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Background: The etiology of male breast cancer is poorly understood, partly due to its relative rarity. Although tobacco and alcohol exposures are known carcinogens, their association with male breast cancer risk remains ill-defined.Methods: The Male Breast Cancer Pooling Project consortium provided 2,378 cases and 51,959 controls for analysis from 10 case–control and 10 cohort studies. Individual participant data were harmonized and pooled. Unconditional logistic regression was used to estimate study design–specific (case–control/cohort) ORs and 95% confidence intervals (CI), which were then combined using fixed-effects meta-analysis.Results: Cigarette smoking status, smoking pack-years, duration, intensity, and age at initiation were not associated with male breast cancer risk. Relations with cigar and pipe smoking, tobacco chewing, and snuff use were also null. Recent alcohol consumption and average grams of alcohol consumed per day were also not associated with risk; only one subanalysis of very high recent alcohol consumption (>60 g/day) was tentatively associated with male breast cancer (ORunexposed referent = 1.29; 95% CI, 0.97–1.71; OR>0– = 1.36; 95% CI, 1.04–1.77). Specific alcoholic beverage types were not associated with male breast cancer. Relations were not altered when stratified by age or body mass index.Conclusions: In this analysis of the Male Breast Cancer Pooling Project, we found little evidence that tobacco and alcohol exposures were associated with risk of male breast cancer.Impact: Tobacco and alcohol do not appear to be carcinogenic for male breast cancer. Future studies should aim to assess these exposures in relation to subtypes of male breast cancer. Cancer Epidemiol Biomarkers Prev; 24(3); 520–31. ©2014 AACR.

Supplementary Table 3. Associations between alcohol consumption exposures and male breast cancer risk

Supplementary Table 2. Associations between tobacco exposures and male breast cancer risk additionally adjusted for total exposure (pack-years)

Supplementary Table 1. Characteristics of the Studies Included in the Male Breast Cancer Pooling Project

Purpose:PIK3CA mutations are frequent in breast cancer and activate the PI3K/Akt pathway. Unexpectedly, PIK3CA mutation appears in general to be associated with better outcome. In a cohort of patients where both primary and metastatic lesions were available, the objective was to assess changes in PIK3CA mutations. We wished to discern whether selective pressures occur and the influence of PIK3CA mutation on time to recurrence.Experimental Design: Formalin-fixed paraffin-embedded tumor blocks were obtained from 104 patients with paired samples from primary tumors and corresponding asynchronous metastatic breast tumors. Samples were analyzed for PIK3CA mutations (exons 9 and 20) as well as immunohistochemical evaluation for PTEN, pAKT, Ki67, ER, and HER2.Results:PIK3CA mutation was detected in 45% of the primary tumors. Overall, there was a net gain in mutation in metastatic disease, to 53%; nonetheless, there were instances where metastases were wild type in patients with PIK3CA mutant primary tumors. Laser capture microdissection on a subset of cases revealed microheterogeneity for PIK3CA mutational status in the primary tumor. PIK3CA mutants overall showed a significantly longer time to first recurrence than wild type cases (P = 0.03).Conclusion:PIK3CA mutations occur at high frequency in primary and metastatic breast cancer; these may not necessarily confer increased aggressiveness as mutants had a longer time to recurrence. Because PIK3CA status quite frequently changes between primary and metastatic disease, it emphasizes the necessity of assessing the PIK3CA status in the metastatic lesion for selection of PIK3CA inhibitor therapy. Clin Cancer Res; 17(4); 667–77. ©2010 AACR.

Supplementary Tables S1-S4.

Background: Little is known about work participation in breast cancer survivors (BCSs) beyond two years after diagnosis. This study aims to report work status at diagnosis and at eight years post-diagnosis in a nation-wide sample of BCSs, investigate factors associated with reduced work status, and report on self-perceived reasons for reduced work status or disability pension. Material and Methods: Women diagnosed with stage I-III BC at the age of 20-65 years in 2011 or 2012 were invited to participate (n=2,803), of which 49 % (n=1361) responded. The response rate was 49 % (n=1361). A final sample of 1324 BCSs with complete questionnaire information regarding work status were included in the present study. Logistic regression analyses were applied to identify factors associated with reduced work status. Results At diagnosis, 78% (n=1038) of the BCSs were in paid work, 12% received disability pension and 4 % held early retirement. At survey, 42% of the BCSs were in paid work, 26% held disability pension and 28% were retired. Of the 845 survivors who were in paid work at diagnosis and within working age at survey, 63% maintained their work status, while 37% reduced their work status. Living with children (OR 0.4, p=.007), older age (OR 1.2, p Citation Format: Synne-Kristin Hoffart Bøhn, Kathrine Vandraas, Cecilie E Kiserud, Alv A Dahl, Marianne Ewertz, Hanne Cathrine Lie, Ragnhild Falk, Kristin Valborg Reinertsen. Work status changes and associated factors in a nation-wide sample of 1324 Norwegian long-term breast cancer survivors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-09.

Introduction Comprehensive geriatric assessment (CGA) has been shown to reduce frailty in older patients in general. In older patients with cancer, frailty affects quality of life (QoL), physical function, and survival. However, few studies have examined the effect of CGA as an additional intervention to antineoplastic treatment. This protocol presents a randomized controlled trial, which aims to evaluate the effects of CGA-based interventions in older patients with cancer and Geriatric 8 (G8) identified frailty. Materials and Methods This randomized controlled trial will include patients, age 70+ years, with solid malignancies and G8 frailty (G8 ≤ 14). Patients will be separated into two groups, with different primary endpoints, depending on palliative or curative antineoplastic treatment initiation, and subsequently randomized 1:1 to either CGA with corresponding interventions or standard of care, along with standardized antineoplastic treatment. A geriatrician led CGA with corresponding interventions and clinical follow-up will be conducted within one month of antineoplastic treatment initiation. The interdisciplinary CGA will cover multiple geriatric domains and employ a standard set of validated assessment tools. Primary endpoints will be physical decline measured with the 30-s Chair-Stand-Test at three months (palliative setting) and unplanned hospital admissions at six months (curative setting). Additional outcomes include QoL, treatment toxicity and adherence, occurrence of polypharmacy, potential drug interactions, potential inappropriate medications, and survival. The primary outcomes will be analyzed using a mixed model regression analysis (30-s chair stand test) and linear regression models (unplanned hospitalizations), with an intention to treat approach. Power calculations reveal the need to enroll 134 (palliative) and 188 (curative) patients. Discussion The present study will examine whether CGA, as an additional intervention to antineoplastic treatment, can improve endpoints valued by older patients with cancer. Inclusion began November 2020 and is ongoing, with 37 and 29 patients recruited April 15th, 2021. Registration: NCT04686851

Tumor heterogeneity in breast cancer tumors is widely recognized but evolution of the breast cancer genome is complex and not yet understood. Characterizing the evolutionary landscape of breast tumors can provide biological understanding of tumor progression and metastasis may be important for directing effective treatments. We performed copy number profiling and mutation detection based on whole exome sequencing of primary tumors, lymph node and distant metastasis as well as on plasma circulating tumor DNA from twelve metastatic breast cancer patients. Preliminary data shows diverse patterns of tumor evolution. Although linear evolution with late dissemination of metastatic cells was common, parallel evolution with early dissemination from primary tumor to distant sites was evident in some cases. Comparing tissue biopsies with plasma samples, we could detect variants mirroring primary tumor and/or metastasis, depending on the time span between the progression steps. The genomic discordance between the different stages of tumor evolution in these patients not only emphasizes the importance of molecular profiling of metastatic tissue but also the possibilities of liquid biopsies for real-time tracking of tumor clonal evolution. Citation Format: Stephanie Kavan, Torben A Kruse, Lars Andersen, Martin Larsen, Malene G Hildebrandt, Anne-Marie Bak Jylling, Marianne Ewertz, Marianne Vogsen, Mads Thomassen. Mapping clonal evolution and tumor heterogeneity by whole exome sequencing of tissue and plasma circulating tumor DNA in metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-07-07.

Background:The time during which there is an increased risk of death for cancer survivors was evaluated in a large twin study, which allows for matching on shared components such as age, genes, and socioeconomic factors in childhood.Methods:By use of data from Danish registers, time to death from initial cancer was studied prospectively in twins in two different settings. The twins were diagnosed with at least one cancer in the period 1943 to 2011. Setting I included 5,680 same-sex twin pairs aged 6 and over, while Setting II included 3,218 twin individuals from age 70 and over. The study provides comparisons within twin pairs and across birth cohorts, age at diagnoses, and time at diagnosis.Results:In 2001 to 2011, the 5-year mortality risk for a twin surviving cancer after the age of 70 was twofold that of the co-twin, regardless of sex and zygosity, and it was 1.5-fold if the twin survived the initial 9 months. After 5 to 6 years, the mortality risk corresponded to that of the co-twin. In previous decades, the excess hazard risk was considerably higher for both older and younger cohorts. There were no indications of change in relative survival across old birth cohorts.Conclusions:This large twin study suggested that for a cancer-treatment survivor diagnosed at age 70 or later, the additional mortality risk was largely absent 5 years later, by which time the survival relative to the co-twin was 60%.Impact:Elevated mortality risk after cancer is offset after 5 to 6 years.

BACKGROUND AND PURPOSE: The increase in the risk of heart disease from incidental exposure of the heart during radiotherapy for breast cancer has been estimated previously from retrospective data in Danish and Swedish women. Here we present an analysis of the Danish material updated with new cases and controls, extended follow-up period, and with refined dose estimates using simulator films or CT data MATERIAL AND METHODS: From the database of the Danish Breast Cancer Cooperative Group, we identified 531 women diagnosed with early-stage breast cancer from 1977 to 2005, who developed subsequent ischemic heart disease (cases) and matched them to 1069 controls without heart disease after radiotherapy. Data were available for precise dose estimation for 196 cases and 413 controls receiving tangential photon techniques.RESULTS: The median of the mean heart doses for the women receiving tangential radiotherapy was 2.41 Gy for left- and 0.68 Gy for right-sided radiotherapy. The mean heart dose was higher for cases than controls (0.84 Gy and 0.71 Gy, respectively; p

Purpose To examine the association between statin use and risk of breast cancer recurrence in a national Danish cohort of postmenopausal breast cancer patients receiving aromatase inhibitors (AI) in the adjuvant setting. Patients and methods We enrolled all postmenopausal patients diagnosed with stage I–III estrogen receptor positive breast cancer during the years 2007–2017, assigned adjuvant AI treatment, and registered in both the Danish Breast Cancer Group database and the Danish Cancer Registry. We ascertained incident statin exposure (≥ 1 prescription post-diagnosis) from the Danish National Prescription Registry and modeled statins as a time-varying exposure lagged by 6 months. Follow-up began 7 months after diagnosis and continued to the first event of recurrence, death, emigration, 5 years elapsed, or 25th September 2018. We estimated incidence rates of recurrence at 5 years and used Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CI), comparing statin exposure with non-exposure. Results We enrolled 14,773 eligible patients. During the 5 years of follow-up, there were 32 recurrences in 3163 person-years of follow-up among statin-exposed patients, and 612 recurrences in 45,655 person-years among unexposed patients (incidence rate per 1000 person-years: 10.12 [95% CI 6.92–14.28] and 13.40 [95% CI 12.36–14.51], respectively). In multivariable models, any statin exposure was associated with a reduced rate of 5-year breast cancer recurrence (adjusted HR 0.72 [95% CI 0.50–1.04]). Considering only lipophilic statins as exposure the results were similar (adjusted HR 0.70 [95% CI 0.48–1.02]). Conclusions Statin use was associated with a reduced risk of breast cancer recurrence among postmenopausal patients diagnosed with early stage breast cancer who received adjuvant AI therapy.

Background Although breast cancer screening reduces breast cancer mortality at the population level, subgroups of women may benefit differently. We investigated the impact of health status on the effect of breast cancer screening. Methods The study included 181 299 women invited in two population‐based screening programs in Denmark and 1 526 446 control subjects, followed from April 1981 to December 2014. Poisson regressions were used to compare the observed breast cancer mortality rate in women invited to screening with the expected rate in the absence of screening among women with and without chronic diseases. Chronic diseases were defined as any diagnosis in the Charlson Comorbidity Index during 4 years before the first invitation to screening. Results Almost 10% of women had chronic diseases before first invitation to screening. Whereas we observed a reduction in breast cancer mortality following invitation to screening of 28% (95% CI, 20% to 35%) among women without chronic diseases, only a 7% (95% CI, −39% to 37%) reduction was seen for women with chronic diseases (P‐value for interaction = .22). For participants, the reduction, corrected for selection bias, was 35% (95% CI 16% to 49%) for women without, and 4% (95% CI −146% to 62%) for women with chronic diseases (P‐value for interaction = .43). Conclusion Our data indicate a marginal effect of mammography screening on breast cancer mortality in women with chronic diseases. If our results are confirmed in other populations, the presence of chronic diseases will be an important factor to take into consideration in personalized screening., Although breast cancer screening reduces breast cancer mortality at the population level, subgroups of women may benefit differently. The paper estimated the effect of screening on breast cancer mortality for women divided by the presence or absence of chronic diseases at the time of invitation to screening. Our results indicate that breast cancer screening might have only a marginal impact on breast cancer mortality in women with chronic diseases.

work ability (WA) is scarce. We aimed to identify factors, including social support, associated with excellent WA in a nation-wide population of long-term BCS. MethodsAll long-term BCSs (20-65 years) diagnosed with early-stage BC in 2011 or 2012 were identified by the Norwegian Cancer Registry in 2019 and invited to participate in a survey (n=2803). WA was assessed using the Work Ability Index. Factors associated with excellent WA were identified using univariate and multivariate logistic regression analyses, adjusted for sociodemographic-, health- and cancer related variables. ResultsThe final sample consisted of 926 BCSs with a mean age of 56 years at survey. WA was reduced from 8.9 (SD 2.3) at diagnosis to 6.3 (SD 3.1) eight years later. One in three BCSs reported poor WA, and seven out of ten reported that their physical WA was reduced due to cancer. Survivors with excellent WA reported high social support from supervisors and colleagues compared to BCSs with low WA. Additionally, cognitive impairment and fatigue were negatively associated with WA. ConclusionWA remains a significant challenge in long-term BC survivorship, with a substantial proportion of BCSs reporting poor WA eight years after diagnosis. Collegial support appears to be a protective factor for sustained WA, whilst survivors struggling with fatigue and cognitive impairments may represent a particularly vulnerable group for discontinued employment. Increased attention to WA in follow-up care is warranted.

Background: In clinical oncology, systemic 5-fluorouracil (5-FU) and its oral pro-drugs are used to treat a broad group of solid tumours. Patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency are at elevated risk of toxicity if treated with standard doses of 5-FU. DPYD genotyping and measurements of plasma uracil concentration (DPD phenotyping) can be applied as tests for DPD deficiency. In April 2020, the European Medicines Agency recommended pre-treatment DPD testing to reduce the risk of 5-FU-related toxicity. Objectives: The objective of this study is to present the current evidence for DPD testing in routine oncological practice. Methods: Two systematic literature searches were performed following the PRISMA guidelines. We identified studies examining the possible benefit of DPYD genotyping or DPD phenotyping on the toxicity risk. Findings: Nine and 12 studies met the criteria for using DPYD genotyping and DPD phenotyping, respectively. Conclusions: The evidence supporting either DPYD genotyping or DPD phenotyping as pre-treatment tests to reduce 5-FU toxicity is poor. Further evidence is still needed to fully understand and guide clinicians to dose by DPD activity.

About half of all Danish cancer patients are 70 years or older at diagnosis. The incidence is expected to increase further over the coming years because of an increasing longevity. Therefore, this review recommends that the Danish health care system develops and implement models to ensure optimal care for older adults with cancer. We are still in need of knowledge about the optimal treatment, rehabilitation, palliation and care for older adults with cancer. We encourage the Danish health authorities to formulate a national strategy for this area.

Background: Global longitudinal strain (GLS) is recommended to detect subclinical changes preceding reduced left ventricular ejection fraction (LVEF) in trastuzumab related cardiotoxicity. Since the possibility to detect signs of acute myocardial deterioration at treatment initiation is not clarified, the objective of this study was to assess changes in GLS and biomarkers within the first 2 weeks of trastuzumab treatment. Methods: In a prospective cohort study, 45 patients with non-metastatic breast cancer (age 54, LVEF 62.8%, GLS -19.9%, 40% hypertension) scheduled for trastuzumab treatment were included. Echocardiography and measurement of troponin and NT-proBrain-Natriuretic-Peptide were conducted before initiation of trastuzumab, at days 3, 7, and 14 and after 3, 6, and 9 months. Results: A significant deterioration in LVEF from 62.8% (SD±3.6) to 58.4% (SD±4.1) (p

Background Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p Interpretation Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes.

This abstract was withdrawn by the authors. Citation Format: Cronin-Fenton DP, Falstie-Jensen AM, Kjaersgaard A, Dupont Jensen J, Lorenzen EL, Reinertsen KV, Dekkers OM, Ewertz M. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD6-11.

Introduction Older patients with cancer constitute a heterogeneous group with varying degrees of frailty; therefore, geriatric assessment with initial geriatric oncology screening is recommended. The Geriatric 8 (G8) and the modified Geriatric 8 (mG8) are promising screening tools with high accuracy and an association with survival. However, evidence is sparse regarding patient-centered outcomes. This protocol describes a study, which aims to address the predictive and prognostic value of the G8 and mG8, with quality of life (QoL) as the primary outcome. Materials and methods In this single-center prospective cohort study, patients, age ≥70 years with solid malignancies, will be screened with the G8 and mG8 prior to receiving 1st line antineoplastic treatment. Patients will contribute medical record data including; cancer type, Charlson comorbidity index score, performance status, and treatment intent, type, and dosage, at baseline. Patients will complete QoL questionnaires (EORTC QLQ-C30 and ELD-14) at baseline, 3, 6, 9, and 12-months follow-up. Two functional measurements (the 30-s chair stand test and the handgrip strength test) will be conducted at baseline to assess the added predictive and prognostic value. At 12 months follow-up, initially administered treatment and treatment adherence will be recorded and assessed with generalized linear models, while overall survival and cancer-specific survival will be assessed using survival analysis models with time-varying covariates. The relationship between frailty (G8 ≤ 14, mG8 ≥ 6) and QoL within 12 months will be examined using mixed regression models. Discussion Geriatric oncology screening may identify a subgroup of older patients with frailty, at risk of experiencing diminishing QoL and poor treatment adherence. With the proposed screening program, patients who require treatment modification and additional support to maintain their QoL may be identified. It is our hope, that these insights may facilitate the formation of national guidelines for the treatment of older patients with cancer. Registration: NCT04644874

Adjuvant treatment of early-stage breast cancer has been associated with bone loss in randomised trials, but evidence from unselected populations is needed. In a single-center study, we assessed the annual percentage change in bone mineral density (∆BMDt) and risk of osteoporosis from two to five years after adjuvant chemotherapy in patients with oestrogen-receptor-positive and oestrogen-receptor-negative tumours.Dual energy X-ray absorptiometry (DXA) was performed in 241 recurrence-free Danish breast cancer patients, among whom 157 had a prior DXA scan within two years of chemotherapy ("early"). Linear regression was used to assess ∆BMDt in spine and hip according to age, different health-related variables and time since early DXA.Based on 157 patients, we observed annual decreases in spine BMD of 1.73% (95% confidence interval (CI): -2.01--1.44, p less than 0.001) and hip BMD of 1.30% (95% CI: -1.51--1.09, p less than 0.001). Patients aged less than 50 years at diagnosis had a significant decrease in mean spine BMD of 2.23% (95% CI: -2.78--1.68), whereas the decline was more limited in patients aged 50-59 years and patients aged 60 years or older with a mean spine BMD of 1.70% (95% CI: -2.07--1.34) and 0.81% (95% CI: -1.42--0.20), respectively. The results persisted in multivariable analyses. Osteoporosis was diagnosed in 9% of patients, all postmenopausal.Adjuvant anthracycline-taxane-based chemotherapy followed by endocrine therapy caused bone loss, especially in younger compared with older patients with early-stage breast cancer, confirming the results from randomised trials.This work was supported by the Region of Southern Denmark (grant number 13/7078); the University of Southern Denmark (grant number 00-101-000); the Danish Cancer Society (grant number R90-A6210-14-52); the Department of Oncology and Department of Endocrinology, Odense University Hospital; and the Consultant Council Scholarship, Odense University Hospital.The study was approved by the Ethics Committee in Region of Southern Denmark (Project ID S-20140142) and the Danish Data Protection Board (ID 2008-58-0035).

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: To investigate the clinical impact of FDG-PET/CT for staging and treatment planning in high-risk primary breast cancer. Methods: Women with high-risk primary breast cancer were enrolled between September 2017 and August 2019 at Odense University Hospital, Denmark. Conventional mammography with/without MRI was performed before staging by FDG-PET/CT. We studied the accuracy of FDG-PET/CT for the detection of distant metastases, the effect on the change of treatment, and the prevalence of incidental findings. Biopsy and follow-up were used as a reference standard for the accuracy analysis. Results: Of 103 women, 24 (23%) were diagnosed with distant metastases by FDG-PET/CT. Among these, breast surgery was omitted in 18 and could have been spared in six. Another sixteen (16%) patients were upstaged to more advanced loco-regional disease, leading to more extensive radiotherapy. Sensitivity and specificity for diagnosing distant metastases were 1.00 (95% confidence interval: 0.86–1.00) and 0.95 (0.88–0.99), respectively. Twenty-nine incidental findings were detected in 24 women (23%), leading to further examinations in 22 and diagnosis of eight (8/22, 36%) synchronous diseases: cancer (n = 4), thyroiditis (n = 2), aorta aneurysm (n = 1), and meningioma (n = 1). Conclusions: FDG-PET/CT had a substantial impact on staging and change of treatment in women with high-risk primary breast cancer, and further examination of incidental findings was considered clinically relevant. Our findings suggest that FDG-PET/CT should be considered for primary staging in high-risk primary breast cancer to improve treatment planning.

Funding Acknowledgements The Danish Heart Foundation, Copenhagen (grant number: 14-R97-A5188-22839 and 15-R99-A5940). The Research Fond of the Region of Southern Denmark. Background Global longitudinal strain (GLS) is recommended to detect subclinical changes preceding reduced left ventricular ejection fraction (LVEF) in trastuzumab related cardiotoxicity. The possibility to detect signs of acute myocardial deterioration at treatment initiation is not thoroughly investigated. Accordingly, the aim of this study was to assess changes in GLS and biomarkers within the first two weeks of trastuzumab treatment. Methods In a prospective cohort study 45 patients with non-metastatic breast cancer (age 54, LVEF 62.8% (SD ± 3.6), GLS -19.9% (SD ± 2.1), 40% hypertension) were included. Examinations including echocardiography and measurement of troponin T and NT-proBrain Natriuretic Peptide were conducted before initiation of trastuzumab, at day 3, 7 and 14 and after 3, 6 and 9 months. Results A significant deterioration in LVEF, GLS, s’, e’ septal and s’RV occurred during the 9 months study period and was proceed by significant changes in all these parameters within the first 14 days. After 14 days 12 patients (27%) had an increase in GLS ≥10 %, which was associated with significantly lower LVEF at nine month at 55.2% (SD ± 4.1) vs. 59.5% (SD ± 3.5) (p = 0.001) compared to patients with Conclusion In this cohort study deteriorations in key echocardiographic parameters were detected within the first two weeks of trastuzumab treatment, and an early 10 % increase in GLS was associated with a lower LVEF at nine months. Abstract P1533 Figure 1

Purpose: Chemotherapy-induced nausea and vomiting (CINV) remain significant clinical problems, especially in the delayed phase (24–120 h after chemotherapy). Amisulpride is a dopamine D2/D3-receptor antagonist previously shown to be an effective intravenous antiemetic. We conducted a randomised, double-blind study to characterise the dose response of oral amisulpride in delayed phase CINV. Methods: Chemotherapy-naïve patients receiving cisplatin ≥ 70 mg/m2 or an anthracycline-cyclophosphamide regimen for breast cancer received, on day 1, 20 mg amisulpride and 8–16 mg ondansetron intravenously followed, once daily on days 2–4, by 10, 20 or 40 mg oral amisulpride or placebo. A control group receiving standard three-drug prophylaxis was enrolled for assay sensitivity purposes. The primary endpoint was complete response (CR), defined as no emesis or rescue medication use, in the delayed phase. Results: Three hundred eighteen subjects were evaluable per protocol. CR rate (24–120 h) was 20% with placebo and 46% with 10 mg amisulpride (p = 0.006 after multiplicity adjustment); in the three-drug control group, it was 59%. Emesis, nausea and 0–120-h CR rate were significantly improved with 10 mg amisulpride compared to placebo. Higher doses of amisulpride were not more effective than 10 mg. In patients with acute phase CR, delayed phase CR rate was 44% for placebo, 75% for 10 mg amisulpride (p = 0.022) and 70% for the 3-drug control. No significant differences were seen between groups in safety parameters. Conclusions: Amisulpride 10 mg orally is safe and superior to placebo at preventing delayed CINV caused by highly emetogenic chemotherapy. Trial registration: NCT01857232

Purpose Incidental cardiac irradiation can cause cardiac injury, but little is known about the effect of radiation on specific cardiac segments. Methods For 456 women who received breast cancer radiotherapy between 1958 and 2001 and then later experienced a major coronary event, information was obtained on the radiotherapy regimen they received and on the location of their cardiac injury. For 414 women, all with documented location of left ventricular (LV) injury, doses to five LV segments were estimated. For 133 women, all with documented location of coronary artery disease with ≥ 70% stenosis, doses to six coronary artery segments were estimated. For each segment, numbers of women with left-sided and right-sided breast cancer were compared. Results Of women with LV injury, 243 had left-sided breast cancer and 171 had right-sided breast cancer (ratio of left v right, 1.42; 95% CI, 1.17 to 1.73), reflecting the higher typical LV radiation doses in left-sided cancer (average dose left-sided, 8.3 Gy; average dose right-sided, 0.6 Gy; left minus right dose difference, 7.7 Gy). For individual LV segments, the ratios of women with left- versus right-sided radiotherapy were as follows: inferior, 0.94 (95% CI, 0.70 to 1.25); lateral, 1.42 (95% CI, 1.04 to 1.95); septal, 2.09 (95% CI, 1.37 to 3.19); anterior, 1.85 (95% CI, 1.39 to 2.46); and apex, 4.64 (95% CI, 2.42 to 8.90); corresponding left-minus-right dose differences for these segments were 2.7, 4.9, 7.2, 10.4, and 21.6 Gy, respectively ( Ptrend < .001). For women with coronary artery disease, the ratios of women with left- versus right-radiotherapy for individual coronary artery segments were as follows: right coronary artery proximal, 0.48 (95% CI, 0.26 to 0.91); right coronary artery mid or distal, 1.69 (95% CI, 0.85 to 3.36); circumflex proximal, 1.46 (95% CI, 0.72 to 2.96); circumflex distal, 1.11 (95% CI, 0.45 to 2.73); left anterior descending proximal, 1.89 (95% CI, 1.07 to 3.34); and left anterior descending mid or distal, 2.33 (95% CI, 1.19 to 4.59); corresponding left-minus-right dose differences for these segements were −5.0, −2.5, 1.6, 3.5, 9.5, and 38.8 Gy ( Ptrend = .002). Conclusion For individual LV and coronary artery segments, higher radiation doses were strongly associated with more frequent injury, suggesting that all segments are sensitive to radiation and that doses to all segments should be minimized.

In animal models of breast cancer, resistance to continuous use of letrozole can be reversed by withdrawal and reintroduction of letrozole. We therefore hypothesised that extended intermittent use of adjuvant letrozole would improve breast cancer outcome compared with continuous use of letrozole in postmenopausal women.We did the multicentre, open-label, randomised, parallel, phase 3 SOLE trial in 240 centres (academic, primary, secondary, and tertiary care centres) in 22 countries. We enrolled postmenopausal women of any age with hormone receptor-positive, lymph node-positive, and operable breast cancer for which they had undergone local treatment (surgery with or without radiotherapy) and had completed 4-6 years of adjuvant endocrine therapy. They had to be clinically free of breast cancer at enrolment and without evidence of recurrent disease at any time before randomisation. We randomly assigned women (1:1) to treatment groups of either continuous use of letrozole (2·5 mg/day orally for 5 years) or intermittent use of letrozole (2·5 mg/day orally for 9 months followed by a 3-month break in years 1-4 and then 2·5 mg/day during all 12 months of year 5). Randomisation was done by principal investigators or designee at respective centres through the internet-based system of the International Breast Cancer Study Group, was stratified by type of previous endocrine therapy (aromatase inhibitors only vs selective oestrogen receptor modulators only vs both therapies), and used permuted block sizes of four and institutional balancing. No one was masked to treatment assignment. The primary endpoint was disease-free survival, analysed by the intention-to-treat principle using a stratified log-rank test. All patients in the intention-to-treat population who initiated protocol treatment during their period of trial participation were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00553410, and EudraCT, number 2007-001370-88; and long-term follow-up of patients is ongoing.Between Dec 5, 2007, and Oct 8, 2012, 4884 women were enrolled and randomised after exclusion of patients at a non-adherent centre, found to have inadequate documentation of informed consent, immediately withdrew consent, or randomly assigned to intervention groups in error. 4851 women comprised the intention-to-treat population that compared extended intermittent letrozole use (n=2425) with continuous letrozole use (n=2426). After a median follow-up of 60 months (IQR 53-72), disease-free survival was 85·8% (95% CI 84·2-87·2) in the intermittent letrozole group compared with 87·5% (86·0-88·8) in the continuous letrozole group (hazard ratio 1·08, 95% CI 0·93-1·26; p=0·31). Adverse events were reported as expected and were similar between the two groups. The most common grade 3-5 adverse events were hypertension (584 [24%] of 2417 in the intermittent letrozole group vs 517 [21%] of 2411 in the continuous letrozole group) and arthralgia (136 [6%] vs 151 [6%]). 54 patients (24 [1%] in the intermittent letrozole group and 30 [1%] in the continuous letrozole group) had grade 3-5 CNS cerebrovascular ischaemia, 16 (nine [1%] vs seven [1%]) had grade 3-5 CNS haemorrhage, and 40 (19 [1%] vs 21 [1%]) had grade 3-5 cardiac ischaemia. In total, 23 (1%) of 4851 patients died while on trial treatment (13 [1%] of 2417 patients in the intermittent letrozole group vs ten [1%] of 2411 in the continuous letrozole group).In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them.Novartis and the International Breast Cancer Study Group.

Purpose Administration of anthracycline and taxane therapy in the adjuvant setting is considered a standard for breast cancer. We evaluated a non-anthracycline-based regimen in TOP2A-normal patients. Patients and Methods In this multicenter, open-label, phase III trial, 2,012 women with early TOP2A-normal breast cancer and at least one high-risk factor were randomly assigned to receive six cycles of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks (DC) or three cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) followed by three cycles of docetaxel (100 mg/m2; EC-D). The primary end point was disease-free survival (DFS) after a median of 5 years of follow-up. Secondary end points were patient-reported toxicity, overall survival (OS), and distant disease-free survival. Results At a median estimated potential follow-up of 69 months, 5-year DFS was 87.9% (95% CI, 85.6% to 89.8%) in the EC-D arm and 88.3% (95% CI, 86.1% to 90.1%) in the DC arm. There was no significant difference in the risk of DFS events (hazard ratio [HR], 1.00; 95% CI, 0.78 to 1.28; P = 1.00), distant disease-free survival (HR, 1.12; 95% CI, 0.86 to 1.47; P = .40), or mortality (HR, 1.15; 95% CI, 0.83 to 1.59; P = .41) in the intent-to-treat analysis. A significant interaction between menopausal status and treatment group was observed for DFS ( P = .04) but not for OS ( P = .07). Patients with grade 3 tumors derived most benefit from DC, and patients with grade 1 to 2 tumors derived most benefit from EC-D (DFS: interaction P = .02; and OS: interaction P = .03). Patients receiving EC-D reported significantly more stomatitis, myalgia or arthralgia, vomiting, nausea, fatigue, and peripheral neuropathy, whereas edema was more frequent after DC. Conclusion This study provides evidence to support no overall outcome benefit from adjuvant anthracyclines in patients with early TOP2A-normal breast cancer. Purpose Administration of anthracycline and taxane therapy in the adjuvant setting is considered a standard for breast cancer. We evaluated a non-anthracycline-based regimen in TOP2A-normal patients. Patients and Methods In this multicenter, open-label, phase III trial, 2,012 women with early TOP2A-normal breast cancer and at least one high-risk factor were randomly assigned to receive six cycles of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks (DC) or three cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) followed by three cycles of docetaxel (100 mg/m2; EC-D). The primary end point was disease-free survival (DFS) after a median of 5 years of follow-up. Secondary end points were patient-reported toxicity, overall survival (OS), and distant disease-free survival. Results At a median estimated potential follow-up of 69 months, 5-year DFS was 87.9% (95% CI, 85.6% to 89.8%) in the EC-D arm and 88.3% (95% CI, 86.1% to 90.1%) in the DC arm. There was no significant difference in the risk of DFS events (hazard ratio [HR], 1.00; 95% CI, 0.78 to 1.28; P = 1.00), distant disease-free survival (HR, 1.12; 95% CI, 0.86 to 1.47; P = .40), or mortality (HR, 1.15; 95% CI, 0.83 to 1.59; P = .41) in the intent-to-treat analysis. A significant interaction between menopausal status and treatment group was observed for DFS ( P = .04) but not for OS ( P = .07). Patients with grade 3 tumors derived most benefit from DC, and patients with grade 1 to 2 tumors derived most benefit from EC-D (DFS: interaction P = .02; and OS: interaction P = .03). Patients receiving EC-D reported significantly more stomatitis, myalgia or arthralgia, vomiting, nausea, fatigue, and peripheral neuropathy, whereas edema was more frequent after DC. Conclusion This study provides evidence to support no overall outcome benefit from adjuvant anthracyclines in patients with early TOP2A-normal breast cancer.

PurposeCombining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67>15%).MethodsThis randomized, multicenter, international, phase II study enrolled postmenopausal women with advanced ER-positive breast cancer previously treated with a nonsteroidal aromatase inhibitor (NCT01234857). Patients were randomized to either oral ridaforolimus 30mg daily for 5 of 7days (once daily [qd]×5days/week) plus intravenous dalotuzumab 10mg/kg/week or oral exemestane 25mg/day, and stratified by Ki67 status. Due to a high incidence of stomatitis in the ridaforolimus-dalotuzumab group, two sequential, nonrandomized, reduced-dose cohorts were explored with ridaforolimus 20 and 10mg qd×5days/week. The primary endpoint was progression-free survival (PFS).ResultsMedian PFS was 21.4weeks for ridaforolimus 30mg qd×5days/week plus dalotuzumab 10mg/kg (n=29) and 24.3weeks for exemestane (n=33; hazard ratio=1.00; P=0.5). Overall survival and objective response rates were similar between treatment arms. The incidence of drug-related, nonserious, and serious adverse events was higher with ridaforolimus/dalotuzumab (any ridaforolimus dose) than with exemestane. Lowering the ridaforolimus dose reduced the incidence of grade 3 stomatitis, but overall toxicity remained higher than acceptable at all doses without improved efficacy.ConclusionsThe combination of ridaforolimus plus dalotuzumab was no more effective than exemestane in patients with advanced ER-positive breast cancer, and the incidence of adverse events was higher. Therefore, the combination is not being further pursued.

Background Research suggests increased risk of hypothyroidism among breast cancer survivors, but whether this risk is modified by treatment modalities is unclear. We estimated the incidence of hypothyroidism in breast cancer survivors, and in strata of treatment modalities. Methods Using nationwide registries, we identified all Danish women aged ≥35 years with non-metastatic breast cancer diagnosed from 1996 through 2009. Each breast cancer survivor was matched with up to five cancer-free women (hereafter ‘controls’) on birth year and area of residence. We excluded all women with prevalent hypothyroidism or hyperthyroidism. We considered cancer-directed treatment as the receipt of chemotherapy (yes/no), with or without radiotherapy—either to the chest wall only or with addition of the lymph nodes. Hypothyroidism was defined using diagnostic codes, and/or levothyroxine prescriptions. We calculated incidence rates (IR) of hypothyroidism per 1000 person-years and associated 95% confidence intervals (CI), and estimated hazard ratios (HR) and 95%CI of hypothyroidism using Cox regression, adjusting for comorbidities. Results We included 45,514 breast cancer survivors and 209,195 matched controls with 2,631,488 person-years of follow-up. Median follow-up was 8.4 years in the breast cancer cohort, and 10.6 years in the control cohort. Median age in both cohorts was 61 years. Breast cancer survivors had more comorbidities than the matched controls. Breast cancer survivors had higher incidence of hypothyroidism than matched controls [IR=4.3 (95%CI=4.2, 4.5), and 3.8 (95%CI=3.7, 3.9), respectively], corresponding to an adjusted HR of 1.15 (95%CI=1.09, 1.21). Breast cancer survivors who received radiotherapy to the lymph nodes with or without chemotherapy had highest risk of hypothyroidism when compared with matched controls [HR=1.66 (95%CI=1.43, 1.93) and HR=1.27 (95%CI=1.10, 1.46), respectively]. This pattern was also evident when comparing breast cancer survivors who received radiotherapy to the lymph nodes with or without chemotherapy with breast cancer survivors who did not undergo radiotherapy or chemotherapy (HR=1.65 (95%CI=1.41, 1.94) and HR=1.37, 95%CI=1.18, 1.58), respectively]. Conclusion Breast cancer survivors treated with radiotherapy to the lymph nodes had excess risk of hypothyroidism compared with age-matched women from the general population, and when compared with breast cancer survivors who do not undergo nodal radiotherapy. The risk of hypothyroidism was particularly high among patients treated with both nodal radiotherapy and chemotherapy. Our findings support systematic screening for hypothyroidism during follow-up among breast cancer survivors who receive nodal radiotherapy, and especially those who receive nodal radiotherapy and chemotherapy.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of paclitaxel. Though no pharmacological agents have been identified to prevent CIPN, cryotherapy with frozen gloves and socks may reduce the risk of developing CIPN and thereby increase the likelihood of patients completing the planned dose of paclitaxel.PATIENTS AND METHODS: Among women with early-stage breast cancer who received at least one cycle of paclitaxel, 119 were included in the 2016 cohort who received cryotherapy when they developed symptoms of CIPN, and 96 patients in the 2017 cohort who received prophylactic cryotherapy. From electronic patient records, data were abstracted on dates and doses of adjuvant paclitaxel, dose reductions, cycle delays, symptoms of CIPN, and whether and when frozen gloves and socks were used. The outcome was the proportion of patients completing the planned 720 mg/m2 of paclitaxel cumulated over nine cycles. The hazard ratio (HR) of a dose-limiting event due to CIPN was estimated in a Cox proportional hazards model.RESULTS: In the 2016 cohort, cryotherapy was needed due to symptoms of CIPN in 54 (45%) patients. Significantly, more patients, 77% in the 2017 cohort, completed the planned dose of 720 mg/m² compared with 64% in the 2016 cohort, p = 0.017. The HR of a dose reduction or cessation due to CIPN, adjusted for age and HER-2 status, was 0.50 (95% confidence interval 0.30-0.84), p = 0.009, for the 2017 cohort compared with the 2016 cohort.CONCLUSIONS: The results of this study suggest that prophylactic cryotherapy may reduce the risk of a dose-limiting event due to CIPN and increase the proportion of patients completing the planned dose of paclitaxel in adjuvant treatment of early-stage breast cancer. Despite this, CIPN remains to be an important dose-limiting toxicity of paclitaxel.

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 HRprevalent 1.01, 95% CI 0.87–1.19; adjusted HRincident 0.93, 95% CI 0.75–1.16, respectively). Furthermore, no differences were seen for all-cause mortality for prevalent or incident hypothyroidism (adjusted HRprevalent 1.02, 95% CI 0.92–1.14, and HRincident 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. Electronic supplementary material The online version of this article (10.1186/s13058-019-1122-3) contains supplementary material, which is available to authorized users.

OBJECTIVES: This study sought to evaluate the long-term risk of developing heart failure (HF) in patients receiving trastuzumab therapy.BACKGROUND: Trastuzumab has improved the prognosis in patients with HER2-positive breast cancer, but it can induce left ventricular dysfunction with reduced ejection fraction or HF during treatment. The long-term risk of HF is less well described.METHODS: In a nationwide Danish retrospective cohort study, 9,901 patients scheduled for adjuvant treatment for early-stage breast cancer were identified in the Danish Breast Cancer Cooperative Group database. Of these, 8,812 patients (25% HER2-positive; 51.7 ± 8.5 years of age) received chemotherapy including anthracycline; and if they were HER2 positive, trastuzumab was added. The primary endpoint was a diagnosis of HF assessed before and after 18 months in a landmark analysis to distinguish short- and long-term risks.RESULTS: Median follow-up was 5.4 years (interquartile range [IQR]: 4.1 to 6.8 years). In the trastuzumab group, 60 patients had HF by 9 years versus 51 in the group who were treated with chemotherapy alone, corresponding to incidence rates per 1,000 patient years of 5.3 (95% confidence interval [CI]: 4.1 to 6.8) versus 1.4 (95% CI: 1.1 to 1.8), respectively. The cumulative incidence of HF was higher in the trastuzumab group at both the short- and long-term (p < 0.01), yielding adjusted hazard ratios of 8.7 (95% CI: 4.6 to 16.5; p < 0.01) for early HF and 1.9 (95% CI: 1.2 to 3.3; p = 0.01) for late HF associated with trastuzumab treatment.CONCLUSIONS: Trastuzumab treatment is associated with a 2-fold increased risk of late HF compared with chemotherapy treatment alone.

To the editor,Aberrant signaling through the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway is a well-known mechanism of resistance to endocrine therapy in pa...

Purpose To prospectively investigate the diagnostic accuracy of [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) with dual-time-point imaging, contrast-enhanced CT (ceCT), and bone scintigraphy (BS) in patients with suspected breast cancer recurrence. Patients and Methods One hundred women with suspected recurrence of breast cancer underwent 1-hour and 3-hour FDG-PET/CT, ceCT, and BS within approximately 10 days. The study was powered to estimate the precision of the individual imaging tests. Images were visually interpreted using a four-point assessment scale, and readers were blinded to other test results. The reference standard was biopsy along with treatment decisions and clinical follow-up (median, 17 months). Results FDG-PET/CT resulted in no false negatives and fewer false positives than the other imaging techniques. Accuracy of results were similar for 1-hour and 3-hour FDG-PET/CT. For distant recurrence, the area under the receiver operating curve was 0.99 (95% CI, 0.97 to 1) for FDG-PET/CT, 0.84 (95% CI, 0.73 to 0.94) for ceCT, and 0.86 (95% CI, 0.77 to 0.94) for the combined ceCT+BS. Of 100 patients, 22 (22%) were verified with distant recurrence, and 18 of these had bone involvement. Nineteen patients (19%) had local recurrence only. In exploratory analyses, diagnostic accuracy of FDG-PET/CT was better than ceCT alone or ceCT combined with BS in diagnosing distant, bone, and local recurrence, shown by a greater area under the receiver operating curve and higher sensitivity, specificity, and superior likelihood ratios. Conclusion FDG-PET/CT was accurate in diagnosing recurrence in breast cancer patients. It allowed for distant recurrence to be correctly ruled out and resulted in only a small number of false-positive cases. Exploratory findings suggest that FDG-PET/CT has greater accuracy than conventional imaging technologies in this patient group.

PURPOSE: Adjuvant chemotherapy has been associated with loss of bone mineral density (BMD) either as a direct effect or due to glucocorticoids used as supportive care medication. A prospective cohort study was conducted to evaluate changes in BMD from baseline to right after completion of chemotherapy, i.e., 4 months.METHODS: Dual-imaging X-ray absorptiometry (DXA) was performed at baseline and after completing anthracycline- and taxane-based chemotherapy to measure BMD in the spine, hip, and forearm in early-stage breast cancer patients. High-dose prednisolone was used at three weekly intervals to reduce nausea and vomiting. Patients were advised a daily calcium/vitamin D supplement. Linear regression was used to assess mean percentage change in BMD and 95 % confidence intervals (95 % CI) according to doses of prednisolone, menopausal status, smoking, and BMI.RESULTS: Eight patients were excluded: seven because of initiation of bisphosphonate treatment due to osteoporosis at baseline, and one had non-interpretable DXA. The final cohort included 97 patients with a mean age of 53 years (range 34-72). Mean cumulative prednisolone dose was 1308 mg (95 % CI 1255; 1362). BMD increased 1.36 % (95 % CI 0.7; 2.0, p CONCLUSIONS: Adjuvant chemotherapy supplemented with prednisolone was not associated with loss of BMD. Postmenopausal women gained bone mass, whereas current smokers lost bone mass.