared to baseline. CD3+4+x10e9/l inclined within Active controls ( p- value=0.009) at 6-month follow-up. At 1-year follow-up CD3+4+x10e9/l inclined within Active controls ( p- value=0.021) and non-MBSR ( p- value=0.007). CD3+4+x10e9/l inclined within MBSR ( p- value=0.001), Active controls ( p- value=<0.001), and in non-MBSR ( p- value=0.012) at 5-years follow-up. There was a significant difference between Active controls and non-MBSR ( p -value=0.025; d Cohen =0.5), indicating a larger decline of CD3+4+x10e9/l in non-MBSR than in Active controls at 6 months follow-up, compared to baseline. CD3+8+Tcy/s% declined within MBSR ( p- value=<0.001), Active controls ( p- value=0.013), and non-MBSR ( p- value=0.044) at 6-month follow-up. At 1-year follow-up CD3+8+Tcy/s% declined in MBSR ( p- value=0.002), Active controls ( p- value=<0.001), and non-MBSR ( p- value=0.003). CD3+8+Tcy/s% declined within MBSR ( p- value=0.006) 5-years follow-up. CD3+8+x10e9/l inclined within non-MBSR at 1-year follow-up ( p- value=0.024). CD3+8+x10e9/l inclined in Active controls at 5-years follow-up ( p- value=0.005). CD3-16+56+NK% showed a significant difference between Active controls and non-MBSR indicating a larger decline of CD3-16+56+NK% in non-MBSR than in Active controls at 3-months follow-up, compared to baseline ( p- value=0.025; d Cohen =0.5). CD3-16+56+NKx10e9/l declined within Active controls ( p- value=0.013) and inclined in non-MBSR ( p- value=0.014) at 6-month follow-up. At 1-year follow-up CD3-16+56+NKx10e9/l inclined within non-MBSR ( p- value=<0.001). CD3-16+56+NKx10e9/l inclined in MBSR ( p- value=0.007), Active controls ( p- value=<0.001) and in non-MBSR ( p- value=0.011) at 5-year follow-up. There was a significant difference between Active controls and non-MBSR indicating a decline of CD3-16+56+NKx10e9/l in Active controls at 3-months follow-up compared to baseline (p-value=0.011; d Cohen =0.5). There was also a significant difference between MBSR and non-MBSR, indicating a decline in CD3-16+56+NKx10e9/l at 3 months follow-up, compared with baseline ( p- value= 0.041; d Cohen =0.4). CD19B% inclined within MBSR ( p- value=<0.001), Active controls ( p- value=0.003), and non-MBSR ( p- value=<0.001) at 6-month follow-up. At 1-year follow-up CD19B% inclined within MBSR ( p- value=<0.001), Active controls ( p- value= <0.001), and non-MBSR ( p- value=<0.001). CD19B% inclined within MBSR ( p- value= 0.002), and non-MBSR ( p- value=<0.001) at 5-year follow-up. CD19Bx10e9/l inclined within MBSR ( p- value=<0.001), Active controls ( p- value=<0.001), and non-MBSR ( p- value=<0.001) at 6-month follow-up. At 1-year follow-up CD19Bx10e9/l inclined within MBSR ( p- value=<0.001), Active controls ( p- value=<0.001) and non-MBSR ( p- value=<0.001). CD19Bx10e9/l inclined within MBSR ( p- value=<0.001), Active controls ( p- value=<0.001) and non-MBSR ( p- value=<0.001) 5-year follow-up. CD3+4+/CD3+8+quotient% decreased within Active controls at 1-year follow-up (p-value=0.023). IL-6 inclined within non-MBSR between baseline and 6-months follow-up ( p -value=0.037). At 5-years follow-up IL-6 inclined within MBSR ( p -value=<0.001), Active controls ( p -value=<0.001), and non-MBSR ( p -value=0.006). There was a significant difference between MBSR and non-MBSR at 6-month follow-up ( p -value=0.049; d Cohen =0.4), indicating a greater incline of IL-6 in non-MBSR than MBSR. IL-8 inclined within MBSR at 1-year follow-up ( p -value=0.018). At 5-years follow-up IL-8 inclined within MBSR ( p- value=0.009); Active controls ( p- value=<0.001); non-MBSR ( p- value=0.037). There was a significant difference between MBSR and non-MBSR at 1-year follow-up indicating inclined IL-8 in MBSR but declined IL-8 in non MBSR ( p- value=0.039; d Cohen =0.4) (Table 6). A summation of changes within group (Table 7) and changes between groups and effect size (Table 8) are presented as Supplementary information. Discussion Our results highlight the significant efficacy of MBSR on depression, immediately after the intervention and with a remaining strong effect in reducing depression at 1-year post-intervention. One-year post-intervention, there was also a strong effect in relieving anxiety. The MBSR significantly improved the symptom experience, especially in psychological symptoms, distress and total symptom burden, as well as mental health and vitality, with a strong remaining effect 1-year post-intervention. Research demonstrate that depression and anxiety are prevalent among breast cancer patients and associated with worse prognosis and increased mortality [ 37 ], implying that early detection and effective sustainable interventions of relieving depression and anxiety in breast cancer survivors may have profound clinical importance [ 38 , 39 ]. It is well-known that coping with breast cancer and its aftermath can be very challenging, and some breast cancers survivors experience a high symptom burden and distress as well as adverse mental health years after diagnosis and treatment [ 40 , 41 ]. Our study results demonstrated that MBSR is beneficial sustainable long-term efficacy to strengthen the capacity to cope with depression and anxiety, distress and symptom burden as well as improved mental health. With increasing breast cancer survival rates, survivorship care should include long-term effective interventions, such as MBSR. Therefore, supportive care, addressing psychological and emotional concerns, is crucial for managing breast cancer over time [ 42 ]. Regarding the immune system a significant increase in NK-cell activity was seen with time since cancer treatment, in all study groups with no obvious differences between the study groups with longer follow-up. Also, for total number of lymphocytes an increase over time since cancer treatment was seen for all study groups, except for a moderate effect in CD3-16 + 56 + NKx10e9/l at 3-months follow-up in MBSR. This was also the case for the cytokines IL-6 and IL-8, with higher values with time since cancer treatment, indicating restorage of the immune system long time after the cancer treatment, only a moderate effect was seen for cytokines IL-6 and IL-8 at 1-year in MBSR. No remaining differences in immune activity with long term follow up could be seen between the study groups with this short-term intervention. Interestingly, an emerging field is personalized medicine, also referred as precision medicine, that aims to modify medical interventions to individual characteristics in genes, environment, and lifestyle [ 43 ], and its application in psychological interventions to tailor treatments based on individual differences to enhance mental health outcomes [ 44 ]. Also, current evidence indicates that personalized psychological interventions is a more effective strategy to improve outcomes from psychological interventions, and the seemingly small effect size advantage of personalization could have important impact at a clinical population level [ 45 ]. Therefore, investigating predictive psychological and biological markers for depression and anxiety onset might lead to improve early identification and potentially lead to more effective personalized interventions. Given the positive long-lasting effects on psychological status and coping observed with MBSR, future studies should examine how continuous mindfulness training after MBSR works to improve long-term outcomes in breast cancer survivors. Since our results appear to be quite promising, use of MBSR should be examined for feasibility and efficacy in other breast cancer populations, such as in metastatic or late-stage breast cancer patients. This RTC is characterized by several strengths including an active control group as well as non-MBSR, inclusion of patient-reported outcomes and biological response in a homogenous population of breast cancer survivors. However, there are several limitations, a notably limitation was that participants, who fulfilled inclusion criteria, were not screened for mood disorder before study invitation. Another limitation is that the amount of continued mindfulness practice, post-intervention during the 5-years follow-up was only partly recorded. Finally, it is important to recognize that MBSR may not be suitable for everyone. MBSR requires dedication and commitment as progress often comes gradually through consistent practice. To maintain mindfulness skills, continuous practice is needed. Conclusions The MBSR show substantial promise as effective long-term non-pharmacological treatment for breast cancer survivors to cope with depression and anxiety, symptom burden and distress affecting their health status. Our results underscore the importance of implementing psychological interventions, such as MBSR, into the comprehensive care of breast cancer survivors to sustainably manage and prevent depression in breast cancer survivors. Declarations Correspondence Elisabeth Kenne Sarenmalm, ( [email protected] ) Consent Informed consent was obtained from all individual participants included in the study. Funding: This RTC was supported by grants from the Swedish Cancer Society, The Health & Medical Care Committee of the Region Västra Götaland, and The Research Fund, Skaraborg Hospital. Author Contribution EKS: Conception and design, Collection and assembly of data, Data analysis and interpretation: Manuscript writing, Final approval of manuscript, funding acquisition. SN; Collection and assembly of data, Data analysis and interpretation: Manuscript writing, Final approval of manuscript. A-LEL: Administrative support, Collection and assembly of data, Data analysis and interpretation: Manuscript writing, Final approval of manuscript. LBM: Conception and design: Manuscript writing, Final approval of manuscript. Per Karlsson: Data analysis and interpretation: Manuscript writing, Final approval of manuscript. Acknowledgement We thank all women that participated in this study. 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J Consult Clin Psychol 91(7):389–397. https://doi.org/10.1037/ccp0000820 Tables Table 1 to 8 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files LongtermefficacyofMindfulnessBasedStressReductionRCTTable16.docx LongtermefficacyofMindfulnessBasedStressReductionRCTTables7and8Supplementaryinformation.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Results from previous meta-analyses exposed that the prevalence of mood disorder among breast cancer survivors was up to 32.2% and 41.9%, respectively [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], with an increased risk of depression and anxiety, severe symptoms and distress, persisting up to least 10 years after diagnosis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDepression and anxiety are associated with reduced Natural Killer (NK) cell activity, which may compromise immune function [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Distress, which often accompanies mood disorder, has been linked to reduced NK cell activity and dysregulated cytokine production [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Research also suggests a significant link between mood disorder and inflammation, with particular attention to pro-inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-8 (IL-8). Multiple studies have reported elevated IL-6 levels in patients with depression, suggesting that IL-6 plays a role in the inflammatory processes associated with depression [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Research have found that IL-8 levels are associated with psychological conditions, suggesting that IL-6 and IL-8 might play an important role in the pathogenesis of psychological disorder [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Furthermore, research suggests that IL-8 may help reduce the risk of depression and higher levels of IL-8 have been linked to fewer symptoms of depression [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. These studies highlight the need for early identification of individuals at risk as well as the need of psychological interventions to help improve long-term mood disorder.\u003c/p\u003e\u003cp\u003eMindfulness-Based Stress Reduction (MBSR) is a structured program to help participants develop mindfulness skills and reduce stress. MBSR focuses on directing attention to the unfolding experience moment-by-moment without judgement, with a high degree of acceptance and openness to reduce stress and promote well-being and quality of life [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The use of MBSR in oncology has received increasing attention during the last decades [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], indicating that MBSR are highly beneficial for reducing symptoms and stress in the short-term [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Previous randomized clinical trials (RTC) demonstrate short-time effects, but long-term effects are unknown. More relevant information on the efficacy of MBSR over time is needed [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHere we present the results of a 5-year longitudinal RCT, to determine the efficacy of MBSR for psychological and biological responses, over time, in breast cancer survivors. The primary aim was to evaluate the long-term effectiveness of MBSR in reducing depression and anxiety in breast cancer survivors. The secondary aims were to assess symptom experience, health status, coping capacity, and immune function.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWomen with breast cancer were consecutively enrolled to participate after completing of adjuvant chemotherapy and/or radiation therapy, with or without endocrine therapy. Exclusion criteria included severe illness, ongoing major depression, ongoing Trastuzumab therapy, or who had previously used mindfulness-based interventions or other mind-body programs. The design and some of the short-time results have been described elsewhere [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe trial was designed in accordance with Consort recommendation [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. A three-armed design was chosen, with the intention to minimize a potential placebo effect in the active intervention group and a \u0026ldquo;frustrebo response\u0026rdquo; [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] in controls.\u003c/p\u003e\u003cp\u003e\u003cem\u003eStudy design and randomization.\u003c/em\u003e In this longitudinal, 5-year follow-up RTC, participants were randomly assigned into one of following groups: 1) MBSR (8 weeks self-instructing MBSR-program\u0026thinsp;+\u0026thinsp;instructor and weekly group-sessions), 2) Active controls (8 weeks self-instructing MBSR program) or 3) non-MBSR (no intervention). Randomization was computerized and conducted in blocks of 9, 12, and 15, randomly varied. The sample size was calculated based on breast cancer patient's mood disorder. A one-unit change on the Hospital Anxiety and Depression scale (HAD)-subscales was regarded as clinically relevant. To achieve a statistical power of 80%, the detection of such a difference would require 50 participants per group (a total of 150 participants). A \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered as statistically significant results.\u003c/p\u003e\u003cp\u003e\u003cem\u003eRecruitment and data collection.\u003c/em\u003e Eligible patients gained oral and written information by research nurses at the first follow-up appointment for patients receiving hormonal therapy or at the last treatment for patients undergoing chemotherapy. After providing written consent, participants were first invited to a baseline health check-up appointment.\u003c/p\u003e\u003cp\u003e\u003cem\u003eMBSR intervention.\u003c/em\u003e Participants allocated to MBSR, attended an 8-week standardized, group-based program, led by a certified MBSR-instructor once a week for an average of 2 h with homework assignments consisting of 20 min sessions, 6 days/week. Participants were provided with information material, a CD with meditation exercises, and a diary to report the time allotted to mindfulness training. Active controls received an 8-week self-instructing training program, as well as the same information material, a CD, and a diary. All participants, including the non-MBSR group, received standard care for breast cancer according to the national and local guidelines.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eMeasurements\u003c/h2\u003e\u003cp\u003e\u003cem\u003eDemographic and clinical data\u003c/em\u003e were collected through chart review and interviews. Patient self-reported outcomes and biomarkers were collected at health checks at baseline and follow-ups. The same procedures, at similar time points, were conducted for those in the non-MBSR group.\u003c/p\u003e\u003cp\u003e\u003cem\u003eDepression and anxiety\u003c/em\u003e were evaluated using the Hospital Anxiety and Depression scale (HAD). The HAD is a 14-item questionnaire consisting of two subscales: depression and anxiety. Subscale scores range from 0 to 21; scores for each subscale are defined as: 0\u0026ndash;7 (normal), 8\u0026ndash;10 (possible cases), and 11\u0026ndash;21 (cases of psychological morbidity) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The HADS has been extensively validated for use in cancer patients across various settings [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003eSymptom experiences\u003c/em\u003e were assessed using the Memorial Symptom Assessment Scale (MSAS). The MSAS questionnaire [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] consists of 32 symptoms and two global indicators: Total Symptom Burden Scale (TMSAS) and the Global Symptom Distress Index (GDI). The MSAS is highly validated for multidimensional assessment of symptom experience in cancer populations [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] including the Swedish version of the MSAS [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003eHealth status\u003c/em\u003e was measured by using the 36-item Short Form Health Survey (SF-36) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. SF-36 consists of eight scaled scores: vitality, physical functioning, bodily pain, general health perceptions, physical, emotional and social role functioning, and mental health. Each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. Validity measurements of the SF-36 are consistently good [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003eCoping capacity\u003c/em\u003e was evaluated using The Sense of Coherence scale (SOC) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. SOC consists of a 7-point Likert scale evaluating perceived comprehensibility, manageability and meaningfulness. Higher scores representing a stronger sense of coherence. The validity of the SOC scale has been demonstrated in cancer populations and in various settings [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003eNK-cell activity\u003c/em\u003e was analyzed using a Flow-cytometric Assay of Natural Killer cell Immune response in Activated whole blood (FANKIA), a modified version of a previously published method using flow cytometry and stained K562 cells as target cells [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Whole blood was mixed with a defined number of target cells transfected with the gene for green fluorescent protein [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. The lytic activity was defined as the reduction in the number of target cells after mixing with the blood, expressed in percentage of target cells.\u003c/p\u003e\u003cp\u003e\u003cem\u003eLymphocytes\u003c/em\u003e distribution in peripheral blood was measured by flow cytometry using a FACSCanto II flow cytometer and the FACSDiva software. The absolute number of blood lymphocytes was determined with Trucount reference beads using the method recommended by the manufacturer. The following subpopulations reported here were CD3\u003csup\u003e+\u003c/sup\u003e, CD3\u003csup\u003e+\u003c/sup\u003e4\u003csup\u003e+\u003c/sup\u003e and CD3\u003csup\u003e+\u003c/sup\u003e8\u003csup\u003e+\u003c/sup\u003eT cells, CD19\u003csup\u003e+\u003c/sup\u003eB cells, and CD3-16\u003csup\u003e+\u003c/sup\u003e56\u003csup\u003e+\u003c/sup\u003eNK cells. The results for each subpopulation were expressed as the percentage of lymphocytes and as the number of cells \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/l. Antibodies to the antigens above. Trucount beads, the FACSCanto II flow cytometer and the FACSDiva software were all from BD Biosciences, Mountain View, CA.\u003c/p\u003e\u003cp\u003e\u003cem\u003eCytokines\u003c/em\u003e concentrations were determined in sera using commercial high sensitivity IL-6 and IL-8 ELISA kits (R\u0026amp;D Systems, Inc., Abingdon, UK) according to the instructions from the manufacturer.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStatistical Methods\u003c/h3\u003e\n\u003cp\u003eDescriptive statistics were used to summarize socio-demographic and clinical characteristics. For categorical variables frequencies and/or percentages were presented and for psychometric variables median with quartiles were presented. As most of the variables we explored were of ordinal data type and most of the continuous variables deal with skewed distributions deviating from normal-distribution, we used nonparametric tests (Wilcoxon's test for comparison within groups and Mann-Whitney's test for comparison between groups). To quantify effect size Cohen\u0026rsquo;s d was calculated [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. For comparisons of change over time between the groups the non-MBSR was used as reference group. IBM SPSS Statistics for Windows, Version 28.0 (Armonk, NY, USA) was used for all statistical analyses.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn this RTC, 177 breast cancer patients were randomly assigned to one of three groups: MBSR, Active controls and non-MBSR. There were 11 dropouts after randomization: two participants were excluded as they did not complete the intervention, two participants withdraw their participation due to breast cancer disease progression, and seven participants did not visit first follow-up (MBSR=4; Active controls=5; non-MBSR=2). A total of 166 participants completed the baseline and first follow-up assessment (MBSR: n=62; Active controls: n=52; non-MBSR: n=52). Post-intervention data were missing for one active control. Partaking participants were at 3-months (n=166); 1 year (n=149); 2-year (n=140), 3-year (n=130), 4-year (n=123), and 116 participants remained at 5-year follow-up. There were 50 dropouts during the study period. Seven participants deceased, and 43 participants dropped out due to a new breast cancer (n=3), breast cancer recurrence (n=13), other cancer disease (n=2), other severe illness (n=11), or other reasons (n=14). During the trial, 15 participants were diagnosed with advanced metastatic breast cancer but remained in this RTC, including all 8 follow-ups.\u003c/p\u003e\n\u003cp\u003eParticipants ranged from 34 to 80 years (mean=57.2; SD=10.2). However, there were differences in clinical characteristics regarding tumor size and type of breast cancer (Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInsert Table 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDepression\u003c/em\u003e significantly decreased within MBSR at 6-month follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.012), and Active controls (\u003cem\u003ep\u003c/em\u003e-value=0.001). There was a significant difference between groups at 3-month follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.015; d\u003csub\u003eCohen\u003c/sub\u003e=0.5), and 1-year follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.013; d\u003csub\u003eCohen\u003c/sub\u003e=0.5) showing remaining improvements regarding depression in MBSR.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAnxiety\u003c/em\u003e significantly increased within non-MBSR at 1-year follow-up (\u003cem\u003ep-\u003c/em\u003evalue=0.026).\u003c/p\u003e\n\u003cp\u003eThere was a significant difference between groups at 1-year follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.023; d\u003csub\u003eCohen\u003c/sub\u003e=0.4) indicating anxiety improvements in MBSR, but an anxiety deterioration in non-MBSR (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePhysical symptoms\u0026nbsp;\u003c/em\u003esignificantly decreased within MBSR at 6-month follow (\u003cem\u003ep\u003c/em\u003e-value=0.014). At 1-year follow-up physical symptoms (\u003cem\u003ep\u003c/em\u003e-value=0.032), and Active controls (\u003cem\u003ep\u003c/em\u003e-value=0.045).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePsychological symptoms\u003c/em\u003e significantly decreased within\u003cem\u003e\u0026nbsp;\u003c/em\u003eMBSR\u003cem\u003e\u0026nbsp;\u003c/em\u003eat 1-year follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.002). There was a significant difference between MBSR and non-MBSR at 3-month follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.019; d\u003csub\u003eCohen\u003c/sub\u003e=0.4), and 1-year follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.005; d\u003csub\u003eCohen\u003c/sub\u003e=0.6), demonstrating psychological symptom improvements in MBSR, but a psychological symptom deterioration in non-MBSR.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eGlobal distress\u003c/em\u003e significantly decreased\u003cem\u003e\u0026nbsp;\u003c/em\u003ewithin MBSR at 6-months follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.034), 1-year follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.031) but increased in non-MBSR (\u003cem\u003ep\u003c/em\u003e-value=0.028).\u003c/p\u003e\n\u003cp\u003eThere was a significant difference between MBSR and non-MBSR at 3-month follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.013;\u0026nbsp;d\u003csub\u003eCohen\u003c/sub\u003e=0.5), and 1-year follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.002;\u0026nbsp;d\u003csub\u003eCohen\u003c/sub\u003e=0.6) proving global distress improvement in MBSR, but global distress deterioration in non-MBSR.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTotal symptom burden\u003c/em\u003e significantly decreased\u003cem\u003e\u0026nbsp;\u003c/em\u003ewithin MBSR at 6-month follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.022), and 1-year follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.003). There was a significant difference between\u0026nbsp;MBSR and non-MBSR at 1-year follow-up (\u003cem\u003ep-\u003c/em\u003evalue=0.046; d\u003csub\u003eCohen\u003c/sub\u003e=0.4) illustrating total symptom burden improvement in MBSR, but total symptom burden deterioration in non-MBSR, Table 3.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eVitality\u003c/em\u003e significantly increased within MBSR at 6-months follow-up MBSR (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001) and in Active controls (\u003cem\u003ep\u003c/em\u003e-value=0.017), 1-year follow-up: MBSR (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001), and Active controls (\u003cem\u003ep\u003c/em\u003e-value=0.011). There was a significant difference in change between MBSR and non-MBSR at 1-year follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.007; d\u003csub\u003eCohen=\u003c/sub\u003e0.5), indicating improvements in all groups, and significantly vitality in MBSR.\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePhysical functioning.\u003c/em\u003e Within MBSR physical functioning significantly increased (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001) but decreased in non-MBSR (\u003cem\u003ep\u003c/em\u003e-value=0.015) at 6-month follow-up and increased in MBSR (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001) but decreased in non-MBSR (\u003cem\u003ep\u003c/em\u003e-value=0.021) at 1-year follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eGeneral health perceptions\u003c/em\u003e significantly increased within MBSR (\u003cem\u003ep\u003c/em\u003e-value=0.029), and Active controls (\u003cem\u003ep\u003c/em\u003e-value=0.048) at 1-year follow-up. There was a significant difference between MBSR and non-MBSR 1-year follow-up (\u003cem\u003ep-\u003c/em\u003evalue=0.031; d\u003csub\u003eCohen=\u003c/sub\u003e0.4), showing general health perceptions improvement in MBSR, but deterioration in non-MBSR.\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePhysical role\u003c/em\u003e \u003cem\u003efunctioning\u003c/em\u003e significantly increased within MBSR (\u003cem\u003ep\u003c/em\u003e-value=0.002), Active controls (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001) and non-MBSR (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001) at 6-month follow-up. At 1-year follow-up\u0026nbsp;physical role functioning\u0026nbsp;increased within MBSR (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001), Active controls (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001) and in non-MBSR (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001).\u0026nbsp;Physical role functioning\u0026nbsp;increased within Active controls (\u003cem\u003ep\u003c/em\u003e-value=0.005), and non-MBSR (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001) at 5-year post-intervention.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEmotional role functioning\u0026nbsp;\u003c/em\u003esignificantly increased\u0026nbsp;within MBSR (\u003cem\u003ep\u003c/em\u003e-value=0.004), increased in Active controls (\u003cem\u003ep\u003c/em\u003e-value=0.038), and increased in non-MBSR (\u003cem\u003ep\u003c/em\u003e-value=0.003) at 6-month follow-up; increased in MBSR (\u003cem\u003ep\u003c/em\u003e-value=0.048) at 1-year follow-up; and increased in non-MBSR (\u003cem\u003ep\u003c/em\u003e-value=0.026) at 5-year post-intervention.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSocial functioning\u003c/em\u003e increased\u003cem\u003e\u0026nbsp;\u003c/em\u003ewithin MBSR (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001), Active controls (\u003cem\u003ep\u003c/em\u003e-value=0.032), and non-MBSR (\u003cem\u003ep\u003c/em\u003e-value=0.031) at 6-month follow-up. At 1-year follow-up\u0026nbsp;social functioning\u003cem\u003e\u0026nbsp;\u003c/em\u003eincreased within MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.007), and Active controls \u003cem\u003e(p\u003c/em\u003e-value=0.008).\u0026nbsp;Social functioning\u0026nbsp;increased in non-MBSR (\u003cem\u003ep\u003c/em\u003e-value=0.005) at 5-year follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMental health\u0026nbsp;\u003c/em\u003eincreased within MBSR at 6-month follow-up (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001), and 1-year follow-up (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001); and at 5-year postintervention (\u003cem\u003ep\u003c/em\u003e-value=0.038). There was a significant difference between MBSR and non-MBSR (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001; d\u003csub\u003eCohen=\u003c/sub\u003e0.662) at 3-month follow-up; and at 6-month follow-up (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.008; d\u003csub\u003eCohen=\u003c/sub\u003e0.5); as well as at 1-year post-intervention (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001; d\u003csub\u003eCohen=\u003c/sub\u003e0.8) demonstrating mental health improvements in MBSR, but deterioration in non-MBSR. There was a significant difference between Active controls and non-MBSR at 3-month follow-up, showing improvements in Active controls but unchanged levels in non-MBSR (\u003cem\u003ep\u003c/em\u003e-value=0.038; d\u003csub\u003eCohen=\u003c/sub\u003e0.4) (Table 4).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSense of coherence\u0026nbsp;\u003c/em\u003esignificantly decreased within non-MBSR at 1-year follow-up\u0026nbsp;(\u003cem\u003ep\u003c/em\u003e-value=0.031).\u0026nbsp;There was a significant difference between MBSR and non-MBSR at 3-month follow-up (\u003cem\u003ep-\u003c/em\u003evalue=0.028; d\u003csub\u003eCohen\u003c/sub\u003e=0.4); 6-month follow-up (\u003cem\u003ep\u003c/em\u003e-value 0.044; d\u003csub\u003eCohen\u003c/sub\u003e=0.4), and 1-year follow-up (\u003cem\u003ep\u003c/em\u003e-value= 0.006; d\u003csub\u003eCohen\u003c/sub\u003e=0.6), demonstrating SOC improvements in MBSR, but deterioration in non-MBSR (Table 5).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNK-cells activity\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/em\u003esignificantly inclined within MBSR (\u003cem\u003ep\u003c/em\u003e-value=0.003), Active controls (\u003cem\u003ep\u003c/em\u003e-value=0.001), and non-MBSR (\u003cem\u003ep\u003c/em\u003e-value=0.003) at 5 years follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLymphocytes x10e9/l\u003c/em\u003e inclined within Active controls at 6-month follow-up (\u003cem\u003ep-\u003c/em\u003evalue=0.003). At 1-year follow-up\u0026nbsp;Lymphocytesx10e9/l inclined in\u0026nbsp;MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.008), Active controls (\u003cem\u003ep-\u003c/em\u003evalue=0.008), and non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001).\u0026nbsp;Lymphocytesx10e9/l\u0026nbsp;inclined in MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.004), Active controls (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001), and in non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.012) at 5-years follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCD3T%\u003c/em\u003e declined within MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001), in Active controls (\u003cem\u003ep-\u003c/em\u003evalue=0.009), and in non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001) at 6-month follow-up. At 1-year follow-up\u0026nbsp;CD3T%\u0026nbsp;declined within MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001), Active controls (\u003cem\u003ep-\u003c/em\u003evalue=0.005), and non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001).\u0026nbsp;CD3T%\u0026nbsp;declined in MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.017), non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001) at 5-years follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere was a significant difference between Active controls and non-MBSR at 1-year follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.040; (d\u003csub\u003eCohen\u003c/sub\u003e=0.4)), indicating that CD3 T% declined more in non-MBSR compared to Active controls.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCD3Tx10e9/l\u003c/em\u003e declined within Active controls at 6-months follow-up (\u003cem\u003ep-\u003c/em\u003evalue=0.039). At 1-year follow-up CD3Tx10e9/l inclined in non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.020). CD3Tx10e9/l inclined within Active controls (\u003cem\u003ep-\u003c/em\u003evalue=0.001) and non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.037) at 5-years follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCD3+4+Th%\u0026nbsp;\u003c/em\u003edeclined within non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001) at 6-month follow-up. At 1-year follow-up CD3+4+Th%\u003cem\u003e\u0026nbsp;\u003c/em\u003edeclined in MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.008), and non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001). CD3+4+Th% declined within non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.046) at 5-years follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere was a significant difference between Active controls and non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.035; d\u003csub\u003eCohen\u003c/sub\u003e=0.4), indicating a larger decline of CD3+4+Th% in non-MBSR than in Active controls at 1-year follow-up, compared to baseline.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCD3+4+x10e9/l\u0026nbsp;\u003c/em\u003einclined\u0026nbsp;within Active controls (\u003cem\u003ep-\u003c/em\u003evalue=0.009) at 6-month follow-up. At 1-year follow-up\u0026nbsp;CD3+4+x10e9/l\u0026nbsp;inclined within Active controls (\u003cem\u003ep-\u003c/em\u003evalue=0.021) and non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.007).\u0026nbsp;CD3+4+x10e9/l\u0026nbsp;inclined within MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.001), Active controls (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001), and in non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.012) at 5-years follow-up.\u003c/p\u003e\n\u003cp\u003eThere was a significant difference between Active controls and non-MBSR (\u003cem\u003ep\u003c/em\u003e-value=0.025; d\u003csub\u003eCohen\u003c/sub\u003e=0.5), indicating a larger decline of\u0026nbsp;CD3+4+x10e9/l\u003cem\u003e\u0026nbsp;\u003c/em\u003ein non-MBSR than in Active controls at 6 months follow-up, compared to baseline.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCD3+8+Tcy/s%\u003c/em\u003e declined within\u003cem\u003e\u0026nbsp;\u003c/em\u003eMBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001), Active controls (\u003cem\u003ep-\u003c/em\u003evalue=0.013), and non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.044) at 6-month follow-up. At 1-year follow-up\u0026nbsp;CD3+8+Tcy/s%\u0026nbsp;declined in MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.002), Active controls (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001), and non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.003).\u0026nbsp;CD3+8+Tcy/s%\u0026nbsp;declined within MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.006) 5-years follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCD3+8+x10e9/l\u003c/em\u003e inclined within non-MBSR at 1-year follow-up (\u003cem\u003ep-\u003c/em\u003evalue=0.024).\u0026nbsp;CD3+8+x10e9/l\u0026nbsp;inclined in Active controls at 5-years follow-up (\u003cem\u003ep-\u003c/em\u003evalue=0.005).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCD3-16+56+NK%\u0026nbsp;\u003c/em\u003eshowed a\u003cem\u003e\u0026nbsp;\u003c/em\u003esignificant difference between Active controls and non-MBSR indicating a larger decline of\u0026nbsp;CD3-16+56+NK%\u0026nbsp;in non-MBSR than in Active controls at 3-months follow-up, compared to baseline (\u003cem\u003ep-\u003c/em\u003evalue=0.025; d\u003csub\u003eCohen\u003c/sub\u003e=0.5).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCD3-16+56+NKx10e9/l\u0026nbsp;\u003c/em\u003edeclined within Active controls (\u003cem\u003ep-\u003c/em\u003evalue=0.013) and inclined in non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.014) at 6-month follow-up. At 1-year follow-up\u0026nbsp;CD3-16+56+NKx10e9/l\u0026nbsp;inclined within non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001).\u0026nbsp;CD3-16+56+NKx10e9/l\u0026nbsp;inclined in MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.007), Active controls (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001) and in non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.011) at 5-year follow-up.\u003c/p\u003e\n\u003cp\u003eThere was a significant difference between Active controls and non-MBSR indicating a decline of\u0026nbsp;CD3-16+56+NKx10e9/l in Active controls\u0026nbsp;at 3-months follow-up compared to baseline (p-value=0.011; d\u003csub\u003eCohen\u003c/sub\u003e=0.5). There was also a significant difference between MBSR and non-MBSR, indicating a decline in\u0026nbsp;CD3-16+56+NKx10e9/l\u0026nbsp;at 3 months follow-up, compared with baseline (\u003cem\u003ep-\u003c/em\u003evalue=\u003csup\u003e\u0026nbsp;\u003c/sup\u003e0.041; d\u003csub\u003eCohen\u003c/sub\u003e=0.4).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCD19B%\u003c/em\u003e inclined within MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001), Active controls (\u003cem\u003ep-\u003c/em\u003evalue=0.003), and non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001) at 6-month follow-up. At 1-year follow-up CD19B%\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003einclined within MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001), Active controls (\u003cem\u003ep-\u003c/em\u003evalue= \u0026lt;0.001), and non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001). CD19B%\u003cem\u003e\u0026nbsp;\u003c/em\u003einclined within MBSR (\u003cem\u003ep-\u003c/em\u003evalue= 0.002), and non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001) at 5-year follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCD19Bx10e9/l\u0026nbsp;\u003c/em\u003einclined within MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001), Active controls (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001), and non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001) at 6-month follow-up. At 1-year follow-up CD19Bx10e9/l inclined within MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001), Active controls (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001) and non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001). CD19Bx10e9/l inclined within MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001), Active controls (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001) and non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001) 5-year follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCD3+4+/CD3+8+quotient%\u003c/em\u003e decreased within Active controls at 1-year follow-up (p-value=0.023).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eIL-6\u003cstrong\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/strong\u003e\u003c/em\u003einclined within non-MBSR between baseline and 6-months follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.037). At 5-years follow-up IL-6\u003cstrong\u003e\u003cem\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003einclined within MBSR (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001), Active controls (\u003cem\u003ep\u003c/em\u003e-value=\u0026lt;0.001), and non-MBSR (\u003cem\u003ep\u003c/em\u003e-value=0.006).\u003c/p\u003e\n\u003cp\u003eThere was a significant difference between MBSR and non-MBSR at 6-month follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.049;\u0026nbsp;d\u003csub\u003eCohen\u003c/sub\u003e=0.4), indicating a greater incline of IL-6 in non-MBSR than MBSR.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eIL-8\u003c/em\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003einclined within MBSR at 1-year follow-up (\u003cem\u003ep\u003c/em\u003e-value=0.018). At 5-years follow-up IL-8 inclined within MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.009); Active controls (\u003cem\u003ep-\u003c/em\u003evalue=\u0026lt;0.001); non-MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.037).\u003c/p\u003e\n\u003cp\u003eThere was a significant difference between MBSR and non-MBSR at 1-year follow-up\u0026nbsp;indicating inclined\u0026nbsp;IL-8\u003cstrong\u003e\u003cem\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003ein MBSR but declined IL-8\u003csup\u003e\u0026nbsp;\u003c/sup\u003ein non MBSR (\u003cem\u003ep-\u003c/em\u003evalue=0.039;\u0026nbsp;d\u003csub\u003eCohen\u003c/sub\u003e=0.4) (Table 6).\u003c/p\u003e\n\u003cp\u003eA summation of changes within group (Table 7) and changes between groups and effect size (Table 8) are presented as Supplementary information.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur results highlight the significant efficacy of MBSR on depression, immediately after the intervention and with a remaining strong effect in reducing depression at 1-year post-intervention. One-year post-intervention, there was also a strong effect in relieving anxiety.\u003c/p\u003e\u003cp\u003eThe MBSR significantly improved the symptom experience, especially in psychological symptoms, distress and total symptom burden, as well as mental health and vitality, with a strong remaining effect 1-year post-intervention.\u003c/p\u003e\u003cp\u003eResearch demonstrate that depression and anxiety are prevalent among breast cancer patients and associated with worse prognosis and increased mortality [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], implying that early detection and effective sustainable interventions of relieving depression and anxiety in breast cancer survivors may have profound clinical importance [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. It is well-known that coping with breast cancer and its aftermath can be very challenging, and some breast cancers survivors experience a high symptom burden and distress as well as adverse mental health years after diagnosis and treatment [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Our study results demonstrated that MBSR is beneficial sustainable long-term efficacy to strengthen the capacity to cope with depression and anxiety, distress and symptom burden as well as improved mental health. With increasing breast cancer survival rates, survivorship care should include long-term effective interventions, such as MBSR. Therefore, supportive care, addressing psychological and emotional concerns, is crucial for managing breast cancer over time [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRegarding the immune system a significant increase in NK-cell activity was seen with time since cancer treatment, in all study groups with no obvious differences between the study groups with longer follow-up. Also, for total number of lymphocytes an increase over time since cancer treatment was seen for all study groups, except for a moderate effect in CD3-16\u0026thinsp;+\u0026thinsp;56\u0026thinsp;+\u0026thinsp;NKx10e9/l at 3-months follow-up in MBSR. This was also the case for the cytokines IL-6 and IL-8, with higher values with time since cancer treatment, indicating restorage of the immune system long time after the cancer treatment, only a moderate effect was seen for cytokines IL-6 and IL-8 at 1-year in MBSR. No remaining differences in immune activity with long term follow up could be seen between the study groups with this short-term intervention.\u003c/p\u003e\u003cp\u003eInterestingly, an emerging field is personalized medicine, also referred as precision medicine, that aims to modify medical interventions to individual characteristics in genes, environment, and lifestyle [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e], and its application in psychological interventions to tailor treatments based on individual differences to enhance mental health outcomes [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Also, current evidence indicates that personalized psychological interventions is a more effective strategy to improve outcomes from psychological interventions, and the seemingly small effect size advantage of personalization could have important impact at a clinical population level [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Therefore, investigating predictive psychological and biological markers for depression and anxiety onset might lead to improve early identification and potentially lead to more effective personalized interventions.\u003c/p\u003e\u003cp\u003eGiven the positive long-lasting effects on psychological status and coping observed with MBSR, future studies should examine how continuous mindfulness training after MBSR works to improve long-term outcomes in breast cancer survivors. Since our results appear to be quite promising, use of MBSR should be examined for feasibility and efficacy in other breast cancer populations, such as in metastatic or late-stage breast cancer patients.\u003c/p\u003e\u003cp\u003eThis RTC is characterized by several strengths including an active control group as well as non-MBSR, inclusion of patient-reported outcomes and biological response in a homogenous population of breast cancer survivors. However, there are several limitations, a notably limitation was that participants, who fulfilled inclusion criteria, were not screened for mood disorder before study invitation. Another limitation is that the amount of continued mindfulness practice, post-intervention during the 5-years follow-up was only partly recorded.\u003c/p\u003e\u003cp\u003eFinally, it is important to recognize that MBSR may not be suitable for everyone. MBSR requires dedication and commitment as progress often comes gradually through consistent practice. To maintain mindfulness skills, continuous practice is needed.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe MBSR show substantial promise as effective long-term non-pharmacological treatment for breast cancer survivors to cope with depression and anxiety, symptom burden and distress affecting their health status. Our results underscore the importance of implementing psychological interventions, such as MBSR, into the comprehensive care of breast cancer survivors to sustainably manage and prevent depression in breast cancer survivors.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCorrespondence\u003c/h2\u003e\u003cp\u003eElisabeth Kenne Sarenmalm, ([email protected])\u003c/p\u003e\u003ch2\u003eConsent\u003c/h2\u003e\u003cp\u003e Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eThis RTC was supported by grants from the Swedish Cancer Society, The Health \u0026amp; Medical Care Committee of the Region V\u0026auml;stra G\u0026ouml;taland, and The Research Fund, Skaraborg Hospital.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eEKS: Conception and design, Collection and assembly of data, Data analysis and interpretation: Manuscript writing, Final approval of manuscript, funding acquisition. SN; Collection and assembly of data, Data analysis and interpretation: Manuscript writing, Final approval of manuscript. A-LEL: Administrative support, Collection and assembly of data, Data analysis and interpretation: Manuscript writing, Final approval of manuscript. LBM: Conception and design: Manuscript writing, Final approval of manuscript. Per Karlsson: Data analysis and interpretation: Manuscript writing, Final approval of manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe thank all women that participated in this study.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data that support the findings of this study are available from corresponding author upon reasonable request. Data is also provided as supplementary information files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTsaras K, Papathanasiou IV, Mitsi D, Veneti A, Kelesi M, Zyga S, Fradelos EC (2018) Assessment of Depression and Anxiety in Breast Cancer Patients: Prevalence and Associated Factors. Asian Pac J Cancer Prev 19(6):1661\u0026ndash;1669. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.22034/apjcp.2018.19.6.1661\u003c/span\u003e\u003cspan address=\"10.22034/apjcp.2018.19.6.1661\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePilevarzadeh M, Amirshahi M, Afsargharehbagh R, Rafiemanesh H, Hashemi SM, Balouchi A (2019) Global prevalence of depression among breast cancer patients: a systematic review and meta-analysis. 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J Consult Clin Psychol 91(7):389\u0026ndash;397. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1037/ccp0000820\u003c/span\u003e\u003cspan address=\"10.1037/ccp0000820\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 8 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Longitudinal Randomized Controlled Trial, Mindfulness Based Stress Reduction, Depression, Anxiety, Symptoms, Distress, Sense of Coherence, Immune Status","lastPublishedDoi":"10.21203/rs.3.rs-7518570/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7518570/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eThis 5-year longitudinal randomized controlled trial explored the long-term efficacy of a MBSR intervention for psychological and biological response in breast cancer survivors.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA total of 166 women were randomly assigned into one of 3 groups: MBSR, Active controls and non-MBSR. Data were collected at baseline, 3-months, 6-months and 1-year follow-up, thereafter yearly up to 5-year. The participants completed the Hospital Anxiety and Depression Scale, the Memorial Symptom Assessment Scale, SF-36, and Sense of Coherence. Blood samples were collected and analyzed for NK cells activity, lymphocytes and cytokine concentrations.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe MBSR intervention demonstrated a strong effect in reducing depression (3-months: 0.015;d\u003csub\u003eCohen\u003c/sub\u003e=0.5; 1-year: 0.013;d\u003csub\u003eCohen\u003c/sub\u003e=0.5), anxiety (1-year: 0.023;d\u003csub\u003eCohen\u003c/sub\u003e=0.4), and a strong effect in psychological symptoms (3-months: 0.019;d\u003csub\u003eCohen\u003c/sub\u003e=0.4; 1-year: 0.005;d\u003csub\u003eCohen\u003c/sub\u003e=0.6), global distress (3-months: 0.013;d\u003csub\u003eCohen\u003c/sub\u003e=0.5; 1-year: 0.002;d\u003csub\u003eCohen\u003c/sub\u003e=0.6), and total symptom burden (1-year: 0.046;d\u003csub\u003eCohen\u003c/sub\u003e=0.4), a very strong effect on mental health (3-months: \u0026lt;0.001;d\u003csub\u003eCohen\u003c/sub\u003e =0.7; 6-months: 0.008;d\u003csub\u003eCohen\u003c/sub\u003e=0.5; 1-year: \u0026lt;0.001;d\u003csub\u003eCohen\u003c/sub\u003e =0.8), vitality (1-year:0.007;d\u003csub\u003eCohen\u003c/sub\u003e=0.5), and general health perceptions (1-year: 0.031;d\u003csub\u003eCohen\u003c/sub\u003e =0.4). Coping capacity strongly over improved time (3-months: 0.028;d\u003csub\u003eCohen\u003c/sub\u003e=0.4; 6-months: 0.044;d\u003csub\u003eCohen\u003c/sub\u003e=0.4; 1-year: 0.006;d\u003csub\u003eCohen\u003c/sub\u003e=0.6). A significant increase in NK-cell activity as well as for total number of lymphocytes was seen in all study groups with time. A moderate difference in CD3-16\u0026thinsp;+\u0026thinsp;56\u0026thinsp;+\u0026thinsp;NKx10e9/l (3-months: 0.041;d\u003csub\u003eCohen\u003c/sub\u003e=0.4), a moderate difference for cytokines IL-6 (6-months: 0.049;d\u003csub\u003eCohen\u003c/sub\u003e=0.4) and IL-8 (1-year: 0.039;d\u003csub\u003eCohen\u003c/sub\u003e=0.4) were seen.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThis RTC showed long-term efficacy in reducing depression, anxiety, psychological symptoms, global distress and total symptom burden, improved coping capacity and health status up to 1-year post-intervention. MBSR also seemed to have some beneficial efficacy on immune status.\u003c/p\u003e","manuscriptTitle":"Long-term efficacy of Mindfulness Based Stress Reduction on Depression and Anxiety, Symptoms and Distress, Health Status, Coping Capacity and Immune Response in Breast Cancer Survivors: A longitudinal Randomized Controlled Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-30 10:44:49","doi":"10.21203/rs.3.rs-7518570/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9572b719-0f66-46d1-a4e5-327132efc9c0","owner":[],"postedDate":"October 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-06T23:23:30+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-30 10:44:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7518570","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7518570","identity":"rs-7518570","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}