Implementation and clinical benefit of DPYD genotyping in a Danish cancer population.

BACKGROUND: In 2020, the European Medicines Agency recommended testing patients for dihydropyrimidine dehydrogenase (DPD) deficiency before systemic treatment with fluoropyrimidines (FP). DPD activity testing identifies patients at elevated risk of severe FP-related toxicity (FP-TOX). The two most used methods for DPD testing are DPYD genotyping and DPD phenotyping (plasma uracil concentration). The primary objective of this study was to compare the overall frequency of overall grade ≥3 FP-TOX before and after the implementation of DPYD genotyping. PATIENTS AND METHODS: Two hundred thirty Danish, primarily gastrointestinal cancer patients, were DPYD-genotyped before their first dose of FP, and blood was sampled for post hoc assessment of P-uracil. The initial dose was reduced for variant carriers. Grade ≥3 FP-TOX was registered after the first three treatment cycles of FP. The frequency of toxicity was compared to a historical cohort of 492 patients with post hoc determined DPYD genotype from a biobank. RESULTS: The frequency of overall grade ≥3 FP-TOX was 27% in the DPYD genotype-guided group compared to 24% in the historical cohort. In DPYD variant carriers, DPYD genotyping reduced the frequency of FP-related hospitalization from 19% to 0%. In the control group, 4.8% of DPYD variant carriers died due to FP-TOX compared to 0% in the group receiving DPYD genotype-guided dosing of FP. In the intervention group, wild-type patients with uracil ≥16 ng/ml had a higher frequency of FP-TOX than wild-type patients with uracil <16 ng/ml (55% versus 28%). CONCLUSIONS: We found no population-level benefit of DPYD genotyping when comparing the risk of grade ≥3 FP-TOX before and after clinical implementation. We observed no deaths or FP-related hospitalizations in patients whose FP treatment was guided by a variant DPYD genotype. The use of DPD phenotyping may add valuable information in DPYD wild-type patients.

Work ability 8 years after breast cancer: exploring the role of social support in a nation-wide survey.

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.

Work status changes and associated factors in a nationwide sample of Norwegian long-term breast cancer survivors.

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.

Effect of cryotherapy on dose of adjuvant paclitaxel in early-stage breast cancer.

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.

Amisulpride prevents nausea and vomiting associated with highly emetogenic chemotherapy: a randomised, double-blind, placebo-controlled, dose-ranging trial.

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.

Persistence of docetaxel-induced neuropathy and impact on quality of life among breast cancer survivors.

BACKGROUND: This study evaluates persistence and severity of docetaxel-induced neuropathy (peripheral neuropathy (PN)) and impact on health related quality of life in survivors from early-stage breast cancer. METHODS: One thousand and thirty-one patients with early-stage breast cancer, who received at least one cycle of docetaxel and provided information on PN during treatment, completed questionnaires on PN as an outcome (Common Toxicity Criteria (CTC) scores, European Organisation for Research and Treatment of Cancer Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC CIPN20) and EORTC Quality of Life Questionnaire (QLQ)-C30) after 1-3years. FINDINGS: Upon completion of docetaxel treatment, 241 patients (23%) reported PN, grades 2-4. PN persisted for 1-3years among 81 (34%) while PN regressed to grades 0-1 among 160 (66%). Among 790 patients (77%) without PN, 76 (10%) developed PN 1-3years later while 714 (90%) stayed free from PN. Significant risk factors for persistent PN were age ⩾55 (p=0.001), maximum grade of PN during docetaxel treatment (p<0.0001), persistent muscle and joint pain (p<0.0001), stomatitis (p=0.047) and fatigue (p=0.001). Persistent PN had a significant negative correlation with health-related quality of life (HRQOL), functional scales and symptom scales. INTERPRETATIONS: Overall, 15% of breast cancer survivors treated with docetaxel report PN 1-3years after treatment with a significant negative impact on HRQOL.

Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials.

BACKGROUND: Postmastectomy radiotherapy was shown in previous meta-analyses to reduce the risks of both recurrence and breast cancer mortality in all women with node-positive disease considered together. However, the benefit in women with only one to three positive lymph nodes is uncertain. We aimed to assess the effect of radiotherapy in these women after mastectomy and axillary dissection. METHODS: We did a meta-analysis of individual data for 8135 women randomly assigned to treatment groups during 1964-86 in 22 trials of radiotherapy to the chest wall and regional lymph nodes after mastectomy and axillary surgery versus the same surgery but no radiotherapy. Follow-up lasted 10 years for recurrence and to Jan 1, 2009, for mortality. Analyses were stratified by trial, individual follow-up year, age at entry, and pathological nodal status. FINDINGS: 3786 women had axillary dissection to at least level II and had zero, one to three, or four or more positive nodes. All were in trials in which radiotherapy included the chest wall, supraclavicular or axillary fossa (or both), and internal mammary chain. For 700 women with axillary dissection and no positive nodes, radiotherapy had no significant effect on locoregional recurrence (two-sided significance level [2p]>0·1), overall recurrence (rate ratio [RR], irradiated vs not, 1·06, 95% CI 0·76-1·48, 2p>0·1), or breast cancer mortality (RR 1·18, 95% CI 0·89-1·55, 2p>0·1). For 1314 women with axillary dissection and one to three positive nodes, radiotherapy reduced locoregional recurrence (2p<0·00001), overall recurrence (RR 0·68, 95% CI 0·57-0·82, 2p=0·00006), and breast cancer mortality (RR 0·80, 95% CI 0·67-0·95, 2p=0·01). 1133 of these 1314 women were in trials in which systemic therapy (cyclophosphamide, methotrexate, and fluorouracil, or tamoxifen) was given in both trial groups and, for them, radiotherapy again reduced locoregional recurrence (2p<0·00001), overall recurrence (RR 0·67, 95% CI 0·55-0·82, 2p=0·00009), and breast cancer mortality (RR 0·78, 95% CI 0·64-0·94, 2p=0·01). For 1772 women with axillary dissection and four or more positive nodes, radiotherapy reduced locoregional recurrence (2p<0·00001), overall recurrence (RR 0·79, 95% CI 0·69-0·90, 2p=0·0003), and breast cancer mortality (RR 0·87, 95% CI 0·77-0·99, 2p=0·04). INTERPRETATION: After mastectomy and axillary dissection, radiotherapy reduced both recurrence and breast cancer mortality in the women with one to three positive lymph nodes in these trials even when systemic therapy was given. For today's women, who in many countries are at lower risk of recurrence, absolute gains might be smaller but proportional gains might be larger because of more effective radiotherapy. FUNDING: Cancer Research UK, British Heart Foundation, UK Medical Research Council.

Risk of docetaxel-induced peripheral neuropathy among 1,725 Danish patients with early stage breast cancer.

Docetaxel-induced peripheral neuropathy (PN) can lead to sub-optimal treatment in women with early breast cancer. Here, we compare the frequency of dose reduction as a result of PN in two different adjuvant regimens. From the Danish Breast Cancer Cooperative Group READ trial we included 1,725 patients with early stage breast cancer who randomly were assigned to three cycles of epirubicin and cyclophosphamide followed by three cycles docetaxel (D100) or six cycles of cyclophosphamide and docetaxel (D75). Eligible patients completed chemotherapy, received docetaxel, and provided information on patient-reported outcome (secondary outcome of trial) including PN. Associations between PN and risk factors were analyzed by multivariate logistic regression. Overall 597 patients (34 %) reported PN, grades 2-4, during treatment, 194 (11 %) after the first cycle [early onset peripheral neuropathy (EPN)] and 403 (23 %) after subsequent cycles [later-onset peripheral neuropathy (LPN)]. The odds ratio (OR) of EPN was significantly increased for the D100 regimen (OR 3.10; 95 % CI 2.18-4.42) while this regimen was associated with reduced OR of LPN (OR 0.69; 95 % CI 0.54-0.88). Patients with PN received significantly lower cumulative doses of docetaxel than patients with no PN. Explorative analysis showed that OR of PN was significantly reduced if patients wore frozen gloves and socks during treatment (OR 0.56; 95 % CI 0.38-0.81) in the EPN group. Patients developing PN after the first cycle are less likely to receive docetaxel at the planned dose intensity and usage of frozen gloves and socks may modify the risk.

Influence of comorbidity on the effect of adjuvant treatment and age in patients with early-stage breast cancer.

BACKGROUND: Prevalence of comorbidity at breast cancer diagnosis increases with age and is likely to influence the likelihood of receiving treatment according to guidelines. The aim of this study was to examine the effect of breast cancer treatment on mortality, taking age at diagnosis and comorbidity into account. METHODS: Four nationwide population registries in Denmark: the Danish Civil Registration System, the Danish Breast Cancer Cooperative Group, the Danish National Patient Register, and the Danish Register of Causes of Death provided information on 62 591 women diagnosed with early-stage breast cancer, 1990-2008, of whom data on treatment were available for 39 943. Comorbidity was measured using the Charlson Comorbidity Index. Adjuvant treatment were categorised as none, chemotherapy, endocrine therapy, and unknown. Multivariable Cox modelling assessed the effect of comorbidity on breast cancer-specific mortality and other cause mortality according to treatment, adjusting for age at diagnosis and other clinical prognostic factors. RESULTS: The impact of comorbidity on mortality was most pronounced in patients aged 50-79 years. Patients receiving chemotherapy with mild to moderate comorbidity had HR 0.99 (95% confidence interval (CI); 0.82-1.19) and 1.06 (95% CI; 0.77-1.46) for breast cancer-specific mortality, respectively, compared with patients without comorbidity. CONCLUSION: Comorbidity at breast cancer diagnosis is an independent adverse prognostic factor for death after breast cancer. We identified a subgroup of patients with mild to moderate comorbidity receiving chemotherapy who had similar breast cancer mortality as patients with no comorbidity.

Breast cancer incidence by estrogen receptor status in Denmark from 1996 to 2007.

During the past 50 years, breast cancer incidence has increased by 2-3 % annually. Despite many years of testing for estrogen receptors (ER), evidence is scarce on breast cancer incidence by ER status. The aim of this paper was to investigate the increase in breast cancer incidence by ER status. Data were obtained from the clinical database of the Danish Breast Cancer Cooperative Group which holds nationwide data on diagnosis, including pathology, treatment, and follow-up on primary breast cancers since 1977. All Danish women <80 years diagnosed with primary breast cancer 1996-2007 were identified in this prospective register based study. ER status was evaluated using immunohistochemical staining by standardized laboratory methods in the Danish Pathology Departments and reported to the database. From 1996 to 2007, breast cancer incidence increased overall with a tendency to level off after 2002. In all women a significant decrease was found in ER unknown tumors. However, in both pre- and postmenopausal women, significant increases were seen in incidence of ER+ tumors; though the increase levelled off for premenopausal women after 2002. In postmenopausal women, the incidence of ER- breast cancer decreased significantly throughout the period. In women <35 years, we found a minor non-significant increase in both ER+ and ER- tumors. ER unknown decreased in all women and was the most distinct in premenopausal women aged 35+. We found a significant increase in ER+ breast cancer incidence in postmenopausal women whereas the incidence in premenopausal women (aged 35+) levelled off after 2002.

MRI and PET/CT of patients with bone metastases from breast carcinoma.

3.0Tesla magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) was compared with combined 18F-fluorodeoxyglucose positron emission tomography and computed tomography (PET/CT) in patients with suspected bone metastases from breast cancer. A prospective clinical study was performed in 13 female breast cancer patients (mean age 61years; range 45-85 years). The spine was imaged in the sagittal plane with T1-weighted (T1), short tau inversion recovery (STIR), and T2-weighted fat-saturated (T2) sequences. The pelvis was imaged similarly in the coronal plane. Axial DWI was performed from the skull base to the mid-thigh. MRI and PET/CT were performed in all patients at a maximum interval of 10 working days and at least 14 days after chemotherapy. MRI was reviewed by two radiologists, and their consensus on potential metastases in 27 predefined locations was recorded. The predefined locations were the vertebral bodies (24), the left (1) and right (1) pelvic bones, and the sacral bone (1). The PET/CT was reviewed by a radiologists and a nuclear medicine physician. MRI detected 59 of the 60 active metastases found with our gold standard modality PET/CT. T1 had the highest sensitivity (98%) but rather low specificity (77%), but with the addition of STIR and DWI, the specificity increased to 95%. The additional metastases detected with MRI most likely represented postherapeutic residual scars without active tumour. In conclusion, 3.0Tesla MRI with T1, STIR, and DWI is useful for the clinical evaluation of bone metastases from breast cancer and compares well to PET/CT.

PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab.

BACKGROUND: This study was conducted to determine the frequency of PIK3CA mutations and human epidermal growth factor receptor-2 (HER2) phosphorylation status (pHER2-Tyr1221/1222) and if PIK3CA, phosphatase and tensin homolog (PTEN), or pHER2 has an impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab. PATIENTS AND METHODS: Two hundred and forty HER2-positive early-stage breast cancer patients receiving adjuvant treatment (cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2) before administration of 1 year trastuzumab were assessable. PTEN and pHER2 expression were assessed by immunohistochemistry. PIK3CA mutations (exons 9 and 20) were determined by pyrosequencing. RESULTS: Five-year overall survival (OS) and invasive disease-free survival were 87.8% and 81.0%, respectively. Twenty-six percent of patients had a PIK3CA mutation, 24% were PTEN low, 45% pHER2 high, and 47% patients had increased PI3K pathway activation (PTEN low and/or PIK3CA mutation). No significant correlations were observed between the clinicopathological variables and PIK3CA, PTEN, and pHER2 status. In both univariate and multivariate analyses, patients with PIK3CA mutations or high PI3K pathway activity had a significant worse OS [multivariate: hazard ratio (HR) 2.14, 95% confidence interval (CI) 1.01-4.51, P=0.046; and HR 2.35, 95% CI 1.10-5.04, P=0.03]. CONCLUSION: Patients with PIK3CA mutations or increased PI3K pathway activity had a significantly poorer survival despite adequate treatment with adjuvant chemotherapy and trastuzumab.

Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials.

BACKGROUND: After breast-conserving surgery, radiotherapy reduces recurrence and breast cancer death, but it may do so more for some groups of women than for others. We describe the absolute magnitude of these reductions according to various prognostic and other patient characteristics, and relate the absolute reduction in 15-year risk of breast cancer death to the absolute reduction in 10-year recurrence risk. METHODS: We undertook a meta-analysis of individual patient data for 10,801 women in 17 randomised trials of radiotherapy versus no radiotherapy after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node-positive (pN+) disease. FINDINGS: Overall, radiotherapy reduced the 10-year risk of any (ie, locoregional or distant) first recurrence from 35·0% to 19·3% (absolute reduction 15·7%, 95% CI 13·7-17·7, 2p<0·00001) and reduced the 15-year risk of breast cancer death from 25·2% to 21·4% (absolute reduction 3·8%, 1·6-6·0, 2p=0·00005). In women with pN0 disease (n=7287), radiotherapy reduced these risks from 31·0% to 15·6% (absolute recurrence reduction 15·4%, 13·2-17·6, 2p<0·00001) and from 20·5% to 17·2% (absolute mortality reduction 3·3%, 0·8-5·8, 2p=0·005), respectively. In these women with pN0 disease, the absolute recurrence reduction varied according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery, and these characteristics were used to predict large (≥20%), intermediate (10-19%), or lower (<10%) absolute reductions in the 10-year recurrence risk. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories were 7·8% (95% CI 3·1-12·5), 1·1% (-2·0 to 4·2), and 0·1% (-7·5 to 7·7) respectively (trend in absolute mortality reduction 2p=0·03). In the few women with pN+ disease (n=1050), radiotherapy reduced the 10-year recurrence risk from 63·7% to 42·5% (absolute reduction 21·2%, 95% CI 14·5-27·9, 2p<0·00001) and the 15-year risk of breast cancer death from 51·3% to 42·8% (absolute reduction 8·5%, 1·8-15·2, 2p=0·01). Overall, about one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10, and the mortality reduction did not differ significantly from this overall relationship in any of the three prediction categories for pN0 disease or for pN+ disease. INTERPRETATION: After breast-conserving surgery, radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth. These proportional benefits vary little between different groups of women. By contrast, the absolute benefits from radiotherapy vary substantially according to the characteristics of the patient and they can be predicted at the time when treatment decisions need to be made. FUNDING: Cancer Research UK, British Heart Foundation, and UK Medical Research Council.

Assessment of the incremental value of recombinant thyrotropin stimulation before 2-[18F]-Fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography imaging to localize residual differentiated thyroid cancer.

PURPOSE: The purpose of the study was to assess prospectively the impact of recombinant human TSH (rhTSH) administration on positron emission tomography (PET)/computed tomography (CT) imaging in differentiated thyroid cancer patients who, after primary treatment, had a suppressed or stimulated serum thyroglobulin greater than 10 ng/ml and no radioactive iodine uptake consistent with thyroid cancer on a whole body scan. PATIENTS AND METHODS: PET/CT was performed before (basal PET) and 24-48 h after rhTSH administration (rhTSH-PET) in 63 patients (52 papillary and 11 follicular thyroid cancers). Images were blindly analyzed by two readers. The proposed treatment plan was prospectively assessed before basal PET, after basal PET, and again after rhTSH-PET. RESULTS: A total of 108 lesions were detected in 48 organs in 30 patients. rhTSH-PET was significantly more sensitive than basal PET for the detection of lesions (95 vs. 81%; P = 0.001) and tended to be more sensitive for the detection of involved organs (94 vs. 79%; P = 0.054). However, basal PET and rhTSH-PET did not have significantly different sensitivity for detecting patients with any lesions (49 vs. 54%; P = 0.42). Changes in treatment management plan occurred in 19% of the patients after basal PET. Lesions found only by rhTSH-PET contributed to an altered therapeutic plan in eight patients, among whom only four were true-positive on pathology (6%). CONCLUSION: The use of rhTSH for 2-[18F]-fluoro-2-deoxy-D-glucose-PET/CT significantly increased the number of lesions detected, but the numbers of patients in whom any lesion was detected were no different between basal and rhTSH-stimulated PET/CT scans. Treatment changes due to true positive lesions occurred in 6% of cases.

Tamoxifen's protection against breast cancer recurrence is not reduced by concurrent use of the SSRI citalopram.

Tamoxifen remains an important adjuvant therapy to reduce the rate of breast cancer recurrence among patients with oestrogen-receptor-positive tumours. Cytochrome P-450 2D6 metabolizes tamoxifen to metabolites that more readily bind the oestrogen receptor. This enzyme also metabolizes selective serotonin reuptake inhibitors (SSRI), so these widely used drugs - when taken concurrently - may reduce tamoxifen's prevention of breast cancer recurrence. We studied citalopram use in 184 cases of breast cancer recurrence and 184 matched controls without recurrence after equivalent follow-up. Cases and controls were nested in a population of female residents of Northern Denmark with stages I-III oestrogen-receptor-positive breast cancer 1985-2001 and who took tamoxifen for 1, 2, or most often for 5 years. We ascertained prescription histories by linking participants' central personal registry numbers to prescription databases from the National Health Service. Seventeen cases (9%) and 21 controls (11%) received at least one prescription for the SSRI citalopram while taking tamoxifen (adjusted conditional odds ratio=0.85, 95% confidence interval=0.42, 1.7). We also observed no reduction of tamoxifen effectiveness among regular citalopram users (>or=30% overlap with tamoxifen use). These results suggest that concurrent use of citalopram does not reduce tamoxifen's prevention of breast cancer recurrence.

Comorbidity and survival of Danish breast cancer patients from 1995 to 2005.

Comorbid diseases can affect breast cancer prognosis. We conducted a population-based study of Danish women diagnosed with a first primary breast cancer from 1995 to 2005 (n=9300), using hospital discharge registry data to quantify comorbidities by Charlson score. We examined the influence of comorbidities on survival, and quantified their impact on relative mortality rates. The prevalence of patients with a Charlson score='0' fell from 86 to 81%, with an increase in those with Charlson score='1-2' from 13 to 16%, and score='3+' from 1 to 2%. One- and five-year survival for patients with Charlson score='0' and '1-2' was better for those diagnosed in 1998-2000 than in 1995-1997. Overall, patients diagnosed in 2001-2004 (mortality ratio (MR)=0.80, 95% CI=0.68-0.95) and 1998-2000 (MR=0.92, 95% CI=0.78-1.09) had lower 1-year age-adjusted mortality compared to those diagnosed in 1995-1997 (reference period). Patients with Charlson scores '1-2' and '3+' had higher age-adjusted 1-year mortality than those with a Charlson score='0' in each time period (2001-2004: MR('1-2')=1.76, 95% CI=1.35-2.30, and MR('3+')=3.78, 95% CI=2.51-5.68; and 1998-2000: MR('1-2')=1.60, 95% CI=1.36-1.88 and MR('3+')=2.34, 95% CI=1.65-3.33). Similar findings were observed for 5-year age-adjusted mortality. Additional analyses, adjusted for stage, indicated that confounding by stage could not explain these findings. Despite continued improvements in breast cancer survival, we found a trend of poorer survival among breast cancer patients with severe comorbidities even after adjusting for age and stage. Such poorer survival is an important public health concern and can be expected to worsen as the population ages.

Use of postmenopausal hormone replacement therapy and risk of non-Hodgkin's lymphoma: a Danish population-based cohort study.

Use of postmenopausal hormone replacement therapy (HRT) has been hypothesised to be associated with a reduced risk of non-Hodgkin's lymphoma (NHL), but the epidemiologic evidence is conflicting. To examine the risk of NHL in HRT users aged 40 and older, we conducted a cohort study in the County of North Jutland, Denmark (population 0.5 million) using data from population-based health registries for the period 1989-2002. We computed age-standardised NHL incidence rates and used Cox regression analysis to compute the relative risk (RR) and corresponding 95% confidence intervals (CI) of NHL among HRT users compared with non-users, adjusting for age and calendar period. The number of prescriptions redeemed (1, 2-4, 5-9, 10-19, or 20 or more prescriptions) was used as a proxy for duration of HRT. We identified 40 NHL cases among HRT users during 179 838 person-years of follow-up and 310 NHL cases among non-users during 1 247 302 person-years of follow-up. The age-standardised incidence rates of NHL were 25.7 per 100,000 among HRT users and 24.2 per 100,000 among non-users, yielding an adjusted RR of 0.99 (95% CI: 0.71-1.39). Our data did not support an association between HRT use and risk of NHL.

Does timing of adjuvant chemotherapy influence the prognosis after early breast cancer? Results of the Danish Breast Cancer Cooperative Group (DBCG).

The purpose of this study was to examine the effect on survival of delaying the start of adjuvant chemotherapy for early breast cancer for up to 3 months after surgery. In the nation-wide clinical trials of the Danish Breast Cancer Cooperative Group, 7501 breast cancer patients received chemotherapy within 3 months of surgery between 1977 and 1999: 352 with classical cyclofosfamide, metotrexate and 5-fluorouracil (CMF); 6065 with CMF i.v. and 1084 with cyclofosfamide, epirubicin and 5-fluorouracil. For the analysis, the time between surgery and the start of chemotherapy was divided into four strata (1-3, 4, 5 and 6-13 weeks). The results show that within the three groups of chemotherapy, there was an even distribution of known prognostic factors across the four strata of initiation of chemotherapy. There was no pattern indicating a benefit from early start of chemotherapy. No significant interactions were found for subgroups of patients with a poorer prognosis (many involved lymph nodes, high-grade malignancies or hormone receptor negative disease). In conclusion, we have found no evidence for a survival benefit due to early initiation of adjuvant chemotherapy within the first 2-3 months after surgery.

Hormone use for menopausal symptoms and risk of breast cancer. A Danish cohort study.

Numerous studies and meta-analyses have shown that hormone replacement therapy (HRT) for menopausal symptoms increases the risk of developing breast cancer, estimated to be 2.3% for each year of use. The influence of different oestrogen-progestin regimens has still not been fully evaluated. Using longitudinal data from the population-based prescription database of the county of North Jutland, Denmark, and the Danish Cancer Registry, we examined the risk of developing breast cancer in relation to HRT in a cohort of 78,380 women aged 40-67 years from 1989 to 2002. A total of 1462 cases of breast cancer were identified during a mean follow-up of 10 years. Use of HRT did not increase the risk of breast cancer in women aged 40-49 years. Restricting the cohort to 48,812 women aged 50 years or more at entry, of whom 15 631 were HRT users, we found an increased risk associated with current use of HRT (relative risk 1.61, 95% confidence interval 1.38-1.88). The risk increased with increasing duration of use and decreased with time since last HRT prescription, reaching unity after 5 years. No material risk difference was observed among the various HRT-regimens. This population-based cohort study provides further confirmation that HRT increases the risk of developing breast cancer in women aged 50 years or more.

Time trends and regional differences in registration, stage distribution, surgical management and survival of breast cancer in Denmark.

The aim of this study was to analyse time trends, stage at diagnosis, survival and registration of population-based cohorts of breast cancer patients in selected Danish counties (in total 2504) in 1986 and 1996-1997. In 1986, no differences in the extent of disease were observed between the counties. Patients from one county (Funen) had centralised surgery, significantly more lymph nodes removed and a better survival in the multivariate analysis. In 1996-1997, mammographical screening had been implemented in Funen, leading to a significantly better stage distribution, whereas stage remained unchanged in the other counties. In Funen, survival was significantly better than in the other counties in univariate, but not in multivariate analysis. Survival increased significantly with time only in Funen. Inclusion in clinical trials increased over time and the coverage of the database in the Danish Breast Cancer Cooperative Group (DBCG) was high. However, patients not notified in DBCG had, beside older age, also worse stage of disease distribution and less extensive surgery. A difference in survival was observed between the counties. In 1986, this may be explained by a centralised surgical system in one county, whereas in 1996-1997 improvements could be due to an early diagnosis and other as yet unknown factors. The DBCG database cannot be considered as representative of the Danish population of breast cancer patients.