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Beta-blockers have shown antineoplastic effects in laboratory studies but epidemiologic evidence in relation to contralateral breast cancer (CBC) is sparse. We investigated postdiagnosis beta-blocker use and risk of CBC in a cohort of 52 723 women with breast cancer by using nationwide Danish health registers and the Danish Breast Cancer Group database. We defined postdiagnosis beta-blocker use as a time-varying covariate starting 1 year after a second prescription was redeemed. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CBC associated with beta-blocker use compared to nonuse. We identified 1444 women with CBC of whom 209 women were beta-blocker users. We found an overall HR of 1.08 (95% CI: 0.93-1.27) for beta-blocker use and risk of CBC with no substantial variation according to cumulative amount, intensity or selectivity of beta-blocker use. Hence, our cohort study of women with breast cancer did not sustain a protective effect of beta-blocker use on risk of CBC, irrespective of beta-blocker type., (© 2022 UICC.)

Laboratory studies suggest that inhibition of the cyclooxygenase (COX)-2 enzymes inhibits breast cancer development. We aimed to evaluate whether postdiagnosis use of COX-2 selective or other nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of contralateral breast cancer (CBC) among Danish breast cancer patients. From the clinical database of the Danish Breast Cancer Group, we identified 52,723 women diagnosed with breast cancer between 1996 and 2012. Data on nonaspirin NSAID use, CBC and potential confounding variables were obtained from nationwide registries. We defined postdiagnosis use (two or more prescriptions) as a time-varying covariate with a one-year lag. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CBC associated with nonaspirin NSAID use. During a median follow-up of 4.8 years (interquartile range: 2.3-9 years), 1,444 patients were diagnosed with CBC. Overall, postdiagnosis use of nonaspirin NSAID was associated with an adjusted HR for CBC of 0.98 (95% CI: 0.87-1.11). The HRs did not vary substantially with duration or intensity of nonaspirin NSAID use. Moreover, similar associations were found for COX-2 selective (HR: 1.02; 95% CI: 0.85-1.23) and nonselective (HR: 0.96; 95% CI: 0.82-1.13) nonaspirin NSAIDs. In conclusion, our nationwide cohort study of breast cancer patients does not suggest a reduced risk of CBC with nonaspirin NSAID use regardless of the COX-2 selectivity., (© 2018 UICC.)

Ionizing radiation (IR) is a breast carcinogen that induces DNA double-strand breaks (DSBs), and variation in genes involved in the DNA DSB response has been implicated in radiation-induced breast cancer. The Women's Environmental, Cancer, and Radiation Epidemiology (WECARE) study is a population-based study of cases with contralateral breast cancer (CBC) and matched controls with unilateral breast cancer. The location-specific radiation dose received by the contralateral breast was estimated from radiotherapy records and mathematical models. One hundred fifty-two SNPs in six genes (CHEK2, MRE11A, MDC1, NBN, RAD50, TP53BP1) involved in the DNA DSBs response were genotyped. No variants or haplotypes were associated with CBC risk (649 cases and 1,284 controls) and no variants were found to interact with radiation dose. Carriers of a RAD50 haplotype exposed to ≥1 gray (Gy) had an increased risk of CBC compared with unexposed carriers (Rate ratios [RR] = 4.31 [95% confidence intervals [CI] 1.93-9.62]); with an excess relative risk (ERR) per Gy = 2.13 [95% CI 0.61-5.33]). Although the results of this study were largely null, carriers of a haplotype in RAD50 treated with radiation had a greater CBC risk than unexposed carriers. This suggests that carriers of this haplotype may be susceptible to the DNA-damaging effects of radiation therapy associated with radiation-induced breast cancer., (© 2011 Wiley Periodicals, Inc.)

BRCA1 and BRCA2 screening in women at high-risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population-based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of which 113 were deleterious mutations. The remaining 357 VUS comprised 185 unique missense changes, 60% were observed only once, while 3% occurred with a frequency of >10%. Deleterious mutations occurred three times more often in women with CBC (15.3%) than in women with UBC (5.2%), whereas combined, VUS were observed in similar frequencies in women with CBC and UBC. A protein alignment algorithm defined 16 rare VUS, occurring at highly conserved residues and/or conferring a considerable biochemical difference, the majority located in the BRCA2 DNA-binding domain. We confirm a multiplicity of BRCA1 and BRCA2 VUS that occur at a wide range of allele frequencies. Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC., ((c) 2010 Wiley-Liss, Inc.)

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.

Primary fallopian tube cancer (PFTC) is a rare disease, and its aetiological factors are poorly understood. Studies on PFTC in the setting of 2nd primary malignant neoplasms can provide clues on aetiology and also define the possible side effects of different treatment modalities for PFTC. A cohort of 2,084 cases with first PFTC was extracted from the data from 13 cancer registries from Europe, Canada, Australia and Singapore and followed for second primary cancers within the period 1943-2000. Standardized incidence ratios (SIRs) were calculated and Poisson regression analyses were done to find out the RRs related to age at, period of and time since the PFTC diagnosis. There were 118 cancer cases observed after first PFTC (SIR 1.4, 95%CI 1.1-1.6). Elevated SIRs were seen for colorectal cancer (1.7, 95%CI 1.0-2.6), for breast cancer (1.5, 95%CI 1.1-2.2), for bladder cancer (2.8, 95%CI 1.0-6.0), for lung cancer (1.8, 95% CI 0.9-3.2) and for nonlymphoid leukaemia (3.7, 95%CI 1.0-9.4). Significant risk increases were detected for colorectal cancer during the 2nd to 5th year after the first PFTC diagnosis, for breast cancer in follow-up 10+ and for nonlymphoid leukaemia during the 2nd to 10th year. The clustering of cancers of the lung and bladder in PFTC patients may suggest shared smoking aetiology. The excess of colorectal and breast cancers after PFTC may indicate a genetic aetiology., ((c) 2007 Wiley-Liss, Inc.)

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.)

Radiotherapy and chemotherapy are known risk factors for second cancers after lymphoma. The role of genetic influences, however, remains largely unknown. We assessed risk of second cancers associated with family history of any cancer in 41,181 patients with Hodgkin lymphoma (HL) (n = 7,476), non-Hodgkin lymphoma (NHL) (n = 25,941), or chronic lymphocytic leukemia (CLL) (n = 7,764), using a large population-based database. Family history of cancer was based on a diagnosis of any cancer in 110,862 first-degree relatives. We found increased relative risk (RR) (1.81, 95% confidence interval (CI): 1.04-3.16) of breast cancer among HL patient with positive (vs. negative) family history of cancer. Among CLL patients with positive (vs. negative) family history of cancer, we observed elevated risks of bladder (RR = 3.53, 95% CI: 1.31-9.55) and prostate cancer (RR = 2.15, 95% CI: 1.17-3.94). For NHL patients with positive (vs. negative) family history of cancer, we observed non-significantly increased risk of non-melanoma skin cancer (RR = 1.94, 95% CI: 0.86-4.38) and lung cancer (RR = 1.99, 95% CI: 0.73-5.39). Our observations suggest that genetic factors, as measured by positive family history of cancer, may be influential risk-factors for selected second tumors following lymphoproliferative disorders., (Copyright 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.

A large number of women survive a diagnosis of breast cancer. Knowledge of their risk of developing a new primary cancer is important not only in relation to potential side effects of their cancer treatment, but also in relation to the possibility of shared etiology with other types of cancer. A cohort of 525,527 women with primary breast cancer was identified from 13 population-based cancer registries in Europe, Canada, Australia and Singapore, and followed for second primary cancers within the period 1943-2000. We used cancer incidence rates of first primary cancer for the calculation of standardized incidence ratios (SIRs) of second primary cancer. Risk of second primary breast cancer after various types of nonbreast cancer was also computed. For all second cancer sites combined, except contralateral breast cancer, we found a SIR of 1.25 (95% CI = 1.24-1.26) on the basis of 31,399 observed cases after first primary breast cancer. The overall risk increased with increasing time since breast cancer diagnosis and decreased by increasing age at breast cancer diagnosis. There were significant excesses of many different cancer sites; among these the excess was larger than 150 cases for stomach (SIR = 1.35), colorectal (SIR = 1.22), lung (SIR = 1.24), soft tissue sarcoma (SIR = 2.25), melanoma (SIR = 1.29), non-melanoma skin (SIR = 1.58), endometrium (SIR = 1.52), ovary (SIR = 1.48), kidney (SIR = 1.27), thyroid gland (SIR = 1.62) and leukaemia (SIR = 1.52). The excess of cancer after a breast cancer diagnosis is likely to be explained by treatment for breast cancer and by shared genetic or environmental risk factors, although the general excess of cancer suggests that there may be additional explanations such as increased surveillance and general cancer susceptibility., (2005 Wiley-Liss, Inc.)

The use of paracetamol has been associated with increased risks for urinary tract cancers and decreased risk for ovarian cancer, although results have been inconsistent. We conducted a population-based cohort study using data from the Prescription Database of North Jutland County and the Danish Cancer Registry. Cancer incidence among 39,946 individuals receiving prescriptions for paracetamol was compared with expected incidence based on the North Jutland population who did not receive paracetamol prescriptions, during a 9-year follow-up period. Standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (95% CIs) were calculated for cancers overall and at selected sites. Overall, 2,173 cancers were observed with 1,973 expected, yielding a SIR of 1.10 (95% CI, 1.06-1.15). Significantly elevated SIRs were found for cancers of the esophagus (1.9; 95% CI, 1.3-2.8) and lung (1.6; 95% CI, 1.4-1.7). Nonsignificantly increased SIRs were observed for cancers of the liver (1.5; 95% CI, 0.96-2.2), renal parenchyma (1.3; 95% CI, 0.9-1.7) and renal pelvis/ureter (1.6; 95% CI, 0.96-2.6), whereas the SIR for cancer of the urinary bladder was close to unity (1.1; 95% CI, 0.9-1.4). For ovarian cancer, the SIR was close to expectation (0.9; 95% CI, 0.6-1.2) with no evidence of trends with duration of follow-up or number of prescriptions. A similar risk pattern was observed after exclusion of person-time experience following prescription for aspirin or other nonsteroidal antiinflammatory drugs in the study cohort and reference population. Our results do not support a major role for paracetamol in the development of cancers of the urinary tract, and we found little evidence of a protective effect of paracetamol against ovarian cancer. The elevated risks for cancers of the esophagus, lung and liver are most likely a result of confounding variables, but may warrant further investigation., (Copyright 2002 Wiley-Liss, Inc.)

Most studies on cancer incidence after breast implantation have focused on breast cancer, while the risk of cancers at other sites has been less well investigated. We examined cancer incidence among 1,653 women who underwent cosmetic breast implant surgery at private clinics of plastic surgery in Denmark and 1,736 women attending the same clinics for other reasons during the period 1973-1995. Furthermore, we updated previously reported results among 1,114 women who received implants for cosmetic indications at public hospitals. All women were followed for cancer through the Danish Cancer Registry. In comparison with the general female population, the overall standardized incidence ratio (SIR) for cancer among women who received implants in private clinics was 1.65 [95% confidence interval (CI) = 1.17-2.27]. This elevated SIR reflected increased incidence ratios for almost all major cancer sites; however, only for non-melanoma skin cancer was there an excess of more than 2 cases. No significant excess of cancer was observed among women who received implants in public hospitals (SIR = 1.10, 95% CI = 0.76-1.52) or among women attending the private clinics for other problems (SIR = 1.10, 95% CI = 0.78-1.52). The SIRs for breast cancer after breast implantation were 1.1 (95% CI = 0.5-2.2) among private clinic patients and 0.9 (95% CI = 0.4-1.7) among public hospital patients. The overall findings of these 2 implant cohorts and results from other investigations suggest that cancer risk is probably not increased among women receiving cosmetic breast implants. The inconsistent results for private clinics and public hospitals are likely related to selection bias and confounding among the private clinic patients, but our data did not permit exploration of these possibilities. Further research into the determinants of these inconsistencies is warranted., (Copyright 2000 Wiley-Liss, Inc.)

The use of artificial joint implants has risen greatly over the past years. However, few investigations of the cancer risk associated with implants have been performed. We investigated cancer risk in patients with finger and hand joint and temporo-mandibular (TMJ) joint implants. A nationwide cohort in Denmark of patients with finger and hand joint prostheses (n = 858) or TMJ implants (n = 389) was followed from January 1, 1977, to December 31, 1995, to evaluate any potential cancer risks subsequent to receiving these implants. Standardized incidence ratios (SIRs) for all cancers were 1.0 (95% CI = 0.8-1.2) for the finger and hand joint cohort and 1.1 (95% CI = 0.8-1.7) for the TMJ cohort. A significant risk for non-Hodgkin's lymphoma was found in the finger and hand joint cohort (SIR = 3.8, 95% CI = 1.5-7.8). When the finger and hand joint cohort was stratified by diagnosis of rheumatoid arthritis, the excess risk was seen only in the group with rheumatoid arthritis. This is consistent with past studies, which have found an association between rheumatoid arthritis and non-Hodgkin's lymphoma. Our results provide evidence that the cancer risk for patients with finger and hand joint prostheses and TMJ implants is similar to that for the general population.

A nationwide cohort study of hip and knee replacement patients in Denmark was undertaken to assess any carcinogenic potential of these implants. A cohort of 22,997 osteoarthritis patients who received hip replacements and of 4,771 osteoarthritis patients who received knee replacements during the period 1977 through 1989 were identified using the nationwide Danish Hospital Discharge Registry. These patients were followed for cancer occurrence through 1993, using the Danish Cancer Registry. There was no overall excess of cancer in either the hip implant cohort [standardized incidence ratio (SIR) = 0.94; 95% confidence interval (CI)= 0.91-0.98] or the knee implant cohort (SIR = 0.97; 95% CI = 0.89-1.06). The risk reduction in both groups of patients reflected for the most part reduced risks for cancers of the respiratory system and the digestive tract, particularly stomach cancer (SIR = 0.69; 95% CI = 0.50-0.81 for hip replacement patients; SIR = 0.46; 95% CI = 0.20-0.91 for knee replacement patients). Elevated risks were observed for melanoma of the skin in both groups of patients. There was no clear excess risk for lymphohematopoietic cancers or malignant neoplasms of the bone or connective tissue among implant patients in either implant group. Contrary to an earlier study in Sweden, we did not find an excess risk for kidney or prostate cancers. In summary, these nationwide results indicate no overall cancer hazard among hip and knee implant patients, but limited follow-up warrants continued surveillance of individuals undergoing these increasingly common surgical procedures.

Although millions of women worldwide have received breast implants for cosmetic or medical reasons, possible late effects (in particular cancer) have not been well studied. To provide quantitative information on cancer occurrence among women undergoing breast implant surgery, 1,135 women treated for cosmetic reasons in Denmark were evaluated. Patients were identified using the nationwide Hospital Discharge Registry with linkage to the nationwide Danish Cancer Registry to determine subsequent cancer incidence. The average age of the women at implant surgery was 31 years, and the average follow-up was 8.4 years, up to a maximum of 17 years. Overall, 27 cancers developed after implant surgery compared with 24.7 expected based on incidence rates from the general population (standardized incidence ratio [SIR] = 1.1; 95% CI: 0.7-1.6). Eight breast cancers were observed vs. 7.8 expected (SIR = 1.0; 95% CI: 0.4-2.0). No evidence was found to link breast implants with increased cancer risk in the decade after surgery. While the results are encouraging, longer follow-up into later life will be necessary to assess fully any possible adverse effects.

Only 2 small population-based studies have previously evaluated cancer risk in splenectomized patients. Our objective was thus to investigate cancer incidence following splenectomy for external trauma or for surgical treatment of non-malignant conditions of adjacent organs. Using the unique personal identification number assigned to each Swedish resident, we linked centralized hospitalization records with nationwide total population and cancer incidence data. We excluded cancers diagnosed within the first 12 months after splenectomy and computed standardized incidence ratios for 1,295 patients (contributing 14,390 person-years) splenectormized for external trauma and for 985 patients (contributing 8,91 1 person-years) whose splenectomy accompanied surgical treatment of non-malignant conditions of adjacent organs (mostly peptic ulcers), using age-, sex- and period-specific rates for cancer incidence derived from the entire Swedish population. Patients undergoing splenectomy for external trauma had no significant excess of total or site-specific cancers. Individuals splenectormized in conjunction with surgery for non-malignant conditions of adjacent organs had a non-significant 40% elevated risk of total cancer, with significant increases of lung and ovarian cancers. The excesses of lung and ovarian cancers may be due to chance, but we could not exclude the conditions for which the surgery was performed, other treatments or common predisposing factors (such as cigarette smoking, which has been linked with both peptic ulcer and lung cancer).

A cohort of 5,546 ulcerative colitis patients was identified from the Danish Hospital Discharge Register for 1977-1989. Patients not included in the cohort comprised those with proctitis, those treated in outpatient clinics and those for whom follow-up was less than 1 year. The cohort was linked to the Danish Cancer Registry in order to assess the risks for colorectal and other cancers. The linkage revealed a significant increase in the number of colorectal cancers over that in the general population (RR = 1.8; n = 42; 95% CI = 1.3-2.4) with consistent relative risks during early and late follow-up. The relative risk was considerably higher among younger (20-39 years: RR = 22; n = 8; 95% CI = 9.7-44) than older patients (> or = 60 years: RR = 1.3; n = 25; 95% CI = 0.8-1.9), but the risk difference between patients and the general population was approximately constant across all ages. In addition, we observed a significant increase in the relative risk of hepatobiliary cancers (RR = 2.3; n = 9; 95% = 1.0-4.3) and a slight but significant increase in the relative risk of non-melanoma skin cancer (RR = 1.4; n = 37; 95% CI = 1.0-1.9). In summary, our population-based study confirms the increased risk of colorectal cancer among patients with ulcerative colitis and provides new leads suggesting that hepatobiliary cancer and non-melanoma skin cancer should be considered as possible sites for future patient monitoring.