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Background: Population-based cancer quality registries are of great importance for the improvement of cancer care. However, little is known about the quality of recurrence data in cancer quality registries. The aim of this study was to evaluate data quality in the regional Breast Cancer Quality Registry of Central Sweden, with emphasis on the validity of recorded information on recurrence., Methods: Validation by re-abstraction was performed on a random sample of 800 women with primary invasive breast cancer stage I-III diagnosed between 1993 and 2010, of which 400 had at least one registered recurrence and 400 had no registered recurrence. Registry data were compared with data from medical records. Exact agreement, correlation and kappa values, sensitivity and specificity were calculated., Results: Seven hundred forty-seven women (93%) were available for analysis. Exact agreement was high for diagnostics, tumor characteristics, surgery, and adjuvant oncological treatment (90% or more for most variables). The registry's sensitivity was low for regional recurrence (47%), but higher for local and distant recurrence (80% and 75%), whereas specificity was overall high (≥ 95%). Combining all recurrence categories irrespective of localization improved sensitivity to 90% with a specificity of 91%. In 87% of women, the date of first recurrence according to medical records fell within ± 90 days of the date recorded in the registry., Conclusions: While the quality of data in the regional Breast Cancer Quality Registry was generally high, data accuracy on recurrences was lower. The overall precision of identifying any recurrence, irrespective of localization, was high. However, the accuracy of classification of recurrences (local, regional or distant) was lower, with evidence of underreporting for each of the recurrence categories. Given the importance of recurrence-related outcomes in the assessment of quality of care, efforts should be made to improve the reporting of recurrences., (© 2024. The Author(s).)

Purpose: This study introduces a novel method for estimating the variance of life expectancy since diagnosis (LE C ) and loss in life expectancy (LLE) for cancer patients within a relative survival framework in situations where life tables based on the entire general population are not accessible. LE C and LLE are useful summary measures of survival in population-based cancer studies, but require information on the mortality in the general population. Our method addresses the challenge of incorporating the uncertainty of expected mortality rates when using a sample from the general population., Methods: To illustrate the approach, we estimated LE C and LLE for patients diagnosed with colon and breast cancer in Sweden. General population mortality rates were based on a random sample drawn from comparators of a matched cohort. Flexible parametric survival models were used to model the mortality among cancer patients and the mortality in the random sample from the general population. Based on the models, LE C and LLE together with their variances were estimated. The results were compared with those obtained using fixed expected mortality rates., Results: By accounting for the uncertainty of expected mortality rates, the proposed method ensures more accurate estimates of variances and, therefore, confidence intervals of LE C and LLE for cancer patients. This is particularly valuable for older patients and some cancer types, where underestimation of the variance can be substantial when the entire general population data are not accessible., Conclusion: The method can be implemented using existing software, making it accessible for use in various cancer studies. The provided example of Stata code further facilitates its adoption., (© 2023. The Author(s).)

Background: Multi-state models are used to study several clinically meaningful research questions. Depending on the research question of interest and the information contained in the data, different multi-state structures and modelling choices can be applied. We aim to explore different research questions using a series of multi-state models of increasing complexity when studying repeated prescriptions data, while also evaluating different modelling choices., Methods: We develop a series of research questions regarding the probability of being under antidepressant medication across time using multi-state models, among Swedish women diagnosed with breast cancer (n = 18,313) and an age-matched population comparison group of cancer-free women (n = 92,454) using a register-based database (Breast Cancer Data Base Sweden 2.0). Research questions were formulated ranging from simple to more composite ones. Depending on the research question, multi-state models were built with structures ranging from simpler ones, like single-event survival analysis and competing risks, up to complex bidirectional and recurrent multi-state structures that take into account the recurring start and stop of medication. We also investigate modelling choices, such as choosing a time-scale for the transition rates and borrowing information across transitions., Results: Each structure has its own utility and answers a specific research question. However, the more complex structures (bidirectional, recurrent) enable accounting for the intermittent nature of prescribed medication data. These structures deliver estimates of the probability of being under medication and total time spent under medication over the follow-up period. Sensitivity analyses over different definitions of the medication cycle and different choices of timescale when modelling the transition intensity rates show that the estimates of total probabilities of being in a medication cycle over follow-up derived from the complex structures are quite stable., Conclusions: Each research question requires the definition of an appropriate multi-state structure, with more composite ones requiring such an increase in the complexity of the multi-state structure. When a research question is related with an outcome of interest that repeatedly changes over time, such as the medication status based on prescribed medication, the use of novel multi-state models of adequate complexity coupled with sensible modelling choices can successfully address composite, more realistic research questions., (© 2023. The Author(s).)

Objectives: A growing body of evidence suggests longer time between symptom onset and start of treatment affects breast cancer prognosis. To explore this association, the International Cancer Benchmarking Partnership Module 4 examined differences in breast cancer diagnostic pathways in 10 jurisdictions across Australia, Canada, Denmark, Norway, Sweden and the UK., Setting: Primary care in 10 jurisdictions., Participant: Data were collated from 3471 women aged >40 diagnosed for the first time with breast cancer and surveyed between 2013 and 2015. Data were supplemented by feedback from their primary care physicians (PCPs), cancer treatment specialists and available registry data., Primary and Secondary Outcome Measures: Patient, primary care, diagnostic and treatment intervals., Results: Overall, 56% of women reported symptoms to primary care, with 66% first noticing lumps or breast changes. PCPs reported 77% presented with symptoms, of whom 81% were urgently referred with suspicion of cancer (ranging from 62% to 92%; Norway and Victoria). Ranges for median patient, primary care and diagnostic intervals (days) for symptomatic patients were 3-29 (Denmark and Sweden), 0-20 (seven jurisdictions and Ontario) and 8-29 (Denmark and Wales). Ranges for median treatment and total intervals (days) for all patients were 15-39 (Norway, Victoria and Manitoba) and 4-78 days (Sweden, Victoria and Ontario). The 10% longest waits ranged between 101 and 209 days (Sweden and Ontario)., Conclusions: Large international differences in breast cancer diagnostic pathways exist, suggesting some jurisdictions develop more effective strategies to optimise pathways and reduce time intervals. Targeted awareness interventions could also facilitate more timely diagnosis of breast cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: A recent overview of cancer survival trends 1990-2016 in the Nordic countries reported continued improvements in age-standardized breast cancer survival among women. The aim was to estimate age-specific survival trends over calendar time, including life-years lost, to evaluate if improvements have benefited patients across all ages in the Nordic countries., Methods: Data on breast cancers diagnosed 1990-2016 in Denmark, Finland, Iceland, Norway, and Sweden were obtained from the NORDCAN database. Age-standardized and age-specific relative survival (RS) was estimated using flexible parametric models, as was reference-adjusted crude probabilities of death and life-years lost., Results: Age-standardized period estimates of 5-year RS in women diagnosed with breast cancer ranged from 87% to 90% and 10-year RS from 74% to 85%. Ten-year RS increased with 15-18 percentage points from 1990 to 2016, except in Sweden (+9 percentage points) which had the highest survival in 1990. The largest improvements were observed in Denmark, where a previous survival disadvantage diminished. Most recent 5-year crude probabilities of cancer death ranged from 9% (Finland, Sweden) to 12% (Denmark, Iceland), and life-years lost from 3.3 years (Finland) to 4.6 years (Denmark). Although survival improvements were consistent across different ages, women aged ≥70 years had the lowest RS in all countries. Period estimates of 5-year RS were 94-95% in age 55 years and 84-89% in age 75 years, while 10-year RS were 88-91% in age 55 years and 69-84% in age 75 years. Women aged 40 years lost on average 11.0-13.8 years, while women lost 3.8-6.0 years if aged 55 and 1.9-3.5 years if aged 75 years., Conclusions: Survival for Nordic women with breast cancer improved from 1990 to 2016 in all age groups, albeit with larger country variation among older women where survival was also lower. Women over 70 years of age have not had the same survival improvement as women of younger age.

The purpose was to review the incidence of in situ carcinoma in Iceland after initiating population-based mammography screening in 1987 and to compare management of ductal carcinoma in situ (DCIS) between Iceland and the Uppsala-Örebro region (UÖR) in Central Sweden. The Icelandic Cancer Registry provided data on in situ breast carcinomas for women between 1957 and 2017. Clinical data for women with DCIS between 2008 and 2014 was extracted from hospital records and compared to women diagnosed in UÖR. In Iceland, in situ carcinoma incidence increased from 7 to 30 per 100 000 women per year, following the introduction of organised mammography screening. The proportion of in situ carcinoma of all breast carcinomas increased from 4 to 12%. More than one third (35%) of women diagnosed with DCIS in Iceland were older than 70 years versus 18% in UÖR. In Iceland, 49% of all DCIS women underwent mastectomy compared to 40% in UÖR. The incidence of in situ carcinoma in Iceland increased four-fold after the uptake of population-based mammography screening causing considerable risk of overtreatment. Differences in treatment of DCIS were seen between Iceland and UÖR, revealing the importance of quality registration for monitoring patterns of management.

Objectives: The overall aim of the Swedish Breast Reconstruction Outcome Study was to investigate national long-term outcomes after mastectomy with or without breast reconstruction. The current report evaluates breast reconstruction (BR) patterns in Sweden over time., Materials and Methods: This is a cross-sectional, registry-based study where all women operated with mastectomy 2000, 2005, 2010 were identified (N = 5853). Geographical differences in type of BR were investigated using heatmaps. Distribution of continuous variables were compared using the Mann-Whitney U test, categorical variables were compared using the chi-square test., Results: Mean age at survey was 69 years (SD=±11.4) and response rate was 50%, responders were on average six years younger than the non-responders and had a more favourable tumor stage (both p < 0.01). Of the 2904 responders, 31% (895/2904) had received a BR: implant-based in 58% (516/895)autologous in 31% (281/895). BR was immediate in 20% (176/895) and delayed in 80% (719/895) women. Women with BR were on average one year older, more often had a normal BMI, reported to be married or had a partner, had a higher educational level and a higher annual income when compared to those without BR (all p < 0.001). The independent factors of not receiving BR were older age and given radiotherapy., Conclusions: To our knowledge, this is the first national long-term follow-up study on women undergoing mastectomy with and without BR. Around 30% of the survey responders have had a BR with a significant geographical variation highlighting the importance of information, availability and standardisation of indications for BR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

Purpose: To examine the influence of type of oncological treatment on sick leave in women of working age with early-stage breast cancer., Methods: We identified 8870 women aged 30-64 diagnosed with stage I-II breast cancer between 2005 and 2012 in the Breast Cancer Data Base Sweden. Associations between type of oncological treatment (radiotherapy, endocrine therapy, and chemotherapy) and sick leave were estimated by hazard ratios, probabilities, and length of sick leave using multi-state survival analysis., Results: During the first 5 years after diagnosis, women aged 50-54 years at diagnosis receiving chemotherapy spent on average 182 (95% CI 151-218) additional days on sick leave compared with women not receiving chemotherapy, but with otherwise similar characteristics. Correspondingly, women initiating endocrine therapy spent 30 (95% CI 18-44) additional days on sick leave and women receiving post-mastectomy radiotherapy 53 (95% CI 37-69) additional days. At year five, the rate of sick leave was increased in women who had received chemotherapy (HR 1.19, 95% CI 1.11-1.28) or endocrine therapy (HR 1.15, 95% CI 1.05-1.26). Chemotherapy and endocrine therapy were associated with increased rates of sick leave due to depression or anxiety., Conclusion: Our findings of increased long-term risks of sick leave after oncological treatment for breast cancer warrant attention from caregivers taking part in cancer rehabilitation. In light of the ongoing debate about overtreatment of early-stage breast cancer, our findings point to the importance of properly selecting patients for chemotherapy not only for the medical toxicity but also the possible impact on their livelihood.

Objectives: Women diagnosed with breast cancer during working age are at increased risk of permanent absence from work, but the underlying medical causes have rarely been studied. We examined the risk of cause-specific sick leave, disability pension, and the competing event death after a breast cancer diagnosis in a population-based cohort study., Materials and Methods: From the Breast Cancer Data Base Sweden, we identified 16,603 women diagnosed with stage I-III breast cancer between 2000 and 2012, and 63,773 control women. Using multi-state modelling, we calculated probabilities and durations of sick leave, disability pension, and death by registered cause, together with cause-specific hazard ratios., Results: Five years after diagnosis, causes other than cancer accounted for around half of all sick leave (3.5% out of 6.8% of women) and disability pension (1.4% out of 2.6%) in women with breast cancer. Compared with control women, women with breast cancer were at increased risk of sick leave and disability pension due to mental disorders (HR 1.24, 95% CI 1.15-1.33 and HR 1.54, 95% CI 1.29-1.85, respectively) and disability pension due to inflammatory diseases (HR 1.46, 95% CI 1.05-2.03). The risk of sick leave and disability pension due to cardiovascular disease was also elevated, although only statistically significant for disability pension in women diagnosed after 2005 (HR 2.24, 95% CI 1.22-4.13)., Conclusion: Follow-up, support, and rehabilitation programs for women diagnosed with breast cancer must address a wide range of psychological and physical conditions to limit the consequences on working life., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Many studies have found evidence of socioeconomic differences in breast cancer survival. This study aimed to quantify the impact of removing differences in stage distribution and stage-specific relative survival between education groups in Swedish women with breast cancer. Using information from a breast cancer research database, the study population contained 62 121 women diagnosed with breast cancer in three healthcare regions of Sweden from 1992 to 2012. The loss in expectation of life and life years lost due to breast cancer were estimated using flexible parametric relative survival models by education group and age at diagnosis. The potential gain in life years and postponable deaths were calculated by applying the 1) stage distribution, 2) stage-specific relative survival, and 3) both stage distribution and stage-specific relative survival of the high education group to the low and medium education groups. For a cohort of around 3500 women diagnosed with breast cancer residing in three Swedish healthcare regions in a typical calendar year, we estimated that removing stage differences would postpone an additional 25 deaths at five years after diagnosis, and result in a gain of approximately 573 life years. Alternatively, if stage-specific breast cancer survival could be equated, approximately 692 life years could be saved and an additional 26 deaths could be postponed five years after diagnosis. Results such as these can help guide decisions on interventions intended to minimise socioeconomic differences in breast cancer outcomes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Women with pregnancy-associated breast cancer (PABC), i.e. diagnosed during or within 2 years of pregnancy, have a poor prognosis. We compared symptoms, diagnostics, treatments, and waiting times from first symptoms to treatment initiation in women diagnosed with PABC and non-PABC., Materials and Methods: Women diagnosed with PABC and non-PABC at ages 15-44 were identified in Swedish healthcare registers. Chart information was retrieved for 546 women (273 PABC cases and 273 age- and hospital-matched non-PABC controls) treated at 11 hospitals across Sweden between 1992 and 2009. Distributions of symptoms, diagnostics and treatments were compared. Median waiting times from initial symptoms to start of treatment, and time periods within, were estimated from Kaplan-Meier curves., Results: Initial symptoms in women with PABC and non-PABC were similar. Women with PABC more often underwent biopsy and ultrasound than mammography at initial examination. Compared to non-PABC, rates of mastectomy and axillary clearance were higher in women with PABC, while endocrine treatment was less common. The time from symptoms to first healthcare contact was non-significantly longer in women diagnosed during or within 6 months of pregnancy. Waiting times from contact with healthcare to diagnosis and treatment were shorter or similar in women with PABC compared to women with non-PABC., Conclusions: These findings do not support the notion that diagnostic and treatment delays following a first healthcare contact are more common in women diagnosed with breast cancer during or shortly after pregnancy. However, there was some evidence of delays in seeking healthcare among pregnant and lactating women.

Background: Results from previous studies indicate that use of low-dose aspirin may improve breast cancer prognosis. We evaluated aspirin use and breast cancer outcomes in relation to clinical characteristics as well as dose and duration of aspirin use., Methods: We used information from the Regional Breast Cancer Quality-of-Care Registries in three Swedish regions to identify 21,414 women diagnosed with a first stage I-III breast cancer between 1 April 2006 and 31 December 2012. The cohort was further linked to nationwide registers to retrieve information about dispensing low-dose aspirin before and after breast cancer diagnosis, comorbidity and causes of death. In a separate analysis, we investigated time to breast cancer death among 621 women with stage IV disease at diagnosis. Associations were evaluated using a multivariable Cox proportional hazards model., Results: Among women with stage I-III breast cancer, 2660 (12.4%) used low-dose aspirin shortly before breast cancer diagnosis and 4091 (19.1%) were users during follow-up. Women were followed for a median of 3.8 years after diagnosis. There was no association between aspirin use and breast cancer-specific death in multivariable analyses (use before diagnosis: hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.77-1.12; use after diagnosis: HR 1.00, 95% CI 0.74-1.37). Similarly, aspirin use was not associated with risk of first recurrence/metastases in a subgroup of stage I-III breast cancer patients (HR 0.97, 95% CI 0.86-1.10). However, in analyses stratified by stage, an inverse association between low-dose aspirin use after diagnosis and breast cancer death was found for women with stage I tumors (HR 0.53, 95% CI 0.29-0.96). Among women with stage IV disease at diagnosis, aspirin use was not associated with time to breast cancer death (HR 0.91, 95% CI 0.67-1.23)., Conclusion: In this large population-based cohort study there was no evidence that low-dose aspirin use before or after breast cancer diagnosis is associated with a reduced risk of adverse outcomes overall in breast cancer. However, a potential benefit was noted among women with stage I tumors, warranting further investigation.

Expected or reference mortality rates are commonly used in the calculation of measures such as relative survival in population-based cancer survival studies and standardized mortality ratios. These expected rates are usually presented according to age, sex, and calendar year. In certain situations, stratification of expected rates by other factors is required to avoid potential bias if interest lies in quantifying measures according to such factors as, for example, socioeconomic status. If data are not available on a population level, information from a control population could be used to adjust expected rates. We have presented two approaches for adjusting expected mortality rates using information from a control population: a Poisson generalized linear model and a flexible parametric survival model. We used a control group from BCBaSe-a register-based, matched breast cancer cohort in Sweden with diagnoses between 1992 and 2012-to illustrate the two methods using socioeconomic status as a risk factor of interest. Results showed that Poisson and flexible parametric survival approaches estimate similar adjusted mortality rates according to socioeconomic status. Additional uncertainty involved in the methods to estimate stratified, expected mortality rates described in this study can be accounted for using a parametric bootstrap, but this might make little difference if using a large control population.

There is evidence of poor prognosis in women with pregnancy-associated breast cancer (PABC) diagnosed during pregnancy or within 2 years of delivery. Using a large, population-based cohort, we examined clinicopathologic features and survival in women with PABC. A cohort of women diagnosed with invasive breast cancer between 1992 and 2009 at ages 15-44 years was identified in the Swedish Cancer Register and the Breast Cancer Quality Registers. Dates of childbirths for each woman were retrieved from the Swedish Multi-Generation Register. Age-standardized distributions of tumor stage (tumor size, nodal status, metastasis), Elston grade and ER/PR/HER2 status were compared between nulliparous women and women with breast cancer during pregnancy and up to 10 years postdelivery. Adjusted hazard ratios for all-cause mortality rates among patients were estimated using Cox regression. We identified 1,661 nulliparous women with breast cancer, 778 women with PABC (97 during pregnancy, 270 within first and 411 within second year postdelivery) and 3,598 during 2-10 years postdelivery. Compared to nulliparous women, women with PABC, and especially women diagnosed 0-12 months after delivery, had more advanced T and N stage, and higher proportions of ER/PR negative, HER2 positive and triple-negative tumors. Increased hazard ratios were observed in women diagnosed within 5 years of delivery after adjustment for age, year, education and region. Following additional adjustment for tumor characteristics, the hazard ratios were attenuated and nonsignificant. The poorer prognosis observed in women with PABC appears to be largely explained by more adverse tumor characteristics at diagnosis., (© 2017 UICC.)

Background: Breast cancer can negatively influence working life, but it is unclear how many working years women with breast cancer can expect to lose., Methods: Women diagnosed with breast cancer between 1997 and 2012 were identified in the Breast Cancer Data Base Sweden (N=19 661), together with breast cancer-free comparison women (N=81 303). Using flexible parametric survival modelling, the loss in working years was calculated as the difference in the remaining years in the work force between women with and without breast cancer., Results: Women aged 50 years at diagnosis with stage I disease lost on average 0.5 years (95% CI, 0.2-0.7) of their remaining working time; the corresponding estimates were 0.9 years (0.5-1.2) in stage II, 2.5 years (1.9-3.1) in stage III and 8.1 years (6.5-9.7) in stage IV. Women with in situ breast cancer did not lose any working years. The strongest treatment determinant was axillary lymph node dissection., Conclusions: We found a loss in working years not only in late but also in early-stage breast cancer. Although it is reassuring that some groups had no or only a modest work loss, the economic consequences for society are considerable given the large number of women annually diagnosed with breast cancer.

Background: The lipid and glucose metabolisms are postulated as possible intermediary mechanisms in linking obesity and breast cancer (BC). Links between serum lipid and glucose biomarkers and BC risk has been observed in the Swedish Apolipoprotein MORtality RISk (AMORIS) cohort. We conducted a follow-up analysis including information on tumour characteristics., Methods: One thousand eight hundred twenty-four women diagnosed with BC, with serum biomarker levels of glucose, triglycerides, cholesterol (total, HDL, and LDL), and apolipoproteins A-1 and B recorded in a routine health check at baseline were included. BC severity was split into categories (good, moderate, and poor prognosis) based on ER status, TNM stage, and age at diagnosis. Proportional odds models were used to obtain odds ratios (ORs) and 95% confidence intervals (CI), with the interval time between baseline measurement and BC diagnosis accounted for., Results: Serum glucose and the ApoB/ApoA-1 ratio showed a non-statistically significant positive association with BC severity (proportional OR: 1.25 (95%CI: 0.92-1.70) for glucose (

Background: Different etiological pathways may precede development of specific breast cancer subtypes and impact prevention or treatment strategies. We investigated the association between gamma-glutamyl transferase (GGT) and development of specific breast cancer subtypes based on oestrogen receptor (ER), progesterone receptor (PR) and HER2 status., Methods: We included 231,283 cancer-free women in a Swedish cohort. Associations between GGT and breast cancer subtypes were investigated with nested case-control and case-case analyses. We used logistic regression models to assess serum GGT in relation to breast cancer subtype, based on individual and combined receptor status., Results: Positive associations were found between serum GGT and development of ER+, ER- and PR+ breast cancers compared to controls (odds ratio (OR) 1.14 (95% confidence interval (CI) 1.08-1.19), 1.11 (1.01-1.23) and 1.18 (1.12-1.24), respectively) and of ER+/PR+ tumours. We found inverse associations between GGT levels and PR- breast cancers compared to PR+ (OR 0.87 (0.80-0.95)), between ER+/PR- tumours compared to ER+/PR+ tumours and between ER-/PR-/HER+ compared to ER+/HER2 or PR+/HER2 tumours (OR 0.55 (95% CI 0.34-0.90)., Conclusion: The observed associations between pre-diagnostic serum GGT and different breast cancer subtypes may indicate distinct underlying pathways and require further investigations to tease out their clinical implications.

Background: Preclinical studies have demonstrated that propranolol inhibits several pathways involved in breast cancer progression and metastasis. We investigated whether breast cancer patients who used propranolol, or other non-selective beta-blockers, had reduced breast cancer-specific or all-cause mortality in eight European cohorts., Methods: Incident breast cancer patients were identified from eight cancer registries and compiled through the European Cancer Pharmacoepidemiology Network. Propranolol and non-selective beta-blocker use was ascertained for each patient. Breast cancer-specific and all-cause mortality were available for five and eight cohorts, respectively. Cox regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CIs) for cancer-specific and all-cause mortality by propranolol and non-selective beta-blocker use. HRs were pooled across cohorts using meta-analysis techniques. Dose-response analyses by number of prescriptions were also performed. Analyses were repeated investigating propranolol use before cancer diagnosis., Results: The combined study population included 55,252 and 133,251 breast cancer patients in the analysis of breast cancer-specific and all-cause mortality respectively. Overall, there was no association between propranolol use after diagnosis of breast cancer and breast cancer-specific or all-cause mortality (fully adjusted HR = 0.94, 95% CI, 0.77, 1.16 and HR = 1.09, 95% CI, 0.93, 1.28, respectively). There was little evidence of a dose-response relationship. There was also no association between propranolol use before breast cancer diagnosis and breast cancer-specific or all-cause mortality (fully adjusted HR = 1.03, 95% CI, 0.86, 1.22 and HR = 1.02, 95% CI, 0.94, 1.10, respectively). Similar null associations were observed for non-selective beta-blockers., Conclusions: In this large pooled analysis of breast cancer patients, use of propranolol or non-selective beta-blockers was not associated with improved survival.

Aims: Sweden has a long history of population-based cancer registration. The aim of our study was to assess the validity of DCIS registration in a regional Breast Cancer Quality Register (BCQR) and to analyze trends in incidence, treatment and outcome of DCIS, over a 20-year period., Material and Methods: All patients with a diagnosis of primary DCIS reported in the BCQR of the Uppsala-Örebro healthcare region in Sweden 1992-2012 were included. Three hundred women were randomly selected and their medical records were compared to register data. The study period was divided into four time periods., Results: A total of 2952 women were registered with a DCIS diagnosis. In the final validation cohort of 295 patients, 23 were found to have either recurrent DCIS or invasive breast cancer and eight had LCIS. The completeness and validity of key variables were 91-99%. Twenty of 31 local recurrences were registered (65%).The proportion of DCIS to all breast cancers was 9.5%. Tumor size increased over time. The frequency of mastectomy increased from 23.0% to 39.0%. The proportion of patients receiving radiotherapy after breast conserving surgery increased from 30.1% to 67.6%. The reported local recurrence rate was 9.7% after 10 years. Reported recurrences after BCS and mastectomy were 12.0 and 7.0%, respectively. The recurrence rate did not differ between women undergoing BCS with or without radiotherapy., Conclusion: Only 89.5% of reported DCIS was a primary pure DCIS. The completeness of primary treatment and tumor data was high. The proportion of reported local recurrences was disappointingly low, 65%. The proportion of DCIS was stable over time with a trend towards more intensified treatment. The reported recurrence rate was low independent of treatment and can reflect adequate patient selection, but also over treatment. Our results address the necessity to validate register data on a regular basis.

To investigate the association between serum calcium and risk of breast cancer using a large cohort and a systematic review with meta-analysis. From the Swedish Apolipoprotein Mortality Risk (AMORIS) Study we included 229,674 women who had baseline measurements of serum total calcium and albumin. Multivariable Cox regression was used to assess the association between total and albumin-corrected calcium and breast cancer risk. For the systematic review, an electronic search of MEDLINE and EMBASE databases was performed to identify other prospective cohorts assessing the relationship between serum calcium and breast cancer risk. We pooled the results of our AMORIS cohort with other eligible studies in a meta-analysis using a random effects model. I² test was used to assess heterogeneity. In the AMORIS study, 10,863 women were diagnosed with breast cancer (mean follow-up: 19 years). We found an inverse association between total serum calcium and breast cancer when comparing the fourth quartile to the first quartile (HR: 0.94, 95% CI: 0.88-0.99, p value for trend 0.04) and similar results using albumin-corrected calcium. In the systematic review, we identified another two prospective cohorts evaluating pre-diagnostic serum total calcium and breast cancer. Combining these studies and our findings in AMORIS in a meta-analysis showed a protective effect of serum calcium against breast cancer, with a summary RR of 0.80 (95% CI: 0.66-0.97). No substantial heterogeneity was observed. Our findings in AMORIS and the meta-analysis support an inverse association between serum calcium and breast cancer risk, which warrants mechanistic investigations., Competing Interests: Niklas Hammar is employed by AstraZeneca. However, the views expressed in this study are his own and not those of AstraZeneca’s. No medical writer was involved in the study or manuscript preparation.

Objectives: This paper describes the methods used in the International Cancer Benchmarking Partnership Module 4 Survey (ICBPM4) which examines time intervals and routes to cancer diagnosis in 10 jurisdictions. We present the study design with defining and measuring time intervals, identifying patients with cancer, questionnaire development, data management and analyses., Design and Setting: Recruitment of participants to the ICBPM4 survey is based on cancer registries in each jurisdiction. Questionnaires draw on previous instruments and have been through a process of cognitive testing and piloting in three jurisdictions followed by standardised translation and adaptation. Data analysis focuses on comparing differences in time intervals and routes to diagnosis in the jurisdictions., Participants: Our target is 200 patients with symptomatic breast, lung, colorectal and ovarian cancer in each jurisdiction. Patients are approached directly or via their primary care physician (PCP). Patients' PCPs and cancer treatment specialists (CTSs) are surveyed, and 'data rules' are applied to combine and reconcile conflicting information. Where CTS information is unavailable, audit information is sought from treatment records and databases., Main Outcomes: Reliability testing of the patient questionnaire showed that agreement was complete (κ=1) in four items and substantial (κ=0.8, 95% CI 0.333 to 1) in one item. The identification of eligible patients is sufficient to meet the targets for breast, lung and colorectal cancer. Initial patient and PCP survey response rates from the UK and Sweden are comparable with similar published surveys. Data collection was completed in early 2016 for all cancer types., Conclusion: An international questionnaire-based survey of patients with cancer, PCPs and CTSs has been developed and launched in 10 jurisdictions. ICBPM4 will help to further understand international differences in cancer survival by comparing time intervals and routes to cancer diagnosis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Reproductive factors are well-known risk factors for premenopausal breast cancer (PBC). It is unknown whether these associations are modified by familial factors, including genetic and early environment factors., Methods: Using Swedish health registries, we performed a nested case-control study with two control groups: sister controls and population controls. The study population included women with live singleton births between 1973 and 2010, who also had a full sister who gave birth during this period. All women subsequently diagnosed with PBC were selected as cases (n = 8327). Sisters with the least age difference and without PBC at the time of her sister's diagnosis were selected as sister controls. For each incident case, one population control without previous PBC was selected.The population controls were individually matched with the sister controls on year of birth. Conditional logistic regression was used to estimate associations between reproductive factors and PBC., Results: Increasing parity was inversely associated with PBC using population controls, and multiparity was a risk factor using sister controls. Very preterm delivery (≤ 31 weeks) was associated with a slightly higher PBC risk using sister controls. Preeclampsia was associated with a slightly protective effect using population controls. With respect to other factors, there were no substantial differences in risks of PBC by choice of control group., Conclusions: The divergent results with regard to parity and PBC risk when using sister and population controls suggest that the influence of childbearing may be modified by genotype. Selection bias when using different control groups must also be considered., (© The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Abnormal glucose and lipids levels may impact survival after breast cancer (BC) diagnosis, but their association to other causes of mortality such as cardiovascular (CV) disease may result in a competing risk problem., Methods: We assessed serum glucose, triglycerides (TG) and total cholesterol (TC) measured prospectively 3 months to 3 years before diagnosis in 1798 Swedish women diagnosed with any type of BC between 1985 and 1999. In addition to using Cox regression, we employed latent class proportional hazards models to capture any heterogeneity of associations between these markers and BC death. The latter method was extended to include the primary outcome (BC death) and competing outcomes (CV death and death from other causes), allowing latent class-specific hazard estimation for cause-specific deaths., Results: A lack of association between prediagnostic glucose, TG or TC with BC death was observed with Cox regression. With latent class proportional hazards model, two latent classes (Class I and II) were suggested. Class I, comprising the majority (81.5 %) of BC patients, had an increased risk of BC death following higher TG levels (HR: 1.87, 95 % CI: 1.01-3.45 for every log TG increase). Lower overall survival was observed in Class II, but no association for BC death was found. On the other hand, TC positively corresponded to CV death in Class II, and similarly, glucose to death from other causes., Conclusion: Addressing cohort heterogeneity in relation to BC survival is important in understanding the relationship between metabolic markers and cause-specific death in presence of competing outcomes.

Inflammation has been linked to cancer but its role in breast cancer is unclear. We investigated common serum markers of inflammation: C-reactive protein (CRP), albumin, haptoglobin and white blood cells (WBC) in relation to breast cancer incidence, severity and survival. A total of 155179 women aged 20 and older without any history of cancer were selected from a large Swedish cohort. Hazard ratios (HRs) for breast cancer were estimated with Cox regression, adjusting for potential confounders. Ordered and binomial logistic regression models were used to assess the associations of serum inflammatory markers with breast cancer severity and oestrogen receptor (ER) positivity at diagnosis, on the other. Cumulative incidence functions by levels of inflammatory markers were assessed for early death from breast cancer and all causes. During a mean follow-up of 18.3 years, 6606 women were diagnosed with breast cancer, of whom 1474 died. A positive association with incident breast cancer was seen for haptoglobin ≥ 1.4g/l [HR 1.09; 95% confidence interval (CI): 1.00-1.18] compared to lower levels. No association was observed between inflammatory markers and breast cancer severity or ER positivity. Higher haptoglobin was linked to risk of early death from breast cancer (HR: 1.27, 95% CI: 1.02-1.59), whereas higher risk of early death from all causes was additionally found with CRP ≥ 10mg/l (HR: 1.19, 95% CI: 1.04-1.36) and WBC ≥ 10×10(9)/l (HR: 1.57, 1.14-2.16). Our findings indicate that prediagnostic serum inflammatory markers were weakly linked to incident breast cancer but corresponded to worse survival after diagnosis., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The risk of breast cancer is at least two-fold increased in young women with a family history of breast cancer. Pregnancy has a dual effect on breast cancer risk; a short-term increase followed by a long-term protection. We investigated if the risk of breast cancer during and within 10 years following pregnancy is affected by a family history of breast cancer. We followed a cohort of women aged 15-44 years between 1963 and 2009 identified in Swedish population-based registers. Family history was defined as having a mother or sister with breast cancer. We estimated incidence rate ratios of breast cancer during pregnancy and time intervals up to 10 years post-delivery, with a focus on pregnancy-associated breast cancer (PABC), defined as breast cancer during pregnancy or within 2 years post-delivery. In 3,452,506 women, there were 15,548 cases of breast cancer (1208 were PABC). Compared to nulliparous women, the risk of breast cancer was decreased during pregnancy, similar during first year and increased during second year post-delivery. The pattern was similar in women with or without family history of breast cancer. A peak in risk was observed 5-6 years following the first birth regardless of family history. After a second birth, this peak was only present in women with a family history. Our results indicate that women with a family history of breast cancer do not have a different breast cancer risk during and within 10 years following pregnancy compared to women without a family history.

Women born from a preeclamptic (PE) pregnancy are associated with a lower risk of breast cancer. Prenatal and early-life exposures are hypothesized to influence breast cancer susceptibility through their effect on stem cells. We examined stem cell populations in umbilical cord blood from PE pregnancies and compared with those from pregnancies without this condition. We isolated mononuclear cells from 58 PE and 197 normotensive (non-PE) umbilical cord blood samples and examined the different stem cell populations. Hematopoietic (CD34(+) and CD34(+)CD38(-)), endothelial (CD34(+)CD133(+), CD34(+)VEGFR2(+), CD133(+)VEGFR2(+) and CD34(+)CD133(+)VEGFR2(+)), and putative breast (EpCAM(+), EpCAM(+)CD49f(+), EpCAM(+)CD49f(+)CD117(+), CD49f(+)CD24(+), CD24(+)CD29(+) and CD24(+)CD29(+)CD49f(+)) stem/progenitor cell subpopulations were quantified by flow cytometry and compared between PE and non-PE samples. Hematopoietic CD34(+) cell counts were significantly lowered in PE compared with non-PE samples (P = 0.039, Kruskal-Wallis test). Levels of CD34(+)CD133(+) endothelial progenitor cells were also lower in PE samples (P = 0.032, multiple regression analysis). EpCAM(+) and EpCAM(+)CD49f(+) putative breast stem cell levels were significantly lowered in PE subjects (multiple regression analysis: P = 0.038 and 0.007, respectively). Stratifying by newborn gender, EpCAM(+) and EpCAM(+)CD49f(+) stem cells were significantly lowered in PE samples of female, but not male, newborns. Umbilical cord blood samples from pregnancies complicated by preeclampsia thus had significantly lower levels of hematopoietic, endothelial, and putative breast stem cells than non-PE controls. With a lowered breast cancer risk for offspring of a PE pregnancy, our findings provide support to the hypothesis that susceptibility to breast oncogenesis may be affected by conditions and processes during the prenatal period., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: To compare sickness absence and disability pension in a population-based cohort of women with breast cancer (n = 463) from 1 year pre-diagnosis until 3 years post-diagnosis with a matched control group (n = 2310), and to investigate predictors of sickness absence during the 2nd and 3rd year post-diagnosis., Results: Following breast cancer, the proportion of disease-free women with sickness absence decreased post-diagnosis (1st-3rd year; 78%-31%-19%), but did not reach the pre-diagnostic level (14%; P < 0.05). Post-diagnosis, patients were more likely than controls to be sickness absent (1st-3rd year; P < 0.001). No between-group differences were observed for disability pension post-diagnosis (P > 0.05). Among patients, chemotherapy, baseline fatigue and pre-diagnosis sick days predicted sickness absence during the 2nd, 3rd, and 2nd and 3rd year post-diagnosis, respectively (P < 0.05)., Conclusions: Breast cancer is associated with increased sickness absence 3 years post-diagnosis. In a clinical setting, prevention and treatment of side effects are important in reducing long-term consequences., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The main aim of this study was to investigate possible associations between measures of offspring size at birth in the most recent pregnancy before premenopausal breast cancer diagnosis and the risks of maternal breast cancer mortality, taking tumor characteristics into account. We also aimed to investigate if these associations are modified by age at childbirth, time since childbirth, parity, and age at diagnosis. We followed 6,019 women from their date of premenopausal breast cancer (diagnosed from 1992 to 2008) until emigration, death or December 31st, 2009, whichever occurred first. We used Cox proportional hazard regression models, adjusted for parity, age at diagnosis, and education level, to estimate associations between women pregnancy, cancer characteristics and offspring birth characteristics, and mothers' mortality risk. In stratified analyses, mortality risks were estimated by tumor stage, ER or PR status. There was no association between offspring birth weight (HR = 1.00, 95 % CI 0.99-1.01, when used as a continuous variable), birth weight for gestational age or ponderal index, and premenopausal breast cancer mortality. Similarly, in analyses stratified by tumor stage, receptor status, and time difference between last pregnancy and date of diagnosis, we found no associations between birth size and breast cancer mortality. Our findings suggest that the hypothesis that "premenopausal breast cancer mortality is associated with offspring birth characteristics in the most recent pregnancy before the diagnosis" may not be valid. In addition, these associations are not modified by tumor characteristics.

Preeclampsia, a complication of pregnancy characterized by hypertension and proteinuria, has been found to reduce the subsequent risk for breast cancer in female offspring. As this protective effect could be due to exposure to preeclampsia-specific proteins during intrauterine life, the proteomic profiles of umbilical cord blood plasma between preeclamptic and normotensive pregnancies were compared. Umbilical cord plasma samples, depleted of 14 abundant proteins, were subjected to proteomic analysis using the quantitative method of nanoACQUITY ultra performance liquid chromatography-mass spectrometry with elevated energy mode of acquisition(E) (NanoUPLC-MS(E)). Sixty-nine differentially expressed proteins were identified, of which 15 and 6 proteins were only detected in preeclamptic and normotensive pregnancies, respectively. Additionally, expression of 8 proteins (gelsolin, complement C5, keratin type I cytoskeletal 10, pigment epithelium-derived factor, complement factor B, complement component C7, hemoglobin subunit gamma-2 and alpha-fetoprotein) were up-regulated in preeclampsia with a fold change of ≥2.0 when compared to normotensive pregnancies. The identification of alpha-fetoprotein in preeclamptic umbilical cord blood plasma supported the validity of this screen as alpha-fetoprotein has anti-estrogenic properties and has previously been linked to preeclampsia as well as a reduced breast cancer risk. The findings of this pilot study may provide new insights into the mechanistic link between preeclampsia and potentially reduced breast cancer susceptibility in adult life., (Copyright © 2013. Production and hosting by Elsevier Ltd.)

Background: The relationship between gestation, childbirth and cancer prognosis is unknown for most cancers (e.g. Hodgkin lymphoma), whereas a body of evidence exists for melanoma and breast cancer., Methods: The national cancer registration and hospital discharge data for women in England (1998-2007) were linked, and the records for Hodgkin lymphoma, melanoma and breast cancer were indexed as to whether women had delivered a child in separate time periods prior to their cancer diagnosis. Survival analyses were conducted in order to characterise prognosis in relation to childbirth, with statistical adjustment for age and (where possible) stage., Findings: For melanoma and breast cancer, survival was strongly reduced in women who gave birth in the year prior to cancer diagnosis. The age-adjusted hazard ratios (HR) with 95% confidence intervals (CI) were 2.06 (1.42-3.01) for melanoma and 1.84 (1.64-2.06) for breast cancer. The associations were only slightly attenuated by further adjustment for tumour stage. For breast cancer, the excess death rate in women with a recent childbirth peaked at 2 years and remained elevated for 6 to 8 years. Previous childbirth had no overall effect on the outcome of Hodgkin lymphoma., Interpretation: Melanoma and breast cancer prognosis are adversely affected by recent gestation and childbirth in a way that is not due to stage of the cancer, but rather to inherent biological properties of the tumours. Possible biological mechanisms include immunosuppression (melanoma), the hormonal milieu in gestation and a tumour promoting microenvironment post-partum (breast cancer)., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate whether longitudinal changes in health-related quality of life (HRQoL) among breast cancer patients vary by prediagnosis occupational status or postdiagnosis changes in working time., Methods: We identified 1573 patients in the Breast Cancer Quality Register of Central Sweden and asked them to participate in a longitudinal questionnaire study. A total of n = 841 women completed three questionnaires within a mean time of 4, 16, and 38 months postdiagnosis. Generalized estimating equation models were used to examine changes in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and the Breast Cancer-Specific Quality of Life Questionnaire subscales stratified by prediagnosis occupational status and postdiagnosis changes in working time., Results: Over time, the proportion of employed women reporting good functioning increased more, and the proportion reporting a high level of symptoms decreased more compared with women on sick leave/disability pension and retirement pensioners (p < 0.001). The latter two also showed a worsening in several subscales (p < 0.05). Among employed women, more consistent improvements in role and social functioning were observed among those with an increase/no change in working time than among those who had decreased it or stopped working (p < 0.05). A decrease in the proportion reporting pain was observed among women with an increase/no change in working time compared with women with decreased working time, among whom the proportion reporting pain increased (p = 0.008)., Conclusions: Being employed prediagnosis and resuming work to the same extent as prior to the breast cancer diagnosis are associated with consistent improvements in HRQoL. These results highlight the importance of interventions to improve HRQoL and policies to support return to work following diagnosis., (Copyright © 2013 John Wiley & Sons, Ltd.)

Converging evidence indicates that women with pregnancy-associated breast cancer (PABC) have increased mortality compared to women with breast cancer not diagnosed near pregnancy (non-PABC). Our aim was to investigate if the stage distribution differs between PABC and non-PABC and if stage at diagnosis can explain the poorer prognosis observed among women with PABC. We identified 3,282 breast cancers in women aged 15-44 years at diagnosis for whom staging data (tumor size, nodal involvement, metastasis) were available in the Swedish Cancer Register between 2002 and 2009. Information on reproductive history and vital status was obtained from the Multi-Generation Register and the Cause of Death Register. PABC was defined as breast cancers diagnosed during pregnancy and up to 2 years after delivery (n = 317). Non-PABC was defined as cases diagnosed before pregnancy or more than 2 years postpartum. Stage distributions were compared between PABC and non-PABC, and mortality rates were modeled using Cox regression. Compared to women with non-PABC, the mortality was almost 50 % higher in women with PABC [unadjusted hazard ratio (HR) 1.47 (95 % CI 1.04-2.08)], a difference which was reduced after adjustment for age and calendar year of diagnosis [HR 1.27 (95 % CI 0.88-1.83)]. Although advanced stage of breast cancer at diagnosis was more common among PABC than among non-PABC, further adjustment for stage only slightly reduced the HR [1.22 (95 % CI 0.84-1.78)]. The difference in mortality between PABC and non-PABC was more pronounced among women above 35 years and among women with PABC diagnosed within 1 year postpartum. Age, rather than stage at diagnosis, appears to act as the principal driver of the increased mortality observed in women with PABC. However, these findings do not preclude an untoward influence on mortality by pregnancy-associated factors affecting tumor aggressiveness and progression.

Placental weight may be regarded as an indirect marker of hormone exposures during pregnancy. There is epidemiological evidence that breast cancer mortality in premenopausal women increases with placental weight in the most recent pregnancy. We investigated if this association differs by tumor characteristics, including expression of estrogen and progesterone receptors. In a Swedish population-based cohort, we followed 1,067 women with premenopausal breast cancer diagnosed from 1992 to 2006. Using Cox regression models, we estimated hazard ratios for the association between placental weight and risk of premenopausal breast cancer mortality. In stratified analyses, we estimated mortality risks in subjects with different tumor stages, estrogen receptor (ER) or progesterone receptor (PR) status. Compared with women with placental weight less than 600 g, women with a placental weight between 600 and 699 g were at a 50 % increased risk of mortality, however, not significant change in risk was observed for women with placental weight ≥ 700 g. Mortality risks associated with higher placental weight were more pronounced among ER(-) and PR(-) breast cancer tumors, where both a placental weight 600-699 g and ≥ 700 g were associated with a more than doubled mortality risks compared with tumors among women with placental weight less than 600 g. Moreover, stratified analyses for joint receptor status revealed that a consistent increased mortality risk by placental weight was only apparent in women with ER(-)/PR(-) breast cancer. The increased mortality risk in premenopausal breast cancer associated with higher placental weight was most pronounced among ER(-) and PR(-) tumors.

Purpose: The number of breast cancer survivors at risk of developing contralateral breast cancer (CBC) is increasing. However, ambiguity remains regarding risk factors and prognosis for women with CBC., Patients and Methods: In a cohort of 42,670 women with breast cancer in the Uppsala/Örebro and Stockholm regions in Sweden in 1992 to 2008, we assessed risk factors for and prognosis of metachronous CBC by using survival analysis. Breast cancer-specific survival for women with CBC was evaluated and compared with results for women with unilateral breast cancer (UBC) by using time-dependent Cox-regression modeling., Results: An increased risk for CBC was observed among women who had primary breast cancer with ≥ 10 involved lymph nodes compared with node-negative women (adjusted hazard ratio [HR], 1.8; 95% CI, 1.2 to 2.7). The prognosis was poorer in women with CBC than with UBC. The hazard of dying from breast cancer was especially high for women with a short interval time to CBC (adjusted HR, 2.3; 95% CI, 1.8 to 2.8 for CBC diagnosed ≤ 5 years v UBC) and gradually decreased with longer follow-up time but remained higher than the hazard originating from the primary tumor for ≥ 10 years., Conclusion: Women with advanced-stage primary breast cancer had an increased risk of developing CBC. CBC is associated with an increased risk of dying from breast cancer throughout a long period of follow-up after the primary tumor. Our findings suggest that the event of CBC marks a new clinical situation in terms of investigations for metastases, treatment considerations, and follow-up strategy.

Purpose: We examined changes in working time 16 months after a breast cancer diagnosis and identified factors associated with job discontinuation and/or decreased working time., Patients and Methods: This was a population-based cohort study with 735 patients identified in the Regional Breast Cancer Quality Register of Central Sweden. The study sample consisted of 505 women (age < 63 years at diagnosis) who completed questionnaires at baseline and at follow-up (on average 4 and 16 months after diagnosis, respectively). Clinical register data and questionnaire data on sociodemographic factors were obtained at baseline. Self-reported work-related data were obtained at follow-up. Odds ratios were estimated by using logistic regression models., Results: Compared with prediagnosis working time, 72% reported no change in working time, 2% reported an increase, 15% reported a decrease, and 11% did not work at follow-up. Chemotherapy increased the likelihood (odds ratio [OR], 2.45; 95% CI, 1.38 to 4.34) of job discontinuation/decreased working time. Among chemotherapy recipients, associated factors included full-time work prediagnosis (OR, 3.25; 95% CI, 1.51 to 7.01), cancer-related work limitations (OR, 5.26; 95% CI, 2.30 to 12.03), and less value attached to work (OR, 3.69; 95% CI, 1.80 to 7.54). In the nonchemotherapy group, older age (OR, 1.09; 95% CI, 1.02 to 1.17) and less value attached to work (OR, 5.00; 95% CI, 2.01 to 12.45) were associated with the outcome., Conclusion: The majority of women treated for breast cancer returned to their prediagnosis working time. Chemotherapy and cancer-related work limitations are important factors to take into account in identifying women in need of support. Moreover, it is important to consider the woman's own valuation of labor market participation.

To investigate associations between comorbidity burden, management, and mortality in women with breast cancer. A total of 42,646 women diagnosed with breast cancer between 1992 and 2008 were identified in two Clinical Quality Registers in Central Sweden. Breast cancer-specific, conditional breast cancer, competing-cause and all-cause mortality were estimated in relation to comorbidity burden assessed by the Charlson comorbidity index. All analyses were stratified by stage at diagnosis using competing risk analyses, and all-cause mortality was estimated as a function of follow-up time. Following adjustment for age and calendar period, breast conserving surgery was significantly less likely to be offered to women with severe comorbidity (OR 0.63; 95 % CI 0.58-0.69). Similarly, the proportion treated with radiotherapy, tamoxifen, or chemotherapy was lower in women with severe compared to those with no comorbidity. In women with early stage disease, breast cancer-specific mortality was higher among patients with severe comorbidity (sHR 1.47; 95 % CI 1.11-1.94). In all stages of breast cancer, conditional breast cancer and competing-cause mortality were elevated in women with severe comorbidity. For all stages, the relative risk of all-cause mortality between women with severe versus no comorbidity varied by time since diagnosis, and was most pronounced at early follow-up. Comorbidity affects treatment decisions and mortality. In women with early stage breast cancer, severe comorbidity was associated not only with conditional breast cancer, competing-cause and all-cause mortality, but also breast cancer-specific mortality. The observed differences in breast cancer-specific mortality may be due to less extensive treatment, impaired tumor defense and differences in general health status and lifestyle factors.

Background: Obesity is a risk factor for breast and ovarian cancer; the mechanisms of action are not completely understood. Perturbed lipid metabolism often accompanies obesity; we therefore ascertained the associations between lipid components and breast and ovarian cancer risk in a prospective cohort study., Methods: A total of 234,494 women with baseline measurements of triglycerides and total cholesterol and glucose were selected from the AMORIS database.A total of 27,394 had measurements of high-density lipoprotein, low-density lipoprotein, apolipoprotein (Apo) B, and A-I. Associations between quartiles and dichotomized values of lipid components and breast and ovarian cancer risk were analyzed using Cox proportional hazard models., Results: We identified 6,105 women diagnosed with breast cancer and 808 women diagnosed with ovarian cancer. A weak trend was observed between triglycerides and breast cancer (HR, 1.01, 95% Confidence Interval, 0.94-1.09; 0.93 (0.86-1.00) 0.91 (0.84-0.99), second, third, and fourth quartiles; P = 0.01). No other associations between lipid components and risk of breast cancer or ovarian cancer showed statistical significance., Conclusions: A weak protective association was found between levels of triglycerides and risk of breast cancer., Impact: An analysis including information on tumour characteristics of ovarian cancer and breast cancer may provide more insight in possible links between lipid metabolism and the risk of these cancers., (©2012 AACR.)

Adherence to long-term pharmacological treatment for chronic conditions is often less than optimal. Till date, a limited number of population-based studies have assessed adherence to adjuvant hormonal therapy in breast cancer, a therapy with proven benefits in terms of reductions of recurrence and mortality. We aimed to examine rates of adherence and early discontinuation in Sweden where prescribed medications are subsidized for all residents and made available at reduced out-of-pocket costs. Individual-level data were obtained from Regional Clinical Quality Breast Cancer Registers, the Swedish Prescribed Drug Register, and several other population-based registers. Multivariate logistic regression was used to analyze factors associated with adherence to prescribed medication for a period of 3 years. Between January 1 and December 31, 2005, 1,741 patients in central Sweden were identified with estrogen receptor positive breast cancer, and at least one prescription dispensation of either tamoxifen or an aromatase inhibitor. Of these women, 1,193 (69%) were fully adherent to therapy for 3 years (medication possession ratio of 80% or higher and a maximum of 180 days between refills). During the 3-year follow-up, 215 women (12%) had prematurely discontinued therapy. Adherence was positively associated with younger age, large tumor size, being married, and being born in the Nordic countries, while no clear association was observed with education or income. During the 3 years of follow-up, 31% of women were non-adherent to therapy. Further efforts must be undertaken to promote adherence over the entire recommended treatment period.

Purpose: Although the central role of the immune system for tumor prognosis is generally accepted, a single robust marker is not yet available., Experimental Design: On the basis of receiver operating characteristic analyses, robust markers were identified from a 60-gene B cell-derived metagene and analyzed in gene expression profiles of 1,810 breast cancer; 1,056 non-small cell lung carcinoma (NSCLC); 513 colorectal; and 426 ovarian cancer patients. Protein and RNA levels were examined in paraffin-embedded tissue of 330 breast cancer patients. The cell types were identified with immunohistochemical costaining and confocal fluorescence microscopy., Results: We identified immunoglobulin κ C (IGKC) which as a single marker is similarly predictive and prognostic as the entire B-cell metagene. IGKC was consistently associated with metastasis-free survival across different molecular subtypes in node-negative breast cancer (n = 965) and predicted response to anthracycline-based neoadjuvant chemotherapy (n = 845; P < 0.001). In addition, IGKC gene expression was prognostic in NSCLC and colorectal cancer. No association was observed in ovarian cancer. IGKC protein expression was significantly associated with survival in paraffin-embedded tissues of 330 breast cancer patients. Tumor-infiltrating plasma cells were identified as the source of IGKC expression., Conclusion: Our findings provide IGKC as a novel diagnostic marker for risk stratification in human cancer and support concepts to exploit the humoral immune response for anticancer therapy. It could be validated in several independent cohorts and carried out similarly well in RNA from fresh frozen as well as from paraffin tissue and on protein level by immunostaining., (©2012 AACR.)

Purpose: Male breast cancer (MBC) is an uncommon disease. In the absence of randomized studies, current guidelines are mainly based on data on the management of female breast cancer (FBC). In light of concerns regarding the quality and extent of management in men, the aim of the present study was to investigate whether there are differences in tumor characteristics, treatment and outcome in male compared with FBC patients., Methods: Cohorts of male and female breast cancer were retrospectively analyzed. All male patients diagnosed with invasive breast cancer between 1993 and 2007 were identified from the Regional Breast Cancer Register of the Uppsala-Örebro Region in Sweden. To increase the power of the study and obtain comparable cohorts we sampled four FBC patients (n = 396) for each MBC patient (n = 99) with similar age at diagnosis and time of diagnosis., Results: No differences were seen in stage at diagnosis between MBC and FBC. Men underwent mastectomy more often than women (92% vs. 44%, p < 0.001). Radiotherapy was delivered less often to MBC than FBC (44% vs. 56%, p = 0.034), but radiotherapy given after mastectomy (44% vs. 39%, p = 0.47) did not differ between the groups. No differences were found regarding adjuvant chemotherapy (16% vs. 21%; p = 0.31) or adjuvant endocrine therapy (59% vs. 52%, p = 0.24). Both overall survival (41% vs. 55%, p = 0.001) and relative survival (74% vs. 88%, p = 0.015) were inferior in MBC compared to FBC., Conclusion: Concerns regarding less extensive treatment in MBC patients were not supported by this study. Although no differences in the stage of the disease or treatment intensity could be demonstrated, outcome was inferior in the male group.

Background: High incidence rates of breast cancer emphasize the importance of increased knowledge about the health-related quality of life (HRQoL) in this patient group. The aim of the present study was to describe and compare HRQoL among breast cancer patients shortly after diagnosis with normative data from the general population, and to investigate how clinical, demographic, and socio-economic factors and social support are associated with HRQoL., Material and Methods: Participants were identified in a population-based Breast Cancer Quality Register in central Sweden. Of 1573 women newly diagnosed with breast cancer during a one-year period (2007-2008), 69% (n = 1086) completed a questionnaire including the EORTC QLQ-C30, BR23 and the HADS., Results: Compared to age-adjusted normative data, breast cancer patients (mean age 62 years, range 25-94), especially younger women (<50 years), experienced clinically meaningful poorer HRQoL. Clinically significant levels of anxiety and depressive symptoms were found among 14% and 6% of the patients, respectively. Factors associated with more problems/symptoms among study participants included chemotherapy, lack of social support, sick leave and a poor financial situation. Adding socio-economic factors diminished the association between age and HRQoL (p > 0.05)., Conclusion: Recently diagnosed breast cancer patients reported poorer HRQoL in several dimensions compared to normative data. In addition to clinical and demographic factors, an unfavorable socio-economic standing was associated with more problems/symptoms. The present findings emphasize the importance of taking a variety of factors into account when assessing HRQoL in the clinical setting.

Background: Because of a continued trend toward postponed childbearing, the incidence of pregnancy-associated breast cancer (PABC) is likely to increase. This study investigated the mortality in women with PABC in relation to when the tumor was detected (during pregnancy, different postpartum periods) and by time since diagnosis, compared with women with non-PABC., Methods: A population-based cohort study of 15,721 Swedish women diagnosed with breast cancer between ages 15 to 44 years, of whom 1,110 (7%) had a PABC (diagnosed during or within two years after pregnancy). Information on outcome and potential confounders was obtained from population-based health registers. Mortality rates and HRs with 95% CIs were estimated., Results: Women with PABC had higher mortality compared with women with non-PABC diagnosed at the same age and calendar period. Among women with PABC, 46% died within 15 years after diagnosis, whereas 34% died among non-PABC patients. The mortality in both groups peaked at around two years after diagnosis, with the highest peak occurring in women diagnosed 4 to 6 months after delivery (HR = 3.8, 95% CI: 2.4-5.9). An increased mortality among women with PABC remained until 10 years after diagnosis., Conclusions: Women with PABC had a poorer prognosis compared with women with breast cancer and no recent birth. The mortality increase was most pronounced in the subgroup of women diagnosed shortly after delivery., Impact: An increased awareness among clinicians may help reduce the mortality in women with PABC, for example, by avoiding undue delays in diagnosis and treatment.

Background: Epidemiological evidence indicates that individuals with type 2 diabetes are at an increased risk of cancer. Elevated glucose levels, below the diagnostic threshold for diabetes, have also been suggested to be associated with increased cancer risks., Methods: We investigated possible associations between glucose levels and the risk of breast, endometrial, and ovarian cancer in a cohort of more than 230,000 women, for which information on outcome and potential confounders was obtained by record linkage to population-based registers., Results: Diabetes was associated with an increased risk of postmenopausal breast cancer (HR = 1.22, 95% CI 1.04-1.43). An indication of a slightly elevated breast cancer risk was also found in postmenopausal women with impaired glucose metabolism (HR = 1.11, 95% CI 0.96-1.28). Diabetes (HR = 1.46, 95% CI 1.09-1.96) and impaired glucose metabolism (HR = 1.41, 95% CI 1.08-1.85) were associated with an increased risk of endometrial cancer. No associations were found between glucose levels and ovarian cancer risk. Following adjustment for BMI, estimates were attenuated for endometrial cancer, while point estimates for breast and ovarian cancer remained essentially unchanged., Conclusions: Our results indicate that glucose levels below the diagnostic threshold for diabetes modify the risk not only of endometrial cancer but possibly also of postmenopausal breast cancer.

Background: Improved cancer survival poses important questions about future life conditions of the survivor. We examined the possible influence of a breast cancer diagnosis on subsequent working and marital status, sickness absence and income., Materials: We conducted a matched cohort study including 4,761 women 40-59 years of age and registered with primary breast cancer in a Swedish population-based clinical register during 1993-2003, and 2,3805 women without breast cancer. Information on socioeconomic standing was obtained from a social database 1 year prior and 3 and 5 years following the diagnosis. In Conditional Poisson Regression models, risk ratios (RRs) and 95% confidence intervals (CIs) were estimated to assess the impact of a breast cancer diagnosis., Findings: Three years after diagnosis, women who had had breast cancer more often had received sickness benefits (RR = 1.49, 95% CI 1.40-1.58) or disability pension (RR = 1.47, 95% CI 1.37-1.58) than had women without breast cancer. We found no effect on income (RR = 0.99), welfare payments (RR = 0.98), or marital status (RR = 1.02). A higher use of sickness benefits and disability pension was evident in all stages of the disease, although the difference in use of sickness benefits decreased after 5 years, whereas the difference in disability pension increased. For woman with early stage breast cancer, the sickness absence was higher following diagnosis among those with low education, who had undergone mastectomy, and had received chemo- or hormonal therapy. Neither tumour size nor presence of lymph nodes metastasis was associated with sickness absence after adjustment for treatment., Interpretation: Even in early stage breast cancer, a diagnosis negatively influences working capacity both 3 and 5 years after diagnosis, and it seems that the type of treatment received had the largest impact. A greater focus needs to be put on rehabilitation of breast cancer patients, work-place adaptations and research on long-term sequelae of treatment.

Studies from Western countries have found evidence of a recent decline in breast cancer incidence rates in postmenopausal women, findings which have been hypothesized to reflect a reduced use of hormonal replacement therapy (HRT). We examined breast cancer incidence trends in Sweden between 1997 and 2007, a period characterized by a drop in the use of HRT. Incidence trends were assessed using data from three population-based Regional Clinical Registries on breast cancer covering 2/3 of the Swedish population. Information on HRT sales was obtained from national pharmacy data. The prevalence of HRT use in age group 50-59 years decreased from a peak of 36% in 1999 to 27% in 2002 and further to 9% in 2007. Incidence rates of breast cancer in women 50 years and older increased between 1997 and 2003. A significant decrease in incidence between 2003 and 2007 was confined to women 50-59 years of age, the group in which the prevalence of HRT use has been highest and the decrease in use most pronounced. As opposed to the immediate effects reported from the United States and other regions, there was a time lag between the drop in HRT use and clear reductions in breast cancer incidence. This may reflect between country differences with regard to types of HRT used, and the rate, magnitude and pattern of change in use. The present findings give further support to the notion that HRT use is a driver of breast cancer incidence trends on the population level.

Background: Many cancers arise from sites of infection and inflammation. Results from animal studies indicate that inflammatory cells may facilitate neoplastic processes by orchestrating the tumor microenvironment. Little is known about the role of inflammation in the etiology of breast cancer. The aim of this study was to examine possible associations between a history of mastitis requiring hospitalization and subsequent risk of breast cancer., Methods: This cohort study of 2,577,565 women used data from several Swedish population-based registers, including the Inpatient Register and the Cancer Register. The risk of breast cancer was assessed by Poisson regression modeling., Results: We identified 8411 women in the Inpatient Register with a discharge diagnosis of mastitis. Of these, 106 had a subsequent diagnosis of breast cancer recorded in the Cancer Register. Compared with women who had no recorded mastitis, the incidence rate of breast cancer (regardless of laterality) was higher in women with mastitis, with an incidence rate ratio of 1.23 (95% confidence interval [CI] = 1.02-1.49) following adjustment for age, calendar time, age at first birth and parity. In the group of women among whom information on laterality was available for both the mastitis and the malignancy (n = 87), side of lesions corresponded for 52% (95% CI = 41%-62%), which is what could be expected by chance., Conclusions: The overall risk of breast cancer was slightly elevated in women with a history of mastitis recorded in the Inpatient Register. The absence of a correlation between laterality of lesions, however, does not support a causal association between inflammation and the development of breast cancer.

Objective: To estimate the incidence of pregnancy-associated breast cancer during different calendar periods and when pregnancy-associated breast cancer was diagnosed in relation to delivery., Methods: This was a population-based cohort study using data from Swedish registers between 1963 and 2002, encompassing women aged 15-44 years at the date of breast cancer diagnosis. Outcome measures included incidence of pregnancy-associated breast cancer per 100,000 deliveries, the proportion of pregnancy-associated breast cancer among all breast cancers, and observed-to-expected rates., Results: Between 1963 and 2002, 1,161 cases of pregnancy-associated breast cancer among a total of 16,620 breast cancers were identified in women aged 15 to 44 years. The incidence of pregnancy-associated breast cancer increased from 16.0 to 37.4 per 100,000 deliveries comparing the first and last calendar periods under study. During pregnancy, the overall incidence was 2.4 per 100,000 deliveries; the incidence during the first and second year after delivery was 10.6 and 15.0 per 100,000 deliveries, respectively. Fewer pregnancy-associated breast cancers than expected were diagnosed during pregnancy and the first 6 months after delivery. Thereafter, there was no difference between observed compared with expected number of breast cancers., Conclusion: The incidence of pregnancy-associated breast cancer increased during the study period, partly caused by a trend of postponement of childbearing to an older age. The present findings suggest that breast cancer is underdiagnosed during pregnancy and lactation., Level of Evidence: III.

A growing body of evidence indicates that reproductive history influences survival in breast cancer, especially among women diagnosed during or shortly after a pregnancy. However, little is known about the underlying mechanisms. We hypothesized that increasing placental weight, as an indirect marker of exposure to elevated hormone levels during pregnancy, would be associated with reduced survival in breast cancer. A cohort of 1873 women with at least one pregnancy after January 1st, 1973, and a subsequent breast cancer diagnosis before the end of 1991 were followed up for death or emigration through 2006. Information on placental weight and potential confounding factors were collected from medical records and from nationwide registers, which resulted in data on placental weight in the most recent pregnancy before diagnosis for 1,057 cases. For each 100-gram increase in placental weight, the adjusted hazard ratio of death was 1.09 [95% confidence interval (CI), 0.99-1.19]. The association was stronger among primiparous women (adjusted hazard ratio, 1.26; 95% CI, 1.09-1.47), and among women diagnosed during pregnancy or within 2 years from last birth (adjusted hazard ratio, 1.30; 95% CI, 1.06-1.59). Increasing placental weight is associated with reduced breast cancer survival. These findings are consistent with the hypothesis that the reduced survival in breast cancer among women with a recent childbirth is linked to pregnancy hormone exposure.

Epidemiologic studies have shown that cancer survival is poorer in low compared with high socioeconomic groups. We investigated whether these differences were associated with disparities in tumour characteristics and management. This cohort study was based on 9,908 women aged 20-79 years at diagnosis with primary breast cancer identified in a Swedish population-based clinical register. Information on socioeconomic standing was obtained from a social database. The 5-year cause-specific survival (CSS) and mortality hazard ratios (HR) were estimated by Cox proportional hazard models to assess differences in survival between socioeconomic groups while adjusting for diagnostic intensity, tumour characteristics and treatment. Following adjustment for age, year and stage at diagnosis, the risk of dying of breast cancer was 35% lower among women with high education compared with that of low education (HR = 0.65, 95% CI 0.53-0.80). When compared with women with high education, a lower percentage of women with low education had been investigated for proliferation (84 vs. 76%) or hormone receptor status (89 vs. 81%), had tumours