Early change in fatigue, insomnia, and cognitive impairment and symptom severity at 3-years post-treatment in breast cancer survivors

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Lee, Joshua A. Rash, Melanie Seal, Joy McCarthy, Sheila N. Garland This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3581028/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Mar, 2024 Read the published version in Supportive Care in Cancer → Version 1 posted 7 You are reading this latest preprint version Abstract Purpose Breast cancer is the most common form of cancer among Canadian women. Survivorship challenges include fatigue, sleep disturbance, and cognitive impairment. This study examined: 1) symptom trajectory from diagnosis to three years; 2) whether symptom change in the first four months was associated with prolonged difficulties after three years; and 3) which factors were associated with deterioration in symptoms during the first four months. Methods This prospective observational cohort study examined 53 women ( M age = 58.6, 96.2% White, 67.9% Stage I) with newly diagnosed breast cancer over three years. Women completed assessments before starting treatment, four months, and three years after diagnosis. Three-way repeated-measures ANOVAs evaluated symptom trajectories. A repeated-measures mediation analysis was performed to determine if change from pre-treatment to four months accounted for change from pre-treatment to three years. A series of between-subjects ANOVAs were used to determine what variables significantly differed by deterioration status. Results Perceived cognitive impairment and fatigue increased linearly from diagnosis to three years. Change in fatigue in the first four months fully accounted for its change over three years. Insomnia severity and sleep quality deteriorated from diagnosis to four months, but returned to pre-treatment levels at three years. Those whose fatigue and cognitive ability deteriorated during the first four months were younger. Conclusion Efforts to identify those who are at risk of experiencing fatigue, sleep disturbance, and cognitive impairment; monitor patients early after receiving a diagnosis; and provide targeted interventions may prevent long-term deterioration and improve well-being. breast cancer fatigue insomnia cognitive impairment sleep quality Figures Figure 1 Introduction Breast cancer (BCa) is the most common form of cancer among Canadian women [1]; 1 in 8 women in Canada are estimated to develop BCa in their lifetime [2]. The five-year relative survival rate for BCa is 88% [2], which can be attributed to successful screening efforts leading to early detection [1] and advances in cancer treatment [3]. BCa survivors must navigate long-lasting survivorship challenges including fatigue, sleep disturbance, and cognitive impairment. Cancer-Related Fatigue Fatigue is one of the most common side effects of BCa [4]. Estimates suggest that 60% to 94% of BCa patients experience cancer-related fatigue (CRF) at varying degrees of severity [5, 6]. CRF is a multidimensional symptom [7] defined as "a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning” [8]. CRF persists beyond treatment and is rated as the most disruptive symptom for BCa survivors [9]. Fatigue is experienced by BCa survivors both during [4, 6] and after [10, 11] treatment at a higher rate than the general population. Approximately 30% of post-treatment BCa survivors experience CRF [12]. Insomnia Symptoms and Poor Sleep BCa patients also experience poor sleep and insomnia symptoms, with prevalence estimates ranging from 30% to 80% depending on definition and measurement tool [10, 13]. Insomnia disorder is characterized in the DSM-V as having difficulty initiating, maintaining, or returning to sleep occurring at least 3 nights a week for at least 3 months, leading to significant distress and daytime impairment [14]. Others experience sleep disturbance that decreases quality of life but does not meet clinical thresholds of a sleep disorder. The stress of a cancer diagnosis and its side effects, such as pain, may precipitate sleep disruption [15]. Sufficient sleep quality and quantity is one of the most important contributors to a person’s overall health; chronic sleep disturbance can initiate or worsen several physical and psychological health challenges [16]. High rates of insomnia and poor sleep often persist for years after completing BCa treatment, affecting an estimated 23% to 57% [11, 17]. Cognitive Impairment Cognitive impairment is considered one of the most distressing and disruptive impacts of BCa and its treatment [16]. It is reported by up to 75% of those on treatment [18, 19]. While certain treatments have been associated with higher levels of cognitive impairment [18], it is a complex and multifaceted construct. Perceived cognitive impairment (PCI) uses subjective, self-reported measures to quantify the level and impact of cognitive impairment experienced. PCI may be more clinically relevant than objective cognitive impairment as it allows an understanding of the experience of BCa survivors that are not captured using objective measures [18, 20]. PCI is correlated with fatigue and depressed mood [21], sleep quality [16], and insomnia [22]. Cognitive impairment persists beyond treatment for up to 35% of BCa survivors [19] and can be observed up to 10 years after treatment [23]. Fatigue, Sleep, and Cognitive Impairment in Survivorship Fatigue and impaired sleep are often believed to be expected consequences of cancer and go unreported and/or untreated [24]. While typically of greatest concern during active treatment and tending to subsequently improve, these symptoms often persist well after and may not return to pre-treatment levels [3]. Sleep disruption and fatigue can be perpetuated by maladaptive sleep behaviours that cancer patients engage in, such as frequent napping and more time spent in bed [12, 13, 15], as well as other factors (e.g., pain, nausea, hot flashes, psychological distress, and depression) [18]. Further, when sleep disruption and fatigue coexist, they exacerbate each other and may intensify cognitive impairment [25], negatively impacting quality of life [12, 13]. It is imperative to prioritize prevention and early intervention beginning at diagnosis given that these harmful symptoms can persist long after treatment is completed. Much of the research examining fatigue, sleep, and cognitive impairment among BCa survivors is cross sectional and conducted several years after diagnosis (e.g., [17, 25]). Moreover, few prospective observational designs that have evaluated the trajectory of sleep, fatigue, or cognitive impairment among BCa survivors from pre-treatment to at least three years later; no studies have prospectively examined the trajectories of sleep, fatigue, and cognitive impairment together from pre-treatment to three years. Prospective observational studies are needed to get a better understanding of the symptoms experienced by BCa survivors, identify who may be more at risk of experiencing these symptoms, and determine optimal windows of opportunity to intervene. The Present Study The present study examined the trajectory of fatigue, sleep disturbance, and cognitive impairment from diagnosis to three years among women with BCa using a prospective observational cohort design. To support efforts for prevention, early identification, and treatment, we sought to identify whether symptom change in the first four months was associated with prolonged difficulties with sleep, fatigue, and cognitive ability three years after diagnosis. Lastly, we explored which individual factors were associated with deterioration of symptoms during the first four months. Methods Study Design This prospective observational cohort study examined 53 women with newly diagnosed BCa over three years. Women completed assessments of their fatigue, sleep, and cognitive impairments before starting treatment, four months, and three years after diagnosis. All potential patients were identified from their clinical charts by their treating oncologist after diagnosis, but prior to beginning main treatment. Treatments completed prior to the study include lumpectomy, mastectomy, lymph node and tissue removal, and sentinel and axillary node dissection. Some participants received neoadjuvant therapy, including chemotherapy ( n = 7), radiation ( n = 1), and hormone therapy ( n = 29). Patients Patients were eligible if they were: 1) female; 2) English-speaking; 3) over 18-years old; 4) had a diagnosis of stage I-III BCa; 5) were scheduled to receive adjuvant hormone therapy (i.e., tamoxifen or an aromatase inhibitor), chemotherapy, radiation, or trastuzumab; and 6) were not previously treated for cancer or already undergoing cancer treatment. Patients were excluded if they had a sleep disorder other than insomnia that was not adequately managed, another psychological disorder that was not stable and/or would impair ability to participate, or if they received a score lower than 24 on the Mini-Mental State Examination suggesting the presence of severe cognitive impairments. Study Procedure Assessments with interested women occurred shortly after their clinic visit and were completed by trained research assistant in-person or remotely via telehealth with surveys sent through the mail. After informed consent was obtained, the Mini-Mental State Examination was administered and patients were screened for any sleep, medical, or psychological disorders. Assessments took place online via Zoom or Webex, or over the phone beginning in March of 2020 due to restrictions imposed by the COVID-19 pandemic. No compensation was provided for participation. Measures Medical history and demographics A medical history and demographics questionnaire was administered at the pre-treatment assessment. This questionnaire obtained patient demographic information (e.g., sex, age, marital status, ethnicity, employment status), medical history (e.g., cancer stage, dates of diagnosis, types of treatment), psychiatric history, and current medication use. Clinical and cancer-related information was confirmed by reviewing medical charts. The Multidimensional Fatigue Inventory-Short Form (MFSI-SF) The MFSI-SF is a 30-item self-report measure that assesses fatigue symptoms in cancer patients [ 7 ]. It is comprised of five subscales (general, emotional, physical, mental, vigor) with each question rated on a scale from 0, “not at all,” to 4, “extremely.” A total fatigue score is calculated ranging from − 24 to 96 with higher scores indicating higher levels of fatigue. A minimal clinically important difference (MCID) of 10.79 is the most conservative estimate for the MFSI-SF [ 26 ]. Insomnia Severity Index (ISI) The ISI is one of the few well-validated patient-reported outcome measures designed to assess the severity of insomnia symptoms, impact on daytime functioning, and amount of associated distress [ 27 ]. Each of the seven items are scored on a 5-point scale ranging from 0 to 4 with higher scores representing more severe insomnia symptoms. Optimal cut-off scores for insomnia symptoms are 0–7 (none), 8–14 (mild), 15–21 (moderate), and 22–28 (severe) [ 28 ]. A MCID of 6 has been identified for the ISI [ 29 ]. The Pittsburgh Sleep Quality Index (PSQI) The PSQI is a 19-item questionnaire that assesses seven component scores of sleep quality in clinical populations (subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, sleeping medication, and daytime dysfunction) plus a global score [ 30 ]. Questions are scored on a 0 to 3 scale and components are summed into a total score ranging from 0 to 21 with higher scores indicating worse sleep quality. It has sensitivity of 89.6% and specificity of 86.5% in distinguishing good and poor sleepers at a total score of > 5 [ 30 ]. Acceptable measures of internal consistency, consistency, and validity have been demonstrated [ 30 ]. A MCID of 4.4 has been identified for the PSQI [ 31 ]. The Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog) The FACT-Cog, version 3, assesses cognitive problems related to cancer therapy. It is a 33-item questionnaire with three cognitive subscales: perceived cognitive impairments, impact on quality of life, and perceived cognitive abilities [ 32 ]. A total score is calculated ranging from 0-132 with higher scores indicating higher levels of PCI and better quality of life. Responses range from 0, “never,” or “not at all,” to 4, “several times a day,” or “very much.” The FACT-Cog has a MCID of -10.6 [ 33 ]. While this MCID was calculated for the 37-item FACT-Cog, it is still within estimates for the 33-item version [ 34 ]. Statistical Analysis Evaluating Symptom Trajectory Over Time Three (Time; pre-treatment, four months, three years) repeated-measures ANOVAs were performed to evaluate symptom trajectories. See Table 2 for results. Does Early Change Mediate Change Observed Over 3-Years? A repeated-measures mediation analysis was performed using Mediation and Moderation analysis for Repeated measures designs (MEMORE) version 2.1 [ 35 ] to determine if change from pre-treatment to four months accounted for change from pre-treatment to three years where statistically significant change from pre-treatment to three years was observed (i.e., to evaluate whether change during the first four months of treatment should be the optimal window to intervene). What Factors are Associated with Deterioration Status? A change score from pre-treatment to four-months was calculated for the MFSI-SF, ISI, FACT-Cog, and PSQI and compared against recommended MCID to group individuals according to whether they deteriorated or improved/did not change. A series of between-subjects ANOVAs to were used to determine what variables significantly differed by deterioration status, including age, depression, anxiety, and fatigue, sleep quality, insomnia severity, and cognitive impairment at pre-treatment and 4 months. Missing Data Missing data were handled using single imputation performed using estimation maximization in SPSS version 28.0.1.0. Little’s test of missing completely at random (MCAR) was not significant ( X 2 = .000, p = 1.000), suggesting that data were missing at random, and no correction for missingness was required. Results The mean age was 58.6 years ( SD = 10.7) and most women identified as White (96.2%). Two thirds were diagnosed with stage I breast cancer (67.9%) using tumor, node, metastates (TNM) classification. Hormone therapy (98.1%) was the most common adjuvant therapy, followed by radiation (52.8%), then chemotherapy (26.4%). Most patients received surgery, including simple mastectomy (54.7%), lumpectomy (37.7%), or modified radical mastectomy (3.8%). Table 1 shows the sociodemographic characteristics and cancer information of the sample. Table 1. Patient Characteristics at Diagnosis Mean (SD) Frequency (%) n = 53 Age (years) 58.6 (10.7) Race/Ethnicity White 51 (96.2%) Indigenous 2 (3.8%) Employment Status Currently employed 19 (35.8%) Not currently employed 33 (62.3%) Education (years) 14.3 (3.8) 7–13 years 25 (47.2%) 14 + years 28 (52.8%) Relationship Status Single 4 (7.5%) Committed Relationship/Married 41 (77.4%) Divorced 4 (7.5%) Widowed 4 (7.5%) Number of Children None 4 (7.5%) One 11 (20.8%) Two 17 (32.1%) Three or more 21 (39.6%) Premenopausal No 39 (73.6%) Yes 12 (22.6%) Unsure 2 (3.8%) Hormone Status Estrogen Receptor (ER) Positive 52 (98.1%) Progesterone Receptor (PR) Positive 50 (94.3%) HER2 Positive 3 (5.7%) Cancer Stage Stage 1 36 (67.9%) Stage 2 15 (28.3%) Stage 3 2 (3.8%) Type of Treatment Lumpectomy 20 (37.7%) Simple Mastectomy 29 (54.7%) Modified Radical Mastectomy 4 (7.5%) Sentinel Lymph Node Biopsy 40 (75.5%) Axillary Dissection 8 (15.1%) Chemotherapy 14 (26.4%) Trastuzumab 2 (3.8%) Radiation 28 (52.8%) Hormone Therapy 52 (98.1%) Change in Symptoms over Time Fatigue Fatigue significantly increased from pre-treatment ( M = 4.58, SD = 16.83) to four months ( M = 12.38, SD = 18.68) to three years ( M = 12.64, SD = 16.70), F (1.77, 91.81) = 7.57, p = .001, η p 2 = .127, in a linear manner (Fig. 1a). Change in fatigue observed between pre-treatment and three years, b =-8.06, SE = 2.46, t (52) = 3.28, p = .018, was fully mediated by change in fatigue from pre-treatment to four months, b =-3.57, SE = 1.20, LCI =-5.94, UCI =-1.25. No significant direct effect from pre-treatment to three years remained after accounting for change during the first four months, b =-4.50, SE = 2.40, t (50) = 1.87, p = .067. Insomnia Symptoms and Sleep Quality Symptoms of insomnia significantly changed from pre-treatment ( M = 7.26, SD = 6.13) to four months ( M = 9.41, SD = 6.05) to three years ( M = 6.51, SD = 5.70), F (2, 104) = 7.74, p < .001, η p 2 = .130, in a quadratic manner (Fig. 1b). Post-hoc comparisons using the Tukey HSD test indicated that the mean score at pre-treatment did not significantly differ from the mean score three year later ( p = .598). Sleep quality significantly changed from pre-treatment ( M = 7.11, SD = 3.94) to four months ( M = 8.89, SD = 3.88) to three years ( M = 7.78, SD = 4.62), F (1.784, 92.750) = 5.10, p = .010, η p 2 = .089, in a quadratic manner (Fig. 1c). Post-hoc comparisons using the Tukey HSD test indicated that the mean score at pre-treatment did not significantly differ from the mean score three years later (p = .512). Perceived Cognitive Impairment Perceived cognitive ability significantly decreased from pre-treatment ( M = 93.02, SD = 16.37) to four months ( M = 87.67, SD = 17.58) to three years ( M = 82.20, SD = 20.74), F (1.652, 85.921) = 11.02, p < .001, η p 2 = .175, in a linear manner (Fig. 1d). Change in cognitive ability observed between pre-treatment and three years, b = 10.82, SE = 2.48, t (52) = 4.36, p < .001, was not mediated by change in cognitive ability from pre-treatment to four months, b = 2.24, SE = 1.80, LCI =-0.18, UCI = 6.57. Table 2. Three-Way Repeated Measures ANOVA of Dependent Variables Across Time Pre-treatment Mean (SD) Four Months Mean (SD) Three Years Mean (SD) F p η p 2 Fatigue Symptoms 4.58 (16.83) 12.38 (18.68) 12.64 (16.70) 7.57 .001 .127 Insomnia Symptoms 7.26 (6.13) 9.41 (6.05) 6.51 (5.70) 7.74 < .001 .130 Sleep Quality 7.11 (3.94) 8.89 (3.88) 7.78 (4.62) 5.10 .01 .089 Cognitive Function 93.02 (16.37) 87.67 (17.58) 82.20 (20.74) 11.02 < .001 .175 Factors Associated with Clinically Significant Symptom Change The group whose fatigue clinically deteriorated in the first four months ( n = 20) were younger ( M = 54.85, SD = 8.52) than the group who did not change or who improved ( n = 33) ( M = 60.94, SD = 11.30), F (1, 51) = 4.31, p = .043, η 2 = .078. The facets of fatigue contributing to this difference were vigor ( F (1, 51) = 4.39, p = .043), general ( F (1, 51) = 22.15, p < .001), and physical fatigue ( F (1, 51) = 14.25, p < .001). There were no significant differences between groups based on type of treatment or cancer stage. There were no significant differences between the groups whose insomnia worsened in the first four months ( n = 16) and the group who did not change or who improved ( n = 37). The group whose sleep quality clinically worsened in the first four months ( n = 9) had less severe insomnia symptoms at pre-treatment ( M = 3.00, SD = 3.24) than the group who did not change or improved ( n = 44) ( M = 7.86, SD = 6.25), F (2, 50) = 3.99, p = .025, η 2 = .138. There were no significant differences between groups based on type of treatment or cancer stage. The group whose cognitive impairment clinically worsened in the first four months ( n = 17) were significantly younger ( M = 53.29, SD = 8.99) than the group who did not change or improved ( n = 36) ( M = 61.17, SD = 10.58), F (1, 51) = 7.00, p = .011, η 2 = .121. There were no significant differences between groups based on type of treatment or cancer stage. Discussion The present study prospectively surveyed BCa survivors’ fatigue, sleep, and cognitive impairment over three years post diagnosis. Perceived cognitive function deteriorated and fatigue symptoms increased linearly from diagnosis to three years. Insomnia symptom severity and sleep quality deteriorated from diagnosis to four months but returned to pre-treatment levels at three years. Those whose fatigue and cognitive ability deteriorated during the first four months were younger and those whose sleep quality deteriorated during the first four months had lower insomnia symptoms at pre-treatment. Fatigue Among BCa patients, fatigue worsened within the first four months post-diagnosis and continued to worsen, reaching its peak at three years. Many studies examine fatigue cross-sectionally (e.g., [ 25 ]), with limited research examining the trajectory of fatigue over time. Some existing longitudinal studies report a deterioration in fatigue during cancer treatment (e.g., [ 6 ]), and find improved fatigue post-treatment (e.g.,[ 36 ]). Others reveal fatigue trajectories that appear directionless (e.g., [ 37 ]). Future research should examine factors associated with high fatigue and whether this persists beyond three years. Moreover, change in fatigue during the first four months after diagnosis predicted the change observed over three years. This has important clinical implications; clinicians should monitor patients for CRF closely within the first four months of diagnosis and intervene with an evidence-based treatment, such as exercise or a psychological intervention, to avoid continuing decline. Insomnia Symptoms and Sleep Quality Aggregate data of insomnia severity was at sub-clinical levels at diagnosis, worsened to mild insomnia severity at four months, and returned to pre-treatment levels at three years. Sleep quality demonstrated a similar pattern; BCa survivors had poor sleep quality at pre-treatment that worsened in the first four months and returned to pre-treatment levels at three years. However, the average score fell into the “poor sleep” category across all timepoints. Although sleep quality is often negatively impacted by treatment, many BCa survivors experience poor sleep quality at diagnosis, before beginning treatment [ 38 ]. This could be attributed to pain from pre-treatment surgery or psychological distress [ 38 ]. Previous research has observed that higher distress and trauma associated with a BCa diagnosis was associated with continued sleep disturbance up to five years after diagnosis [ 39 ]. In the current study, those whose sleep quality clinically worsened during the first four months had less severe insomnia symptoms at pre-treatment. Insomnia symptoms are common among BCa survivors [ 10 , 11 ] and can be precipitated and/or worsened by the emotional impact or direct physiologic effects and side effects of treatments [ 15 ]. Although aggregate levels of insomnia returned to pre-treatment at three years, insomnia symptoms can persist for up to 10 years post-treatment for some BCa survivors [ 17 ]. Thus, clinicians should monitor their patients for insomnia symptoms from diagnosis and implement an effective intervention if symptoms begin to worsen, such as cognitive behavioural therapy for insomnia. Perceived Cognitive Impairment Perceived cognitive impairment consistently deteriorated over the first three years post-diagnosis. BCa patients in the present study demonstrated poorer levels of PCI at pre-treatment than estimates of healthy adults [ 40 ] and this worsened. Our sample scored 8–13 points worse than cancer patients with brain tumors [ 41 ], gynecological cancer patients who did not receive chemotherapy [ 40 ], and previous estimates of disease-free BCa survivors [ 42 ]. The level of PCI in the present sample is comparable only to gynecological cancer patients who received chemotherapy [ 40 ]. More research is needed that compares PCI between cancer types, treatments, and regions to determine which patients experience poorer PCI. Clinicians should monitor PCI in BCa patients from the time of diagnosis and opt for early intervention to avoid continuing decline. Age, Perceived Cognitive Impairment, and Cancer-Related Fatigue Those whose fatigue and PCI clinically worsened over the first four months were significantly younger. This is consistent with previous research indicating that CRF is greater among younger cancer survivors [ 43 ]. Age-related deficits in cognition are well-known, so it may seem counterintuitive that younger individuals in the present study experienced greater PCI. However, PCI represents the inner experience of BCa survivors. While a cancer diagnosis at any age is upsetting, it is particularly distressing among younger individuals as it presents unique challenges regarding financial burdens, body image, disconnection from peers, and greater fear of cancer recurrence [ 44 ]. Elevated distress and fear of cancer recurrence are also correlated with CRF [ 45 ]. Moreover, PCI is positively associated with CRF [ 25 ]. The increased PCI and CRF experienced by younger BCa survivors in the present study may reflect elevated distress about symptoms that they did not anticipate experiencing given their age. Future research should examine whether younger individuals experience greater objective cognitive impairment or only PCI and distress. Limitations While among the longest prospective studies of BCa survivors’ fatigue, sleep and perceived cognitive impairment, limitations of this study should be acknowledged. First, our sample size was small, which reduces statistical power. Further, several statistical tests were run without adjusting alpha for inflation of familywise error, which increases the likelihood of spurious results. Given the exploratory nature of this study, these results should be considered hypothesis generating and not hypothesis testing. Finally, some data collection took place over the course of the COVID-19 pandemic. While it was a strength that we were able to switch to fully virtual assessments, it is unclear whether the global pandemic may have impacted sleep, fatigue, or cognitive impairment in addition to cancer. Future research should replicate this study to determine whether this outside, historical event may have impacted results. Conclusion and Clinical Implications Many women with BCa report symptoms of fatigue, insomnia, poor sleep quality, and perceived cognitive impairment at diagnosis, concerns that often worsen over the first four months during treatment. Fatigue and cognitive impairment may not return to pre-treatment levels up to three years post-diagnosis and may impact long-term well-being. Clinicians would benefit from: 1) identifying those who are at risk of experiencing fatigue, sleep disturbance, and cognitive impairment; 2) consistently monitor patients in the early months after receiving a diagnosis; and 3) providing targeted interventions to avoid long-term deterioration. Future research should examine the impact of early interventions on long-term outcomes in fatigue, insomnia, perceived cognitive impairment, and sleep quality. Declarations Funding Declaration : Rachel M. Lee is a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds generously provided by the Canadian Cancer Society's JD Irving, Limited - Excellence in Cancer Research Fund. Sheila N. Garland is funded by a Canadian Cancer Society Emerging Scholar Award (Survivorship: grant #707146). Competing Interests: The authors have no relevant financial or non-financial interests to disclose. Author Contributions: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Rachel M. Lee and Sheila N. Garland. The first draft of the manuscript was written by Rachel M. Lee and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Ethics Approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Health Ethics Research Board at Memorial University of Newfoundland (May 2, 2016/No 2016.092). Consent to Participate : Informed consent was obtained from all individual participants included in the study. References Brenner, D.R., et al., Projected estimates of cancer in Canada in 2022. CMAJ, 2022. 194 (17): p. E601-E607. Committee, C.C.S.A. Canadian Cancer Statistics 2022 . 2022 [cited 2022 December 14, 2022]. Yang, G.S., et al., Longitudinal Analysis of Sleep Disturbance in Breast Cancer Survivors. Nurs Res, 2022. 71 (3): p. 177-188. Cella, D., et al., Fatigue in cancer patients compared with fatigue in the general United States population. Cancer, 2002. 94 (2): p. 528-38. Bardwell, W.A. and S. Ancoli-Israel, Breast Cancer and Fatigue. Sleep Med Clin, 2008. 3 (1): p. 61-71. Jacobsen, P.B., et al., Fatigue in women receiving adjuvant chemotherapy for breast cancer: characteristics, course, and correlates. J Pain Symptom Manage, 1999. 18 (4): p. 233-42. Stein, K.D., et al., A multidimensional measure of fatigue for use with cancer patients. Cancer Pract, 1998. 6 (3): p. 143-52. Berger, A.M., et al., Cancer-Related Fatigue, Version 2.2015. J Natl Compr Canc Netw, 2015. 13 (8): p. 1012-39. Ruiz-Casado, A., et al., Cancer-related Fatigue in Breast Cancer Survivors: A Review. Clin Breast Cancer, 2021. 21 (1): p. 10-25. Bean, H.R., et al., Insomnia and Fatigue Symptom Trajectories in Breast Cancer: A Longitudinal Cohort Study. Behav Sleep Med, 2021. 19 (6): p. 814-827. Janz, N.K., et al., Symptom experience and quality of life of women following breast cancer treatment. J Womens Health (Larchmt), 2007. 16 (9): p. 1348-61. Alexander, S., et al., A comparison of the characteristics of disease-free breast cancer survivors with or without cancer-related fatigue syndrome. Eur J Cancer, 2009. 45 (3): p. 384-92. Davidson, J.R., et al., Sleep disturbance in cancer patients. Soc Sci Med, 2002. 54 (9): p. 1309-21. APA, The Diagnostic and Statistical Manual of Mental Disorders . Fifth Edition ed. 2013, Washington, DC: American Psychiatric Association. Savard, J. and C.M. Morin, Insomnia in the context of cancer: a review of a neglected problem. J Clin Oncol, 2001. 19 (3): p. 895-908. Henneghan, A.M., et al., Relationships between self-reported sleep quality components and cognitive functioning in breast cancer survivors up to 10 years following chemotherapy. Psychooncology, 2018. 27 (8): p. 1937-1943. Lowery-Allison, A.E., et al., Sleep problems in breast cancer survivors 1-10 years posttreatment. Palliat Support Care, 2018. 16 (3): p. 325-334. Bower, J.E., Behavioral symptoms in patients with breast cancer and survivors. J Clin Oncol, 2008. 26 (5): p. 768-77. Janelsins, M.C., et al., An update on cancer- and chemotherapy-related cognitive dysfunction: current status. Semin Oncol, 2011. 38 (3): p. 431-8. Savard, J. and P.A. Ganz, Subjective or Objective Measures of Cognitive Functioning-What's More Important? JAMA Oncol, 2016. 2 (10): p. 1263-1264. Castellon, S.A., et al., Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen. J Clin Exp Neuropsychol, 2004. 26 (7): p. 955-69. Caplette-Gingras, A., et al., Is insomnia associated with cognitive impairments in breast cancer patients? Behav Sleep Med, 2013. 11 (4): p. 239-57. Ahles, T.A., et al., Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol, 2002. 20 (2): p. 485-93. Stone, P., et al., Cancer-related fatigue: inevitable, unimportant and untreatable? Results of a multi-centre patient survey. Cancer Fatigue Forum. Ann Oncol, 2000. 11 (8): p. 971-5. Henneghan, A., et al., Modifiable correlates of perceived cognitive function in breast cancer survivors up to 10 years after chemotherapy completion. J Cancer Surviv, 2018. 12 (2): p. 224-233. Chan, A., et al., Minimal Clinically Important Difference of the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) for Fatigue Worsening in Asian Breast Cancer Patients. J Pain Symptom Manage, 2018. 55 (3): p. 992-997 e2. Morin, C.M., Insomnia: Psychological Assessment and Management . 1993, New York: Guilford. Morin, C.M., et al., The Insomnia Severity Index: psychometric indicators to detect insomnia cases and evaluate treatment response. Sleep, 2011. 34 (5): p. 601-8. Yang, M., et al., Interpreting score differences in the Insomnia Severity Index: using health-related outcomes to define the minimally important difference. Curr Med Res Opin, 2009. 25 (10): p. 2487-94. Buysse, D.J., et al., The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res, 1989. 28 (2): p. 193-213. Longo, U.G., et al., Minimal Clinically Important Difference and Patient Acceptable Symptom State for the Pittsburgh Sleep Quality Index in Patients Who Underwent Rotator Cuff Tear Repair. Int J Environ Res Public Health, 2021. 18 (16). Wagner, L.I., et al., Measuring patient self-reported cognitive function: development of the functional assessment of cancer therapy-cognitive function instrument. The Journal of Supportive Oncology, 2009. 7 (6): p. W32-W39. Cheung, Y.T., et al., Minimal clinically important difference (MCID) for the functional assessment of cancer therapy: cognitive function (FACT-Cog) in breast cancer patients. J Clin Epidemiol, 2014. 67 (7): p. 811-20. Bell, M.L., et al., Important differences and meaningful changes for the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog). Journal of Patint-Reported Outcomes, 2018. 2 (48). Montoya, A.K. and A.F. Hayes, Two-condition within-participant statistical mediation analysis: A path-analytic framework. Psychol Methods, 2017. 22 (1): p. 6-27. Williams, A.M., et al., Fatigue, anxiety, and quality of life in breast cancer patients compared to non-cancer controls: a nationwide longitudinal analysis. Breast Cancer Res Treat, 2021. 187 (1): p. 275-285. Geinitz, H., et al., Fatigue, serum cytokine levels, and blood cell counts during radiotherapy of patients with breast cancer. Int J Radiat Oncol Biol Phys, 2001. 51 (3): p. 691-8. Sanford, S.D., et al., Longitudinal prospective assessment of sleep quality: before, during, and after adjuvant chemotherapy for breast cancer. Support Care Cancer, 2013. 21 (4): p. 959-67. Weng, Y.P., et al., Sleep Quality and Related Factors in Patients with Breast Cancer: A Cross-Sectional Study in Taiwan. Cancer Manag Res, 2021. 13 : p. 4725-4733. Zeng, Y., et al., Subjective cognitive impairment and brain structural networks in Chinese gynaecological cancer survivors compared with age-matched controls: a cross-sectional study. BMC Cancer, 2017. 17 (1): p. 796. Adak, S., et al., Cognitive score in patients with primary brain tumors undergoing systemic therapy – a cross-sectional study. Cancer Research, Statistics, and Treatment, 2020. 3 (3): p. 455-460. Vardy, J.L., et al., A mechanistic cohort study evaluating cognitive impairment in women treated for breast cancer. Brain Imaging Behav, 2019. 13 (1): p. 15-26. Brownstein, C.G., et al., Physiological and psychosocial correlates of cancer-related fatigue. J Cancer Surviv, 2022. 16 (6): p. 1339-1354. Schulte, F.S.M., et al., Quality of life among survivors of adolescent and young adult cancer in Canada: A Young Adults With Cancer in Their Prime (YACPRIME) study. Cancer, 2021. 127 (8): p. 1325-1333. Vanrusselt, D., et al., Associations between cancer-related distress and fatigue in childhood cancer survivors: A longitudinal study. Psychooncology, 2023. 32 (3): p. 393-400. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 17 Mar, 2024 Read the published version in Supportive Care in Cancer → Version 1 posted Editorial decision: Revision requested 24 Jan, 2024 Reviews received at journal 29 Dec, 2023 Reviewers agreed at journal 27 Dec, 2023 Reviewers invited by journal 27 Dec, 2023 Editor assigned by journal 24 Dec, 2023 Submission checks completed at journal 09 Nov, 2023 First submitted to journal 08 Nov, 2023 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3581028","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":247825851,"identity":"e3fc495d-e064-4e32-b5c2-166e683033e5","order_by":0,"name":"Rachel M. Lee","email":"","orcid":"","institution":"Memorial University of Newfoundland","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rachel","middleName":"M.","lastName":"Lee","suffix":""},{"id":247825852,"identity":"d79e573d-076c-48d5-a361-19f1216efbdd","order_by":1,"name":"Joshua A. Rash","email":"","orcid":"","institution":"Memorial University of Newfoundland","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Joshua","middleName":"A.","lastName":"Rash","suffix":""},{"id":247825853,"identity":"531954a7-e2df-47b8-a67c-4b79273b8ded","order_by":2,"name":"Melanie Seal","email":"","orcid":"","institution":"Eastern Health","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Melanie","middleName":"","lastName":"Seal","suffix":""},{"id":247825854,"identity":"2911e0c1-90fd-447e-b5a0-04d14684b586","order_by":3,"name":"Joy McCarthy","email":"","orcid":"","institution":"Eastern Health","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Joy","middleName":"","lastName":"McCarthy","suffix":""},{"id":247825855,"identity":"96e8d40d-33f4-45a4-82b6-04f2445ffd5b","order_by":4,"name":"Sheila N. Garland","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYDACCQaGAw/ALOYGBgY2GyK1JIBZjCAtacRpYUDScpiwDvnZzQcPJNQw2PXPPtj4uaDsfLTB7QbGDz/waDG4cyzhQMIxhuQZ5xKbpWecu5274c4BZskefFokcgwOJLAxJDOcYWyQ5m0DarkB5PLgc9iM/A8HEv4xJMufYWz+zdt2DqyF8Q8+z9zIYTiQ2MZgZ3CGsQ1oywGwFmZ8thjcSDM4kNgnkWAI1GLNcy45d+YNoKdk8Dos+fGHD99s7OXOMB++zVNml9t3I/ngxzf4HAYBEokNCA5jAy5lKMCeKFWjYBSMglEwMgEAo+hUamsPNz8AAAAASUVORK5CYII=","orcid":"","institution":"Memorial University of Newfoundland","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Sheila","middleName":"N.","lastName":"Garland","suffix":""}],"badges":[],"createdAt":"2023-11-08 20:14:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3581028/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3581028/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00520-024-08418-1","type":"published","date":"2024-03-18T00:47:57+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":46382156,"identity":"bbb190bb-be3e-4dbd-b172-5b084d5c57ed","added_by":"auto","created_at":"2023-11-14 03:09:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":14190,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3581028/v1/cfa6391edc3a32ad039f37f7.png"},{"id":52940274,"identity":"ebf12972-ccfd-45f3-a13c-a0f96a48d8bc","added_by":"auto","created_at":"2024-03-19 00:48:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":630953,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3581028/v1/2b1af7de-e8ce-42e7-bb72-984ddad385f9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Early change in fatigue, insomnia, and cognitive impairment and symptom severity at 3-years post-treatment in breast cancer survivors","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBreast cancer (BCa) is the most common form of cancer among Canadian women\u0026nbsp;[1]; 1 in 8 women in Canada are estimated to develop BCa in their lifetime\u0026nbsp;[2]. The five-year relative survival rate for BCa is 88%\u0026nbsp;[2], which can be attributed to successful screening efforts leading to early detection\u0026nbsp;[1]\u0026nbsp;and advances in cancer treatment\u0026nbsp;[3]. BCa survivors must navigate long-lasting survivorship challenges including fatigue, sleep disturbance, and cognitive impairment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCancer-Related Fatigue\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFatigue is one of the most common side effects of BCa\u0026nbsp;[4]. Estimates suggest that 60% to 94% of BCa patients experience cancer-related fatigue (CRF) at varying degrees of severity\u0026nbsp;[5, 6]. CRF is a multidimensional symptom\u0026nbsp;[7]\u0026nbsp;defined as \u0026quot;a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning\u0026rdquo;\u0026nbsp;[8]. CRF persists beyond treatment and is rated as the most disruptive symptom for BCa survivors\u0026nbsp;[9]. Fatigue is experienced by BCa survivors both during\u0026nbsp;[4, 6]\u0026nbsp;and after\u0026nbsp;[10, 11]\u0026nbsp;treatment at a higher rate than the general population. Approximately 30% of post-treatment BCa survivors experience CRF\u0026nbsp;[12].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInsomnia Symptoms and Poor Sleep\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBCa patients also experience poor sleep and insomnia symptoms, with prevalence estimates ranging from 30% to 80% depending on definition and measurement tool\u0026nbsp;[10, 13]. Insomnia disorder is characterized in the DSM-V\u0026nbsp;as having difficulty initiating, maintaining, or returning to sleep occurring at least 3 nights a week for at least 3 months, leading to significant distress and daytime impairment\u0026nbsp;[14]. Others experience sleep disturbance that decreases quality of life but does not meet clinical thresholds of a sleep disorder.\u0026nbsp;The stress of a cancer diagnosis and its side effects, such as pain, may precipitate sleep disruption\u0026nbsp;[15]. Sufficient sleep quality and quantity is one of the most important contributors to a person\u0026rsquo;s overall health;\u0026nbsp;chronic sleep disturbance can initiate or worsen several physical and psychological health challenges\u0026nbsp;[16].\u0026nbsp;High rates of insomnia and poor sleep often persist for years after completing BCa treatment, affecting an estimated 23% to 57%\u0026nbsp;[11, 17].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCognitive Impairment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCognitive impairment is considered one of the most distressing and disruptive impacts of BCa and its treatment\u0026nbsp;[16]. It is reported by up to 75% of those on treatment\u0026nbsp;[18, 19]. While certain treatments have been associated with higher levels of cognitive impairment\u0026nbsp;[18], it is a complex and multifaceted construct. Perceived cognitive impairment (PCI) uses subjective, self-reported measures to quantify the level and impact of cognitive impairment experienced. PCI may be more clinically relevant than objective cognitive impairment as it allows an understanding of the experience of BCa survivors that are not captured using objective measures\u0026nbsp;[18, 20]. PCI is correlated with fatigue and depressed mood\u0026nbsp;[21], sleep quality\u0026nbsp;[16], and insomnia\u0026nbsp;[22]. Cognitive impairment persists beyond treatment for up to 35% of BCa survivors\u0026nbsp;[19]\u0026nbsp;and can be observed up to 10 years after treatment\u0026nbsp;[23].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFatigue, Sleep, and Cognitive Impairment in Survivorship\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFatigue and impaired sleep are often believed to be expected consequences of cancer and go unreported and/or untreated\u0026nbsp;[24].\u0026nbsp;While typically of greatest concern during active treatment and tending to subsequently improve, these symptoms often persist well after and may not return to pre-treatment levels\u0026nbsp;[3]. Sleep disruption and fatigue can be perpetuated by maladaptive sleep behaviours that cancer patients engage in, such as frequent napping and more time spent in bed\u0026nbsp;[12, 13, 15], as well as other factors (e.g.,\u0026nbsp;pain, nausea, hot flashes, psychological distress, and depression)\u0026nbsp;[18]. Further, when sleep disruption and fatigue coexist, they exacerbate each other and may intensify cognitive impairment\u0026nbsp;[25], negatively impacting quality of life\u0026nbsp;[12, 13].\u0026nbsp;It is imperative to prioritize prevention and early intervention beginning at diagnosis given that these harmful symptoms can persist long after treatment is completed.\u003c/p\u003e\n\u003cp\u003eMuch of the research examining fatigue, sleep, and cognitive impairment among BCa survivors is cross sectional and conducted several years after diagnosis (e.g.,\u0026nbsp;[17, 25]). Moreover, few prospective observational designs that have evaluated the trajectory of sleep, fatigue, or cognitive impairment among BCa survivors from pre-treatment to at least three years later; no studies have prospectively examined the trajectories of sleep, fatigue, and cognitive impairment \u003cem\u003etogether\u003c/em\u003e from pre-treatment to three years. Prospective observational studies are needed to get a better understanding of the symptoms experienced by BCa survivors, identify who may be more at risk of experiencing these symptoms, and determine optimal windows of opportunity to intervene.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe Present Study\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present study examined the trajectory of fatigue, sleep disturbance, and cognitive impairment from diagnosis to three years among women with BCa using a prospective observational cohort design. To support efforts for prevention, early identification, and treatment, we sought to identify whether symptom change in the first four months was associated with prolonged difficulties with sleep, fatigue, and cognitive ability three years after diagnosis. Lastly, we explored which individual factors were associated with deterioration of symptoms during the first four months.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThis prospective observational cohort study examined 53 women with newly diagnosed BCa over three years. Women completed assessments of their fatigue, sleep, and cognitive impairments before starting treatment, four months, and three years after diagnosis. All potential patients were identified from their clinical charts by their treating oncologist after diagnosis, but prior to beginning main treatment. Treatments completed prior to the study include lumpectomy, mastectomy, lymph node and tissue removal, and sentinel and axillary node dissection. Some participants received neoadjuvant therapy, including chemotherapy (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7), radiation (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1), and hormone therapy (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;29).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatients\u003c/h3\u003e\n\u003cp\u003ePatients were eligible if they were: 1) female; 2) English-speaking; 3) over 18-years old; 4) had a diagnosis of stage I-III BCa; 5) were scheduled to receive adjuvant hormone therapy (i.e., tamoxifen or an aromatase inhibitor), chemotherapy, radiation, or trastuzumab; and 6) were not previously treated for cancer or already undergoing cancer treatment. Patients were excluded if they had a sleep disorder other than insomnia that was not adequately managed, another psychological disorder that was not stable and/or would impair ability to participate, or if they received a score lower than 24 on the Mini-Mental State Examination suggesting the presence of severe cognitive impairments.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStudy Procedure\u003c/h2\u003e \u003cp\u003eAssessments with interested women occurred shortly after their clinic visit and were completed by trained research assistant in-person or remotely via telehealth with surveys sent through the mail. After informed consent was obtained, the Mini-Mental State Examination was administered and patients were screened for any sleep, medical, or psychological disorders. Assessments took place online via Zoom or Webex, or over the phone beginning in March of 2020 due to restrictions imposed by the COVID-19 pandemic. No compensation was provided for participation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eMeasures\u003c/h2\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003eMedical history and demographics\u003c/h2\u003e \u003cp\u003eA medical history and demographics questionnaire was administered at the pre-treatment assessment. This questionnaire obtained patient demographic information (e.g., sex, age, marital status, ethnicity, employment status), medical history (e.g., cancer stage, dates of diagnosis, types of treatment), psychiatric history, and current medication use. Clinical and cancer-related information was confirmed by reviewing medical charts.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eThe Multidimensional Fatigue Inventory-Short Form (MFSI-SF)\u003c/h2\u003e \u003cp\u003eThe MFSI-SF is a 30-item self-report measure that assesses fatigue symptoms in cancer patients [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. It is comprised of five subscales (general, emotional, physical, mental, vigor) with each question rated on a scale from 0, \u0026ldquo;not at all,\u0026rdquo; to 4, \u0026ldquo;extremely.\u0026rdquo; A total fatigue score is calculated ranging from \u0026minus;\u0026thinsp;24 to 96 with higher scores indicating higher levels of fatigue. A minimal clinically important difference (MCID) of 10.79 is the most conservative estimate for the MFSI-SF [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eInsomnia Severity Index (ISI)\u003c/h2\u003e \u003cp\u003eThe ISI is one of the few well-validated patient-reported outcome measures designed to assess the severity of insomnia symptoms, impact on daytime functioning, and amount of associated distress [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Each of the seven items are scored on a 5-point scale ranging from 0 to 4 with higher scores representing more severe insomnia symptoms. Optimal cut-off scores for insomnia symptoms are 0\u0026ndash;7 (none), 8\u0026ndash;14 (mild), 15\u0026ndash;21 (moderate), and 22\u0026ndash;28 (severe) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. A MCID of 6 has been identified for the ISI [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eThe Pittsburgh Sleep Quality Index (PSQI)\u003c/h2\u003e \u003cp\u003eThe PSQI is a 19-item questionnaire that assesses seven component scores of sleep quality in clinical populations (subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, sleeping medication, and daytime dysfunction) plus a global score [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Questions are scored on a 0 to 3 scale and components are summed into a total score ranging from 0 to 21 with higher scores indicating worse sleep quality. It has sensitivity of 89.6% and specificity of 86.5% in distinguishing good and poor sleepers at a total score of \u0026gt;\u0026thinsp;5 [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Acceptable measures of internal consistency, consistency, and validity have been demonstrated [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. A MCID of 4.4 has been identified for the PSQI [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eThe Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog)\u003c/h2\u003e \u003cp\u003eThe FACT-Cog, version 3, assesses cognitive problems related to cancer therapy. It is a 33-item questionnaire with three cognitive subscales: perceived cognitive impairments, impact on quality of life, and perceived cognitive abilities [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. A total score is calculated ranging from 0-132 with higher scores indicating higher levels of PCI and better quality of life. Responses range from 0, \u0026ldquo;never,\u0026rdquo; or \u0026ldquo;not at all,\u0026rdquo; to 4, \u0026ldquo;several times a day,\u0026rdquo; or \u0026ldquo;very much.\u0026rdquo; The FACT-Cog has a MCID of -10.6 [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. While this MCID was calculated for the 37-item FACT-Cog, it is still within estimates for the 33-item version [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eEvaluating Symptom Trajectory Over Time\u003c/strong\u003e \u003cp\u003eThree (Time; pre-treatment, four months, three years) repeated-measures ANOVAs were performed to evaluate symptom trajectories. See Table\u0026nbsp;2 for results.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eDoes Early Change Mediate Change Observed Over 3-Years?\u003c/b\u003e A repeated-measures mediation analysis was performed using Mediation and Moderation analysis for Repeated measures designs (MEMORE) version 2.1 [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] to determine if change from pre-treatment to four months accounted for change from pre-treatment to three years where statistically significant change from pre-treatment to three years was observed (i.e., to evaluate whether change during the first four months of treatment should be the optimal window to intervene).\u003c/p\u003e \u003cp\u003e \u003cb\u003eWhat Factors are Associated with Deterioration Status?\u003c/b\u003e A change score from pre-treatment to four-months was calculated for the MFSI-SF, ISI, FACT-Cog, and PSQI and compared against recommended MCID to group individuals according to whether they deteriorated or improved/did not change. A series of between-subjects ANOVAs to were used to determine what variables significantly differed by deterioration status, including age, depression, anxiety, and fatigue, sleep quality, insomnia severity, and cognitive impairment at pre-treatment and 4 months.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eMissing Data\u003c/h2\u003e \u003cp\u003eMissing data were handled using single imputation performed using estimation maximization in SPSS version 28.0.1.0. Little\u0026rsquo;s test of missing completely at random (MCAR) was not significant (\u003cem\u003eX\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.000, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.000), suggesting that data were missing at random, and no correction for missingness was required.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe mean age was 58.6 years (\u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.7) and most women identified as White (96.2%). Two thirds were diagnosed with stage I breast cancer (67.9%) using tumor, node, metastates (TNM) classification. Hormone therapy (98.1%) was the most common adjuvant therapy, followed by radiation (52.8%), then chemotherapy (26.4%). Most patients received surgery, including simple mastectomy (54.7%), lumpectomy (37.7%), or modified radical mastectomy (3.8%). Table\u0026nbsp;1 shows the sociodemographic characteristics and cancer information of the sample.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eTable\u0026nbsp;1.\u003c/p\u003e \u003cp\u003e\u003cem\u003ePatient Characteristics at Diagnosis\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eMean\u003c/p\u003e \u003cp\u003e(SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eFrequency (%)\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e58.6 (10.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRace/Ethnicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51 (96.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndigenous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (3.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmployment Status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrently employed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (35.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot currently employed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33 (62.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEducation (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e14.3 (3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u0026ndash;13 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (47.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u0026thinsp;+\u0026thinsp;years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 (52.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelationship Status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (7.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCommitted Relationship/Married\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41 (77.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDivorced\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (7.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWidowed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (7.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of Children\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (7.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOne\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (20.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTwo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (32.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThree or more\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (39.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePremenopausal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39 (73.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (22.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnsure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (3.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHormone Status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstrogen Receptor (ER) Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52 (98.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgesterone Receptor (PR) Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50 (94.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER2 Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (5.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCancer Stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36 (67.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (28.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (3.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of Treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLumpectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (37.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSimple Mastectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (54.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModified Radical Mastectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e4 (7.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSentinel Lymph Node Biopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e40 (75.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAxillary Dissection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e8 (15.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e14 (26.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTrastuzumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e2 (3.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e28 (52.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHormone Therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e52 (98.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eChange in Symptoms over Time\u003c/h2\u003e \u003cdiv id=\"Sec20\" class=\"Section3\"\u003e \u003ch2\u003eFatigue\u003c/h2\u003e \u003cp\u003eFatigue significantly increased from pre-treatment (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.58, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.83) to four months (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12.38, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;18.68) to three years (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12.64, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.70), \u003cem\u003eF\u003c/em\u003e(1.77, 91.81)\u0026thinsp;=\u0026thinsp;7.57, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.127, in a linear manner (Fig.\u0026nbsp;1a). Change in fatigue observed between pre-treatment and three years, \u003cem\u003eb\u003c/em\u003e=-8.06, \u003cem\u003eSE\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.46, \u003cem\u003et\u003c/em\u003e(52)\u0026thinsp;=\u0026thinsp;3.28, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.018, was fully mediated by change in fatigue from pre-treatment to four months, \u003cem\u003eb\u003c/em\u003e=-3.57, \u003cem\u003eSE\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.20, \u003cem\u003eLCI\u003c/em\u003e=-5.94, \u003cem\u003eUCI\u003c/em\u003e=-1.25. No significant direct effect from pre-treatment to three years remained after accounting for change during the first four months, \u003cem\u003eb\u003c/em\u003e=-4.50, \u003cem\u003eSE\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.40, \u003cem\u003et\u003c/em\u003e(50)\u0026thinsp;=\u0026thinsp;1.87, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.067.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eInsomnia Symptoms and Sleep Quality\u003c/h2\u003e \u003cp\u003eSymptoms of insomnia significantly changed from pre-treatment (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.26, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.13) to four months (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.41, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.05) to three years (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.51, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.70), \u003cem\u003eF\u003c/em\u003e(2, 104)\u0026thinsp;=\u0026thinsp;7.74, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.130, in a quadratic manner (Fig.\u0026nbsp;1b). Post-hoc comparisons using the Tukey HSD test indicated that the mean score at pre-treatment did not significantly differ from the mean score three year later (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.598).\u003c/p\u003e \u003cp\u003eSleep quality significantly changed from pre-treatment (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.11, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.94) to four months (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.89, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.88) to three years (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.78, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.62), \u003cem\u003eF\u003c/em\u003e(1.784, 92.750)\u0026thinsp;=\u0026thinsp;5.10, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.010, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.089, in a quadratic manner (Fig.\u0026nbsp;1c). Post-hoc comparisons using the Tukey HSD test indicated that the mean score at pre-treatment did not significantly differ from the mean score three years later (p\u0026thinsp;=\u0026thinsp;.512).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003ePerceived Cognitive Impairment\u003c/h2\u003e \u003cp\u003e Perceived cognitive ability significantly decreased from pre-treatment (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;93.02, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.37) to four months (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;87.67, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17.58) to three years (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;82.20, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;20.74), \u003cem\u003eF\u003c/em\u003e(1.652, 85.921)\u0026thinsp;=\u0026thinsp;11.02, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.175, in a linear manner (Fig.\u0026nbsp;1d). Change in cognitive ability observed between pre-treatment and three years, \u003cem\u003eb\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.82, \u003cem\u003eSE\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.48, \u003cem\u003et\u003c/em\u003e(52)\u0026thinsp;=\u0026thinsp;4.36, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001, was not mediated by change in cognitive ability from pre-treatment to four months, \u003cem\u003eb\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.24, \u003cem\u003eSE\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.80, \u003cem\u003eLCI\u003c/em\u003e=-0.18, \u003cem\u003eUCI\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.57.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eTable\u0026nbsp;2.\u003c/p\u003e \u003cp\u003e\u003cem\u003eThree-Way Repeated Measures ANOVA of Dependent Variables Across Time\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePre-treatment Mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFour Months\u003c/p\u003e \u003cp\u003eMean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eThree Years\u003c/p\u003e \u003cp\u003eMean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eF\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue Symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.58 (16.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.38 (18.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.64 (16.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.127\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInsomnia Symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.26 (6.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.41 (6.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.51 (5.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.130\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSleep\u003c/p\u003e \u003cp\u003eQuality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.11 (3.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.89 (3.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.78 (4.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.089\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCognitive Function\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93.02 (16.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87.67 (17.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e82.20 (20.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e.175\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eFactors Associated with Clinically Significant Symptom Change\u003c/h2\u003e \u003cp\u003eThe group whose fatigue clinically deteriorated in the first four months (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;20) were younger (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;54.85, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.52) than the group who did not change or who improved (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;33) (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;60.94, SD\u0026thinsp;=\u0026thinsp;11.30), \u003cem\u003eF\u003c/em\u003e(1, 51)\u0026thinsp;=\u0026thinsp;4.31, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.043, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.078. The facets of fatigue contributing to this difference were vigor (\u003cem\u003eF\u003c/em\u003e(1, 51)\u0026thinsp;=\u0026thinsp;4.39, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.043), general (\u003cem\u003eF\u003c/em\u003e(1, 51)\u0026thinsp;=\u0026thinsp;22.15, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001), and physical fatigue (\u003cem\u003eF\u003c/em\u003e(1, 51)\u0026thinsp;=\u0026thinsp;14.25, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001). There were no significant differences between groups based on type of treatment or cancer stage. There were no significant differences between the groups whose insomnia worsened in the first four months (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16) and the group who did not change or who improved (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;37). The group whose sleep quality clinically worsened in the first four months (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9) had less severe insomnia symptoms at pre-treatment (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.00, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.24) than the group who did not change or improved (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;44) (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.86, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.25), \u003cem\u003eF\u003c/em\u003e(2, 50)\u0026thinsp;=\u0026thinsp;3.99, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.025, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.138. There were no significant differences between groups based on type of treatment or cancer stage. The group whose cognitive impairment clinically worsened in the first four months (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17) were significantly younger (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;53.29, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.99) than the group who did not change or improved (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;36) (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;61.17, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.58), \u003cem\u003eF\u003c/em\u003e(1, 51)\u0026thinsp;=\u0026thinsp;7.00, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.011, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.121. There were no significant differences between groups based on type of treatment or cancer stage.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study prospectively surveyed BCa survivors\u0026rsquo; fatigue, sleep, and cognitive impairment over three years post diagnosis. Perceived cognitive function deteriorated and fatigue symptoms increased linearly from diagnosis to three years. Insomnia symptom severity and sleep quality deteriorated from diagnosis to four months but returned to pre-treatment levels at three years. Those whose fatigue and cognitive ability deteriorated during the first four months were younger and those whose sleep quality deteriorated during the first four months had lower insomnia symptoms at pre-treatment.\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section2\"\u003e \u003ch2\u003eFatigue\u003c/h2\u003e \u003cp\u003eAmong BCa patients, fatigue worsened within the first four months post-diagnosis and continued to worsen, reaching its peak at three years. Many studies examine fatigue cross-sectionally (e.g., [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]), with limited research examining the trajectory of fatigue over time. Some existing longitudinal studies report a deterioration in fatigue during cancer treatment (e.g., [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]), and find improved fatigue post-treatment (e.g.,[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]). Others reveal fatigue trajectories that appear directionless (e.g., [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]). Future research should examine factors associated with high fatigue and whether this persists beyond three years. Moreover, change in fatigue during the first four months after diagnosis predicted the change observed over three years. This has important clinical implications; clinicians should monitor patients for CRF closely within the first four months of diagnosis and intervene with an evidence-based treatment, such as exercise or a psychological intervention, to avoid continuing decline.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section2\"\u003e \u003ch2\u003eInsomnia Symptoms and Sleep Quality\u003c/h2\u003e \u003cp\u003eAggregate data of insomnia severity was at sub-clinical levels at diagnosis, worsened to mild insomnia severity at four months, and returned to pre-treatment levels at three years. Sleep quality demonstrated a similar pattern; BCa survivors had poor sleep quality at pre-treatment that worsened in the first four months and returned to pre-treatment levels at three years. However, the average score fell into the \u0026ldquo;poor sleep\u0026rdquo; category across all timepoints. Although sleep quality is often negatively impacted by treatment, many BCa survivors experience poor sleep quality at diagnosis, before beginning treatment [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. This could be attributed to pain from pre-treatment surgery or psychological distress [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Previous research has observed that higher distress and trauma associated with a BCa diagnosis was associated with continued sleep disturbance up to five years after diagnosis [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. In the current study, those whose sleep quality clinically worsened during the first four months had less severe insomnia symptoms at pre-treatment. Insomnia symptoms are common among BCa survivors [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] and can be precipitated and/or worsened by the emotional impact or direct physiologic effects and side effects of treatments [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Although aggregate levels of insomnia returned to pre-treatment at three years, insomnia symptoms can persist for up to 10 years post-treatment for some BCa survivors [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Thus, clinicians should monitor their patients for insomnia symptoms from diagnosis and implement an effective intervention if symptoms begin to worsen, such as cognitive behavioural therapy for insomnia.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section2\"\u003e \u003ch2\u003ePerceived Cognitive Impairment\u003c/h2\u003e \u003cp\u003ePerceived cognitive impairment consistently deteriorated over the first three years post-diagnosis. BCa patients in the present study demonstrated poorer levels of PCI at pre-treatment than estimates of healthy adults [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] and this worsened. Our sample scored 8\u0026ndash;13 points worse than cancer patients with brain tumors [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], gynecological cancer patients who did not receive chemotherapy [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e], and previous estimates of disease-free BCa survivors [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. The level of PCI in the present sample is comparable only to gynecological cancer patients who received chemotherapy [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. More research is needed that compares PCI between cancer types, treatments, and regions to determine which patients experience poorer PCI. Clinicians should monitor PCI in BCa patients from the time of diagnosis and opt for early intervention to avoid continuing decline.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec28\" class=\"Section2\"\u003e \u003ch2\u003eAge, Perceived Cognitive Impairment, and Cancer-Related Fatigue\u003c/h2\u003e \u003cp\u003eThose whose fatigue and PCI clinically worsened over the first four months were significantly younger. This is consistent with previous research indicating that CRF is greater among younger cancer survivors [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Age-related deficits in cognition are well-known, so it may seem counterintuitive that younger individuals in the present study experienced greater PCI. However, PCI represents the \u003cem\u003einner\u003c/em\u003e experience of BCa survivors. While a cancer diagnosis at any age is upsetting, it is particularly distressing among younger individuals as it presents unique challenges regarding financial burdens, body image, disconnection from peers, and greater fear of cancer recurrence [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Elevated distress and fear of cancer recurrence are also correlated with CRF [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Moreover, PCI is positively associated with CRF [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The increased PCI and CRF experienced by younger BCa survivors in the present study may reflect elevated distress about symptoms that they did not anticipate experiencing given their age. Future research should examine whether younger individuals experience greater objective cognitive impairment or only PCI and distress.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eWhile among the longest prospective studies of BCa survivors\u0026rsquo; fatigue, sleep and perceived cognitive impairment, limitations of this study should be acknowledged. First, our sample size was small, which reduces statistical power. Further, several statistical tests were run without adjusting alpha for inflation of familywise error, which increases the likelihood of spurious results. Given the exploratory nature of this study, these results should be considered hypothesis generating and not hypothesis testing. Finally, some data collection took place over the course of the COVID-19 pandemic. While it was a strength that we were able to switch to fully virtual assessments, it is unclear whether the global pandemic may have impacted sleep, fatigue, or cognitive impairment in addition to cancer. Future research should replicate this study to determine whether this outside, historical event may have impacted results.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion and Clinical Implications","content":"\u003cp\u003eMany women with BCa report symptoms of fatigue, insomnia, poor sleep quality, and perceived cognitive impairment at diagnosis, concerns that often worsen over the first four months during treatment. Fatigue and cognitive impairment may not return to pre-treatment levels up to three years post-diagnosis and may impact long-term well-being. Clinicians would benefit from: 1) identifying those who are at risk of experiencing fatigue, sleep disturbance, and cognitive impairment; 2) consistently monitor patients in the early months after receiving a diagnosis; and 3) providing targeted interventions to avoid long-term deterioration. Future research should examine the impact of early interventions on long-term outcomes in fatigue, insomnia, perceived cognitive impairment, and sleep quality.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding Declaration\u003c/strong\u003e: Rachel M. Lee is a trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds generously provided by the Canadian Cancer Society\u0026apos;s JD Irving, Limited - Excellence in Cancer Research Fund.\u0026nbsp;Sheila N. Garland is funded by a Canadian Cancer Society Emerging Scholar Award (Survivorship: grant #707146).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u003c/strong\u003e The authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Rachel M. Lee and Sheila N. Garland. The first draft of the manuscript was written by Rachel M. Lee and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval:\u003c/strong\u003e This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Health Ethics Research Board at Memorial University of Newfoundland (May 2, 2016/No 2016.092).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e: Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBrenner, D.R., et al., \u003cem\u003eProjected estimates of cancer in Canada in 2022.\u003c/em\u003e CMAJ, 2022. \u003cstrong\u003e194\u003c/strong\u003e(17): p. E601-E607.\u003c/li\u003e\n\u003cli\u003eCommittee, C.C.S.A. \u003cem\u003eCanadian Cancer Statistics 2022\u003c/em\u003e. 2022 [cited 2022 December 14, 2022].\u003c/li\u003e\n\u003cli\u003eYang, G.S., et al., \u003cem\u003eLongitudinal Analysis of Sleep Disturbance in Breast Cancer Survivors.\u003c/em\u003e Nurs Res, 2022. \u003cstrong\u003e71\u003c/strong\u003e(3): p. 177-188.\u003c/li\u003e\n\u003cli\u003eCella, D., et al., \u003cem\u003eFatigue in cancer patients compared with fatigue in the general United States population.\u003c/em\u003e Cancer, 2002. \u003cstrong\u003e94\u003c/strong\u003e(2): p. 528-38.\u003c/li\u003e\n\u003cli\u003eBardwell, W.A. and S. Ancoli-Israel, \u003cem\u003eBreast Cancer and Fatigue.\u003c/em\u003e Sleep Med Clin, 2008. \u003cstrong\u003e3\u003c/strong\u003e(1): p. 61-71.\u003c/li\u003e\n\u003cli\u003eJacobsen, P.B., et al., \u003cem\u003eFatigue in women receiving adjuvant chemotherapy for breast cancer: characteristics, course, and correlates.\u003c/em\u003e J Pain Symptom Manage, 1999. \u003cstrong\u003e18\u003c/strong\u003e(4): p. 233-42.\u003c/li\u003e\n\u003cli\u003eStein, K.D., et al., \u003cem\u003eA multidimensional measure of fatigue for use with cancer patients.\u003c/em\u003e Cancer Pract, 1998. \u003cstrong\u003e6\u003c/strong\u003e(3): p. 143-52.\u003c/li\u003e\n\u003cli\u003eBerger, A.M., et al., \u003cem\u003eCancer-Related Fatigue, Version 2.2015.\u003c/em\u003e J Natl Compr Canc Netw, 2015. \u003cstrong\u003e13\u003c/strong\u003e(8): p. 1012-39.\u003c/li\u003e\n\u003cli\u003eRuiz-Casado, A., et al., \u003cem\u003eCancer-related Fatigue in Breast Cancer Survivors: A Review.\u003c/em\u003e Clin Breast Cancer, 2021. \u003cstrong\u003e21\u003c/strong\u003e(1): p. 10-25.\u003c/li\u003e\n\u003cli\u003eBean, H.R., et al., \u003cem\u003eInsomnia and Fatigue Symptom Trajectories in Breast Cancer: A Longitudinal Cohort Study.\u003c/em\u003e Behav Sleep Med, 2021. \u003cstrong\u003e19\u003c/strong\u003e(6): p. 814-827.\u003c/li\u003e\n\u003cli\u003eJanz, N.K., et al., \u003cem\u003eSymptom experience and quality of life of women following breast cancer treatment.\u003c/em\u003e J Womens Health (Larchmt), 2007. \u003cstrong\u003e16\u003c/strong\u003e(9): p. 1348-61.\u003c/li\u003e\n\u003cli\u003eAlexander, S., et al., \u003cem\u003eA comparison of the characteristics of disease-free breast cancer survivors with or without cancer-related fatigue syndrome.\u003c/em\u003e Eur J Cancer, 2009. \u003cstrong\u003e45\u003c/strong\u003e(3): p. 384-92.\u003c/li\u003e\n\u003cli\u003eDavidson, J.R., et al., \u003cem\u003eSleep disturbance in cancer patients.\u003c/em\u003e Soc Sci Med, 2002. \u003cstrong\u003e54\u003c/strong\u003e(9): p. 1309-21.\u003c/li\u003e\n\u003cli\u003eAPA, \u003cem\u003eThe Diagnostic and Statistical Manual of Mental Disorders\u003c/em\u003e. Fifth Edition ed. 2013, Washington, DC: American Psychiatric Association.\u003c/li\u003e\n\u003cli\u003eSavard, J. and C.M. Morin, \u003cem\u003eInsomnia in the context of cancer: a review of a neglected problem.\u003c/em\u003e J Clin Oncol, 2001. \u003cstrong\u003e19\u003c/strong\u003e(3): p. 895-908.\u003c/li\u003e\n\u003cli\u003eHenneghan, A.M., et al., \u003cem\u003eRelationships between self-reported sleep quality components and cognitive functioning in breast cancer survivors up to 10 years following chemotherapy.\u003c/em\u003e Psychooncology, 2018. \u003cstrong\u003e27\u003c/strong\u003e(8): p. 1937-1943.\u003c/li\u003e\n\u003cli\u003eLowery-Allison, A.E., et al., \u003cem\u003eSleep problems in breast cancer survivors 1-10 years posttreatment.\u003c/em\u003e Palliat Support Care, 2018. \u003cstrong\u003e16\u003c/strong\u003e(3): p. 325-334.\u003c/li\u003e\n\u003cli\u003eBower, J.E., \u003cem\u003eBehavioral symptoms in patients with breast cancer and survivors.\u003c/em\u003e J Clin Oncol, 2008. \u003cstrong\u003e26\u003c/strong\u003e(5): p. 768-77.\u003c/li\u003e\n\u003cli\u003eJanelsins, M.C., et al., \u003cem\u003eAn update on cancer- and chemotherapy-related cognitive dysfunction: current status.\u003c/em\u003e Semin Oncol, 2011. \u003cstrong\u003e38\u003c/strong\u003e(3): p. 431-8.\u003c/li\u003e\n\u003cli\u003eSavard, J. and P.A. Ganz, \u003cem\u003eSubjective or Objective Measures of Cognitive Functioning-What\u0026apos;s More Important?\u003c/em\u003e JAMA Oncol, 2016. \u003cstrong\u003e2\u003c/strong\u003e(10): p. 1263-1264.\u003c/li\u003e\n\u003cli\u003eCastellon, S.A., et al., \u003cem\u003eNeurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen.\u003c/em\u003e J Clin Exp Neuropsychol, 2004. \u003cstrong\u003e26\u003c/strong\u003e(7): p. 955-69.\u003c/li\u003e\n\u003cli\u003eCaplette-Gingras, A., et al., \u003cem\u003eIs insomnia associated with cognitive impairments in breast cancer patients?\u003c/em\u003e Behav Sleep Med, 2013. \u003cstrong\u003e11\u003c/strong\u003e(4): p. 239-57.\u003c/li\u003e\n\u003cli\u003eAhles, T.A., et al., \u003cem\u003eNeuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma.\u003c/em\u003e J Clin Oncol, 2002. \u003cstrong\u003e20\u003c/strong\u003e(2): p. 485-93.\u003c/li\u003e\n\u003cli\u003eStone, P., et al., \u003cem\u003eCancer-related fatigue: inevitable, unimportant and untreatable? Results of a multi-centre patient survey. Cancer Fatigue Forum.\u003c/em\u003e Ann Oncol, 2000. \u003cstrong\u003e11\u003c/strong\u003e(8): p. 971-5.\u003c/li\u003e\n\u003cli\u003eHenneghan, A., et al., \u003cem\u003eModifiable correlates of perceived cognitive function in breast cancer survivors up to 10 years after chemotherapy completion.\u003c/em\u003e J Cancer Surviv, 2018. \u003cstrong\u003e12\u003c/strong\u003e(2): p. 224-233.\u003c/li\u003e\n\u003cli\u003eChan, A., et al., \u003cem\u003eMinimal Clinically Important Difference of the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) for Fatigue Worsening in Asian Breast Cancer Patients.\u003c/em\u003e J Pain Symptom Manage, 2018. \u003cstrong\u003e55\u003c/strong\u003e(3): p. 992-997 e2.\u003c/li\u003e\n\u003cli\u003eMorin, C.M., \u003cem\u003eInsomnia: Psychological Assessment and Management\u003c/em\u003e. 1993, New York: Guilford.\u003c/li\u003e\n\u003cli\u003eMorin, C.M., et al., \u003cem\u003eThe Insomnia Severity Index: psychometric indicators to detect insomnia cases and evaluate treatment response.\u003c/em\u003e Sleep, 2011. \u003cstrong\u003e34\u003c/strong\u003e(5): p. 601-8.\u003c/li\u003e\n\u003cli\u003eYang, M., et al., \u003cem\u003eInterpreting score differences in the Insomnia Severity Index: using health-related outcomes to define the minimally important difference.\u003c/em\u003e Curr Med Res Opin, 2009. \u003cstrong\u003e25\u003c/strong\u003e(10): p. 2487-94.\u003c/li\u003e\n\u003cli\u003eBuysse, D.J., et al., \u003cem\u003eThe Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research.\u003c/em\u003e Psychiatry Res, 1989. \u003cstrong\u003e28\u003c/strong\u003e(2): p. 193-213.\u003c/li\u003e\n\u003cli\u003eLongo, U.G., et al., \u003cem\u003eMinimal Clinically Important Difference and Patient Acceptable Symptom State for the Pittsburgh Sleep Quality Index in Patients Who Underwent Rotator Cuff Tear Repair.\u003c/em\u003e Int J Environ Res Public Health, 2021. \u003cstrong\u003e18\u003c/strong\u003e(16).\u003c/li\u003e\n\u003cli\u003eWagner, L.I., et al., \u003cem\u003eMeasuring patient self-reported cognitive function: development of the functional assessment of cancer therapy-cognitive function instrument.\u003c/em\u003e The Journal of Supportive Oncology, 2009. \u003cstrong\u003e7\u003c/strong\u003e(6): p. W32-W39.\u003c/li\u003e\n\u003cli\u003eCheung, Y.T., et al., \u003cem\u003eMinimal clinically important difference (MCID) for the functional assessment of cancer therapy: cognitive function (FACT-Cog) in breast cancer patients.\u003c/em\u003e J Clin Epidemiol, 2014. \u003cstrong\u003e67\u003c/strong\u003e(7): p. 811-20.\u003c/li\u003e\n\u003cli\u003eBell, M.L., et al., \u003cem\u003eImportant differences and meaningful changes for the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog).\u003c/em\u003e Journal of Patint-Reported Outcomes, 2018. \u003cstrong\u003e2\u003c/strong\u003e(48).\u003c/li\u003e\n\u003cli\u003eMontoya, A.K. and A.F. Hayes, \u003cem\u003eTwo-condition within-participant statistical mediation analysis: A path-analytic framework.\u003c/em\u003e Psychol Methods, 2017. \u003cstrong\u003e22\u003c/strong\u003e(1): p. 6-27.\u003c/li\u003e\n\u003cli\u003eWilliams, A.M., et al., \u003cem\u003eFatigue, anxiety, and quality of life in breast cancer patients compared to non-cancer controls: a nationwide longitudinal analysis.\u003c/em\u003e Breast Cancer Res Treat, 2021. \u003cstrong\u003e187\u003c/strong\u003e(1): p. 275-285.\u003c/li\u003e\n\u003cli\u003eGeinitz, H., et al., \u003cem\u003eFatigue, serum cytokine levels, and blood cell counts during radiotherapy of patients with breast cancer.\u003c/em\u003e Int J Radiat Oncol Biol Phys, 2001. \u003cstrong\u003e51\u003c/strong\u003e(3): p. 691-8.\u003c/li\u003e\n\u003cli\u003eSanford, S.D., et al., \u003cem\u003eLongitudinal prospective assessment of sleep quality: before, during, and after adjuvant chemotherapy for breast cancer.\u003c/em\u003e Support Care Cancer, 2013. \u003cstrong\u003e21\u003c/strong\u003e(4): p. 959-67.\u003c/li\u003e\n\u003cli\u003eWeng, Y.P., et al., \u003cem\u003eSleep Quality and Related Factors in Patients with Breast Cancer: A Cross-Sectional Study in Taiwan.\u003c/em\u003e Cancer Manag Res, 2021. \u003cstrong\u003e13\u003c/strong\u003e: p. 4725-4733.\u003c/li\u003e\n\u003cli\u003eZeng, Y., et al., \u003cem\u003eSubjective cognitive impairment and brain structural networks in Chinese gynaecological cancer survivors compared with age-matched controls: a cross-sectional study.\u003c/em\u003e BMC Cancer, 2017. \u003cstrong\u003e17\u003c/strong\u003e(1): p. 796.\u003c/li\u003e\n\u003cli\u003eAdak, S., et al., \u003cem\u003eCognitive score in patients with primary brain tumors undergoing systemic therapy \u0026ndash; a cross-sectional study.\u003c/em\u003e Cancer Research, Statistics, and Treatment, 2020. \u003cstrong\u003e3\u003c/strong\u003e(3): p. 455-460.\u003c/li\u003e\n\u003cli\u003eVardy, J.L., et al., \u003cem\u003eA mechanistic cohort study evaluating cognitive impairment in women treated for breast cancer.\u003c/em\u003e Brain Imaging Behav, 2019. \u003cstrong\u003e13\u003c/strong\u003e(1): p. 15-26.\u003c/li\u003e\n\u003cli\u003eBrownstein, C.G., et al., \u003cem\u003ePhysiological and psychosocial correlates of cancer-related fatigue.\u003c/em\u003e J Cancer Surviv, 2022. \u003cstrong\u003e16\u003c/strong\u003e(6): p. 1339-1354.\u003c/li\u003e\n\u003cli\u003eSchulte, F.S.M., et al., \u003cem\u003eQuality of life among survivors of adolescent and young adult cancer in Canada: A Young Adults With Cancer in Their Prime (YACPRIME) study.\u003c/em\u003e Cancer, 2021. \u003cstrong\u003e127\u003c/strong\u003e(8): p. 1325-1333.\u003c/li\u003e\n\u003cli\u003eVanrusselt, D., et al., \u003cem\u003eAssociations between cancer-related distress and fatigue in childhood cancer survivors: A longitudinal study.\u003c/em\u003e Psychooncology, 2023. \u003cstrong\u003e32\u003c/strong\u003e(3): p. 393-400.\u003c/li\u003e\n\u003c/ol\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":"breast cancer, fatigue, insomnia, cognitive impairment, sleep quality","lastPublishedDoi":"10.21203/rs.3.rs-3581028/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3581028/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eBreast cancer is the most common form of cancer among Canadian women. Survivorship challenges include fatigue, sleep disturbance, and cognitive impairment. This study examined: 1) symptom trajectory from diagnosis to three years; 2) whether symptom change in the first four months was associated with prolonged difficulties after three years; and 3) which factors were associated with deterioration in symptoms during the first four months.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis prospective observational cohort study examined 53 women (\u003cem\u003eM\u003c/em\u003e\u003csub\u003e\u003cem\u003eage\u003c/em\u003e\u003c/sub\u003e = 58.6, 96.2% White, 67.9% Stage I) with newly diagnosed breast cancer over three years. Women completed assessments before starting treatment, four months, and three years after diagnosis. Three-way repeated-measures ANOVAs evaluated symptom trajectories. A repeated-measures mediation analysis was performed to determine if change from pre-treatment to four months accounted for change from pre-treatment to three years. A series of between-subjects ANOVAs were used to determine what variables significantly differed by deterioration status.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePerceived cognitive impairment and fatigue increased linearly from diagnosis to three years. Change in fatigue in the first four months fully accounted for its change over three years. Insomnia severity and sleep quality deteriorated from diagnosis to four months, but returned to pre-treatment levels at three years. Those whose fatigue and cognitive ability deteriorated during the first four months were younger.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eEfforts to identify those who are at risk of experiencing fatigue, sleep disturbance, and cognitive impairment; monitor patients early after receiving a diagnosis; and provide targeted interventions may prevent long-term deterioration and improve well-being.\u003c/p\u003e","manuscriptTitle":"Early change in fatigue, insomnia, and cognitive impairment and symptom severity at 3-years post-treatment in breast cancer survivors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-11-14 03:09:47","doi":"10.21203/rs.3.rs-3581028/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-01-24T19:23:43+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-12-29T21:22:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"d544d917-61a1-44c9-8a52-eace8913c6d0","date":"2023-12-27T20:24:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-12-27T19:47:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-12-24T18:40:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-11-10T03:44:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"Supportive Care in Cancer","date":"2023-11-08T20:02:56+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":"fadb8bf3-ffcd-4efa-96b7-463578423414","owner":[],"postedDate":"November 14th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-03-19T00:47:57+00:00","versionOfRecord":{"articleIdentity":"rs-3581028","link":"https://doi.org/10.1007/s00520-024-08418-1","journal":{"identity":"supportive-care-in-cancer","isVorOnly":false,"title":"Supportive Care in Cancer"},"publishedOn":"2024-03-18 00:47:57","publishedOnDateReadable":"March 18th, 2024"},"versionCreatedAt":"2023-11-14 03:09:47","video":"","vorDoi":"10.1007/s00520-024-08418-1","vorDoiUrl":"https://doi.org/10.1007/s00520-024-08418-1","workflowStages":[]},"version":"v1","identity":"rs-3581028","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3581028","identity":"rs-3581028","version":["v1"]},"buildId":"ehx78VzkSd0WSzXnipQa-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}