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Background: In utero exposure to maternal cancer and cancer treatment might influence the child's cognitive development. This study investigated if exposure to maternal cancer during fetal life impacted school performance and educational achievement as adults., Methods: This nationwide retrospective cohort study identified all live-born children in Denmark between January 1978 and December 2013. Exposure was defined as maternal cancer diagnosis during pregnancy. Four partly overlapping birth cohorts were constructed depending on the outcome of interest: (1) receiving special educational support for birth years 2001-2013; (2) grade point average (GPA) at the final exams after 10th grade for 1986-2003; (3) educational achievement at 20 years for 1978-1998; and (4) education at 30 years for 1978-1988. Logistic and linear models were adjusted for birth year, maternal age, maternal education and maternal death., Results: The estimated probability of receiving special educational support was similar in the exposed group and the reference (adjusted OR 0.96; 95% CI 0.46 to 1.77, non-significant). The GPA did not statistically differ (0.13 grade points; 95% CI -0.18 to 0.45, non-significant). The achieved educational levels were similar for the exposed group and the reference at 20 years, with an adjusted OR of 1.07 (95% CI 0.82 to 1.40) for low versus medium educational level, and at 30 years with an adjusted OR of 0.73 (95% CI 0.35 to 1.50) for low versus high educational level and of 1.07 (95% CI 0.66 to 1.72) for medium versus high educational level., Conclusion: Our findings did not indicate poorer performance in compulsory school nor impairment of adult educational achievement after exposure to maternal cancer in utero., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We aimed to investigate the risk of first primary cancer in patients with RA treated with janus kinase inhibitors (JAKi) compared with those who received biologic DMARDs (bDMARDs) in a real-world setting., Methods: We performed an observational cohort study using the nationwide registers in Denmark. Patients with RA aged 18+ years, without a previous cancer diagnosis, and who initiated treatment with JAKi or bDMARDs from 1 January 2017 to 31 December 2020 were followed for any cancer (except non-melanoma skin cancer). We applied inverse probability of treatment weighting (IPTW) to account for covariate differences between treatment groups. IPTW-generated weights were used with cause-specific Cox (CSC) models to calculate hazard ratios (HRs) for cancer incidence in JAKi-treated compared with bDMARD-treated patients with RA., Results: We identified 875 and 4247 RA patients treated with JAKi and bDMARDs, respectively. The JAKi group contributed 1315 person years (PYRS) and 19 cancers, the bDMARD group contributed 8597 PYRS and 111 cancers, with corresponding crude incidence rates per 1000 PYRS of 14.4 and 12.9. Comparing the two groups using weighted CSC models, a HR of 1.41 (95% CI 0.76, 2.37, 95% CIs) was seen for JAKi- vs bDMARD-treated patients with RA., Conclusion: JAKi treatment in real-world patients with RA was not associated with a statistically significant increased risk of first primary cancer compared with those who received bDMARDs. However, several numerically increased risk estimates were detected, and a clinically important excess risk of cancer among JAKi recipients cannot be dismissed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Previous studies have established associations between body mass index and breast cancer, but fat mass is a more direct measure of the amount of fat tissue in the body than body mass index. This study examined the association between body fat mass, fat-free mass, and other anthropometric measures and breast cancer in postmenopausal women according to use of hormone replacement therapy (HRT)., Methods: From the Danish Diet, Cancer and Health cohort established during 1993-1997, 24,219 postmenopausal women were included who had anthropometric and bioimpedance measurements performed by a laboratory technician at baseline. Information on breast cancer incidence (outcome), other cancer diagnoses, and vital status (censoring variables) through 2016 was obtained from nationwide registers. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) while adjusting for known breast cancer risk factors and stratifying by HRT use and running age., Results: During a total of 431,104 person-years, 1919 women developed breast cancer. Among never-users of HRT, the HR for breast cancer at or after age 65 years was 1.06 (95% CI, 1.03-1.08) per 1 kg/m 2 higher body fat mass index (BFMI), and 1.30 (95% CI, 1.14-1.47) per 10% higher body fat percentage. The corresponding HRs for breast cancer before age 65 years were close to unity. The HRs were 1.11 (95% CI, 1.02-1.21) and 1.17 (95% CI, 1.10-1.23) for each 1 kg/m 2 increase in fat-free mass index, respectively, for breast cancer below and above age 65 years. Mutual adjustment attenuated the HRs for BFMI and body fat percentage, whereas the HRs for fat-free mass index were largely unaffected. Among ever-users of HRT, there was no statistical significant association between any of the body composition measures and breast cancer incidence in the two age groups., Conclusions: Among postmenopausal women who never used HRT, BFMI was associated with breast cancer in women aged 65 years or older. Fat-free mass index was found to be more strongly associated with postmenopausal breast cancer incidence than BFMI independently of age in never-users of HRT., Competing Interests: Conflicts of interest statement Lene Mellemkjær has an immediate family member employed at Novo Nordisk, and has an immediate family member who owns stocks in Novo Nordisk. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: In utero exposure to maternal cancer and cancer treatment might influence the child's short- and long-term health and development. The objective of the study was to investigate short- and long-term somatic and psychiatric outcomes in children exposed to maternal cancer in utero., Methods: This nationwide cohort study identified all liveborn children in Denmark between January 1978 and December 2018. Exposure was defined as maternal cancer diagnosis during pregnancy, and in a subgroup analysis, exposure to chemotherapy in utero. The main outcomes of interest were overall mortality, somatic diagnoses, and psychiatric diagnoses identified in the National Health Registers. Follow-up started at birth and ended at an event, death, emigration, or end of 2018. Hazard ratios of end points adjusted for potential confounders were estimated using Cox regression analysis., Results: Of 2,526,163 included liveborn children, 690 (0.03%) were exposed to maternal cancer in utero. Compared with unexposed fetuses, children exposed in utero had no higher overall mortality, adjusted hazard ratio 0.8 (95% CI, 0.4 to 1.5), nor increased risk of congenital malformations, overall somatic or psychiatric disease. During the period 2002-2018, of 378 (0.03%) children exposed to cancer in utero, 42 (12.5%) were exposed to chemotherapy. Among these 42 children, in utero exposure to chemotherapy was not associated with selected somatic diseases nor to congenital malformations when compared with in utero exposure to maternal cancer without chemotherapy., Conclusion: Overall, findings did not indicate excess risk of mortality or severe morbidity among children exposed to cancer in utero. Fetal exposure to chemotherapy was not associated with adverse health outcomes in childhood.

A high childhood body mass index (BMI) may be protective against benign breast disease (BBD), but little is known about the effects of other early life body size measures. Thus, we examined associations between birthweight, childhood BMI, height, and pubertal timing and BBD risks. We included 171,272 girls, born from 1930 to 1996, from the Copenhagen School Health Records Register, which contains information on birthweight, childhood anthropometry (7-13 years), age at onset of the growth spurt (OGS), and peak height velocity (PHV). During follow-up, 9361 BBD cases (15-50 years) were registered in the Danish National Patient Register. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox regressions. At all childhood ages, BMI was inversely but non-linearly associated with BBD. The association was slightly stronger in magnitude for BMI z-scores above 0 (HR age 7  = 0.86; 95%CI: 0.83-0.90 per z-score) than below 0 (HR age 7  = 0.95; 95%CI 0.91-0.99 per z-score). Associations between childhood height and BBD differed by age; at 7 years the association was an inverted U-shape, whereas at 13 years height was not associated with BBD. Ages at OGS and PHV were positively associated with BBD. Low and high birthweights were associated with lower BBD risks.   Conclusion: A high childhood BMI, a short or tall stature at young childhood ages, an early pubertal onset, and low or high birthweights are associated with reduced risks of BBD. These complex associations suggest that the role of these factors in breast tissue development during early life warrants further investigation in relation to BBD etiology. What is Known: • Benign breast disease (BBD) is common and may be an intermediary marker of breast cancer risks. • Early life body size may relate to the development of BBD, but currently little is known. What is New: • Girls with a high body mass index at school ages or with an early pubertal timing have decreased risks of BBD. • Short and tall heights at young childhood ages and low and high birthweights are associated with lower BBD risks., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Late breast cancer (BC) recurrence (ie, ≥ 10 years after primary diagnosis) may have a more favorable prognosis than earlier recurrence. We investigated the risk of BC death after late recurrence, identified prognostic factors, and compared survival after early and late recurrence., Methods: Using the Danish Breast Cancer Group and other nationwide databases, we identified women with early or late BC recurrence during 2004-2018, who were alive 6 months after recurrence. We followed them until BC death, death from other causes, emigration, 10 years, or December 31, 2018, whichever came first. We calculated mortality rates (MRs) per 1,000 person-years (PY) and cumulative BC mortality, for early versus late recurrence, and by characteristics of the primary tumor and the late recurrence. Using Cox regression, we calculated adjusted hazard ratios (HRs) for BC death, accounting for death from other causes as competing risks., Results: Among 2,004 patients with late recurrence, 721 died of BC with a median survival time of 10 years (MR = 84.8 per 1,000 PY; 10-year cumulative mortality = 50%). Among 1,528 patients with early recurrence, 1,092 BC deaths occurred with a median survival time of 4 years (MR = 173.9 per 1,000 PY; 10-year cumulative mortality = 72%). We observed a lower hazard of BC-specific death among patients who developed late compared with early recurrence (hazard ratio = 0.72; 95% CI, 0.62 to 0.85). Advanced stage at primary diagnosis, distant metastases, adjuvant treatment for locoregional recurrence, and systemic treatment for distant recurrence were associated with increased mortality after late recurrence. Breast-conserving surgery at primary diagnosis, locoregional recurrence, and surgery for recurrence were associated with lower mortality after late recurrence., Conclusion: Patients with late recurrence had more favorable prognosis than patients with early recurrence. The localization of recurrent disease was the main prognostic factor for BC death., Competing Interests: Lene MellemkjærEmployment: Novo Nordisk (I)Stock and Other Ownership Interests: Novo Nordisk (I) Bent EjlertsenResearch Funding: Roche (Inst), Novartis (Inst), Pfizer (Inst), AstraZeneca (Inst), MSD (Inst)Travel, Accommodations, Expenses: Roche, AstraZeneca, MSD Mette NørgaardResearch Funding: Amgen (Inst), Merck KGaA (Inst)No other potential conflicts of interest were reported.

Objective: To investigate if cancer in pregnancy causes a higher risk of venous thromboembolism (VTE) during pregnancy and postpartum compared with pregnant women without cancer., Design: A historical prospective cohort study using data from nationwide registries., Setting and Population: We assessed all pregnancies in Denmark between 1 January 1977 and 31 December 2017., Methods: We linked information concerning cancer diagnosis, pregnancy and VTE diagnosis and potential confounders. Event rates of VTE for women with pre-pregnancy cancer, cancer in pregnancy and without cancer were calculated per 10 000 pregnancies and compared using logistic regression analysis., Main Outcome Measures: Occurrence of VTE during pregnancy or the postpartum period., Results: A total of 3 581 214 pregnancies were included in the study and we found 1330 women with cancer in pregnancy. In pregnant women with cancer, the event rate of VTE was 75.2 per 10 000 pregnancies compared with 10.7 per 10 000 pregnancies in the no cancer group. The findings correspond to an increased adjusted odds ratio of 6.50 (95% CI3.5-12.1) in the cancer in pregnancy group in comparison with the no cancer group., Conclusions: Women with cancer in pregnancy have a markedly higher risk of pregnancy-associated VTE compared with women without cancer. In pregnancy-related VTE risk assessment, the presence of cancer alone may be sufficient to indicate thromboprophylaxis., Tweetable Abstract: Cancer in pregnancy increases the risk of VTE during pregnancy and the postpartum period., (© 2021 John Wiley & Sons Ltd.)

Purpose: Large-scale population-based registry studies investigating the risk of breast cancer after removal of both ovaries at hysterectomy for benign conditions in women with no known genetic predisposition to cancer are needed. We aimed to perform such a study taking into account the age at surgery status and use of hormone replacement therapy (HRT)., Methods: Within the female population of Denmark born 1937-1996, we evaluated breast cancer incidence after unilateral or bilateral oophorectomy concomitant with or after benign hysterectomy in comparison with no surgery and with hysterectomy alone using health registry data during 1978-2016. In a subpopulation followed from 1996, the analyses were stratified according to use of HRT., Results: We found a reduced risk of breast cancer among women aged < 45 years at bilateral oophorectomy compared with women with hysterectomy alone (HR = 0.78; 95% CI 0.66, 0.92), whereas slightly increased risks were seen in women above 50 years. In the subpopulation, non-users of HRT aged ≥ 50 years at oophorectomy had a HR of 0.74 (95% CI 0.56, 0.98) for breast cancer after bilateral oophorectomy compared with hysterectomy alone., Conclusions: Our large-scale study covering four decades provides evidence that bilateral oophorectomy performed at young age in women with benign indications for hysterectomy is associated with a reduction in breast cancer risk. The finding of a negative association at older ages in women not using HRT deserves further attention.

Objective: The few studies on the association between benign ovarian tumors and endometrial cancer have been inconclusive. Using data from a large Danish register-based cohort study, we assessed the overall and type-specific risk of endometrial cancer among women with a benign ovarian tumor., Methods: We identified all Danish women diagnosed with a benign ovarian tumor during 1978-2016 in the Danish National Patient Register (n = 149,807). The study population was followed for subsequent development of endometrial cancer by linkage to the Danish Cancer Register and standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (CIs) were calculated after correction for hysterectomy., Results: After a one-year delayed study entry, women with benign ovarian tumors had a decreased incidence of endometrial cancer (SIR = 0.74, 95% CI: 0.68-0.81) compared with women in the general Danish population. Both solid benign ovarian tumors (SIR = 0.79, 95% CI 0.70-0.88) and cystic benign ovarian tumors (SIR = 0.68, 95% CI 0.58-0.78) were associated with decreased incidences of endometrial cancer. Likewise, women with benign ovarian tumors had decreased incidences of both type I and type II endometrial cancer. The incidence of endometrial cancer was decreased to virtually the same magnitude irrespective of the age at diagnosis of a benign ovarian tumor and the reduction persisted throughout the follow-up period., Conclusions: The risk of endometrial cancer was decreased beyond the first year after a benign ovarian tumor and the decrease persisted for 20 or more years. The possible underlying mechanisms are not known and should be investigated further., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Preclinical studies have shown both pro- and antineoplastic effects of antihistamines. Here, we evaluated the effect of H1 antihistamines on contralateral breast cancer (CBC) risk, and whether cationic amphiphilic (CAD) antihistamines could increase the sensitivity to chemotherapy., Methods: From the Danish Breast Cancer Group clinical database, we identified all women aged ≥20 years with a first-time diagnosis of breast cancer during 1996-2012. Information on drug use, CBC and potential confounding factors was retrieved from nationwide registries. Using Cox proportional hazard regression models, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for CBC associated with H1-antihistamine use., Results: We identified 52,723 patients with breast cancer with a total of 310,583 person-years of follow-up. Among them, 1444 patients developed a new primary tumour in the contralateral breast. Post-diagnosis use of H1 antihistamines (≥2 prescriptions) was not strongly associated with CBC risk (HR 1.08, 95% CI: 0.90-1.31) compared with non-use (<2 prescriptions). Use of CAD antihistamines among patients receiving chemotherapy was not associated with a decrease in CBC risk., Conclusions: Taken together, our findings do not suggest any association of H1-antihistamine use with CBC development.

Purpose: To assess the association between benign ovarian tumors and subsequent risk of breast cancer, and to examine this association according to type of benign ovarian tumors., Methods: This nationwide cohort study comprised all Danish women diagnosed with a benign ovarian tumor during 1978-2016 (n = 158,221) identified through the Danish National Patient Register. The cohort was linked to the Danish Cancer Registry to identify all cases of breast cancer, and standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated., Results: Overall, women with a benign ovarian tumor were at significantly increased risk of breast cancer. The risk was confined to women with a solid ovarian tumor (SIR 1.09; 95% CI 1.05-1.13), particularly in women ≥ 50 years at benign tumor diagnosis (SIR 1.19; 95% CI 1.12-1.26). The risk remained increased up to 20 years or more after the diagnosis of a solid ovarian tumor (SIR 1.11; 95% CI 1.04-1.18), and women with a solid tumor were at increased risk of ductal, lobular, and other types of breast cancer, although most consistent for the lobular subtype. For cystic tumors, this association was confined to ductal breast cancer in women with the tumor diagnosed at age ≥ 50 years., Conclusions: Women with a benign ovarian tumor were at increased risk of breast cancer. This association was largely confined to women with a solid ovarian tumor, and the excess risk was present 20 years or more after the ovarian tumor diagnosis. The underlying mechanism is unknown and should be investigated further.

Background: Statins have demonstrated antineoplastic effects in breast cancer cell lines, particularly in oestrogen receptor (ER)-negative cell lines. However, epidemiological studies have not supported a preventive effect of statin use against breast cancer. Therefore, we examined the association between statin use and contralateral breast cancer (CBC) risk among women with breast cancer., Methods: We identified 52,723 women with non-metastatic breast cancer during 1996-2012 from the Danish Breast Cancer Group database. We defined time-varying post-diagnosis statin use as minimum two prescriptions lagged by 1 year. Cox regression analyses were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CBC associated with statin use., Results: Statin use was associated with a lower CBC risk (HR = 0.88; 95% CI = 0.73-1.05). The inverse association was strongest for long-term use overall (HR = 0.64; 95% CI = 0.43-0.96), although the HR specifically for long-term consistent use and high-intensity use approached unity. Among ER-negative breast cancer patients, statin use was associated with a CBC risk reduction (HR = 0.67; 95% CI = 0.45-1.00)., Conclusions: We found some indication that statins reduce the risk of CBC. Further evaluations are needed to disentangle the equivocal results for long-term use and to establish if ER-negative breast cancer patients may benefit most from statin use.

Observational studies of aspirin use and breast cancer risk have provided inconsistent results. The occurrence of contralateral breast cancer (CBC) among breast cancer survivors may serve as a useful high-risk model to identify preventive drug effects. Using this model, we examined the association between post-diagnosis use of low-dose aspirin and risk of CBC. We identified all women recorded with a first primary breast cancer in the Danish Breast Cancer Cooperative Group Database between 1996 and 2012. Information on drug use, tumor and patient characteristics, treatment, and CBC was obtained from nationwide registries. In the main analysis, we defined time-varying post-diagnosis low-dose aspirin use as two or more prescriptions filled during follow-up and applied a one-year exposure lag. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnosis low-dose aspirin use and CBC risk. Among 52,723 breast cancer patients, 1,444 women developed CBC during a median follow-up of 4.8 years. The adjusted HR for CBC associated with post-diagnosis use of low-dose aspirin was 0.91 (95% CI: 0.75-1.09). We observed no substantial variation in HRs according to pattern of low-dose aspirin use or estrogen receptor status of the first or the contralateral breast cancer. In conclusion, this large nationwide cohort study of breast cancer survivors does not provide strong evidence suggesting an association between post-diagnosis use of low-dose aspirin and risk of CBC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: How a second breast cancer diagnosis affects survival in comparison with unilateral breast cancer (UBC) is unclear. Prognostic factors for contralateral breast cancer (CBC) are also not well established. We aimed to investigate the survival pattern after CBC with particular focus on time between first and second breast cancer diagnosis and age at CBC diagnosis., Methods: Within the nationwide Danish Breast Cancer Cooperative Group database, we identified 68,466 breast cancer patients diagnosed during 1978-2012. Patients who subsequently developed CBC were identified in a previously established database (N = 3004). Patients were followed for breast cancer-specific death in the Danish Register of Causes of Death until 2015. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazard regression models. Cumulative breast cancer mortality from date of CBC was estimated using the Aalen-Johansen method., Results: Compared with UBC patients, the rate of dying from breast cancer was more than twofold higher following a CBC diagnosis, after adjustment for age, period, tumor characteristics, and treatment of the first breast cancer (HR 2.48; 95% CI 2.31-2.66). Short time interval (< 5 years) was associated with higher breast cancer-specific mortality after CBC among patients < 70 years at CBC diagnosis compared with longer time intervals, but not among patients ≥ 70 years at CBC diagnosis., Conclusion: Breast cancer-specific mortality rates were markedly higher after compared with before a CBC diagnosis. We found higher breast cancer-specific mortality after CBC associated with a short interval between diagnoses among patients diagnosed with CBC before age 70 years.

Purpose The Women's Environmental Cancer and Radiation Epidemiology (WECARE) study demonstrated the importance of breast cancer family history on contralateral breast cancer (CBC) risk, even for noncarriers of deleterious BRCA1/2 mutations. With the completion of WECARE II, updated risk estimates are reported. Additional analyses that exclude women negative for deleterious mutations in ATM, CHEK2*1100delC, and PALB2 were performed. Patients and Methods The WECARE Study is a population-based case-control study that compared 1,521 CBC cases with 2,212 individually matched unilateral breast cancer (UBC) controls. Participants were younger than age 55 years when diagnosed with a first invasive breast cancer between 1985 and 2008. Women were interviewed about breast cancer risk factors, including family history. A subset of women was screened for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2. Rate ratios (RRs) were estimated using multivariable conditional logistic regression. Cumulative absolute risks (ARs) were estimated by combining RRs from the WECARE Study and population-based SEER*Stat cancer incidence data. Results Women with any first-degree relative with breast cancer had a 10-year AR of 8.1% for CBC (95% CI, 6.7% to 9.8%). Risks also were increased if the relative was diagnosed at an age younger than 40 years (10-year AR, 13.5%; 95% CI, 8.8% to 20.8%) or with CBC (10-year AR, 14.1%; 95% CI, 9.5% to 20.7%). These risks are comparable with those seen in BRCA1/2 deleterious mutation carriers (10-year AR, 18.4%; 95% CI, 16.0% to 21.3%). In the subset of women who tested negative for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2, estimates were unchanged. Adjustment for known breast cancer single-nucleotide polymorphisms did not affect estimates. Conclusion Breast cancer family history confers a high CBC risk, even after excluding women with deleterious mutations. Clinicians are urged to use detailed family histories to guide treatment and future screening decisions for young women with breast cancer.

Purpose: A history of anorexia nervosa has been associated with a reduced risk of developing breast cancer. We investigated survival after breast cancer among women with a prior anorexia nervosa diagnosis compared with women in a population comparison group., Methods: This register-based study included combined data from Sweden, Denmark and Finland. A total of 76 and 1462 breast cancer cases identified among 22,654 women with anorexia nervosa and 224,619 women in a population comparison group, respectively, were included in the study. Hazard ratios (HR) for overall and breast cancer-specific mortality after breast cancer diagnosis were estimated using Cox regression. Cause of death was available only for Swedish and Danish women; therefore, the analysis on breast cancer-specific mortality was restricted to these women., Results: We observed 23 deaths after breast cancer among anorexia nervosa patients and 247 among population comparisons. The overall mortality after the breast cancer diagnosis was increased in women with a history of anorexia nervosa compared with population comparisons (HR 2.5, 95% CI 1.6-3.9) after adjustment for age, period and extent of disease. Results were similar for overall (HR 2.3, 95% CI 1.4-3.6) and breast cancer-specific mortality (HR 2.1, 95% CI 1.3-3.6) among Swedish and Danish women., Conclusions: We found that female breast cancer patients with a prior diagnosis of anorexia nervosa have a worse survival compared with other breast cancer patients.

Objective: To study the risk of a second malignant neoplasm (SMN) and mortality in patients with rheumatoid arthritis (RA) with a history of a primary cancer diagnosis and treated with biological disease-modifying antirheumatic drugs (bDMARD)., Methods: Among patients with RA (n=15 286) registered in the DANBIO Register during 2000-2011, 1678 had a primary cancer according to the Danish Cancer Registry. HRs for SMN and death were calculated., Results: During follow-up there were 279 patients with RA contributing person-years to the bDMARDs use before their primary cancer diagnosis, 220 to the only after , 92 to the both before and after, while 1203 patients with RA contributed to the non-use strata. Ever use of bDMARDs was associated with a HR of 1.11 (95% CI 0.74 to 1.67) for developing a SMN compared with non-use (cancer site adjusted). The HR for death associated with bDMARD use before the primary cancer diagnosis was increased 1.53 (95% CI 1.13 to 2.09). After further adjustment for extent of the primary cancer, the HR for death was 1.20 (95% CI 0.88 to 1.63) for bDMARDs use before cancer, 1.36 (95% CI 0.78 to 2.39) for bDMARD use only after cancer and 1.22 (95% CI 0.70 to 2.13) for use both before and after the cancer., Conclusions: Among patients with RA with a history of cancer, treatment with bDMARDs was not associated with increased risk of SMN. No clear conclusion can be drawn regarding mortality in bDMARD-treated patients with RA., Competing Interests: Competing interests: LD: have received speaking fees outside the submitted work from UCB, MSD and Janssen pharmaceutica; IMJ: Roche Pharmaceuticals; LEK: Pfizer, AbbVie, Amgen, UCB, Celgene, BMS, Biogen, Forward Pharma, MSD, Novartis, Eli Lilly and Janssen Pharmaceuticals; MLH: AbbVie, BMS, MSD, Pfizer, Orion, Novartis, Biogen, Eli Lilly, Celltrion., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: The long-term cancer risk for patients treated for granulomatosis with polyangiitis (GPA) is not well characterized. We assessed the risk of early and late-occurring cancers among 293 patients diagnosed with GPA from 1973 to 1999 and followed throughout 2010., Methods: Cancer incidence in the cohort was determined by linkage with the Danish Cancer Registry and compared with that in the general population by calculation of standardized incidence ratios (SIRs)., Results: The median duration of follow-up was 9.7 years (range 0-36). Seventy-three cancers occurred, of which 30 were non-melanoma skin cancers (NMSCs) and 11 were bladder carcinomas. A high occurrence of NMSC was observed from the second year of follow-up onwards, with a SIR of 7.0 (95% CI 2.3, 16) for cases diagnosed ≥20 years after GPA. The incidence of bladder cancer increased after 5-9, 10-14 and 15-19 years of follow-up, with SIR estimates for these latency periods of 5.3 (95% CI 1.1, 15), 14.4 (95% CI 5.3, 31) and 10.5 (95% CI 1.2, 38), respectively. The incidence of myeloid leukaemia was significantly increased during years 5-9 [SIR 23.9 (95% CI 2.7, 86)]. Increased incidence of NMSC, bladder cancer and myeloid leukaemia was observed among patients exposed to cumulative CYC doses >36 g, while the only malignancy type observed in excess among those treated with lower CYC doses was NMSC. The cancer risk among CYC-naive patients was not significantly increased., Conclusion: GPA patients experience a greater than expected number of specific malignancies following conventional therapies. Our analyses demonstrate a substantially increased risk of very late-occurring NMSC and bladder cancer in this patient group., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A diet with restricted energy content reduces the occurrence of cancer in animal experiments. It is not known if the underlying mechanism also exists in human beings. To determine whether cancer incidence is reduced among patients with anorexia nervosa who tend to have a low intake of energy, we carried out a retrospective cohort study of 22 654 women and 1678 men diagnosed with anorexia nervosa at ages 10-50 years during 1968-2010 according to National Hospital Registers in Sweden, Denmark and Finland. The comparison group consisted of randomly selected persons from population registers who were similar to the anorexia nervosa patients in respect to sex, year of birth and place of residence. Patients and population comparisons were followed for cancer by linkage to Cancer Registries. Incidence rate ratios (IRR) were estimated using Poisson models. In total, 366 cases of cancer (excluding non-melanoma skin cancer) were seen among women with anorexia nervosa, and the IRR for all cancer sites was 0.97 (95% CI = 0.87-1.08) adjusted for age, parity and age at first child. There were 76 breast cancers corresponding to an adjusted IRR of 0.61 (95% CI = 0.49-0.77). Significantly increased IRRs were observed for esophageal, lung, and liver cancer. Among men with anorexia nervosa, there were 23 cases of cancer (age-adjusted IRR = 1.08; 95% CI = 0.71-1.66). There seems to be no general reduction in cancer occurrence among patients with anorexia nervosa, giving little support to the energy restriction hypothesis.

Objective: To assess the association between polycystic ovary syndrome (PCOS) and cancer, especially of the endometrium, breast and ovary., Methods: The Danish National Patient Register was used to identify 12,070 in- and outpatients in whom PCOS was diagnosed when they were aged 9-49 years during 1977-2012. Using the Danish Cancer Registry, we followed the cohort through 2012 and compared the women's cancer incidence with that of the general Danish female population by means of standardized incidence ratios (SIRs)., Results: Cancer was diagnosed in 279 women with PCOS (SIR = 1.19; 95% CI = 1.06-1.34). We found an almost fourfold increased risk for endometrial cancer (numbers observed (N) = 16, SIR = 3.9; 95% CI = 2.2-6.3), the large majority of cases being type 1 (N = 14, SIR = 4.7; 95% CI = 2.6-7.9). We found no association between PCOS and breast (N = 59, SIR = 1.1; 95% CI = 0.8-1.4) or ovarian cancer (N = 10, SIR = 1.8; 95% CI = 0.8-3.2); however, significantly increased risks were found for kidney, colon and brain cancers., Conclusion: The results of this large cohort study support those of case-control studies showing that women with PCOS are at increased risk for endometrial cancer, whereas their risks for breast and ovarian cancer are similar to those of women in the general population. Our finding that women with PCOS also are at increased risk for cancers of the kidney, colon and brain requires further study., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Incidence of contralateral breast cancer (CBC) is much less studied than primary breast cancer. We aimed to assess incidence rates of CBC in relation to age, calendar period and time since first breast cancer., Methods: Using the nationwide Danish Cancer Registry, we identified 85 863 women with a first primary invasive breast cancer without distant metastases in Denmark during 1978-2009. Among these, 3120 women developed metachronous CBC. Crude incidence rates for CBC were calculated by age and calendar period at first breast cancer as well as time since first breast cancer. Mutual adjustments were made by use of Poisson regression models., Results: The incidence of CBC decreased with increasing age at first breast cancer. Before 1998, incidence rates of CBC showed little variation. The rates decreased by period of first primary from 546 per 10(5) person-years in 1993-97 to 328 per 10(5) person-years in 2003-09. After adjustment for age and calendar period, no clear trend was observed in the overall incidence according to time since first breast cancer., Conclusions: Occurrence of cancer in the contralateral breast seems to be rather independent of time passed since the first primary. The finding of a decreasing incidence of CBC after 1997 is likely to be due to more women receiving systemic adjuvant therapy such as tamoxifen and longer duration of this treatment as well as the introduction of aromatase inhibitors., (© The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Purpose: Tamoxifen reduces the risk of contralateral breast cancer (CBC), but little is known about the long-term risk., Methods: From the database under the Danish Breast Cancer Cooperative Group (DBCG), we identified 15,863 users and 21,670 nonusers of tamoxifen among women diagnosed with breast cancer during 1977 to 2007. Information on CBC was obtained from the Danish Cancer Registry and the Danish Breast Cancer Cooperative Group database. Cox regression analyses were carried out with estimation of hazard ratios (HRs) of CBC. We also estimated the HRs of current and past use of tamoxifen., Results: Current use of tamoxifen was associated with reduced HRs of CBC independently of menopausal status and calendar-period. The HRs associated with past use of tamoxifen, however, varied among postmenopausal users from 1.50 (95% confidence interval [CI], 1.20-1.87) among users in 1977 to 1989 to 0.87 (95% CI, 0.70-1.06) and 1.05 (95% CI, 0.68-1.63) among users in 1990 to 1998 and 1999 to 2007, respectively. No excesses or deficits of CBC were found 10 or more years since the last use in postmenopausal women in any calendar-period., Conclusions: Our study confirms that tamoxifen protects against CBC while being treated. The effect of tamoxifen after cessation of treatment was not clear because of the inconsistency in results by calendar-period., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Cardiovascular disease has emerged as a serious late effect in survivors of adolescent and young adult cancer, but risk has not been quantified comprehensively in a population-based setting., Methods: In the Danish Cancer Registry, we identified 43153 1-year survivors of cancer diagnosed at ages 15 to 39 years (1943-2009) and alive in 1977; from the Danish Civil Registration System, we randomly selected a comparison cohort of the same age and sex. Subjects were linked to the Danish Patient Register, and observed numbers of first hospitalizations for cardiovascular disease (International Classification of Diseases, Tenth Revision codes I10-I79) were compared with the expected numbers derived from the comparison cohort. We calculated the absolute excess risks attributable to status as a survivor of cancer and standardized hospitalization rate ratios (RRs). All statistical tests were two-sided., Results: During follow-up, 10591 survivors (24.5%) were discharged from the hospital with cardiovascular disease, whereas 8124 were expected (RR = 1.30; 95% confidence interval [CI)] = 1.28 to 1.33; P < .001). The absolute excess risks were 400 and 350 extra cases of cardiovascular disease per 100000 person-years for people aged 20 to 59 and 60 to 79 years at discharge, respectively. Survivors of Hodgkin lymphoma experienced high risks for being hospitalized with valvular disease (RR = 12.2; 95% CI = 9.9 to 15.0; P < .001). Survivors of leukemia had high risks for cerebral hemorrhage (RR = 10.3; 95% CI = 5.5 to 19.1; P < .001) and cardiomyopathy (RR = 8.6; 95% CI = 4.3 to 17.3; P < .001)., Conclusions: Survivors of adolescent and young adult cancer are at increased risk for cardiovascular disease throughout life, although each main type of adolescent and young adult cancer had its own risk profile., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: To estimate the incidence of pregnancy-associated cancer during a 30-year period in Denmark on the basis of both births and abortions with and without age adjustment and age standardization., Methods: Using data from the nationwide Danish registries, we investigated the occurrence of pregnancy-associated cancer (defined as cancer diagnosed during pregnancy and up to 1 year after pregnancy has ended) in pregnancies resulting in a birth (live birth or stillbirth) or an abortion. We included patients with primary cancer diagnosed at ages 15-44 years during 1977-2006 according to the Danish Cancer Registry. The patients were linked to the Medical Birth Registry, the Registry for Induced Abortions, and the National Patient Registry to obtain information on pregnancies., Results: We identified 2,426 patients with pregnancy-associated cancer. The three most frequent types were melanoma, cervical cancer, and breast cancer. We found an increase in the total numbers of all pregnancy-associated cancers from 572 cases during 1977-1986 to 1,052 cases during 1997-2006. The proportions of all pregnancy-associated cancers among all cancers increased from 5.4% to 8.3% during the same periods. The overall crude incidence rate of all pregnancy-associated cancer was 89.6 out of 100,000 pregnancies. The crude incidence increased over time, with an average annual percentage change of 2.9% (95% confidence interval [CI] 2.4-3.3). After age adjustment, the increase was still statistically significant (1.6%, 95% CI 1.1-2.1)., Conclusion: We found a statistically significant increase in pregnancy-associated cancer during the 30-year study period. The tendency to postpone childbirth only partly explains the increase in incidence rates., Level of Evidence: III.

Background and Purpose: To analyze the long-term risk of second primary solid non-breast cancer in a national population-based cohort of 46,176 patients treated for early breast cancer between 1982 and 2007., Patients and Methods: All patients studied were treated according to the national guidelines of the Danish Breast Cancer Cooperative Group. The risk of second primary cancers was estimated by Standardised incidence ratios (SIRs) and multivariate Cox regression models were used to estimate adjusted hazard ratios (HR) among irradiated women compared to non-irradiated. All irradiated patients were treated on linear accelerators. Second cancers were a priori categorized into two groups; radiotherapy-associated- (oesophagus, lung, heart/mediastinum, pleura, bones, and connective tissue) and non-radiotherapy-associated sites (all other cancers)., Results: 2358 second cancers had occurred during the follow-up. For the radiotherapy-associated sites the HR among irradiated women was 1.34 (95% CI 1.11-1.61) with significantly increased HRs for the time periods of 10-14 years (HR 1.55; 95% CI 1.08-2.24) and ≥ 15 years after treatment (HR 1.79; 95% CI 1.14-2.81). There was no increased risk for the non-radiotherapy-associated sites (HR 1.04; 95% CI 0.94-1.1). The estimated attributable risk related to radiotherapy for the radiotherapy-associated sites translates into one radiation-induced second cancer in every 200 women treated with radiotherapy., Conclusions: Radiotherapy treated breast cancer patients have a small but significantly excess risk of second cancers., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To investigate the incidence of cancer in arthritis patients treated with or without TNFα inhibitors (TNF-I)., Methods: Arthritis patients from the DANBIO database were followed-up for cancer in the Danish Cancer Registry during 2000-2008., Results: Hazard ratio for cancer overall was 1.02 (95% confidence interval (CI) 0.80-1.30) in 3347 TNF-I-treated RA patients compared to non-treated. Excess among TNF-I-treated was found for colon cancer (HR 3.52 (95%CI 1.11-11.15), whereas 6 and 0 ovarian cancer cases were observed in treated and non-treated patients, respectively. Compared to the general population, TNF-I-treated RA patients had increased risk for cancer overall, cancer in lymphatic-haematopoietic tissue and non-melanoma skin cancer, while non-RA patients had no increase in overall cancer risk., Conclusions: Our results suggest that TNF-I therapy in routine care is not associated with an overall excess of cancer in arthritis patients, but observed increased risks of colon and ovarian cancer need further investigation.

Background: Tallness has consistently been associated with an increased risk of breast cancer. We investigated the association further by decomposing height into leg length and sitting height., Methods: From the prospective Danish cohort 'Diet, Cancer and Health', 23 864 postmenopausal women enrolled during 1993-1997 were followed for a diagnosis of breast cancer in the Danish Cancer Registry through 2009., Results: The incidence rate ratios for breast cancer were 1.11 (95% CI=1.06-1.16) for each 5 cm increase in total height and 1.09 (95% CI=1.01-1.17) and 1.14 (95% CI=1.04-1.25) for each 5 cm increase in leg length and sitting height, respectively. There was no statistical significant difference between the associations for leg length and sitting height (P=0.47)., Conclusion: Leg length does not seem to be more strongly associated with breast cancer among postmenopausal women than sitting height.

Objective: To investigate the occurrence of ischemic heart disease (IHD) in a cohort of 104 Danish patients with biopsy-proven lupus nephritis (LN)., Methods: Information on all hospitalizations in Denmark for IHD between 1977 and 2006 was obtained from the Danish National Hospital Register. Occurrence of IHD after date of first renal biopsy in the LN cohort was compared to the occurrence of IHD in the general population by calculation of standardized ratios of observed to expected events (O:E ratios) for different manifestations of IHD registered during inpatient and outpatient hospital visits., Results: The median duration of followup was 14.7 (range 0.1-30.0) years. Thirty-one first-time hospitalizations for IHD occurred in the cohort, yielding an overall O:E ratio for IHD of 6.8 (95% CI 4.6-9.7). Increased risks were found for angina pectoris (O:E ratio 6.0, 95% CI 3.0-11), myocardial infarction (O:E ratio 7.9, 95% CI 3.8-15), and other IHD-related diagnoses combined (O:E ratio 6.9, 95% CI 3.3-13). A high IHD risk was observed for patients aged < 31 years at time of first renal biopsy (O:E ratio 17.1, 95% CI 9.1-29) and for patients aged 30-39 years during followup (O:E ratio 42.3, 95% CI 21-76). Patients undergoing chronic renal replacement therapy also had a pronounced risk of IHD (O:E ratio 19.4, 95% CI 7.8-40)., Conclusion: LN is associated with markedly increased morbidity from IHD. Our findings indicate that patients with early-onset LN have a disturbingly high risk of IHD compared to the general population.

Background: Women diagnosed with breast cancer at young age have been shown to be at higher risk of developing a new primary cancer than women diagnosed at older ages, but little is known about whether adjustment for calendar year of breast cancer diagnosis, length of follow-up, and/or breast cancer treatment alters the risk pattern by age., Methods: We identified 304,703 women diagnosed with breast cancer during 1943 to 2006 in the Cancer Registries of Denmark, Norway, and Finland. Relative risks (RR) of subsequent non-breast cancer by age at cancer diagnosis were calculated using Poisson regression models adjusted for country, calendar period, length of follow-up, and treatment. Excess absolute risks (EAR) were also calculated., Results: The RR for all cancer sites except breast cancer decreased with increasing age both with and without adjustments. The RR and the EAR differed for each age at diagnosis category until the women reached their late 70s. Many specific cancer forms contributed to the overall risk pattern by age with endometrial cancer as 1 exception., Conclusions: The age at breast cancer diagnosis is an essential risk factor for being diagnosed with a new primary non-breast cancer and the level of risk for specific ages at diagnosis may hold for many years after the diagnosis. Occurrence of endometrial cancer after breast cancer seems to follow a distinct age pattern different from that seen for most other cancer types., Impact: Future studies should aim at exploring the underlying explanations for the age-related findings., (©2011 AACR.)

Introduction: We investigated the risk for a second primary cancer in pre- and postmenopausal women with breast cancer treated by surgery alone, to assess the importance of non-treatment factors and menopausal status., Patients and Methods: The cohort comprised 14,151 women with breast cancer diagnosed during 1977-2006, who did not receive radiotherapy or systemic adjuvant therapy. They were identified in the nationwide clinical database of the Danish Breast Cancer Cooperative Group. The women were followed for a second primary cancer other than breast cancer in the Danish Cancer Registry, and risk was quantified as standardised incidence ratios (SIRs)., Results: Women with breast cancer diagnosed before menopause had an 18% greater overall risk for a second primary non-breast cancer than the general female population (95% confidence interval [CI], 1.06-1.32). The excess was confined to cancers of the endometrium (1.5; 95% CI, 1.0-2.0) and ovaries (1.8; 95% CI, 1.2-2.4). Rare histological subtypes of breast cancer were associated with these two cancer sites. Women with breast cancer after menopause had no overall excess risk for a second cancer (SIR, 0.98; 95% CI, 0.92-1.04)., Conclusion: An excess risk for second non-breast cancers related to non-treatment factors is seen primarily in breast cancer patients who were premenopausal at diagnosis., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose: Women with breast cancer diagnosed early in life comprise a substantial portion of those tested for BRCA1/BRCA2 mutations; however, little information is available on the subsequent risks of contralateral breast cancer in mutation carriers. This study assessed the risk of subsequent contralateral breast cancer associated with carrying a BRCA1 or BRCA2 mutation., Patients and Methods: In this nested case-control study, patients with contralateral breast cancer diagnosed 1 year or more after a first primary breast cancer (n = 705) and controls with unilateral breast cancer (n = 1,398) were ascertained from an underlying population-based cohort of 52,536 women diagnosed with a first invasive breast cancer before age 55 years. Interviews and medical record reviews were used to collect risk factor and treatment histories. All women were tested for BRCA1/BRCA2 mutations. Relative (rate ratios) and absolute (5- and 10-year cumulative) risks of developing contralateral breast cancer following a first invasive breast cancer were computed., Results: Compared with noncarriers, BRCA1 and BRCA2 mutation carriers had 4.5-fold (95% CI, 2.8- to 7.1-fold) and 3.4-fold (95% CI, 2.0- to 5.8-fold) increased risks of contralateral breast cancer, respectively. The relative risk of contralateral breast cancer for BRCA1 mutation carriers increased as age of first diagnosis decreased. Age-specific cumulative risks are provided for clinical guidance., Conclusion: The risks of subsequent contralateral breast cancer are substantial for women who carry a BRCA1/BRCA2 mutation. These findings have important clinical relevance regarding the assessment of BRCA1/BRCA2 status in patients with breast cancer and the counseling and clinical management of patients found to carry a mutation.

Objective: To investigate whether patients with WG have an increased risk of malignancies prior to and/or around the time of the vasculitis diagnosis, as suggested by previous studies., Methods: A total of 293 WG patients were included in the study. Ten gender- and age-matched controls were selected randomly for each patient from the Danish Central Population Register. Information on malignancies was obtained through the Danish Cancer Registry. Occurrence of malignancies before WG diagnosis among patients and before WG diagnosis of their matched case among controls (reference date) was compared by calculation of prevalence odds ratios (OR)., Results: Twenty-six patients were diagnosed with cancer before WG, while 194 controls were diagnosed with cancer before the reference date (OR 1.4; 95% CI 0.9, 2.2). Among specific malignancies, a significantly increased prevalence was found for testis cancer (OR 6.4; 95% CI 1.1, 38) based on two patients, who developed testis cancer >10 years before WG. The overall prevalence of malignancies diagnosed <2 years before WG was not significantly increased (OR: 1.6; 95% CI: 0.8, 3.4), but non-melanoma skin cancer occurred with an increased prevalence within this time interval (OR 4.0; 95% CI 1.4, 12)., Conclusions: We did not find clear evidence of an increased prevalence of preceding cancer in our WG cohort, indicating that shared risk factors are of minor importance for the excess of malignancies that occur in WG patients after the vasculitis diagnosis. Furthermore, our current and previously reported latency analyses do not substantiate that serious malignancies play a significant role in the pathogenic events that trigger development of WG.

Objective: Experimental studies indicate that patients with Wegener's granulomatosis (WG) experience accelerated atherosclerosis. The purpose of this study was to investigate whether the occurrence of overt ischemic heart disease (IHD) is increased in WG., Methods: A total of 293 WG patients were included in the study. Information on all hospitalizations for IHD in Denmark from 1977 to 2006 was obtained from the Danish National Hospital Register. The WG patients were compared with the Danish background population with respect to rates of hospitalization for clinical manifestations of IHD after the date of vasculitis diagnosis by calculating standardized ratios of observed to expected (O:E) events., Results: Sixty-three first IHD events were registered in the WG group during the 2,482 patient-years of followup, corresponding to a significantly increased O:E ratio for IHD of 1.9 (95% confidence interval [95% CI] 1.4-2.4). A significantly increased risk was found for acute myocardial infarction (MI) (O:E ratio 2.5 [95% CI 1.6-3.7]), but not for angina pectoris (O:E ratio 1.3 [95% CI 0.7-2.1]). In analyses stratified according to the time between the diagnosis of vasculitis and the cardiovascular event, increased O:E ratios were found for IHD and acute MI occurring <5.0 years after WG diagnosis (2.1 [95% CI 1.4-3.0] for IHD and 3.6 [95% CI 2.0-5.9] for acute MI) and for IHD occurring > or =10.0 years after WG diagnosis (2.2 [95% CI 1.3-3.4]). Significantly increased O:E ratios for IHD and acute MI were found in patients who were > or =50.0 years of age at the time of diagnosis of WG, in male patients, and in patients who received high cumulative doses of cyclophosphamide., Conclusion: Compared with the background population, WG patients seem to experience an increased number of both early and late cardiovascular events due to IHD.

Background: The incidence rate of breast cancer in first-degree relatives of women with breast cancer has been hypothesized to become constant at a predetermined age in accordance with observations of a high, roughly constant incidence rate of contralateral breast cancer by age. We attempted to test this hypothesis in the Danish population with cancer registry data., Methods: We determined the age-specific incidence rates of contralateral breast cancer in Danish women who had a first breast cancer before they were 50 years of age and the rates of breast cancer among their first-degree female relatives during 1943 to 1999. The observed rates were tested for trends chi test or evaluated in Cox proportional hazard models., Results: A high incidence rate of contralateral breast cancer was observed in women aged 25-44 years, followed by a decreasing rate, which reached a level corresponding to the rate per breast in the general female population at age 65. At ages older than the index patients age at diagnosis, their first-degree female relatives showed significantly increasing incidence rates of breast cancer by age, with a relatively constant absolute difference of 187 breast cancers per 100,000 person-years between the observed rates and the expected rates., Conclusion: The rate of contralateral breast cancer is particular high at young ages but the excess ebbs as the cohort ages, perhaps due to elimination of predisposed individuals at early ages from the cohort of survivors. First-degree relatives seem to share breast cancer susceptibility genes with the family proband resulting in a constant excess rate of breast cancer throughout life.

Introduction: The use of anti-tumour necrosis factor (anti-TNF) therapy is increasing in the treatment of rheumatoid arthritis (RA), spondyloarthropathy, psoriasis and inflammatory bowel disease. It is being debated whether treatment of patients with rheumatic diseases with anti-TNF therapy is associated with an increased cancer incidence., Material and Methods: A descriptive study of cancer cases among 3,688 patients with rheumatic diseases who received anti-TNF therapy was performed. The patients were identified in the nationwide database DANBIO and had a total number of treatment years of 6,092 years. All cancer cases were identified and the cancer diagnoses were subsequently confirmed by medical record review., Results: A total of 30 cancers in 28 of 3,688 patients were registered in the DANBIO after initiation of anti-TNF therapy in the period from October 2000 to June 2007. Among these six men and 20 women had RA, and two men had Morbus Becterew. The following cancer types were observed: malignant lymphoma 2 (7%), lung 4 (13%), plicae vocalis 2 (7%), breast 4 (13%), pancreatic 3 (10%), colorectal 2 (7%), prostate 1 (3%), malignant melanoma 3 (10%) and non-melanoma skin cancer 9 (30%)., Conclusion: In our descriptive study from the nationwide database DANBIO, a total of 30 cancers were observed in 3,688 patients with rheumatic diseases within a cumulated period of treatment with anti-TNF of 6,092 years. Follow-up for anti-rheumatic and adverse effects in patients in the DANBIO database will continue. Future studies must reveal whether anti-TNF therapy is associated with an increased cancer risk. Planned Danish studies will include relevant control groups and adjustment for confounders.

Purpose: Genetic factors are important in the etiology and pathogenesis of chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma (HL), and non-Hodgkin's lymphoma (NHL). Only a few small studies have assessed clinical characteristics and prognosis for familial patients, with inconsistent findings., Methods: Using population-based registries from Sweden and Denmark, 7,749 patients with CLL, 7,476 patients with HL, and 25,801 patients with NHL with linkable first-degree relatives were identified. Kaplan-Meier curves were constructed to compare survival in patients with lymphoma with and without a family history of lymphoma. The risk of dying was assessed using adjusted Cox proportional hazard models., Results: We found 85 patients with CLL (1.10%), 95 patients with HL (1.28%), and 206 patients with NHL (0.80%) with a family history of any lymphoma. Five-year mortality was similar for patients with CLL (hazard ratio [HR], 1.28; 95% CI, 0.95 to 1.72), HL (HR, 0.78; 95% CI, 0.49 to 1.25), and NHL (HR, 0.91; 95% CI, 0.74 to 1.12) versus without a family history of any lymphoma. Mortality was also similar for patients with versus without a family history of the same lymphoma. T-cell/anaplastic lymphoma patients with a family history of NHL had poorer outcome 5-years after diagnosis (HR, 5.38; 95% CI, 1.65 to 17.52). Results were similar for 10 years of follow-up., Conclusion: With the exception of T-cell/anaplastic lymphoma, survival patterns for patients with CLL, HL, and NHL with a family history of lymphoma were similar to those for sporadic patients, suggesting that most familial lymphomas do not have an altered clinical course. Our findings provide no evidence to modify therapeutic strategies for patients with CLL, HL, or NHL based solely on family history.

We investigated the effects of socioeconomic, demographic and health-related indicators on the incidence of and survival from haematological cancers diagnosed in 1994-2003 with follow-up through 2006 in Denmark using information from nationwide registers. The analyses were based on data on 636 patients with Hodgkin lymphoma (HL), 4516 with non-Hodgkin lymphoma (NHL) and 3486 with leukaemia in a cohort of 3.22 million people born between 1925 and 1973 and aged >or=30 years. No consistent differences in incidence were seen by socioeconomic position, but an association with comorbidity was found. Patients in the lowest socioeconomic groups and those with other serious illnesses, especially men, had a worse survival of NHL. Survival results for leukaemia tended to be similar to those for NHL, although associations were generally weaker and insignificant. Thus, there were no strong associations between socioeconomic position and the incidence of these cancers; survival after NHL might be affected.

Benign breast disease is associated with increased risk of breast cancer. To further clarify whether there is a genetic link between benign and malignant breast lesions, the authors identified 14,648 first-degree female relatives of 8,807 patients in whom breast cancer was diagnosed at <50 years of age by using Danish nationwide cancer and population registers. Hospital register data were used to follow the relatives for occurrence of benign breast disease from 1977 to 2003 and to calculate rates of benign breast disease in the general population of Danish women for comparison. Risk for relatives was increased for benign breast diseases (observed/expected ratio = 1.54, 95% confidence interval: 1.42, 1.66), particularly for relatives aged <40 years. Higher risks were observed after breast cancer had been diagnosed in the family; however, an increased risk for relatives aged <50 years (observed/expected ratio = 1.24, 95% confidence interval: 1.02, 1.51) was present before breast cancer was diagnosed in the family. Enhanced surveillance of close relatives of breast cancer patients seems to be an important factor to address when investigating the association between benign breast disease and familial breast cancer. A genetic link between benign breast disease and breast cancer was indicated by our data but needs to be confirmed in future studies.

Low hormone levels among persons with osteoporosis may decrease risk of some cancers. Other osteoporosis risk factors, such as smoking and alcohol consumption, however, may increase risk. As these deleterious factors are more often associated with osteoporosis diagnosed prior to age 70 years, cancer risk may be higher in these younger persons than in the general population. To examine this hypothesis, a cohort study of 23,935 persons with osteoporosis was conducted in Denmark. Patients hospitalized with osteoporosis between 1978 and 1993 were identified in the Danish Inpatient Register. Linkage to the Danish Cancer Registry identified all cancer outcomes through 2003. Standardized incidence ratios (SIR) and 95% confidence intervals (95%CI) were calculated to compare cancer incidence in the cohort with that in the general population. Persons diagnosed prior to age 70 years were at increased cancer risk (women: SIR = 1.11, 95%CI = 1.04-1.19; men: SIR = 1.31, 95%CI = 1.13-1.50) due, in part, to increased risks of cancers of the buccal cavity, esophagus, liver, pancreas and lung. Persons diagnosed at ages 70 and older were at decreased risk (women: SIR = 0.91, 95%CI = 0.87-0.96; men: SIR = 0.89, 0.77-1.01) due, in part, to decreased risks of breast, endometrial, colon, rectal and brain cancers in women and prostate cancer in men. These results suggest that risk factors associated with earlier onset osteoporosis may be associated with increased risk of cancer. Conversely, factors associated with later onset osteoporosis may be related to a decreased risk of cancer.

Objective: Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome have been consistently associated with an increased risk of non-Hodgkin's lymphoma (NHL). This study was initiated to evaluate the risks of NHL associated with a personal or family history of a wide range of autoimmune diseases., Methods: A population-based case-control study was conducted that included 24,728 NHL patients in Denmark (years 1977-1997) and Sweden (years 1964-1998) and 55,632 controls. Using univariate logistic and hierarchical regression models, we determined odds ratios (ORs) of NHL associated with a personal history of hospital-diagnosed autoimmune conditions. Risks of NHL associated with a family history of the same autoimmune conditions were assessed by similar regression analyses that included 25,941 NHL patients and 58,551 controls., Results: A personal history of systemic autoimmune diseases (RA, SLE, Sjögren's syndrome, systemic sclerosis) was clearly linked with NHL risk, both for individual conditions (hierarchical odds ratios [OR(h)] ranged from 1.6 to 5.4) and as a group (OR(h) 2.64 [95% confidence interval (95% CI) 1.72-4.07]). In contrast, a family history of systemic autoimmune diseases was modestly and nonsignificantly associated with NHL (OR(h) 1.31 [95% CI 0.85-2.03]). An increased risk of NHL was found for a personal history of 5 nonsystemic autoimmune conditions (autoimmune hemolytic anemia, Hashimoto thyroiditis, Crohn's disease, psoriasis, and sarcoidosis) (OR(h) ranged from 1.5 to 2.6) of 27 conditions examined., Conclusion: Overall, our results demonstrate a strong relationship of personal history of systemic autoimmune diseases with NHL risk and suggest that shared susceptibility may explain a very small fraction of this increase, at best. Positive associations were found for a personal history of some, though far from all, nonsystemic autoimmune conditions.

Objective: To describe the incidence of malignancies in a cohort of Danish patients with Wegener's granulomatosis (WG) and to investigate the cancer risk associated with cyclophosphamide (CYC) -therapy in WG., Methods: In total, 293 patients diagnosed with WG between 1973 and 1999 were studied. Cancer incidence in the cohort was assessed through 2003 by linkage to the Danish Cancer Registry and compared to that of the general population by calculation of standardized incidence ratios (SIR). Analyses were stratified according to treatment with low cumulative CYC doses (< or = 36 g) and high doses (> 36 g, corresponding to treatment with 100 mg CYC/day for > 1 year)., Results: Fifty cancers occurred during 2121 person-years of followup (SIR of cancer of 2.1, 95% CI 1.5-2.7). Significantly increased SIR were observed for acute myeloid leukemia (AML; SIR 19.6, 95% CI 4.0-57), bladder cancer (SIR 3.6, 95% CI 1.2-8.3), and non-melanoma skin cancers (SIR 4.7, 95% CI 2.8-7.3). Leukemias and bladder cancers were diagnosed 6.9-18.5 years after initiation of CYC therapy. The risk of these malignancies was not increased for patients who never received CYC or for patients treated with cumulative CYC doses < or = 36 g. In contrast, high risks of AML (SIR 59.0, 95% CI 12-172) and bladder cancer (SIR 9.5, 95% CI 2.6-24) were observed for patients treated with cumulative CYC doses > 36 g., Conclusion: Treatment with high cumulative CYC doses implies a substantial risk of late-occurring, serious malignancies in WG. Patients with WG should be monitored for development of cancer for several decades after cessation of CYC therapy. These findings emphasize the need for development of new treatment regimens in WG.

Objective: Several chronic diseases have been hypothesized to affect the risk of subsequent gynecologic malignancies, possibly through shared hormonal mechanisms., Methods: Using record linkage techniques, we assessed the relationships between hospital and outpatient admissions for gallbladder disease, diabetes, hypertension, thyroid diseases and obesity and the subsequent development of uterine and ovarian cancers in Denmark between 1978 and 1998. Based on a subsample of more than 99,000 women, including 1398 uterine and 2491 ovarian cancers, we derived relative risks (RRs) and 95% confidence intervals (CIs) associated with overall and histology-specific cancer risks after adjustment for age, calendar time and reproductive characteristics., Results: Uterine cancers were related to previous diagnoses of thyroid diseases (RR=1.52, 95% CI 1.17-1.98) and obesity (2.05, 1.40-3.00). Associations with diabetes were confounded by obesity, but there were some elevations in risk for subjects diagnosed with obesity prior to age 45 (RRs 1.66-1.79). Although the "usual types" of endometrial cancer largely accounted for the observed associations, there was some evidence that uterine sarcomas (n=137) were related to prior diagnoses of thyroid diseases (2.78, 1.41-5.50). In contrast, ovarian cancers were not strongly related to most documented chronic diseases. Serous carcinomas were associated with gallbladder diseases of short durations, but detection bias or misdiagnosis probably accounts for this association. An association of obesity and endometrioid ovarian cancer was not identified., Conclusions: Uterine cancers, including sarcomas, appear to be influenced by selected chronic diseases. Further attention should focus on possible biologic mechanisms underlying observed associations with thyroid diseases and obesity.

Although several risk factors are common to endometriosis and breast cancer, the results of observational studies of an association have so far been inconsistent. We evaluated the relationship between endometriosis and breast cancer on the basis of data on selected cancers and medical histories from the Danish nationwide cancer and hospital registries used in a large case-cohort study. A total of 114,327 women were included in the study of whom 1,978 women had received a diagnosis of endometriosis and 16,983 had had a diagnosis of breast cancer between 1978 and 1998. Of the women with endometriosis, 236 subsequently received a diagnosis of breast cancer. The crude overall rate ratio for breast cancer after endometriosis was 1.00 and after adjustment for reproductive factors, calendar-period, bilateral oophorectomy and benign breast disease, the rate ratio was 0.97 (95% confidence interval, 0.85-1.11). The risk for breast cancer increased with age at diagnosis of endometriosis, so that women in whom endometriosis was diagnosed at a young age (approximately <40 years) had a reduced risk for breast cancer and women in whom endometriosis was diagnosed at older ages (approximately > or =40 years) tended to have an increased risk for breast cancer. The reduced risks observed among young women may reflect their exposure to drugs with antiestrogenic effects. The increased risk associated with endometriosis among postmenopausal women may be due to common risk factors between postmenopausal endometriosis and breast cancer or an altered endogenous estrogen., ((c) 2006 Wiley-Liss, Inc.)

Recently, the incidence of intrahepatic cholangiocarcinoma (ICC) has been increasing in a number of developed (Western) countries. However, risk factors in these low-risk populations are poorly understood. In this nationwide population based case-control study in Denmark, we examined the relationship between selected medical conditions and subsequent ICC risk to provide additional clues to etiopathogenesis. All histologically confirmed ICC cases diagnosed in Denmark between 1978 and 1991 were identified from the Danish cancer registry. Population controls were selected from the central population registry and were matched 4:1 to cases on sex and year of birth. Cases and controls were linked to the Danish hospital discharge registry to obtain information on prior hospital diagnoses. Odds ratios (OR) and 95% confidence intervals (95% CI) were derived using conditional logistic regression. A total of 764 ICC cases and 3,056 population controls were included in the study. Chronic liver diseases were significantly related to ICC: alcoholic liver disease (OR = 19.22, 95% CI = 5.55-66.54), unspecified cirrhosis (OR = 75.9, 95% CI 10.2-565.7). Bile duct diseases were also associated with risk: cholangitis (OR = 6.3, 95% CI = 2.3-17.5), choledocholithiasis (OR = 23.97, 95% CI = 2.9-198.9), cholecystolithiasis (OR = 4.0, 95% CI = 2.0-7.99), though gallbladder removal did not change risk (OR = 1.6, 95% CI = 0.65-3.7). Among other conditions, chronic inflammatory bowel disease (OR = 4.7, 95% CI = 1.65-13.9) was significantly associated with ICC. Diabetes was associated with risk in the year prior to diagnosis of ICC (OR = 3.02, 95% CI = 1.05-8.69). Obesity was unrelated to risk. These results confirm that prior bile duct diseases increase risk of ICC and suggest that alcoholic liver disease and diabetes may also increase risk.

Objective: To analyze whether fibromyalgia (FM) and FM-like symptoms are related to an increased incidence of cancer., Methods: We identified 1361 patients referred on suspicion of FM in the period 1984-99 from hospital records. Following the American College of Rheumatology (ACR) criteria, patients were divided into subgroups with and without confirmed FM. The cohort was followed to the end of 1999 and linked to the files of the Danish Cancer Register. Site-specific standardized incidence ratios (SIR) were calculated., Results: We found no association between FM and cancer in 1132 female patients with confirmed FM at our institution (SIR 1.2, 95% CI 0.8-1.8). In 106 women referred for muscle pain and/or tenderness who did not meet the criteria for FM, an increased overall SIR was observed (SIR 2.5, 95% CI 1.2-4.6), with increased risk for breast cancer (SIR 4.8, 95% CI 1.6-11.3) and lymphatic and hematological cancers (SIR 10.6, 95% CI 1.2-38.2). There were 4 lung cancers in 84 men with confirmed FM (SIR 12.6, 95% CI 3.4-32.4)., Conclusion: Neither confirmed FM nor those without confirmed FM predicted cancer. An increased risk of breast cancer was found among those who did not meet the ACR criteria for FM. These patients should be investigated if they develop any new or warning symptoms of malignancy, and treating physicians should be vigilant with screening procedures such as mammography.

Encounter with infectious antigens has been proposed to initiate the cascade of events associated with progression from premalignancy (monoclonal gammopathy of undetermined significance, MGUS) to multiple myeloma (MM). We conducted a population-based case-control study to evaluate risk of developing MM associated with a personal history of various respiratory tracts infections occurring >1 year prior to MM. Inpatient (1977-1997) and outpatient (1994-1997) diagnoses were obtained for all MM patients (n=4,476) diagnosed in Denmark (1977-1997) and 16,727 matched controls. A personal history of pneumonia was associated with a 1.6-fold (95%CI 1.3-2.0) increased risk of MM; the elevated risk was restricted to 1-4.99 years prior to the diagnosis of MM (OR=1.7,95%CI 1.3-2.2). Individuals with two and three or more previous episodes of pneumonia had a 1.7-fold (95%CI 1.0-3.0; p=0.05) and a 1.5-fold (95%CI 0.6-3.9) elevated MM risk, respectively. Pneumonia could be a trigger to the development of MM or a manifestation of immune disturbances in late-stage MGUS.

Background: Malignant degeneration of chronic ulcers such as nonhealed burn wounds has been described in the literature, but this phenomenon has never been quantified in an epidemiologic study. We investigated the risks for skin and other cancers among patients with a prior burn., Methods: We identified 16,903 patients from the Danish Hospital Discharge Register who had been admitted to a hospital with a thermal or chemical burn during 1978 to 1993. The cohort was followed for cancer in the Danish Cancer Registry through 2002, and the cancer incidence in the cohort was compared with that in the general population of Denmark., Results: Patients with burn had 139 skin cancers, with 189 expected, yielding a standardized incidence ratio of 0.7 (95% confidence interval = 0.6-0.9). This reduced risk was due mainly to deficits of basal cell carcinoma and malignant melanoma, whereas the number of squamous cell carcinomas observed was close to expected. We saw no consistent increases in risk for skin cancer in the subgroups of patients with the most severe injuries or with the longest periods of follow up., Conclusions: The tendency to malignant degeneration of burn scars, described in previous reports of case series, did not result in an excess of squamous cell carcinoma of the skin or of any other type of skin cancer during up to 25 years' follow up of a large unselected cohort of patients hospitalized for burn injuries.

Objective: To assess the importance of body fat mass (BFM) and fat free mass (FFM) for the established positive association between BMI and breast cancer among post-menopausal women., Research Methods and Procedures: A prospective cohort of 23,788 postmenopausal women included in the Danish study Diet, Cancer, and Health during 1993 to 1997 was linked to the Danish Cancer Registry to identify all cases of breast cancer occurring during 1993 to 2002. Breast cancer incidence rate ratios for anthropometric measurements with adjustment for known risk factors for breast cancer were calculated by Cox regression analyses., Results: Among the most commonly used anthropometric measurements, BMI was positively associated with breast cancer among never users of hormone replacement therapy (HRT). By splitting BMI into two indices, BFM index and FFM index, we found that the incidence rate ratio with each 1 kg/m(2) among never users of HRT was 0.98 (95% confidence interval, 0.93 to 1.03) for BFM index and 1.12 (95% confidence interval, 1.00 to 1.26) for FFM index after mutual adjustment., Discussion: The finding for BMI was in accordance with previous findings. Our results indicate that the FFM component of BMI may play a role for development of breast cancer among never users of HRT.

Background: Personal history of autoimmune diseases is consistently associated with increased risk of non-Hodgkin lymphoma. In contrast, there are limited data on risk of Hodgkin lymphoma following autoimmune diseases and almost no data addressing whether there is a familial association between the conditions., Methods: Using population-based linked registry data from Sweden and Denmark, 32 separate autoimmune and related conditions were identified from hospital diagnoses in 7476 case subjects with Hodgkin lymphoma, 18,573 matched control subjects, and more than 86,000 first-degree relatives of case and control subjects. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) as measures of relative risks for each condition using logistic regression and also applied multivariable hierarchical regression models. All P values are two-sided., Results: We found statistically significantly increased risks of Hodgkin lymphoma associated with personal histories of several autoimmune conditions, including rheumatoid arthritis (OR = 2.7, 95% CI = 1.9 to 4.0), systemic lupus erythematosus (OR = 5.8, 95% CI = 2.2 to 15.1), sarcoidosis (OR = 14.1, 95% CI = 5.4 to 36.8), and immune thrombocytopenic purpura (OR = infinity, P = .002). A statistically significant increase in risk of Hodgkin lymphoma was associated with family histories of sarcoidosis (OR = 1.8, 95% CI = 1.01 to 3.1) and ulcerative colitis (OR = 1.6, 95% CI = 1.02 to 2.6)., Conclusions: Personal or family history of certain autoimmune conditions was strongly associated with increased risk of Hodgkin lymphoma. The association between both personal and family histories of sarcoidosis and a statistically significantly increased risk of Hodgkin lymphoma suggests shared susceptibility for these conditions.