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Purpose: Breast cancer and psychiatric disorders negatively impact work life, both positively associated with unemployment and early retirement. Our purpose was to assess whether being prescribed psychiatric medication, 2-4 yrs prior to a diagnosis of breast cancer, could impact the likelihood of returning to work after cancer therapy. Methods: 16,868 self-supporting women, diagnosed with breast cancer in Denmark from 2000 to 2012, were identified from a population-based clinical database, then cross-referenced to data held for psychiatric medication usage, sociodemographics, and labour-market participation. The association between historic psychiatric medication and return to work was estimated using a modified Poisson regression model. 'Return to work' was defined as being self-supporting one year after diagnosis of breast cancer. Results: 16% of our cohort had used psychiatric medical treatment 2-4 years before their diagnosis. Sixty-three per cent of these individuals had returned to work one year later, compared to 69% of the patient group with no prior history of using psychiatric medication treatments. In the fully adjusted model, prior use of psychiatric medication diminished the likelihood of returning to work one year after cancer diagnosis (RR = 0.91 (0.87-0.94)). High income and older age were positively associated with returning to work; negative correlates included those related to disease severity. Conclusions: Historic use of psychiatric medication provoked a minor, although statistically significant reduction in the resumption of working life one year after a diagnosis of breast cancer. Implications for cancer survivors: Although historic use of psychiatric medication may incur a minor effect on working life, further research is needed on the long-term social consequences for sub-groups.

Background: Gene expression profiles of normal and tumor tissue reflect both differences in biological processes taking place in vivo and differences in response to stress during surgery and sample handling. The effect of cold (room temperature) ischemia in the time interval between surgical removal of the specimen and freezing is described in a few studies. However, not much is known about the effect of warm (body temperature) ischemia during surgery., Methods: Three women with primary operable breast cancer underwent in situ biopsies from normal breast and tumor tissue prior to radical mastectomy. Ex vivo biopsies from normal and tumor tissue were collected immediately after surgical excision. The putative effects on gene expression of malignancy (tumor versus normal), surgical manipulation (post- versus pre-surgical) and interaction between the two (differences in effect of surgical manipulation on tumor and normal samples) were investigated simultaneously by Generalized Estimating Equation (GEE) analysis in this self-matched study., Results: Gene set enrichment analysis (GSEA) demonstrates a marked difference in effect of surgical manipulation on tumor compared to normal tissue. Interestingly, a large proportion of pathways affected by ischemia especially in tumor tissue are pathways considered to be specifically up regulated in tumor tissue compared to normal., Conclusion: The results of this study suggest that a large contribution to this differential expression originates from altered response to stress in tumor cells rather than merely representing in vivo differences. It is important to bear this in mind when using gene-expression analysis to deduce biological function, and when collecting material for gene expression profiling.

Background: A breast cancer diagnosis affects an individual's affiliation to labour market, but the long-term consequences of breast cancer on income in a Danish setting have not been examined. The present study investigated whether breast cancer affected future income among Danish women that participated in the work force. We also examined the roles of sociodemographic factors and prior psychiatric medical treatment., Methods: This registry-based cohort study was based on information retrieved from linked Danish nationwide registries. We compared the incomes of 13,101 women (aged 30-59 years) diagnosed with breast cancer (exposed) to those of 60,819 women without breast cancer (unexposed). Changes in income were examined during a 10-year follow-up; for each follow-up year, we calculated the mean annual income and the relative change compared to the income earned one year prior to diagnosis. Expected changes in Danish female income, according to calendar year and age, were estimated based on information from Statistics Denmark. For exposed and unexposed groups, the observed income changes were dichotomized to those above and those below the expected change in income in the Danish female population. We examined the impact of breast cancer on income each year of follow-up with logistic regression models. Analyses were stratified according to educational level, marital status, and prior psychiatric medical treatment., Results: Breast cancer had a temporary negative effect on income. The effect was largest during the first three years after diagnosis; thereafter, the gap narrowed between exposed and unexposed cohorts. The odds ratio for an increase in income in the cancer cohort compared to the cancer-free cohort was 0.81 (95% CI 0.77-0.84) after three years. After seven years, no significant difference was observed between cohorts. Stratified analyses demonstrated that the negative effect of breast cancer on income lasted longest among women with high educational levels. Being single or having received psychiatric medical treatment increased the chance to experience an increase in income among women with breast cancer., Conclusion: A breast cancer diagnosis led to negative effects on income, which ameliorated over the following seven years. Sociodemographic factors and prior psychiatric medical treatment might influence long-term consequences of breast cancer on income.

Background: The aim of this study was to investigate the use of sentinel lymph node dissection (SLND) in the treatment of patients with locally recurrent breast cancer., Methods: A total of 147 patients with locally recurrent breast cancer were included from five different breast surgery departments in Denmark. Data on previous breast and axillary surgery, adjuvant treatment, second operation in the breast and axilla, and lymphoscintigraphy were collected retrospectively from the original patient files., Results: SLND after recurrence (SLNDAR) was successful in 72 of 144 patients (50 %). The detection rate was significantly higher after previous SLND (66 %) compared with previous ALND (34 %) [p = 0.0001]. Thirty-seven patients (51 %) who had previous SLND had a negative sentinel node. These patients could be spared an ALND. Six patients (8 %) who had a previous ALND had a metastatic sentinel node at recurrence; 17 % of patients had a sentinel node located outside the ipsilateral axilla; and eight patients with negative sentinel node at SLNDAR underwent completion ALND. None of these patients had metastases at completion ALND, corresponding to a false negative rate of 0 %., Conclusions: SLNDAR seems to be a feasible procedure in locally recurrent breast cancer and can spare a clinically significant number of patients an unnecessary ALND and the following risk of sequelae. In patients who had previous ALND, SLNDAR identified metastases that would have been overlooked following the current guidelines. A large proportion of patients had aberrant drainage, suggesting a need for lymphoscintigraphy.

Background: It remains unknown whether incident chronic diseases are more often fatal among breast cancer survivors than among women free of breast cancer., Methods: We conducted a nationwide matched cohort study of all Danish breast cancer patients diagnosed between 1994 and 2007, who survived for five years. We compared their long-term mortality with five times as many women from the general population without breast cancer, matched on age. We used time-varying methods to compute mortality rate ratios (MRRs) for incident diseases included in the Charlson Comorbidity Index (CCI)., Results: One third of five-year breast cancer survivors developed incident diseases during 14 years of follow-up, with about the same incidence as women without breast cancer. Mortality associated with any incident disease was similar among breast cancer survivors (MRR = 7.1, 95% confidence interval (CI): 6.7, 7.4) and comparison women (MRR = 7.5, 95% CI: 7.3, 7.7). Among breast cancer patients, relative mortality associated with incident diseases was higher among patients treated with chemotherapy (MRR = 10, 95% CI: 8.7, 12) and radiotherapy (MRR = 9.8, 95% CI: 8.8, 11) than among patients who received surgery (MRR = 7.0, 95% CI: 6.7, 7.4) or hormonal therapy (MRR = 6.3, 95% CI: 5.8, 6.9)., Conclusion: There were no marked differences in mortality of diseases among breast cancer survivors and women from the general population. Among breast cancer patients, new diseases were more often fatal in patients treated with chemotherapy and radiotherapy. Five-year breast cancer survivors have similar risk of dying from new chronic medical conditions as women from the general population without breast cancer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Age is an important risk factor for breast cancer, but previous data has been contradictory on whether patient age at diagnosis is also related to breast cancer survival. The present study evaluates age at diagnosis as a prognostic factor for breast cancer on a large cohort of patients at a single institution., Methods: All 4,453 women diagnosed with breast cancer in Malmö University Hospital, Sweden between 1961 and 1991 were followed up on for 10 years with regards to breast cancer-specific mortality (BCSM) in different age groups. Corresponding relative risks (RR), with 95% confidence intervals, were obtained using Cox's proportional hazards analysis. All analyses were adjusted for potential confounders and stratified for axillary lymph node involvement (ALNI) and diagnostic period., Results: As compared to women aged 40 to 49 years, those who were aged under 40 (RR: 1.40; 95% CI: 1.04 to 1.88) and 80 or more years (RR: 1.80; 95% CI: 1.45 to 2.25) had a statistically significant higher 10-year mortality rate. When adjusted for potential confounders, including stage at diagnosis, the associations only remained statistically significant for women aged 80 years or more. In the analyses stratified on ALNI, ALNI-negative women under 40 years had a statistically significant higher five-year mortality rate (RR: 2.65; 95% CI: 1.23 to 5.70). In the analyses stratified on diagnostic period, the positive association between women aged under 40 or aged 80 or more years and high BCSM rate remained, with statistically significant results for women aged 80 years or more in all periods., Conclusions: Women under 40 years of age had a poor prognosis, and this association was strongest among young women with axillary lymph node negative breast cancer. An age of 80 years or more was a prognostic factor for poor survival, independent of stage at diagnosis and diagnostic period.

Objectives: To assess the interaction between comorbidity and breast cancer (BC) on the rate of venous thromboembolism (VTE) beyond what can be explained by the independent effects of BC and comorbidity., Design: Population-based matched cohort study., Setting: Denmark., Participants: Danish patients with BC (n=62 376) diagnosed in 1995-2010 and a comparison cohort of women without BC (n=304 803) from the general population were matched to the patients with BC on year of birth in 5-year intervals and on the specific diseases included in the Charlson Comorbidity Index (CCI) and atrial fibrillation and obesity., Measures: The rate ratios of VTE per 1000 person-years (PY) were computed by comorbidity levels using the CCI, and interaction contrasts (IC) were calculated as a measure of the excess or deficit VTE rate not explained by the independent effects of BC and comorbidity., Results: Among patients with BC with a CCI score of 1, the 0-1 year VTE rate was 12/1000 PY, and interaction accounted for 10% of the rate (IC=3.2, 95% CI 0.5 to 5.9). Among patients with BC with CCI ≥4, the VTE rate was 17, and interaction accounted for 8% of the rate (IC=1.2, 95% CI -1.8 to 4.2). There was no interaction during 2-5 years of follow-up., Conclusions: There was only little interaction between BC and the CCI score on the rate of VTE., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: During the last decades the diagnosis, treatment, and prognosis of breast cancer have changed and improved in Denmark. The first mammography screening programme started in 1991. However, for many years only about 20% of Danish women aged 50-69 were offered screening. The national roll-out of screening took place in 2008-2010., Material and Methods: Based on published Danish data, this overview describes the status of diagnosis and treatment, and the screening programme. For further evaluating the potential overdiagnosis and overtreatment, additional Danish Breast Cancer Cooperative Group (DBCG) data are included., Results and Conclusion: Using incidence-based mortality method, reduction in breast cancer mortality was estimated to be 25% in the target group of women after 10 years of screening in Copenhagen; an outcome comparable to that of randomised controlled trials. A recent Danish study has indicated overdiagnosis to be around 4%. Others have estimated overdiagnosis to be 33%. National DBCG data showed that the rude breast cancer incidence increased during the period 1990-2011 from 126 to 206 per 100 000. The incidence was almost constant for women younger than 50 years. In regions not offering screening, the incidence increased with 3% per year for women aged 50-69 years with similar trends for small and large tumours. After introduction of screening the increase in the age group 50-69 years was confined to small tumours ≤ 20 mm, and most pronounced for node negative patients. From the 1990s, the use of breast conserving surgery has increased from around 25% to 69% in 2010. Screening has not increased the number of mastectomies. Breast cancer treatment in Denmark is evidence based and in agreement with international recommendations. After the introduction of mammography screening the absolute number of patients with a more advanced stage at diagnosis and the absolute number of patients undergoing mastectomy have decreased.

Background: Manganese superoxide dismutase (MnSOD) inhibits oxidative damage and cancer therapy effectiveness. A polymorphism in its encoding gene (SOD2: Val16Ala rs4880) may confer poorer breast cancer survival, but data are inconsistent. We examined the association of SOD2 genotype and breast cancer recurrence (BCR) among patients treated with cyclophosphamide-based chemotherapy (Cyclo). We compared our findings with published studies using meta-analyses., Methods: We conducted a population-based case-control study of BCR among women in Jutland, Denmark. Subjects were diagnosed with non-metastatic breast cancer from 1990-2001, received adjuvant Cyclo, and were registered in the Danish Breast Cancer Cooperative Group. We identified 118 patients with BCR and 213 matched breast cancer controls. We genotyped SOD2 and used conditional logistic regression to compute the odds ratio (OR) and associated 95% confidence intervals (95% CI) of BCR. We used random-effects meta-analytic models to evaluate the association of SOD2 polymorphisms and BCR., Results: The frequency of the SOD2-Ala allele was 70% in cases versus 71% in controls; 40% versus 44% were heterozygotes, and 30% versus 25% were homozygotes, respectively. Heterozygote and homozygote carriers of the Ala allele had no increased rate of BCR (OR = 1.1, 95%CI = 0.65, 2.0, and OR = 0.87, 95%CI = 0.47, 1.6, respectively). Five studies informed the meta-analytic models; summary estimates associating BCR for homozygote, or any inheritance of the variant Ala allele were 1.18 (95%CI = 0.74, 1.88), and 1.18, (95%CI = 0.91, 1.54), respectively., Conclusion: Our findings do not suggest that MnSOD enzymatic activity, as measured by SOD2 genotype, affects rates of BCR among patients treated with Cyclo.

Background: Survival of breast cancer patients with comorbidity, compared to those without comorbidity, has been well characterized. The interaction between comorbid diseases and breast cancer, however, has not been well-studied., Methods: From Danish nationwide medical registries, we identified all breast cancer patients between 45 and 85 years of age diagnosed from 1994 to 2008. Women without breast cancer were matched to the breast cancer patients on specific comorbid diseases included in the Charlson comorbidity Index (CCI). Interaction contrasts were calculated as a measure of synergistic effect on mortality between comorbidity and breast cancer., Results: The study included 47,904 breast cancer patients and 237,938 matched comparison women. In the first year, the strongest interaction between comorbidity and breast cancer was observed in breast cancer patients with a CCI score of ≥4, which accounted for 29 deaths per 1000 person-years. Among individual comorbidities, dementia interacted strongly with breast cancer and accounted for 148 deaths per 1000 person-years within one year of follow-up. There was little interaction between comorbidity and breast cancer during one to five years of follow-up., Conclusions: There was substantial interaction between comorbid diseases and breast cancer, affecting mortality. Successful treatment of the comorbid diseases or the breast cancer can delay mortality caused by this interaction in breast cancer patients.

Purpose: To estimate associations between use of β-blockers, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs) and breast cancer recurrence in a large Danish cohort., Patients and Methods: We enrolled 18,733 women diagnosed with nonmetastatic breast cancer between 1996 and 2003. Patient, treatment, and 10-year recurrence data were ascertained from the Danish Breast Cancer Cooperative Group registry. Prescription and medical histories were ascertained by linkage to the National Prescription Registry and Registry of Patients, respectively. β-Blocker exposure was defined in aggregate and according to solubility, receptor selectivity, and individual drugs. ACE inhibitor and ARB exposures were defined in aggregate. Recurrence associations were estimated with multivariable Cox regression models in which time-varying drug exposures were lagged by 1 year., Results: Compared with never users, users of any β-blocker had a lower recurrence hazard in unadjusted models (unadjusted hazard ratio [HR] = 0.91; 95% CI, 0.81 to 1.0) and a slightly higher recurrence hazard in adjusted models (adjusted HR = 1.3; 95% CI, 1.1 to 1.5). Associations were similar for exposures defined by receptor selectivity and solubility. Although most individual β-blockers showed no association with recurrence, metoprolol and sotalol were associated with increased recurrence rates (adjusted metoprolol HR = 1.5, 95% CI, 1.2 to 1.8; adjusted sotalol HR = 2.0, 95% CI, 0.99 to 4.0). ACE inhibitors were associated with a slightly increased recurrence hazard, whereas ARBs were not associated with recurrence (adjusted ACE inhibitor HR = 1.2, 95% CI, 0.97 to 1.4; adjusted ARBs HR = 1.1, 95% CI, 0.85 to 1.3)., Conclusion: Our data do not support the hypothesis that β-blockers attenuate breast cancer recurrence risk.

Background: Estrogen receptor (ER) expression predicts tamoxifen response, which halves the risk of breast cancer recurrence. We examined clinical factors associated with concordance between ER expression at diagnosis and centralized re-assay, and the association of concordance with breast cancer recurrence., Material and Methods: We used immunohistochemistry to assess ER expression on archived fixed, paraffin-embedded breast carcinoma tissue excised from women aged 35-69 years, diagnosed 1985-2001 in Jutland, Denmark. We calculated the percentage agreement, positive predictive value (PPV) and negative predictive value (NPV) of ER status at diagnosis and re-assay. We used logistic regression to investigate factors associated with concordance, and its association with recurrence (odds ratios (OR) and associated 95% confidence intervals (95%CI))., Results: ER was re-assayed in 91% of patients (n = 1530). Concordance was better in ER + than ER- tumors (PPV = 94% vs. NPV = 75%). Factors associated with concordance included menopausal status, tumor size, surgical procedure, diagnostic period, lymph node status and time to recurrence. ER + women at diagnosis who re-assayed ER + were less likely to have recurrent disease (OR = 0.49, 95% CI = 0.28, 0.86) than those who re-assayed ER-. In originally ER- women, concordance was not associated with recurrence (OR = 0.97, 95% CI = 0.66, 1.42)., Conclusions: Several clinical factors were associated with ER assay concordance. Some women were ineffectively treated with tamoxifen, or required but did not receive tamoxifen. We observed almost exactly the protective effect of endocrine therapy among tamoxifen-treated ER + women whose tumors expressed the ER on re-assay, compared with those ER- on re-assay. Diagnostic pathology results for ER + tumors appear a valid and useful resource for research studies. However, those for ER- tumors have lower validity. Study-specific considerations regarding the aims, diagnostic period, and consequences of including ER- patients with truly ER + disease ought to be examined when using diagnostic pathology results for ER- tumors in research studies.

Introduction: Chronic diseases and their complications may increase breast cancer risk through known or still unknown mechanisms, or by shared causes. The association between morbidities and breast cancer risk has not been studied in depth., Methods: Data on all Danish women aged 45 to 85 years, diagnosed with breast cancer between 1994 and 2008 and data on preceding morbidities were retrieved from nationwide medical registries. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression associating the Charlson comorbidity score (measured using both the original and an updated Charlson Comorbidity Index (CCI)) with incident breast cancer. Furthermore, we estimated associations between 202 morbidity categories and incident breast cancer, adjusting for multiple comparisons using empirical Bayes (EB) methods., Results: The study included 46,324 cases and 463,240 population controls. Increasing CCI score, up to a score of six, was associated with slightly increased breast cancer risk. Among the Charlson diseases, preceding moderate to severe renal disease (OR = 1.25, 95% CI: 1.06, 1.48), any tumor (OR = 1.17, 95% CI: 1.10, 1.25), moderate to severe liver disease (OR = 1.86, 95% CI: 1.32, 2.62), and metastatic solid tumors (OR = 1.49, 95% CI: 1.17, 1.89), were most strongly associated with subsequent breast cancer. Preceding myocardial infarction (OR = 0.89, 95% CI: 0.81, 0.99), connective tissue disease (OR = 0.87, 95% CI: 0.80, 0.94), and ulcer disease (OR = 0.91, 95% CI: 0.83, 0.99) were most strongly inversely associated with subsequent breast cancer. A history of breast disorders was associated with breast cancer after EB adjustment. Anemias were inversely associated with breast cancer, but the association was near null after EB adjustment., Conclusions: There was no substantial association between morbidity measured with the CCI and breast cancer risk.

Background: Accumulating evidence suggests that statins affect diseases other than cardiovascular disease, including cancer, and that these effects may depend on the lipid solubility of specific statins. Though many studies have reported an association between statin use and breast cancer incidence, the relationship between statin use and breast cancer recurrence has not been well studied., Methods: We conducted a nationwide, population-based prospective cohort study of all female residents in Denmark diagnosed with stage I-III invasive breast carcinoma who were reported to the Danish Breast Cancer Cooperative Group registry between 1996 and 2003 (n = 18,769). Women were followed for a median of 6.8 years after diagnosis. Prescriptions for lipophilic and hydrophilic statins were ascertained from the national electronic pharmacy database. Associations between statin prescriptions and breast cancer recurrence were estimated with generalized linear models and Cox proportional hazards regression with adjustment for age and menopausal status at diagnosis; histological grade; estrogen receptor status; receipt of adjuvant therapy; type of primary surgery received; pre-diagnosis hormone replacement therapy; and co-prescriptions of aspirin, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or anticoagulants. All statistical tests were two-sided., Results: Most prescriptions for lipophilic statins in the study population were for simvastatin. Exclusive simvastatin users experienced approximately 10 fewer breast cancer recurrences per 100 women after 10 years of follow-up (adjusted 10-year risk difference = -0.10, 95% confidence interval = -0.11 to -0.08), compared with women who were not prescribed a statin. Exclusive hydrophilic statin users had approximately the same risk of breast cancer recurrence as women not prescribed a statin over follow-up (adjusted 10-year risk difference = 0.05, 95% confidence interval = -0.01 to 0.11)., Conclusions: Simvastatin, a highly lipophilic statin, was associated with a reduced risk of breast cancer recurrence among Danish women diagnosed with stage I-III breast carcinoma, whereas no association between hydrophilic statin use and breast cancer recurrence was observed.

Background: Tamoxifen is oxidized by cytochrome-P450 enzymes (e.g., CYP2D6) to two active metabolites, which are eliminated via glucuronidation by UDP-glucuronosyl transferases (UGT). We measured the association between functional polymorphisms in key UGTs (UGT2B15*2, UGT2B7*2, and UGT1A8*3) and the recurrence rate among breast cancer survivors., Methods: We used the Danish Breast Cancer Cooperative Group registry to identify 541 cases of recurrent breast cancer among women with estrogen receptor-positive tumors treated with tamoxifen for at least 1 year (ER(+)/TAM(+)), and 300 cases of recurrent breast cancer among women with estrogen receptor-negative tumors who were not treated with tamoxifen (ER(-)/TAM(-)). We matched one control to each case on ER status, menopausal status, stage, calendar period, and county. UGT polymorphisms were genotyped from archived primary tumors. We estimated the recurrence OR for the UGT polymorphisms by using logistic regression models, with and without stratification on CYP2D6*4 genotype., Results: No UGT polymorphism was associated with breast cancer recurrence in either the ER(+)/TAM(+) or ER(-)/TAM(-) groups [in the ER(+)/TAM(+) group, compared with two normal alleles: adjusted OR for two UGT2B15*2 variant alleles = 1.0 (95% CI, 0.70-1.5); adjusted OR for two UGT2B7*2 variant alleles = 0.96 (95% CI, 0.65-1.4); adjusted OR for one or two UGT1A8*3 variant alleles = 0.95 (0.49-1.9)]. Associations were similar within strata of CYP2D6*4 genotype., Conclusions: Functional polymorphisms in key tamoxifen-metabolizing enzymes were not associated with breast cancer recurrence risk., Impact: Our results do not support the genotyping of key metabolic enzyme polymorphisms to predict response to tamoxifen therapy.

Mammography screening is offered healthy women, and a high standard on professional and organizational level is mandatory not only in the screening programme but even in the diagnostic work-up and treatment. The main goal is to achieve a substantial reduction in disease specific mortality, but it is not possible to evaluate the effect on mortality until several years later, and continuously monitoring of the quality of all aspects of a screening programme is necessary. Based on other European guidelines, 11 quality indicators have been defined, and guidelines concerning organizational requirements for a Danish screening programme as well as recommendations for the radiographic and radiological work have been drawn up.

Background: Cytochrome P450 2D6 (CYP2D6) inhibition reduces the concentration of 4-hydroxylated tamoxifen metabolites, but the clinical relevance remains uncertain., Methods: We conducted a large case-control study nested in the population of 11 251 women aged 35-69 years at diagnosis of stage I-III breast cancer between 1985 and 2001 on Denmark's Jutland Peninsula and registered with the Danish Breast Cancer Cooperative Group. We identified 541 recurrent or contralateral breast cancers among women with estrogen receptor-positive (ER+) disease treated with tamoxifen for at least 1 year and 300 cancers in women with ER-negative (ER-) disease never treated with tamoxifen. We matched one control subject per case patient on ER status, menopausal status, stage, calendar time, and county, genotyped the CYP2D6*4 allele to assess genetic inhibition, and ascertained prescription history to assess drug-drug inhibition. We estimated the odds ratio (OR), associating CYP2D6 inhibition with breast cancer recurrence and adjusted for potential confounding with logistic regression. To address bias from incomplete information on CYP2D6 function, we used Monte Carlo simulation to complete a record-level probabilistic bias analysis. All statistical tests were two-sided., Results: The frequency of the CYP2D6*4 minor allele was 24% in case patients with ER+ tumors, 23% in case patients with ER- tumors, and 22% each in control subjects with ER+ and ER- tumors. In women with ER+ tumors, the associations of one functional allele with recurrence (OR = 0.99; 95% confidence interval = 0.76 to 1.3) and no functional allele with recurrence (OR = 1.4; 95% confidence interval = 0.84 to 2.3) were near null, as were those for women with ER- tumors. The near-null associations persisted when evaluated by intake of medications, by combining genotype with medication history, in the probabilistic bias analysis, or by restricting the analysis to women with ER expression confirmed by re-assay., Conclusion: The association between CYP2D6 inhibition and recurrence in tamoxifen-treated patients is likely null or small.

Background: Up to one-quarter of breast cancer patients suffer clinically significant depression in the year after diagnosis, which may respond to intervention. About half may be prescribed a psychotropic medication, such as a selective serotonin reuptake inhibitor (SSRI), while completing breast cancer therapy. Cytochrome P-450 2D6 (CYP2D6) metabolizes SSRIs and also metabolizes tamoxifen to more active forms. Therefore, concurrent use of SSRIs may reduce tamoxifen's effectiveness at preventing breast cancer recurrence. The SSRI citalopram has limited potency to inhibit CYP2D6 activity, so has been recommended for breast cancer patients taking tamoxifen. This study provides epidemiologic evidence to support this recommendation., Material and Methods: We conducted a case-control study of breast cancer recurrence nested in the population of female residents of Denmark who were diagnosed with non-metastatic estrogen-receptor positive breast cancers between 1994 and 2001 and who took tamoxifen for at least one year. We ascertained complete prescription histories by linking cases' and controls' civil registration numbers to the Danish national prescription registry. We estimated the association between SSRI use while taking tamoxifen and risk of recurrent breast cancer., Results: About the same proportion of recurrent cases (37 of 366) and matched controls (35 of 366) received at least one prescription for citalopram or its s-stereoisomer while taking tamoxifen (adjusted odds ratio = 1.1, 95% confidence interval = 0.7, 1.7). Breast cancer patients taking other SSRIs were also at no increased risk of recurrence (adjusted odds ratio = 0.9, 95% confidence interval = 0.5, 1.8)., Discussion: Breast cancer patients with indications for an SSRI may be prescribed citalopram - and possibly other SSRI - without adversely affecting the outcome of adjuvant therapy with tamoxifen.

Objectives: Overweight is associated with advanced stage at diagnosis in breast cancer patients. This could be explained by specific tumour characteristics or tumour promoting factors in the obese, but a diagnostic delay could also be of importance. Mammographic screening has caused a change towards diagnosis of less advanced tumours. This study investigates invitation to mammographic screening and the association between overweight and tumour size/axillary lymph node involvement at breast cancer diagnosis in postmenopausal women., Methods: In 1976 a randomized mammographic screening trial, inviting 50% of all women aged 45-69 was set up in Malmö, Sweden. The present analysis examined overweight (body mass index >or=25) as a determinant for large tumours (>20mm) and axillary lymph node involvement in postmenopausal women. These associations were studied separately in patients diagnosed prior to the mammographic screening trial, in invited women and in non-invited subjects (controls). In all, 2478 postmenopausal women were diagnosed with invasive breast cancer in these groups between 1961 and 1991. Logistic regression analysis allowed adjustment for other potential determinants of tumours size and axillary lymph node involvement., Results: In women diagnosed before the onset of the screening trial and in women not invited to mammography in the trial (controls), overweight was positively associated with large tumour size and axillary node involvement. There was no statistically significant association between overweight and these factors in women invited to mammographic screening., Conclusion: Invitation to mammographic screening may be particularly important for overweight postmenopausal women in order to detect breast tumours early.

Using hospital discharge data from the counties in Northern Denmark and the Danish Cancer Registry, we examined the trend in the prevalence of breast-conserving surgery (BCS) to treat primary breast cancer from 1982 through 2002, with an emphasis on publications that may have influenced surgical practice in Denmark. Overall, the prevalence of BCS increased from less than 1% of breast cancer operations in 1982 to approximately 25% by 2002. The rise in prevalence was most pronounced for the treatment of young women and women with early-stage breast cancer. Of three pivotal clinical trials, the most significant trigger of the upward trend appeared to be a study conducted by the Danish Breast Cancer Cooperative Group, published in 1988. After 1988, there was a steep rise in the prevalence of BCS. By 2002, BCS prevalence appeared to reach a threshold at 25% of breast cancer operations, seemingly defined by the proportion of new breast cancer cases who are good candidates for BCS.

Background: The validation series of sentinel lymph node biopsy (SLNB) in the treatment of breast cancer have shown that 10-20% more lymph node metastases are detected. However, their impact has never been studied in populations where the method has been fully implemented. In a population-based setting, the objective of the current study was to estimate the increased risk of metastases after introduction of the sentinel lymph node biopsy technique., Methods: We identified all new breast cancer patients in three different counties in two time periods (1996-1997 and 2002-2003). The study cohort was comprised of 2 932 patients. The main outcome was the frequency of patients with metastases. The frequencies of patients with metastases were compared as well as adjusted (using a multivariate logistic regression) and unadjusted odds-ratio for detecting lymph node metastases., Results: In counties where sentinel lymph node biopsy was implemented, the frequency of patients with lymph node metastases increased significantly 7.3% (95% CI: 1.0-13.7%) and 13.3% (95% CI: 7.3-19.3%), respectively. In the county without sentinel lymph node biopsy, an insignificant increase of 6.9% (-0.1-13.9%) in the frequency of patients with metastases was seen. The adjusted odds- ratio for detecting lymph node metastases was 1.41 (1.07-1.87) and 1.70 (1.30-2.23) in the counties with SLNB., Conclusion: The frequency of patients with metastases increased significantly in counties where sentinel lymph node biopsy was implemented.

Prior to the initiation of a nationwide study of the sentinel node staging technique the Danish Breast Cancer Cooperative Group (DBCG) defined a set of minimum requirements to be met by surgical departments before they could include patients in the study. The requirements specified a minimum patient load in the individual surgical unit, a minimum surgical training in the sentinel node biopsy technique and a minimum quality outcome in a validating learning series of SNLB procedures. A working group assisted departments in meeting these terms and later audited and certified departments before they could include patients into the study. As a result of this strategy the sentinel lymph node staging was fully implemented in all Danish surgical breast cancer centres within three years and all sentinel node biopsies in the period were recorded in the DBCG data centre. Furthermore, the strategy accelerated the ongoing process of centralizing breast surgery in specialized departments.

Objective: To evaluate the rate of over-diagnosis of breast cancer 15 years after the end of the Malmö mammographic screening trial., Design: Follow-up study., Setting: Malmö, Sweden., Subjects: 42 283 women aged 45-69 years at randomisation., Interventions: Screening for breast cancer with mammography or not (controls). Screening was offered at the end of the randomisation design to both groups aged 45-54 at randomisation but not to groups aged 55-69 at randomisation., Main Outcome Measures: Rate of over-diagnosis of breast cancer (in situ and invasive), calculated as incidence in the invited and control groups, during period of randomised design (period 1), during period after randomised design ended (period 2), and at end of follow-up., Results: In women aged 55-69 years at randomisation the relative rates of over-diagnosis of breast cancer (95% confidence intervals) were 1.32 (1.14 to 1.53) for period 1, 0.92 (0.79 to 1.06) for period 2, and 1.10 (0.99 to 1.22) at the end of follow-up., Conclusion: Conclusions on over-diagnosis of breast cancer in the Malmö mammographic screening trial can be drawn mainly for women aged 55-69 years at randomisation whose control groups were never screened. Fifteen years after the trial ended the rate of over-diagnosis of breast cancer was 10% in this age group.

Breast cancer survival differs 9 percentage points between the neighbouring countries of Denmark and Sweden. The authors' aim was to analyse whether this was caused by early detection in Sweden. The extent of disease and outcome was compared in two population-based breast cancer cohorts in 1983-1989. Breast cancer management was decentralized in Denmark without mammography screening whereas treatment in Sweden was centralized and the population partly screened. Ten- and 15-year relative survival was 15% and 6% higher in Sweden (p<0.001) with corresponding differences in crude and disease-specific survival. Stage distribution was significantly more favourable in the Swedish cohort. In multivariate analysis age, tumour size, extent of axillary surgery, and spread affected survival; however, the impact of region persisted (p<0.001). Reanalysis without screening-detected patients only slightly affected the impact of region. It was concluded that early detection had significant impact on survival but other regional differences might be of importance.

One hundred and twenty-four patients with palpable tumours underwent sentinel lymph node biopsy (SLNB) and subsequent axillary lymph node dissection. Ultrasound of the axilla was used as part of the diagnostic work-up on all patients and those with lymph node metastasis verified by fine-needle aspiration biopsy (FNAB) were not included. For identifying the SLNs, a combination of Tc-99m-labelled human albumin (Solco-ALBU-RES) and blue dye (Patent Blue V) was used. No lymphoscintigraphy was performed. The SLN was successfully identified in 122 out of 124 (98%) patients and 66 (54%) patients were found to have metastatic involvement of the axillary lymph nodes. In 52 (79%) of these patients, the SLNs were the only nodes involved, 28 (54%) had micrometastasis only. The false-negative rate was 1.5%. This method has proven valid in the staging of the axilla in patients with breast cancer. The advanced techniques of serial sectioning and immunohistochemical staining further improve the diagnostic advantage offered by the SLNB, as it increases the possibility of diagnosing micrometastatic deposits.