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Abstract Purpose To relate the development of post-treatment hypothyroidism with the dose distribution within the thyroid gland in breast cancer (BC) patients treated with loco-regional radiotherapy (RT). Methods and materials In two groups of BC patients postoperatively irradiated by computer tomography (CT)-based RT, the individual dose distributions in the thyroid gland were compared with each other; Cases developed post-treatment hypothyroidism after multimodal treatment including 4-field RT technique. Matched patients in Controls remained free for hypothyroidism. Based on each patient's dose volume histogram (DVH) the volume percentages of the thyroid absorbing respectively 20, 30, 40 and 50 Gy were then estimated (V20, V30, V40 and V50) together with the individual mean thyroid dose over the whole gland (MeanTotGy). The mean and median thyroid dose for the included patients was about 30 Gy, subsequently the total volume of the thyroid gland (VolTotGy) and the absolute volumes (cm3) receiving respectively < 30 Gy and ≥ 30 Gy were calculated (Vol < 30 and Vol ≥ 30) and analyzed. Results No statistically significant inter-group differences were found between V20, V30, V40 and V50Gy or the median of MeanTotGy. The median VolTotGy in Controls was 2.3 times above VolTotGy in Cases (ρ = 0.003), with large inter-individual variations in both groups. The volume of the thyroid gland receiving < 30 Gy in Controls was almost 2.5 times greater than the comparable figure in Cases. Conclusions We concluded that in patients with small thyroid glands after loco-radiotherapy of BC, the risk of post-treatment hypothyroidism depends on the volume of the thyroid gland.

Background: Although anthracycline-related cardiotoxicity is widely studied, only a limited number of echocardiographic studies have assessed cardiac function in breast cancer survivors (BCSs) beyond ten years from anthracycline treatment, and the knowledge of long-term cardiorespiratory fitness (CRF) in this population is scarce. This study aimed to compare CRF assessed as peak oxygen uptake (V̇O 2 ), cardiac morphology and function, and cardiovascular (CV) risk factors between long-term BCSs treated with anthracyclines and controls with no history of cancer., Methods: The CAUSE (Cardiovascular Survivors Exercise) trial included 140 BCSs recruited through the Cancer Registry of Norway, who were diagnosed with breast cancer stage II to III between 2008 and 2012 and had received treatment with epirubicin, and 69 similarly aged activity level-matched controls. All the participants underwent blood sampling, blood pressure measurements, echocardiography and cardiopulmonary exercise testing from October 2020 to August 2022., Results: BCSs were aged 59 ± 6 years and had received a cumulative dose of 357 (243 to 366) mg/m 2 of epirubicin on average 11 ± 1 years before inclusion. There was no difference between BCSs and controls with respect to peak V̇O 2 (27.6 ± 5.4 mL/kg/min vs. 27.1 ± 5.4 mL/kg/min, P = 0.25), 2D left ventricular ejection fraction (57 ± 3% vs. 57 ± 3%, P = 0.43), left ventricular global longitudinal strain (-20.5 ± 1.0% vs. -20.6 ± 1.0%, P = 0.46) or the proportion with N-terminal pro-brain natriuretic peptide ≥ 125 (22% vs. 20%, P = 0.93). The proportions with hypertension, dyslipidemia or diabetes did not differ between the groups., Conclusion: We found that CRF, cardiac function, and CV risk profile in BCSs examined a decade after treatment with anthracyclines were similar to that in women with no history of cancer., Trial Registration: clinicaltrials.gov (NCT04307407) https://clinicaltrials.gov/ct2/show/NCT04307407 ., Competing Interests: Declarations. Ethical approval: Written informed consent was given by all study participants. The study complies with the Declaration of Helsinki and was approved by the Regional Committees for Medical and Health Research Ethics (2019/1318) and the Data Protection Services for Research (865175). Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Breast cancer is the most commonly occurring form of cancer in pregnancy. Among women aged between 25 and 29 years, one in five cases of breast cancer will occur in pregnancy or during the first postnatal year. The prevalence is increasing, presumably because of the increase in maternal age at pregnancy. Interdisciplinary cooperation is needed to ensure a good outcome for both mother and child. The prognosis is good but depends on rapid diagnosis and optimal treatment. In this clinical review article, the most important aspects of breast cancer treatment during pregnancy are reviewed.

Purpose: A breast cancer (BC) diagnosis may negatively affect health-related quality of life (HRQoL). However, there are few comparisons of HRQoL at several time points for women with BC, and particular when subdivided into invasive and in situ tumors. The purpose of this study was to investigate various aspects of HRQoL in women recently diagnosed with invasive BC or ductal carcinoma in situ (in situ) compared to age-matched BC free controls in a population-wide sample recruited through the Cancer Registry of Norway., Methods: This cross-sectional study utilized HRQoL data collected in 2020-2022 from a digital survey including 4117 cases (3867 women with invasive BC and 430 with in situ) and 2911 controls. HRQoL was assessed ≥ 21 days after diagnosis, using EORTC QLQ-C30. This includes scores assessing global quality of life (gHRQoL) and HRQoL functions and symptoms. Multivariable regression analyses were used to compare HRQoL between cases and controls and to identify factors associated with gHRQoL and fatigue. Additionally, HRQoL 14 months after diagnosis was analyzed in 1989 of the included cases and in 1212 of the controls. Score differences of ≥ 10 points were considered clinically relevant and thus presented in the results., Results: Invasive BC cases had lower gHRQoL, role- and social functioning in addition to more fatigue than controls. In situ cases had lower role-and social functioning than controls. Invasive BC cases scored worse than in situ on all domains, but the differences were not considered clinically relevant. Physical activity was associated with better gHRQoL and less fatigue in invasive BC, in situ and controls. Both invasive BC and in situ cases improved their role- and social functioning scores from diagnosis to 14 months follow-up, however no improvement was seen for fatigue., Conclusion: Women with invasive BC and in situ reported lower role- and social functioning scores than controls right after diagnosis with improvements 14 months after diagnosis. Physical activity was associated with better gHRQoL and less fatigue and should, whenever possible, play a key role in the care for BC patients., (© 2024. The Author(s).)

Background: EMIT-1 is a national, observational, single-arm trial designed to assess the value of the Prosigna, Prediction Analysis of Microarray using the 50 gene classifier (PAM50)/Risk of Recurrence (ROR), test as a routine diagnostic tool, examining its impact on adjuvant treatment decisions, clinical outcomes, side-effects and cost-effectiveness. Here we present the impact on treatment decisions., Patients and Methods: Patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative pT1-pT2 lymph node-negative early breast cancer (EBC) were included. The Prosigna test and standard histopathology assessments were carried out. Clinicians' treatment decisions were recorded before (pre-Prosigna) and after (post-Prosigna) the Prosigna test results were disclosed., Results: Of 2217 patients included, 2178 had conclusive Prosigna results. The pre-Prosigna treatment decisions were: no systemic treatment (NT) in 27% of patients, endocrine treatment alone (ET) in 38% and chemotherapy (CT) followed by ET (CT + ET) in 35%. Post-Prosigna treatment decisions were 25% NT, 51% ET and 24% CT + ET, respectively. Adjuvant treatment changed in 28% of patients, including 21% change in CT use. Among patients assigned to CT + ET pre-Prosigna, 45% were de-escalated to ET post-Prosigna. Of patients assigned to ET, 12% were escalated to CT + ET and 8% were de-escalated to NT; of those assigned to NT, 18% were escalated to ET/CT + ET. CT was more frequently recommended for patients aged ≤50 years. In the subgroup with pT1c-pT2 G2 and intermediate Ki67 (0.5-1.5× local laboratory median Ki67 score), the pre-Prosigna CT treatment decision varied widely across hospitals (3%-51%). Post-Prosigna, the variability of CT use was markedly reduced (8%-24%). The correlation between Ki67 and ROR score within this subgroup was poor (r = 0.25-0.39). The median ROR score increased by increasing histological grade, but the ROR score ranges were wide (for G1 0-79, G2 0-90, G3 16-94)., Conclusion: The Prosigna test result changed adjuvant treatment decisions in all EBC clinical risk groups, markedly decreased the CT use for patients categorized as higher clinical risk pre-Prosigna and reduced treatment decision discrepancies between hospitals., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: The study aims to describe work status at diagnosis and 8 years post-diagnosis in a nationwide sample of breast cancer survivors (BCSs), and investigate associated and self-reported factors of reduced work status., Methods: Women aged 20-65 years when diagnosed with stage I-III breast cancer (BC) in 2011 or 2012 were invited to participate in a questionnaire study in 2019 (n = 2803), of whom 49% (n = 1361) responded. For this sub-study, we included 974 BCSs below the legal retirement age in Norway (< 67 years) at survey and with complete work status data. Reduced work status was defined as being in paid work at BC diagnosis and not working at time of survey. Logistic regression analyses were applied to identify factors associated with reduced work status., Results: Of BCSs who were in paid work at diagnosis (n = 845), 63% maintained their work status to 8 years later. Reduced work status was associated with not living with children (OR .44, 95% CI .24-.82), age (OR 1.16, 95% CI 1.11-1.21), chemotherapy (OR 2.83, 95% CI 1.24-6.61), > 2 comorbid conditions (OR 2.27, 95% CI 1.16-4.32), cognitive function (OR .99, 95% CI .98-.99), fatigue (OR 1.02, 95% CI 1.01-1.03), and neuroticism (OR 1.57, 95% CI 1.00-2.46). BC and late effects were reported as reasons for reduced work status and disability., Conclusions: The majority of BCSs who were in paid work at diagnosis were working 8 years later., Implications for Cancer Survivors: Our results suggest a need to focus on fatigue and reduced cognitive function among long-term BCSs, with the ultimate aim of improving work sustainability., (© 2022. The Author(s).)

Purpose: Treatment-related sexual problems are common, but understudied, among survivors of Childhood, Adolescent, and Young Adult Cancer Survivors (CAYACS). We investigated awareness of, and information needs regarding, sexual problems as late effects in a nation-wide sample of long-term CAYACS. Methods: Five-year survivors were identified by the Cancer Registry of Norway, diagnosed between 1985 and 2009 with any childhood cancer (0-18 years of age, excluding central nervous system tumors), leukemia, colorectal cancer, breast cancer, non-Hodgkin lymphoma, or malignant melanoma (19-39 years of age). Malignant melanoma survivors treated with local surgery only served as an unmatched reference group. Survivors were mailed a survey, including items on awareness and information needs. Descriptive statistics and logistic regression analyses were used for data analyses. Results: Of 5361 CAYACS invited, 2104 responded (39%), of which 1870 were eligible for inclusion. In all, 62% were aware of sexual problems as late effects (46% aware only, 16% experienced it) and 31% reported information needs. Of all groups, childhood cancer survivors reported the lowest level of awareness (43% aware, 7% experienced it) and the highest information needs (38%). In multivariable models, awareness was associated with higher education, shorter time since treatment, more intense treatments, and experiencing hormonal changes and reduced fertility. Information needs were associated with having experienced sexual problems, female gender, higher treatment intensity, chronic fatigue, and increased depressive symptoms. Conclusions: A substantial proportion of long-term CAYACS report being unaware of, and have information needs regarding sexual problems as late effects decades beyond treatment. Addressing such issues during follow-up care is important.

Little is known about how health-related quality of life (HRQoL) in breast cancer cases differed from that of controls during and after the COVID-19 pandemic. This study used data from an ongoing, nationwide HRQoL survey of 4279 newly diagnosed breast cancer cases and 2911 controls to investigate how breast cancer patients fared during different phases of the pandemic compared to controls. Responders during 2020-2022 were categorized into three COVID-19-related phases: the social restrictions phase, the high infection rate phase, and the post-pandemic phase. Across phases, breast cancer cases had significantly worse scores in most HRQoL domains compared to controls. Apart from slightly more insomnia in the high infection rate phase for both cases and controls, and better social functioning for young cases in the post-COVID-19 phase, the case-control differences in HRQoL remained consistent across phases. When the phases were assessed as one period, young women and those living with children <18 years of age fared the worst among breast cancer cases, while single women fared the worst among controls. In contrast, controls living with children <18 years of age exhibited better HRQoL than controls without children. In summary, women with breast cancer did not appear to fare differently than controls in terms of HRQoL across COVID-19 phases. However, breast cancer cases with young children fared worse in their HRQoL than other breast cancer cases.

Background: Long-term breast cancer survivors (BCSs) may experience several late effects (LEs) simultaneously. This study aimed to identify subgroups of 8-year BCSs with higher burden of LEs who could benefit from closer survivorship care, explore variables associated with higher symptom burden, and describe how symptom burden may affect general functioning., Methods: All Norwegian women aged 20 to 65 years when diagnosed with stage I-III breast cancer in 2011 and 2012 were invited (n = 2803). The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire/BR23, the Fatigue Questionnaire, Assessment of Survivor Concerns, and Scale for Chemotherapy Induced Long-term Neurotoxicity were used to assess 10 common LEs and general functioning. Using latent class analysis, subgroups of BCSs with similar burden of LEs were identified. Multinominal regression analysis were performed to examine variables associated with higher symptom burden., Results: The final sample consisted of 1353 BCSs; 46% had low, 37% medium, and 17% high symptom burden. Younger age, short education, axillary dissection, higher systemic treatment burden, higher body mass index, and physical inactivity were associated with higher symptom burden. General functioning scores were lower, and the proportion on disability pension were higher among BCSs in the two most burdened subgroups compared with those in the low burden subgroup., Conclusion: More than half of long-term BCSs suffered from medium or high symptom burden and experienced impaired general functioning compared with BCS with low symptom burden. Younger age and systemic treatment were important risk factors for higher symptom burden. BCSs at risk of higher symptom burdens should be identified and offered closer and extended survivorship care., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: Neuroticism is a basic personality trait characterized by negative emotions triggered by stress such as a breast cancer diagnosis and its treatment. Due to lack of relevant research, the purpose of this study was to examine if high neuroticism is associated with seven common late adverse effects (LAEs) in long-term (≥ 5 years) breast cancer survivors (BCSs)., Methods: All female Norwegian BCSs aged 20-65 years when diagnosed with stage I-III breast cancer in 2011 or 2012 were invited to a questionnaire study in 2019 (N = 2803), of whom 48% participated (N = 1355). Neuroticism was self-rated using the abridged version of the Eysenck Personality Questionnaire, and scores dichotomized into high and low neuroticism. LAEs were defined by categorization of ratings on the EORTC QLQ-C30 (cognitive function, pain, and sleep problems) and QLQ-BR23 (arm problems) questionnaires, and categorizations of scale scores on mental distress, fatigue, and neuropathy. Associations between high neuroticism and LAEs were explored using multivariate logistic regression analyses., Results: High neuroticism was found in 40% (95%CI 37-42%) of BCSs. All LAEs were significantly more common among BCSs with high compared to low neuroticism. In multivariable analyses, high neuroticism was positively associated with all LAEs except neuropathy. Systemic treatment, somatic comorbidity, and not being in paid work were also significantly associated with all LAEs., Conclusions: High neuroticism is prevalent and associated with increased risks of LAEs among BCSs. Identification of high neuroticism could improve the follow-up care of BCSs as effective interventions for the condition exist., (© 2023. The Author(s).)

Purpose: Sexual health is an important aspect of quality of life. Knowledge concerning sexual health in long-term breast cancer survivors (BCSs) is limited. This study compared sexual health in BCSs 8 years after diagnosis with similarly aged controls and examined the impact of menopausal status at diagnosis and systemic breast cancer treatments on sexual health., Methods: Women aged 20-65 years when diagnosed with stage I-III breast cancer in 2011-2012 were identified by the Cancer Registry of Norway (n = 2803) and invited to participate in a nationwide survey. Controls were women from the Trøndelag Health Study (HUNT4). Sexual functioning and sexual enjoyment were measured by the EORTC QLQ-BR23 subscales scored from 0 to 100, and sexual discomfort by the Sexual Activity Questionnaire scored from 0 to 6. Linear regression analyses with adjustments for sociodemographic and health-related variables were performed to compare groups. Differences of ≥ 10% of range score were considered clinically significant., Results: The study samples consisted of 1241 BCSs and 17,751 controls. Sexual enjoyment was poorer (B - 13.1, 95%CI - 15.0, - 11.2) and discomfort higher (B 0.9, 95%CI 0.8, 1.0) among BCSs compared to controls, and larger differences were evident between premenopausal BCSs and controls (B - 17.3, 95%CI - 19.6, - 14.9 and B 1.2, 95%CI 1.0, 1.3, respectively). BCSs treated with both endocrine- and chemotherapy had lower sexual functioning (B - 11.9, 95%CI - 13.8, - 10.1), poorer sexual enjoyment (B - 18.1, 95%CI - 20.7, - 15.5), and more sexual discomfort (B 1.4, 95% 1.3, 1.6) than controls., Conclusion: Sexual health impairments are more common in BCSs 8 years after diagnosis compared to similar aged population controls. During follow-up, attention to such impairments, especially among women diagnosed at premenopausal age and treated with heavy systemic treatment, is warranted., (© 2023. The Author(s).)

Objective: The aim of this study was to provide sex-, age-, and morbidity-specific Norwegian general population normative values for the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires QLQ-C30, the sexual health questionnaire QLQ-SHQ22 and the sexual domains of the breast modules QLQ-BR23 and QLQ-BR45., Methods: A random nationwide sample stratified by sex and age groups (18-29, 30-39, 40-49, 50-59, 60-69 and ≥70 years) was drawn from the Norwegian National Population Register. Participants were notified through national online health services (HelseNorge) and postal mail. The survey included sociodemographic background information, health-related quality of life assessed by the EORTC questionnaires, and morbidity assessed by the Self-Administered Comorbidity Questionnaire. Multivariable linear regression was carried out to estimate the associations of age, sex and morbidity with the EORTC scale and item scores., Results: Of the 15,627 eligible individuals, 5135 (33%) responded. Women and persons with morbidities reported lower functioning and higher symptom burden than men and persons without morbidities, respectively, on nearly all EORTC scales. Sex differences were most prominent for emotional functioning, pain, fatigue and insomnia (QLQ-C30), body image, sexual functioning (QLQ-BR23/45), importance of sexual activity, libido and fatigue (QLQ-SHQ22). The score differences between persons with and without morbidity were highly significant and largest in the youngest and middle-aged groups., Conclusion: This is the first study to provide normative values for the EORTC sexual health questionnaire QLQ-SHQ22 and the sexual subscales of the QLQ-BR23 and QLQ-BR45 for all, separately in age groups by sex and morbidity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Breast cancer is the most common cancer among women in Norway. Nine out of ten will become long-term survivors. Being cancer-free does not necessarily mean feeling healthy, and many experience troublesome late effects, such as fatigue, pain and fear of recurrence. General practitioners represent the most important medical support for the majority of these women. This clinical review article summarises up-to-date knowledge about late effects after breast cancer treatment. Non-pharmacological interventions can have a positive effect on many of the most common late effects.

Background: Fear of cancer recurrence (FCR) in breast cancer survivors (BCSs) is common, associated with reduced quality of life and effective interventions exist. There are knowledge gaps concerning FCR among long-term, early-stage BCSs and its associations with other late effects. Within a national cohort, we explored these knowledge gaps, with the ultimate aim of improved care for BCSs experiencing long-term FCR., Methods: In this cross-sectional study, all BCSs aged 20-65 years with early-stage breast cancer in 2011-2012 ( n  = 2803), were identified by the Cancer Registry of Norway in 2019 and mailed a survey including the Assessment of Survivor Concerns used to measure FCR. Factors associated with moderate/high FCR (defined as a sum score of ≥ 6 of a possible range 3-12, or a single score on one of the items of ≥ 3) were explored using a three-block regression analyses including relevant sociodemographic-, health- and cancer-related variables., Results: In total, 1311 BCSs were included (47%). Median age at survey was 60 years. Fifty-six % reported moderate-to-high FCR, associated with younger age (OR 0.96, 95% CI 0.95-0.97) and receiving chemo- and endocrine therapy (OR 1.59, 95% CI 1.15-2.20). After adding late effects into the model, FCR remained significantly associated with these variables, in addition to sleep disturbances (OR 1.58, 95% CI 1.18-2.10). In the final block, adding mental distress, FCR remained significantly associated with younger age (OR 0.97, 95% CI 0.96-0.99), receiving chemo- and endocrine therapy (OR 1.14, 95% CI 1.00-1.97), sleep disturbances (OR 1.44, 95% CI 1.08-1.94) and anxiety (OR 2.67, 95% CI 1.38-5.19)., Conclusions: FCR was prevalent eight years after early-stage breast cancer. Being younger, receiving intensive treatment, experiencing sleep disturbances and/or anxiety were associated with moderate/high FCR. Addressing FCR should be part of standard follow-up care of long-term BCSs.

Background: One-third or more of breast cancer survivors report stress and other psychological and physical complaints that can negatively impact their quality of life. Psychosocial stress management interventions, shown to mitigate the negative impact of these complaints, can now be delivered as accessible and convenient (for the patient and provider) eHealth interventions. In this randomized controlled trial (RCT), Coping After Breast Cancer (CABC), 2 modified versions of the stress management eHealth intervention program StressProffen were created: one with predominantly cognitive behavioral stress management content (StressProffen-cognitive behavioral therapy intervention [StressProffen-CBI]) and another with predominantly mindfulness-based stress management content (StressProffen-mindfulness-based intervention [StressProffen-MBI])., Objective: This study aims to investigate the effects in breast cancer survivors of using StressProffen-CBI and StressProffen-MBI compared with a control group (treatment as usual)., Methods: Women diagnosed with breast cancer (stage I-III, unequivocally human epidermal growth factor receptor 2-positive or estrogen receptor-negative tumors) or ductal carcinoma in situ (DCIS) aged 21-69 years who completed the Cancer Registry of Norway-initiated health survey on quality of life are invited to the CABC trial about 7 months after diagnosis. Women who give consent to participate are randomized (1:1:1) to either the StressProffen-CBI, StressProffen-MBI, or control group. Both StressProffen interventions consist of 10 modules of stress management content delivered through text, sound, video, and images. The primary outcome is between-group changes in perceived stress at 6 months, assessed with Cohen 10-item Perceived Stress Scale. The secondary outcomes comprise changes in quality of life, anxiety, depression, fatigue, sleep, neuropathy, coping, mindfulness, and work-related outcomes approximately 1, 2, and 3 years after diagnosis. Long-term effects of the interventions on work participation, comorbidities, relapse or new cancers, and mortality will be assessed using data from national health registries., Results: Recruitment is scheduled from January 2021 to May 2023. The goal is to recruit 430 participants (100 in each group). As of April 14 2023, 428 participants have been enrolled., Conclusions: The CABC trial is possibly the largest ongoing psychosocial eHealth RCT in patients with breast cancer. If 1 or both interventions prove to be effective in reducing stress and improving psychosocial and physical complains, the StressProffen eHealth interventions could be beneficial, inexpensive, and easily implementable tools for breast cancer survivors when coping with late effects after cancer and cancer treatments., Trial Registration: Clinicaltrials.gov NCT04480203; https://clinicaltrials.gov/ct2/show/NCT04480203., International Registered Report Identifier (irrid): DERR1-10.2196/47195., (©Karianne Svendsen, Lise Solberg Nes, Anders Meland, Ine Marie Larsson, Ylva M Gjelsvik, Elin Børøsund, Christine M Rygg, Tor Åge Myklebust, Kristin V Reinertsen, Cecilie E Kiserud, Helle Skjerven, Michael H Antoni, Trudie Chalder, Ingvil Mjaaland, Linda E Carlson, Hege R Eriksen, Giske Ursin. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 24.05.2023.)

Objective: Breast cancer and breast cancer-directed radiation therapy (RT) may increase the risk of late effects, such as hypothyroidism. We conducted a systematic review and meta-analysis to investigate the association between breast cancer, RT, and risk of hypothyroidism in breast cancer survivors., Methods: Through February 2022, we searched PubMed, EMBASE, and references of relevant articles, to identify papers on breast cancer and breast cancer-directed RT and subsequent risk of hypothyroidism. Articles were screened by title and abstract and reviewed for eligibility. We used a pre-formed data extraction sheet and identified key design elements that could potentially introduce bias. The main outcome was the confounder-adjusted relative risk (RR) of hypothyroidism in breast cancer survivors versus women without breast cancer, and in breast cancer survivors according to the receipt of RT to the supraclavicular lymph nodes. We used a random-effects model to calculate pooled RRs and associated 95% confidence intervals (95% CI)., Results: From 951 papers screened by title and abstract, 34 full-text papers were reviewed for eligibility. We included 20 studies published between 1985 and 2021-19 were cohort studies. Compared with women without breast cancer, the pooled RR of hypothyroidism in breast cancer survivors was 1.48 (95% CI: 1.17, 1.87), with highest risk associated with RT to the supraclavicular region (RR = 1.69, 95% CI: 1.16, 2.46). The most important limitations of the studies were small sample size yielding estimates with low precision, and lack of data on potential confounders., Conclusion: Breast cancer and radiation therapy to the supraclavicular lymph nodes is associated with an increased risk of hypothyroidism., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Anthracycline-based chemotherapy has been mainstay of adjuvant breast cancer therapy for decades. Although effective, anthracyclines place long-term breast cancer survivors at risk of late effects, such as reduced cardiorespiratory fitness and increased risk of cardiovascular disease. Previous research has shown beneficial effects of exercise training on cardiorespiratory fitness, but the effects of exercise on limiting factors for cardiorespiratory fitness, cardiovascular risk factors, and patient-reported outcomes in long-term survivors are less clear. Whether previous exposure to breast cancer therapy modulates the effects of exercise is also unknown., Objective: The primary aim of the CAUSE (Cardiovascular Survivors Exercise) trial is to examine the effect of aerobic exercise on cardiorespiratory fitness in anthracycline-treated long-term breast cancer survivors. Secondary aims are to examine effects of exercise training on limiting factors for cardiorespiratory fitness, cardiovascular risk factors, and patient-reported outcomes, and to compare baseline values and effects of exercise training between similar-aged women with and those without prior breast cancer. A third aim is to examine the 24-month postintervention effects of aerobic exercise on primary and secondary outcomes., Methods: The CAUSE trial is a 2-armed randomized controlled trial, where 140 long-term breast cancer survivors, 8-12 years post diagnosis, are assigned to a 5-month nonlinear aerobic exercise program with 3 weekly sessions or to standard care. Seventy similar-aged women with no history of cancer will undergo the same exercise program. Cardiorespiratory fitness measured as peak oxygen consumption (VO 2peak ), limiting factors for VO 2peak (eg, cardiac function, pulmonary function, hemoglobin mass, blood volume, and skeletal muscle characteristics), cardiovascular risk factors (eg, hypertension, diabetes, dyslipidemia, obesity, physical activity level, and smoking status), and patient-reported outcomes (eg, body image, fatigue, mental health, and health-related quality of life) will be assessed at baseline, post intervention, and 24 months post intervention., Results: A total of 209 patients were included from October 2020 to August 2022, and postintervention assessments were completed in January 2023. The 24-month follow-up will be completed in February 2025., Conclusions: The findings from the CAUSE trial will provide novel scientific understanding of the potential benefits of exercise training in long-term breast cancer survivors., Trial Registration: ClinicalTrials.gov NCT04307407; https://clinicaltrials.gov/ct2/show/NCT04307407., International Registered Report Identifier (irrid): DERR1-10.2196/45244., (©Tormod Skogstad Nilsen, Mali Sæter, Sebastian Imre Sarvari, Kristin Valborg Reinertsen, Sara Hassing Johansen, Elisabeth Rustad Edvardsen, Jostein Hallén, Elisabeth Edvardsen, May Grydeland, Cecilie Essholt Kiserud, Hanne Cathrine Lie, Paul André Solberg, Torbjørn Wisløff, Adam Philip Sharples, Truls Raastad, Kristina Hermann Haugaa, Lene Thorsen. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 15.03.2023.)

Background: Poor health literacy may hamper health management and long-term outcomes in breast cancer survivorship. Knowledge of factors associated with poor health literacy is needed to identify survivors in need of additional support and to improve the quality of health care, but is currently scant. Here, we explore health literacy and associated factors in a nationwide sample of long-term survivors of breast cancer., Material and Methods: All survivors aged 20-65 years when diagnosed with stage I-III breast cancer in 2011 or 2012 were identified through the Norwegian Cancer Registry, and invited to participate in the Survivorship, Work and Sexual Health (SWEET) study. Health literacy was measured using The European Health Literacy Survey Questionnaire-12 (HLS-EU-Q12) and analyzed as a continuous and categorical variable. Associations between health literacy and socioeconomic, physical, and mental health variables, including the most common late effects after cancer treatment, were explored in uni- and multivariable linear regression models., Results: The final sample consisted of 1355 survivors (48%) with a mean age of 60 years at survey (SD 8.7). Eight years had passed since diagnosis (SD.0.7), and the majority of survivors had high socioeconomic status. Advanced judgment calls concerning treatment and health risks were reported to be the most difficult for survivors to handle. Mean health literacy sum score was 36.2 (range 12-48, SD 5.4). Thirty-nine percent had intermediate, while 19.3% reported marginal or inadequate health literacy. Education, income, age at diagnosis, the personality trait neuroticism, and fear of cancer recurrence were significantly associated with health literacy in the multivariate model, explaining 12% of the variance in health literacy scores., Conclusion: Low levels of health literacy were prevalent in this population-based sample of long-term survivors of breast cancer, despite high socioeconomic status. Communicating and interpreting risks seem to be especially challenging. Attention to health literacy at a societal and individual level is necessary in order to provide survivorship care of high quality., (© 2022. The Author(s).)

Neuroticism is a basic personality trait concerning negative feelings under stressful conditions. Our purpose was to examine the rate of high neuroticism and factors associated with high neuroticism in long-term (≥ 5 years) survivors of childhood, adolescent, and young adult cancer (CAYACSs). Norwegian CAYACSs aged 0-39 years when diagnosed and treated between 1985 and 2009 for cancer in childhood/adolescence (0-18 years), or as young adults (19-39 years) and alive in 2015 were mailed a questionnaire. Data from 1629 CAYACSs (481 children/adolescents and 1148 young adults) were analyzed. High neuroticism was found in 44% of survivors of childhood/adolescent cancers versus 34% in survivors of young adult cancer (p < 0.001). The rate of high neuroticism in female CAYACSs was 40% and in males 30% (p < 0.001). The corresponding difference between male survivor group was non-significant. In multivariable analysis, young age at survey, more adverse effects, poor self-rated health, female sex, chronic fatigue, and increased depression remained significantly associated with high neuroticism. Cancer treatment, comorbidity, and lifestyle were significant in bivariate analyses. Cancer at earlier age could increase the risk of high neuroticism among adult survivors. Screening for neuroticism could identify CAYACSs at risk for experiencing multiple health concerns and needing special follow-up attention., (© 2022. The Author(s).)

Introduction: As the 5-year survival rate after breast cancer in Norway is 92%, the population of breast cancer survivors (BCSs) is increasing. Knowledge of work ability in this population is scarce. In a population-based cohort of BCSs, we explored work ability 8 years after diagnosis and the association between work ability and social support, and cancer-related variables including late effects and lifestyle factors., Methods: In 2019, all Norwegian women < 59 years when diagnosed with stage I-III breast cancer in 2011 or 2012, were identified by the Cancer Registry of Norway and invited to participate in a survey on work life experiences. Work ability was assessed using the Work Ability Index (scale 0-10). Factors associated with excellent work ability (score ≥ 9) were identified using univariate and multivariate logistic regression analyses, and adjusted for socioeconomic-, health- and cancer-related variables., Results: Of the 1951 eligible BCSs, 1007 (52.8%) responded. After excluding survivors with relapse (n = 1), missing information on work ability score (n = 49), or work status (n = 31), the final sample comprised 926 BCSs within working age at survey (< 67 years). Mean age at survey was 56 years and 8 years (SD 0.7) had passed since diagnosis. Work ability had been reduced from 8.9 (SD 2.3) at diagnosis to 6.3 (SD 3.1). One in three BCSs reported poor work ability (WAS ≤ 5), and seven out of ten reported that their physical work ability had been reduced due to cancer. Social support from colleagues during cancer therapy was associated with excellent work ability, which was not observed for social support provided by supervisors or the general practitioner. Cognitive impairment and fatigue were inversely associated with work ability. None of the cancer-related variables, including treatment, were associated with work ability 8 years after diagnosis., Conclusion: In this population-based sample, one in three BCSs reported poor work ability 8 years after diagnosis. Collegial social support during cancer therapy appears to be a protective factor for sustained work ability, whilst survivors struggling with fatigue and cognitive impairments may represent a particularly vulnerable group for reduced work ability., (© 2022. The Author(s).)

Purpose: Sexual health is a key quality of life issue. Knowledge concerning sexual health in long-term breast cancer survivors (BCSs) is limited. Within a nationwide sample, we aimed to assess the prevalence of sexual inactivity and to explore factors associated with sexual inactivity and reduced sexual functioning among long-term BCSs., Methods: Long-term BCSs aged 20-65 years when diagnosed with early-stage breast cancer in 2011-2012 were identified by the Cancer Registry of Norway in 2019 (n = 2803) and invited to participate in a nationwide survey. Sexual health was measured using the multidimensional Sexual Activity Questionnaire. Factors associated with sexual inactivity and reduced sexual functioning were explored using multivariable logistic- and linear regression analyses with adjustments for relevant sociodemographic, health-, and cancer-related variables., Results: The final sample consisted of 1307 BCSs with a mean age of 52 years at diagnosis. Fifty-two percent of the BCSs were sexually inactive. Lack of interest was the most common reason for sexual inactivity. Treatment with aromatase inhibitor (OR 1.73, 95% CI 1.23, 2.43) and poor body image (OR 0.99, 95% CI 0.99, 0.995) were associated with sexual inactivity. Among sexually active BCSs, depression (B - 1.04, 95% CI - 2.10, - 0.02) and physical inactivity (B - 0.61, 95% CI - 1.21, - 0.02) were inversely related to sexual pleasure. Treatment with aromatase inhibitor (B 0.61, 95% CI 0.20, 1.01), sleep problems (B 0.37, 95% CI 0.04, 0.70), breast symptoms (B 0.01, 95% CI 0.003, 0.02), and chronic fatigue (B 0.43, 95% CI 0.05, 0.81) were associated with sexual discomfort. Chemotherapy (OR 1.91, 95% CI 1.23, 2.97), current endocrine treatment (OR 1.98, 95% CI 1.21, 3.25), and poor body image (OR 0.98, 95% CI 0.98, 0.99) were associated with less sexual activity at present compared to before breast cancer., Conclusion: Treatment with aromatase inhibitor seems to affect sexual health even beyond discontinuation. Several common late effects were associated with sexual inactivity and reduced sexual functioning. To identify BCSs at risk of sexual dysfunction, special attention should be paid to patients treated with aromatase inhibitor or suffering from these late effects., (© 2022. The Author(s).)

Background: A major depressive episode (MDE) is typically self-rated by screening forms identifying probable MDE (pMDE). This population-based cross-sectional questionnaire study examined the prevalence rates of pMDE identified by the PHQ-9 screener in long-term survivors of childhood and adolescence (CACSs) and young adult cancer (YACSs) and a normative sample (NORMs)., Methods: Data from 488 CACSs, 1202 YACSs, and 1453 NORMs were analyzed, and pMDE was defined both by cut-off ≥10 on the total PHQ-9 score and by an algorithm., Results: The prevalence rates of pMDE among CACSs were 21.5%, 16.6% in YACSs, and 9.2% among NORMs using the cut-off definition. With the algorithm, the prevalence rates of pMDE were 8.0% among CACSs, 8.1% among YACSs, and 3.9% among NORMs. Independent of definition, CACSs and YACSs had significantly increased prevalence rates of pMDE compared to NORMs. Psychosocial factors and self-rated health were significantly associated with both definitions of pMDE in multivariable analyses, while survivor groups, cancer types, and adverse events were not., Conclusion: Since pMDE has negative health consequences and is amenable to treatment, healthcare providers should be attentive and screen for pMDE in young cancer survivors. For PHQ-9, the preferred type of definition of pMDE should be determined.

Purpose: Fear of cancer recurrence (FCR) may be debilitating, yet knowledge of FCR among the growing population of long-term young adult cancer survivors (YACS) is scarce. We explored risk of FCR and associated factors in a nation-wide, population-based cohort of YACS., Methods: All 5-year survivors diagnosed at the ages of 19-39 years with breast cancer (BC), malignant melanoma (MM), colorectal cancer (CRC), leukemia (LEU), or non-Hodgkin lymphoma (NHL) between 1985 and 2009 in Norway were identified by the Cancer Registry of Norway and completed the cross-sectional comprehensive NOR-CAYACS health survey. Univariate and multivariate linear regression modeling was performed., Results: In total, 936 survivors were included, with an average of 16 years since diagnoses. BC was the most prevalent cancer form (38.4%), followed by MM (24.7%), NHL (15.6%), CRC (11.8%), and LEU (9.6%). Survivors worried most about getting another cancer (74%), and (20%) reported quite a bit or a lot of FCR. BC and MM survivors had the highest FCR scores. Post-traumatic stress symptoms (PTSS) had the strongest association with FCR (Std B 0.21, p < 0.01), above demographic and clinical variables., Conclusions: FCR is prevalent even among long-term YACS, including survivors of MM with favorable prognoses., Implications for Cancer Survivors: Attention to ongoing risks of PTSS and FCR in this growing survivor population is warranted to optimize future survivorship care., (© 2020. The Author(s).)

Background: In breast cancer, immunohistochemistry (IHC) subtypes, together with grade and stage, are well-known independent predictors of breast cancer death. Given the immense changes in breast cancer treatment and survival over time, we used recent population-based data to test the combined influence of IHC subtypes, grade and stage on breast cancer death., Methods: We identified 24,137 women with invasive breast cancer aged 20 to 74 between 2005 and 2015 in the database of the Cancer Registry of Norway. Kaplan-Meier curves, mortality rates and adjusted hazard ratios for breast cancer death were estimated by IHC subtypes, grade, tumour size and nodal status during 13 years of follow-up., Results: Within all IHC subtypes, grade, tumour size and nodal status were independent predictors of breast cancer death. When combining all prognostic factors, the risk of death was 20- to 40-fold higher in the worst groups compared to the group with the smallest size, low grade and ER+PR+HER2- status. Among node-negative ER+HER2- tumours, larger size conferred a significantly increased breast cancer mortality. ER+PR-HER2- tumours of high grade and advanced stage showed particularly high breast cancer mortality similar to TNBC. When examining early versus late mortality, grade, size and nodal status explained most of the late (> 5 years) mortality among ER+ subtypes., Conclusions: There is a wide range of risks of dying from breast cancer, also across small breast tumours of low/intermediate grade, and among node-negative tumours. Thus, even with modern breast cancer treatment, stage, grade and molecular subtype (reflected by IHC subtypes) matter for prognosis.

Purpose: To investigate lifestyle in a population-based sample of long-term (≥ 5 years since diagnosis) young adult cancer survivors (YACSs), and explore factors associated with not meeting the lifestyle guidelines for physical activity (PA), body mass index (BMI), and smoking., Methods: YACSs (n = 3558) diagnosed with breast cancer (BC), colorectal cancer (CRC), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), or localized malignant melanoma (MM) between the ages of 19 and 39 years and treated between 1985 and 2009 were invited to complete a mailed questionnaire. Survivors of localized MM treated with limited skin surgery served as a reference group for treatment burden., Results: In total, 1488 YACSs responded (42%), and 1056 YACSs were evaluable and included in the present study (74% females, average age at survey 49 years, average 15 years since diagnosis). Forty-four percent did not meet PA guidelines, 50% reported BMI ≥ 25 and 20% smoked, with no statistically significant differences across diagnostic groups. Male gender, education ≤ 13 years, comorbidity, lymphedema, pain, chronic fatigue, and depressive symptoms were associated with not meeting single and/or an increasing number of lifestyle guidelines., Conclusion: A large proportion of long-term YACSs do not meet the lifestyle guidelines for PA, BMI, and/or smoking. Non-adherence to guidelines is associated with several late effects and/or comorbidities that should be considered when designing lifestyle interventions for YACSs.

Background: Breast cancer survivors (BCS) may have increased risk of hypothyroidism, but risk according to treatment modality is unclear. We estimated the incidence of hypothyroidism in women with breast cancer, and according to cancer treatment., Methods: Using nationwide registries, we identified all Danish women aged ≥ 35 years diagnosed with non-metastatic breast cancer (1996-2009). We matched up to five cancer-free women (controls) for each BCS. We excluded women with prevalent thyroid disease. Cancer treatment was chemotherapy with or without radiotherapy (RT) targeting the breast/chest wall only, or also the lymph nodes (RTn). We identified hypothyroidism using diagnostic codes, and/or levothyroxine prescriptions. We calculated the cumulative incidence, incidence rates (IR) per 1000 person-years, and used Cox regression to estimate hazard ratios (HR) and associated 95% confidence intervals (CIs) of hypothyroidism, adjusting for comorbidities., Results: We included 44,574 BCS and 203,306 matched controls with 2,631,488 person-years of follow-up. BCS had a slightly higher incidence of hypothyroidism than controls [5-year cumulative incidence, 1.8% (95%CI = 1.7-1.9) and 1.6% (95%CI = 1.5-1.6), respectively]. The overall IR was 4.45 (95%CI = 4.25-4.67) and 3.81 (95%CI = 3.73-3.90), corresponding to an adjusted HR = 1.17 (95%CI = 1.11-1.24). BCS who received RTn with chemotherapy (HR = 1.74, 95%CI = 1.50-2.02) or without chemotherapy (HR = 1.31, 95%CI = 1.14-1.51) had an elevated risk of hypothyroidism compared with matched controls and compared with BCS who underwent surgery alone [HR = 1.71, 95%CI = 1.45-2.01 and HR = 1.36, 95%CI = 1.17-1.58, respectively]., Conclusions: BCS have an excess risk of hypothyroidism compared with age-matched controls. BCS and those working in cancer survivorship settings ought to be aware that this risk is highest in women treated with radiation therapy to the lymph nodes and chemotherapy.

Purpose: In young adult cancer survivors (YACSs) to explore the rate of being nonemployed and having low work ability, and to identify factors associated with these two outcomes. Methods: All Norwegian YACSs ( N  = 3558) diagnosed at ages 19-39 years and treated between 1985 and 2009 for breast or colorectal cancer, leukemia, non-Hodgkin lymphoma, or melanoma, and alive in 2015, were mailed a questionnaire. The response rate was 42%. For treatment, a minimal surgery-only group ( N  = 198) was defined as reference group, and 1000 YACSs represented the local, systemic, and systemic plus other treatment groups. Work status was compared with normative data. Results: The sample included 63% females. Median age at survey was 49 years (range 27-65), and median time since first cancer diagnosis was 16 years (range 6-31). At survey, 25% (95% confidence interval [CI]: 22-27) of YACSs were nonemployed, and 38% (95% CI: 35-41) reported low work ability. The rate of being nonemployed was similar to normative data. More female YACSs held disability pension compared with normative data. In multivariable analyses, an increasing number of adverse effects (AEs), cardiovascular diseases, lower basic education, reduced level of self-rated health, and increased level of depression were significantly associated with both being nonemployed and having low work ability. Conclusions: In YACSs surveyed at median 49 years of age, 25% were nonemployed and 38% had low current work ability. An increased mean number of long-term AEs and several other health-related factors were significantly associated with both these outcomes. Health care providers responsible for YACSs should be attentive to such factors and work ability.

Background: Chronic fatigue (CF) is scarcely explored among young adult cancer survivors (YACSs), and more knowledge is needed to develop targeted interventions for YACSs with CF. The present study aimed to investigate the prevalence of CF and associated factors in YACSs. Also, the change of fatigue with time was explored. Material and methods: The present cross-sectional study is part of a nation-wide population based survey of Norwegian survivors of cancer in childhood, adolescence, and young adulthood (The NOR-CAYACS study).YACSs diagnosed at the age of 19-39 years with breast cancer stage ≤ III (BC), colorectal cancer (CRC), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia, or non-metastatic malignant melanoma (MM) were included 5-30 years after diagnosis. Survivors of MM treated with limited surgery were included as a reference group. CF was assessed by the Fatigue Questionnaire. Logistic regression analyses were performed to identify factors associated with CF. Results: In total, 1488 survivors completed the questionnaire (a response rate of 42%), of which 1088 were eligible for the present study. Overall, 25% reported CF. CF was significantly more prevalent among survivors of BC (29%) ( p < .001), CRC (29%) ( p = .001) and NHL (27%) ( p = .003) than among survivors of MM (15%). CF was associated with systemic treatment combined with surgery and/or radiotherapy ( p = .018), comorbidity ( p = .038), pain ( p = .002), numbness in hands/feet ( p = .046), and depressive symptoms ( p < .001) in the multivariable model. Among survivors with CF, 60% reported that they had been tired since cancer treatment, and among these, 65% reported worsening or no change of fatigue with time. Conclusion: One of four YACSs reported CF 15 years from diagnosis (mean). CF was associated with several possibly treatable factors. Health professionals involved in the follow-up of YACSs should have knowledge of CF and approaches to manage it.

Background: Hypothyroidism may occur as a late effect of breast cancer-directed treatment, particularly after radiotherapy, but little is known whether hypothyroidism affects the prognosis after breast cancer. We investigated the association between hypothyroidism and breast cancer recurrence, and all-cause mortality., Methods: In this population-based cohort study, we used national medical registries to identify all Danish women 35 years or older diagnosed with stage I-III, operable breast cancer between 1996 and 2009. Hypothyroidism was defined as hospital diagnoses ascertained via diagnostic codes, or as prescriptions for levothyroxine. Two analytic models were used: (i) hypothyroidism present at the time of the breast cancer diagnosis (prevalent) and (ii) hypothyroidism diagnosed during follow-up as a time-varying exposure lagged by 1 year (incident). Breast cancer recurrence was defined as any local, regional, or distant recurrence or contralateral breast cancer. All-cause mortality included death from any cause in any setting. We used Cox regression models accounting for competing risks to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer recurrence and all-cause mortality., Results: The study cohort included 35,463 women with breast cancer with 212,641 person-years of follow-up. At diagnosis, 1272 women had hypothyroidism and 859 women developed hypothyroidism during follow-up. In total, 5810 patients developed recurrent breast cancer. Neither prevalent nor incident hypothyroidism was associated with breast cancer recurrence (adjusted HR prevalent 1.01, 95% CI 0.87-1.19; adjusted HR incident 0.93, 95% CI 0.75-1.16, respectively). Furthermore, no differences were seen for all-cause mortality for prevalent or incident hypothyroidism (adjusted HR prevalent 1.02, 95% CI 0.92-1.14, and HR incident 1.08, 95% CI 0.95-1.23, respectively). Stratification by menopausal status, oestrogen receptor status, chemotherapy, or radiotherapy did not alter the estimates., Conclusions: Hypothyroidism present at diagnosis or during follow-up was not associated with breast cancer recurrence or all-cause mortality in women with breast cancer. Our findings provide reassurance to patients and their physicians that hypothyroidism is unlikely to impact on the clinical course of breast cancer or survival.

Pronounced fatigue including tiredness and lack of energy are common both during and after cancer treatment. Between 15–35 % of adult cancer survivors experience chronic fatigue. Chronic fatigue has a negative impact on affected individuals’ social, occupational and general functioning, and may lead to a considerably reduced quality of life.

Context: Chronic fatigue (CF) in breast cancer (BC) survivors is multifactorial and may be caused by immune activation triggered by BC or its treatment. In the Neoadjuvant Avastin in Breast Cancer study, BC patients received neoadjuvant chemotherapy (FEC100→taxane) ± bevacizumab, a monoclonal antibody with fatigue as a potential side effect., Objectives: To examine fatigue levels and prevalence of CF before and during chemotherapy and at follow-up, and their associations with C-reactive protein (CRP) and clinical variables., Methods: Eighty-four HER2-negative patients with cT2-4N0-3M0 BC responded to questionnaires and had CRP measured before treatment (T0), after FEC100 (T1), after taxanes before surgery (T2), and at two-year follow-up (T3)., Results: The prevalence of CF increased from 8% at T0 to 36% at T3, P < 0.0001. Fatigue levels peaked during chemotherapy from 12.0 at T0 to 20.0 at T2, and declined to 16.7 at T3, P < 0.001. Women with CF at T3 had higher fatigue levels at T0, T2, and T3 than those without CF (P ≤ 0.01). Psychological distress (P = 0.03) and pain (P = 0.04) at T3 were associated with CF at T3. Only psychological distress remained a significant predictor in multivariate analysis. CRP increased from T0 to T1 (P < 0.01) and declined to baseline values at T3, but changes were not associated with bevacizumab treatment. No association was found between bevacizumab or CRP, and fatigue levels or CF., Conclusion: Neither bevacizumab treatment nor low-grade systemic inflammation as measured by CRP was associated with the increased fatigue levels and raised prevalence of CF, observed during and after BC therapy. Increased fatigue levels at baseline and psychological distress at T3 were associated with CF at T3., (Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background/purpose: We explored the relation between coronary artery calcium (CAC) and cardiac radiation doses in breast cancer survivors (BCS) treated with radiotherapy (RT). Additionally, we examined the impact of other risk factors and biomarkers of coronary artery disease (CAD)., Materials and Methods: 236 BCS (median age 51years [range 30-70], median observation time 12years [9.2-15.7]), treated with 4-field RT of 50GY, were included and examined in 2004 (T1), 2007 (T2) and 2011 (T3) with clinical examination, blood tests and questionnaires. At T3, cardiac computed tomography was performed with quantification of CAC using Agatston score (AS). For 106 patients cardiac dose volume histograms were available., Results: The cohort-based median of the mean cardiac dose was 2.5 (range 0.5-7.0) Gy. There was no correlation between measures of cardiac dose and AS. AS was correlated with high cholesterol at T1/T2 (p=0.022), high proBNP at T1/T2 (p<0.022) and T3 (p<0.022) and high HbA1c at T3 (p=0.022). In addition, a high AS was significantly associated with hypertension (p=0.022). Age (p<0.001) and cholesterol at T1/T2 (p=0.001) retained significant associations in multivariate analysis., Conclusions: Traditional, modifiable risk factors of CAD correlate with CAC and may be important for the long term risk of CAD after RT. With low to moderate cardiac radiation exposure, a contribution of radiation dose to CAC could not be demonstrated., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To explore very-long-term mortality from ischemic heart disease (IHD) after locoregional radiation therapy of breast cancer (BC) in relation to degree of hypofractionation and other treatment variables., Methods and Materials: Two hypofractionated regimens used for locoregional radiation therapy for BC from 1975 to 1991 were considered. Patients received 4.3 Gy × 2/week (10 fractions; target dose 43 Gy; n=1107) or 2.5 Gy × 5/week (20 fractions; target dose 50 Gy; n=459). To estimate cardiac doses, radiation fields were reconstructed in a planning system. Time to death from IHD was the endpoint, comparing the groups with each other and with age-matched, cancer-free control individuals, modeled with the Cox proportional hazards model., Results: Patients given 4.3 Gy × 10 had an increased risk of dying of IHD compared with both the 2.5 Gy group (hazard ratio [HR] = 2.37; 95% confidence interval [CI]: 1.06-5.32; P=.036) and the control group (HR = 1.59; 95% CI: 1.13-2.23; P=.008). Photon beams for parasternal fields gave an increased risk of dying of IHD compared with electron beams (HR = 2.56; 95% CI: 1.12-5.84; P=.025). Multivariate analysis gave an increased risk for the 4.3-Gy versus 2.5-Gy regimen with borderline significance (HR = 2.90; 95% CI: 0.97-8.79; P=.057) but not for parasternal irradiation., Conclusions: The degree of hypofractionation and parasternal photon beams contributed to increased cardiac mortality in this patient cohort. Differences emerged after 12 to 15 years, indicating the need of more studies with observation time of 2 decades., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: The aim of the study was to identify noninvasive markers of treatment-induced side effects. Reactive oxygen species (ROS) are generated after irradiation, and genetic variation in genes related to ROS metabolism might influence the level of radiation-induced adverse effects (AEs)., Methods and Materials: 92 breast cancer (BC) survivors previously treated with hypofractionated radiation therapy were assessed for the AEs subcutaneous atrophy and fibrosis, costal fractures, lung fibrosis, pleural thickening, and telangiectasias (median follow-up time 17.1 years). Single-nucleotide polymorphisms (SNPs) in 203 genes were analyzed for association to AE grade. SNPs associated with subcutaneous fibrosis were validated in an independent BC survivor material (n=283). The influence of the studied genetic variation on messenger ribonucleic acid (mRNA) expression level of 18 genes previously associated with fibrosis was assessed in fibroblast cell lines from BC patients., Results: Subcutaneous fibrosis and atrophy had the highest correlation (r=0.76) of all assessed AEs. The nonsynonymous SNP rs1139793 in TXNRD2 was associated with grade of subcutaneous fibrosis, the reference T-allele being more prevalent in the group experiencing severe levels of fibrosis. This was confirmed in another sample cohort of 283 BC survivors, and rs1139793 was found significantly associated with mRNA expression level of TXNRD2 in blood. Genetic variation in 24 ROS-related genes, including EGFR, CENPE, APEX1, and GSTP1, was associated with mRNA expression of 14 genes previously linked to fibrosis (P≤.005)., Conclusion: Development of subcutaneous fibrosis can be associated with genetic variation in the mitochondrial enzyme TXNRD2, critically involved in removal of ROS, and maintenance of the intracellular redox balance., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Chronic fatigue (CF) in breast cancer survivors (BCSs) has been associated with increased serum C-reactive protein-levels (CRP), pro-inflammatory cytokines and cytokine gene single nucleotide polymorphisms (SNPs). Still, there are few studies on these topics, and due to small study-cohorts the possibility to adjust for other conditions related to inflammatory processes, e.g. depression, has been limited. In 302 BCSs, examined approximately four years after treatment for breast cancer stage II/III, data on high sensitivity (hs)CRP, leukocytes and mRNA interleukin (IL)1β and IL6R expression, depression and chronic fatigue were available. Three years thereafter, 236 BCSs were re-examined. The associations between fatigue and SNPs in inflammation-related genes; IL1β (rs16944), IL6 (rs1800795), IL6receptor (rs4129267, rs4845617, rs2228145), CRP (rs2794521, rs3091244) were investigated, together with the relations between SNPs in IL6R,IL1β and CRP genes and mRNA blood expression levels of IL6R and IL1β and serum hsCRP-levels, respectively. All analyses were repeated after exclusion of depressed individuals and separating BCSs with persistent fatigue from never-fatigued individuals. Even after exclusion of depressed individuals neither the SNPs nor the mRNA IL1β and IL6R expression levels were associated with chronic or persistent fatigue. In the subset of persistent fatigued and never-fatigued individuals the CRP SNP (rs3091244) was associated with hsCRP level (p=0.02). IL1β and IL6R mRNA expression levels were not related to the IL1β and IL6R genotypes. In a large cohort of BCSs the investigated SNPs in inflammation-related genes were not associated with fatigue, though subset analyses indicated an association between the CRP SNP (rs3091244) and serum hsCRP., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: In breast cancer survivors (BCSs) the relation between insomnia symptoms and arm/shoulder problems has hardly been investigated. In cross-sectional and longitudinal designs we examined this association in BCSs and in comparison to age-matched controls from the general population., Methods: Our cross-sectional sample consisted of 337 BCSs stage II/III studied in 2004 at a median of 3.9 years after surgery combined with adjuvant radiotherapy and cytostatics/hormones. In 2007 248 (74%) BCSs were re-examined (median 2.5 years later). The responses of the 2004 sample were compared to those of 1685 controls., Results: Thirty percent of BCSs reported insomnia symptoms in 2004, and arm/shoulder problems were significantly associated with insomnia, as were established variables in bivariate analyses. In 2004 only regular use of hypnotics remained associated with insomnia in multivariate analysis. In bivariate analysis arm/shoulder pain and restricted mobility in 2004 were significant predictors of insomnia in 2007. Only insomnia in 2004 was a significant predictor in multivariate analysis. In bivariate analyses BCSs and controls had several common factors associated with insomnia, but only regular use of hypnotics was common in multivariate analysis., Conclusions: Arm/shoulder problems are factors to consider in BCSs with insomnia, particularly arm/shoulder pain. Factors associated with insomnia in BCSs and general population controls are partially overlapping., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Purpose: To extend knowledge on the mechanisms and pathways involved in maintenance of radiation-induced fibrosis (RIF) by performing gene expression profiling of whole blood from breast cancer (BC) survivors with and without fibrosis 3-7 years after end of radiotherapy treatment., Methods and Materials: Gene expression profiles from blood were obtained for 254 BC survivors derived from a cohort of survivors, treated with adjuvant radiotherapy for breast cancer 3-7 years earlier. Analyses of transcriptional differences in blood gene expression between BC survivors with fibrosis (n=31) and BC survivors without fibrosis (n=223) were performed using R version 2.8.0 and tools from the Bioconductor project. Gene sets extracted through a literature search on fibrosis and breast cancer were subsequently used in gene set enrichment analysis., Results: Substantial differences in blood gene expression between BC survivors with and without fibrosis were observed, and 87 differentially expressed genes were identified through linear analysis. Transforming growth factor-β1 signaling was identified as the most significant gene set, showing a down-regulation of most of the core genes, together with up-regulation of a transcriptional activator of the inhibitor of fibrinolysis, Plasminogen activator inhibitor 1 in the BC survivors with fibrosis., Conclusion: Transforming growth factor-β1 signaling was found down-regulated during the maintenance phase of fibrosis as opposed to the up-regulation reported during the early, initiating phase of fibrosis. Hence, once the fibrotic tissue has developed, the maintenance phase might rather involve a deregulation of fibrinolysis and altered degradation of extracellular matrix components., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: This cross-sectional and longitudinal study of breast cancer survivors (BCSs) examines the associations between arm/shoulder problems (ASPs), which consist of pain, restricted mobility and lymphedema, and different aspects of quality of life (QoL)., Methods: BCSs who had breast surgery, axillary lymph node dissection and radiotherapy (n = 255) were examined in 2004 (mean 4.1 years post-surgery) and a sub-sample (n = 187) was re-examined in 2007. ASPs was rated clinically in 2004 and by self-report (EORTC BR23) in 2004 and 2007. QoL was self-reported with The Short Form-36 (SF-36) and The Impact of Cancer scale (IOC)., Results: In 2004 BCSs with ASPs showed significantly poorer mean scores in most SF-36 domains compared to those without. No group differences were observed for positive IOC domains, while BCSs with ASPs showed significantly poorer mean scores in the negative ones. BCSs with clinically defined movement restriction showed significantly poorer SF-36 and negative IOC mean scores than those with clinically defined lymphedema. The longitudinal sub-study of self-rated pain, restricted mobility and lymphedema showed significant changes over time only for negative IOC domains in the pain group. Self-rated restricted mobility and lymphedema were significantly associated with most SF-36 domains both in 2004 and 2007, while few were associated with pain. Self-rated pain and restricted mobility showed significant associations with negative IOC domains., Implications for Cancer Survivors: Not only lymphedema, but pain and restricted mobility in the arm/shoulder are significantly associated with poor QoL in BCSs at long-term. These problems should be diagnosed and treated in order to improve QoL.

Background: The course of fatigue in long-term breast cancer survivors (BCSs) is unknown. The current study examined chronic fatigue (CF) cross-sectionally and longitudinally in relapse-free women up to 10 years after multimodal treatment for BC stage II/III. The prevalence of persistent fatigue (PF: having CF at two assessments separated by >2 years) and its predictors were also investigated., Methods: Data from questionnaires (including the Fatigue Questionnaire and questions regarding socio-demographics and physical symptoms) were collected twice from 249 BCSs: 2.5-7 years post-BC diagnosis (T1) and 2.5-3 years thereafter (T2). A physical examination including blood sampling was performed at T1., Results: CF was diagnosed in 33% of the women at T1 and in 39% at T2, including 57 (23%) subjects with PF. Current psychological distress, treatment-area related discomfort and high body mass index (BMI) were associated with CF at T1 and predicted PF. Increased leukocyte count also predicted PF. Treatment for mental problems prior to the BC, increased hsCRP-level and respiratory symptoms were associated with CF at T1 but did not predict PF., Conclusions: Women may experience fatigue up to 10 years after multimodal BC treatment, with about one third having CF and about one fourth having PF., Implications for Cancer Survivors: During follow-up, BCSs and their doctors should maximize their efforts to reduce psychological distress, overweight and pain within the BC-treated area, all linked to the development of persistent fatigue.