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Introduction: The long-term risk of cancer among first-degree relatives of ovarian cancer patients, especially their offspring, is of apparent clinical importance. Risks caused by known inherited factors such as BRCA1 or BRCA2 pathogenic variants are well established, but these account for only about 15% of ovarian cancer cases. Less is known about the possible familial risks of sporadic ovarian cancers., Material and Methods: Using registry data, we conducted a retrospective cohort study with a total of 6501 first-degree relatives of 559 epithelial ovarian cancer patients. We studied the occurrence of overall cancer and cancer in specific sites known or suspected to be associated with ovarian cancer (breast, cervix, colon, endometrium, lung and trachea, skin melanoma, ovary, pancreas, prostate, rectum, and stomach)., Results: The overall number of cancers was not increased among the first-degree relatives of epithelial ovarian cancer patients during the up to 48 years of follow up. Among female relatives, the standardized incidence ratio for ovarian cancer was 1.92 (95% CI 1.27-2.79), mostly explained by a 2.30-fold (95% CI 1.46-3.45) risk among the patients' sisters. There was a decreasing trend in the standardized incidence ratio for ovarian cancer among patients' sisters by increasing age of the index patient., Conclusions: In our study cohort, we did not observe an increase in the overall cancer risk among the first-degree relatives of epithelial ovarian cancer patients in comparison with the general population. The risk for ovarian cancer, however, was increased. Current recommendations suggest prophylactic removal of the fallopian tubes and ovaries only with identified inherited risk factors. Our results emphasize the role of genetic counseling and testing, particularly in young ovarian cancer patients and their close female relatives., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Purpose: This case-control study assesses the independent roles of reproductive history, postmenopausal hormonal therapy (HT), socioeconomic status (SES), and occupational physical activity on the risk of breast cancer (BC)., Methods: Odds ratios (OR) were estimated from conditional logistic multivariate regression model in a data set of 19,253 Finnish women diagnosed with BC between 1994 and 2013 and 96,265 age-matched population controls., Results: Both pre- and postmenopausal white-collar workers had significantly increased risk of ductal and lobular BC as compared to manual workers. Moderate occupational physical activity reduced risk of lobular BC by 14%. There was a transient increase in the risk of BC observed after each birth followed by a protective effect starting some years after the delivery. As the number of children increased, the short-term excess risk was lower and protective effect was observed earlier. Continuous estrogen-progestin therapy (EPT) significantly increased the risk of both ductal and lobular BC and the magnitude of risk was directly proportional to duration of use (OR for 5+ years of use 2.26, 95% confidence interval 2.12-2.42). Monthly EPT for 5+ years increased the risk (OR 1.32, 95% CI 1.20-1.45). Users of estradiol plus levonorgestrel intrauterine system devices showed ORs of 1.56 (95% CI 1.45-1.69) and 2.18 (95% CI 1.81-2.64) for ductal and lobular BC, respectively., Conclusion: This study concludes that pregnancy has a dual effect on BC risk, with a transient increase in risk followed by a long-term protective effect. The SES and HT have a large effect on BC risk while occupational physical activity has only a small independent effect., (© 2022. The Author(s).)

Even 30 years after the accident, an association between breast cancer incidence and ionizing radiation exposure from Chernobyl fallout remains uncertain. We studied breast cancer incidence in the most contaminated regions of Belarus (Gomel and Mogilev) and Ukraine (Kyiv, Zhytomyr and Chernihiv) before (1978-1986) and after (1987-2016) the accident. Breast cancer cases and female population size data were received from the national cancer registries and the state departments of statistics. The study included 85 132 breast cancers with 150 million person-years at risk. We estimated annual rayon (district)-average absorbed doses to the breast from external and internal irradiation of the adult female population over the period of 1986-2016. We studied an association between rayon-average cumulative absorbed breast dose with 5-year lag, that is, excluding the exposure in 5 years prior to breast cancer diagnosis, and breast cancer incidence using negative binomial regression models. Mean (median) cumulative breast dose in 2016 was 12.3 (5.0) milligray (mGy) in Belarus and 5.7 (2.3) mGy in Ukraine, with the maximum dose of 55 mGy and 54 mGy, respectively. Breast cancer incidence rates statistically significantly increased with calendar year and attained age, and were higher in urban than in rural residents. Adjusting for time, age and urbanicity effects, we found no evidence of increasing incidence with rayon-average 5-year lagged cumulative breast dose. Owing to ecological study design limitations, a case-control study covering this area with individually reconstructed absorbed breast doses is needed testing for association between low-dose protracted radiation exposure and breast cancer risk after Chernobyl., (© 2021 Union for International Cancer Control.)

Background: Breast cancer incidence has been associated with hypertension, which might worsen disease prognosis, but few nationwide studies have investigated the association between antihypertensive drug use and breast cancer prognosis., Methods: A cohort of 73,170 women diagnosed with breast cancer during 1995-2013 identified from the Finnish Cancer Registry was combined with information on antihypertensive drug use during the same time period from a national prescription database. Antihypertensive drugs were analyzed in groups categorized by mechanism of action. Usage of antihypertensive drugs, statins, antidiabetic, and anticoagulative drugs was analyzed as time-dependent exposure to model for simultaneous use of multiple drug groups. Influence of protopathic bias was evaluated in lag-time analyses., Results: In prediagnostic use, only angiotensin receptor (ATR)-blockers were associated with decreased risk of breast cancer death as compared with nonusers (HR: 0.76, 95% confidence interval, CI: 0.69-0.82), and there was an inverse association with cumulative dose of use. Postdiagnostic use of ATR-blockers, angiotensin-converting enzyme (ACE)-inhibitors, beta-blockers, and calcium-channel blockers was dose dependently associated with better breast cancer survival compared with nonusers. The risk decrease was strongest for ATR-blockers (HR: 0.69, 95% CI: 0.63-0.75) and remained for exposures occurring up to 3 years earlier., Conclusions: Only ATR-blockers were associated with improved breast cancer survival in both prediagnostic and postdiagnostic use. The association was dose dependent and supported by a biological rationale as a causal explanation. In postdiagnostic use, similar reduction was found also for other antihypertensives, supporting a prognostic role of hypertension control., Impact: Inhibition of angiotensin receptor subtype 1 (AT 1 ) could be a promising novel way to affect breast cancer progression., (©2020 American Association for Cancer Research.)

Women with a history of severe mental illness (SMI) have elevated breast cancer mortality. Few studies have compared cancer-specific mortality in women with breast cancer with or without SMI to reveal gaps in breast cancer treatment outcomes. We compared breast-cancer specific mortality in women with or without SMI and investigated effects of stage at presentation, comorbidity, and differences in cancer treatment. Women with their first breast cancer diagnosis in 1990-2013 (n = 80,671) were identified from the Finnish Cancer Registry, their preceding hospital admissions due to SMI (n = 4,837) from the Hospital Discharge Register and deaths from the Causes of Death Statistics. Competing risk models were used in statistical analysis. When controlling for age, year of cancer diagnosis, and comorbidity, breast cancer mortality was significantly elevated in patients with SMI. Relative mortality was highest in breast cancer patients with non-affective psychosis, partly explained by stage at presentation. Mortality was also significantly elevated in breast cancer patients with a substance use disorder and mood disorder. Patients with SMI received radiotherapy significantly less often than patients without SMI. Our findings emphasize the need to improve early detection of breast cancer in women with SMI and the collaboration between mental health care and oncological teams., Competing Interests: Declaration of Competing Interest This work was partly funded by the Cancer Society in Finland. The Finnish Cancer Society had no involvement in the study design, data collection, findings, or decision to publish. The authors declare that they have no conflict of interest in relation to the subject of this study., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: To determine whether cytomegalovirus is causally associated with breast cancer and whether cytomegalovirus should be categorised as an oncogenic virus., Methods: We undertook a review of published epidemiological and laboratory studies, using established causal criteria: Bradford Hill criteria to determine whether cytomegalovirus is associated with breast cancer; and Evans/Mueller criteria to determine whether cytomegalovirus should be categorised as an oncogenic virus., Results: Although there are inconsistencies in the findings of published epidemiological and laboratory studies, these may be explained by factors such as: differences in timing of blood samples, differences in selection of cases and controls, or high cytomegalovirus seroprevalence among participants in the epidemiological studies; and, in the laboratory studies, differences in sample preparations, age of sample, whether or not paired breast cancer and normal breast tissue samples were used, differences in the tests, primers and/or antibodies used, differences in histological types of breast cancer studied, and/or features of the virus., Conclusions: Overall, the results of published studies of cytomegalovirus and breast cancer suggest cytomegalovirus is a causal factor for at least some types of breast cancer. If the evidence for a link between cytomegalovirus and breast cancer continues to strengthen, further research could lead to: targeted screening; therapy using antiviral drugs; and, perhaps, primary prevention of a significant proportion of breast cancer. Vaccination against viruses has already been shown to be effective in preventing cervix and liver cancer; cytomegalovirus vaccines are already under development.

Background: Various components of the coagulation cascade have been linked to breast cancer progression. In vivo results suggest that anticoagulants possess anticancer properties, but there are virtually no studies in human populations. Our nationwide study explored the association between anticoagulant use and breast cancer survival., Methods: All anticoagulants used from 1995 to 2015 in women ( n = 73,170) diagnosed with invasive breast cancer in Finland between 1995 and 2013 were identified from the national prescription database; women were identified from the Finnish Cancer Registry. Cox regressions were performed to analyze breast cancer survival as a function of pre- and postdiagnostic anticoagulant use; analyses were conducted for different anticoagulant subtypes and overall. Models were adjusted for age, mammography screening, tumor clinical characteristics, comorbidities, statin use, antidiabetic use, and antihypertensive use. To control for immortal time bias, postdiagnostic anticoagulant use was analyzed as a time-dependent variable., Results: At a median of 5.8 years after breast cancer diagnosis, 10,900 (15%) women had died from breast cancer. In total, 25,622 (35%) women had used anticoagulants during the study period. Postdiagnostic anticoagulant use increased the risk of breast cancer death (HR = 1.41; 95% confidence interval, 1.33-1.49). The risk was especially high for low-molecular weight heparin, although the effect disappeared in long-term users., Conclusions: Anticoagulant use provides no clinical benefit for breast cancer survival; however, the association between thrombosis and cancer might mask potential survival benefits., Impact: Future pharmacoepidemiologic studies should adjust for anticoagulant use. Research should focus on the use of new oral anticoagulants because these are rarely studied and might be associated with improved breast cancer survival., (©2019 American Association for Cancer Research.)

Introduction: The association between endometriosis and breast cancer is unclear. We assessed the risk of breast cancer in women with surgically verified endometriosis, with special focus on the age at cancer diagnosis, time from endometriosis diagnosis and breast cancer histology., Material and Methods: All women with first endometriosis-associated diagnoses occurring concomitantly with relevant surgical codes during 1987-2012 were retrieved from the Finnish Hospital Discharge Register in Finland. Breast cancers diagnosed after the endometriosis diagnosis were identified from the Finnish Cancer Registry. The Finnish female population served as the reference. The endometriosis cohort consisted of 49 933 women (23 210 cases of ovarian, 20 187 peritoneal and 2372 deep infiltrating endometriosis). The outcome measure was the standardized incidence ratio (SIR) with 95% confidence interval (95% CI) of breast cancer calculated for the whole cohort and for the subtypes of endometriosis, stratified by the age at breast cancer diagnosis, histology and time from endometriosis diagnosis., Results: The overall risk of breast cancer (1555 cases) was similar to the reference population (SIR 0.99; 95% CI 0.94-1.03), did not differ in types of endometriosis, and was similar for ductal and lobular breast cancer. However, the SIR of breast cancer was increased in the age group of 20-29 years (SIR 4.44; 95% CI 2.22-7.94) and in the age group of 30-39 years (SIR 1.28; 95% CI 1.03-1.57). The risk of in situ breast cancer (170 cases) was increased in the entire endometriosis cohort (SIR 1.25; 95% CI 1.07-1.44)., Conclusions: The overall risk of breast cancer in women with surgically verified endometriosis was similar to that of general population. However, the risk of breast cancer at young age was increased. Young women with surgically verified endometriosis represent highly symptomatic patients with more frequent surgeries and additional therapies that might also contribute to the risk of breast cancer., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: The length of interval between successive childbirths (birth interval) might influence the incidence of breast cancer, either by stimulating or by inhibiting the factors that are responsible for the initiation of breast cancer or its early development., Methods: This is a case-control study nested in a cohort of 47,479 Finnish grand-multiparous (GM) women born after 1934, and registered as having had at least five births before 2013. The 1354 women with breast cancer diagnosis were compared with controls (1:5) matched by parity and date of birth of the mother. Conditional logistic regression was used to estimate odds ratios of the risk of ductal and lobular breast cancer subtypes associated with each of the intervals between the 1st and 5th birth, stratified by age at diagnosis. Age at first and last birth before index date were used as covariates., Results: Increased intervals between the 1st and 5th births were associated with an increased risk of lobular breast cancer. In contrast, regarding ductal cancer, premenopausal women with shorter length of interval (< 2 years) between the 1st and 2nd birth had greater risk and longer intervals (3+ years) were associated with reduced risk. Spacing between the 2nd and 5th birth did not influence the risk of ductal breast cancer., Conclusion: The findings of our study suggest that the effect of the length of birth interval on breast cancer depends on the age and histology. The protective effect of shorter birth intervals on lobular breast among postmenopausal women and the opposite effect on ductal cancer in premenopausal women may reflect distinct differentiation and functional roles of lobular and ductal cells, and possibly also different response to hormonal exposure.

Background: Physical activity has been shown to reduce the risk of colon, endometrial and postmenopausal breast cancer. The aim of this study was to quantify the proportion of the cancer burden in the Nordic countries linked to insufficient levels of leisure time physical activity and estimate the potential for cancer prevention for these three sites by increasing physical activity levels., Methods: Using the Prevent macrosimulation model, the number of cancer cases in the Nordic countries over a 30-year period (2016-2045) was modelled, under different scenarios of increasing physical activity levels in the population, and compared with the projected number of cases if constant physical activity prevailed. Physical activity (moderate and vigorous) was categorised according to metabolic equivalents (MET) hours in groups with sufficient physical activity (15+ MET-hours/week), low deficit (9 to <15 MET-hours/week), medium deficit (3 to <9 MET-hours/week) and high deficit (<3 MET-hours/week)., Results: If no one had insufficient levels of physical activity, about 11,000 colon, endometrial and postmenopausal breast cancer cases could be avoided in the Nordic countries in a 30-year period, which is 1% of the expected cases for the three cancer types. With a 50% reduction in all deficit groups by 2025 or a 100% reduction in the group of high deficit, approximately 0.5% of the expected cases for the three cancer types could be avoided. The number and percentage of avoidable cases was highest for colon cancer., Conclusion: 11,000 cancer cases could be avoided in the Nordic countries in a 30-year period, if deficit in physical activity was eliminated., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: This study aimed to determine occupational variations in the incidence of breast cancer in the population-based cohort of Nordic Occupational Cancer Study (NOCCA)., Methods: The study included long-term follow-up data from almost 7.5 million Nordic women. Participants were assigned to one of the 54 occupational categories based on census records at the ages of 30-64 years. Sixty-two thousand cases of breast cancer were identified through record linkages between nationwide cancer registries in Finland, Sweden, Norway, Denmark, and Iceland, followed up between 1961 and 2005. Country-specific standardized incidence ratios (SIRs) with 95% confidence intervals were estimated., Results: Overall, the highest risk elevations were seen among military personnel (SIR 1.58, 95% CI 1.03-2.32), dentists (SIR 1.43, 95% CI 1.31-1.56), and physicians (SIR 1.35, 95% CI 1.26-1.46). The lowest risks were observed among gardeners (SIR 0.76, 95% CI 0.74-0.78), farmers (SIR 0.80, 95% CI 0.78-0.82), and woodworkers (SIR 0.75, 95% CI 0.70-0.81). Welders, tobacco workers, and painters had higher SIRs for breast cancer diagnosed at age < 50. A reduced risk was observed among forestry workers, welders, and fishery workers for breast cancers diagnosed both before and after age 50. The SIRs for breast cancer did not vary substantially by histology. A significantly increased risk of breast cancer was observed among laboratory workers in the latest calendar period (1991-2005) compared with earlier periods (1976-1990 and 1961-1975). Occupations such as farming, forestry, driving, and gardening had low SIRs during all periods., Conclusions: The study suggests that the risk of breast cancer varies by occupation. Heterogeneity is also observed in some occupational categories according to age (before or after 50), histology, and calendar period.

Breast cancer (BC) and diabetes mellitus (DM) are major health problems. We examined the association between DM and BC stage at diagnosis and subsequent survival in a Finnish cohort of female BC patients. All BC cases (N = 73,170) diagnosed in 1995-2013 with dates and causes of death were identified from the Finnish Cancer Registry. Participation in organized mammography screening was obtained from Mass Inspection Registry. Information on DM diagnoses and background conditions recorded during 1995-2013 were obtained from national Care Register for Health Care and merged to data on medication use from the national Prescription Register. Logistic regression with adjustment for mammography screening and age at BC diagnosis was used to evaluate the risk of advanced stage BC at diagnosis. Cox regression was used to evaluate overall and BC survival. Analyses were adjusted for age, background conditions and mammography screening. Survival analyses were further adjusted for tumor extent, histology and primary treatment. Of the cohort 11,676 (16.0%) had DM. Screening participation did not differ by diabetes. Compared to non-diabetic women, diabetics had more often locally advanced (odds ratio, OR 1.26; 95% CI 1.18-1.35) or metastatic BC (OR 1.59; 95% CI 1.44-1.75) at diagnosis. During a median follow-up of 5.8 years after BC diagnosis 10,900 (14.9%) women died of BC. Risk of BC death was higher among diabetic compared to non-diabetic women (HR 1.36; 95% CI 1.27-1.46). Risk of BC death increased with duration of DM. This supports DM as a risk factor for fatal BC., (© 2018 UICC.)

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.

Background: It has been suggested that long-term activation of the body's stress-response system and subsequent overexposure to stress hormones may be associated with increased morbidity. However, evidence on the impact of major life events on mortality from breast cancer (BC) remains inconclusive. The main aim of this study is to investigate whether major negatively or positively experienced life events before or after diagnosis have an effect on BC-specific mortality in women who have survived with BC for at least 2 years., Methods: We conducted a case fatality study with data on life events from a self-administered survey and data on BC from the Finnish Cancer Registry. Cox models were fitted to estimate BC mortality hazard ratios (MRs) between those who have undergone major life events and those who haven't., Results: None of the pre-diagnostic negative life events had any effect on BC-specific mortality. Regarding post-diagnostic events, the effect was greatest in women with moderate scores of events. As for event-specific scores, increased BC mortality was observed with spouse unemployment, relationship problems, and death of a close friend. By contrast, falling in love and positive developments in hobbies were shown to be associated with lower BC mortality (MRs 0.67, 95%CI: 0.49-0.92 and 0.74, 95%CI: 0.57-0.96, respectively). In an analysis restricted to recently diagnosed cases (2007), also death of a child and of a mother was associated with increased BC mortality., Conclusions: Some major life events regarding close personal relationships may play a role in BC-specific mortality, with certain negative life events increasing BC mortality and positive events decreasing it. The observed favorable associations between positive developments in romantic relationships and hobbies and BC mortality are likely to reflect the importance of social interaction and support., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Human chorionic gonadotropin (hCG) is necessary for the maintenance of early pregnancy and promotes normal breast cell differentiation. Administered hCG reduces risk of carcinogen-induced breast cancer in animal models, and higher circulating hCG concentrations were associated with significantly lower long-term risk of breast cancer in a prior nested case-control study. In this study, we investigated early-pregnancy hCG concentrations and subsequent breast cancer risk. We conducted a nested case-control study with 1,191 cases and 2,257 controls (matched on age and date at blood collection) in the Finnish Maternity Cohort, a cohort with serum samples from 98% of pregnancies registered in Finland since 1983. This study included women with a serum sample collected early (<140 days gestation) in their first pregnancy resulting in a live, term birth. Breast cancer cases were identified via the Finnish Cancer Registry. Age at breast cancer diagnosis ranged from 22 to 58 years (mean: 41 years). hCG was measured using a solid-phase competitive chemiluminescence assay. Odds ratios (OR) were calculated using conditional logistic regression. We observed no association between hCG and breast cancer risk, overall [Quartile 4 vs. 1, OR, 1.14; 95% confidence interval (CI), 0.94-1.39], by estrogen and progesterone receptor status, or by ages at first-term birth or diagnosis. Associations did not differ by time between pregnancy and diagnosis (e.g., <5 years, OR Q4 vs. Q1 , 1.10; 95% CI, 0.64-1.89; ≥15 years, OR Q4 vs. Q1 , 1.36; 95% CI, 0.86-2.13; p heterogeneity = 0.62). This large prospective study does not support an inverse relationship between early pregnancy serum hCG concentrations and breast cancer risk. Cancer Res; 77(1); 134-41. ©2016 AACR., Competing Interests: The authors disclose no potential conflicts of interest., (©2016 American Association for Cancer Research.)

Purpose: Main aim was to estimate the association between use of exogenous hormones and breast cancer (BC) risk in a large population-based survey, and to assess the representativeness and overall validity of the data., Methods: The survey 'Women's Health and Use of Hormones' was conducted in Finland in 2009, including 7,000 BC cases and 20,000 matched population controls. Conditional logistic regression was used to estimate odds ratios and their 95 % confidence interval. For validation, exposure prevalences were compared with population data from Statistics Finland and two large population-based surveys., Results: We found positive associations with BC risk and exclusive use of hormone-releasing intrauterine device (HR IUD) in postmenopausal women (1.48, 95 % CI 1.10-1.99), when compared to never-users of any hormonal contraceptive and considering only prediagnostic use in cases. Regarding use of other hormonal contraceptives (HC), a positive association between long HC use (≥2 years) and BC was observed in both groups, OR being 1.37 (95 % CI 1.12-1.68) for premenopausal and 1.11 (95 % CI 1.03-1.20) for postmenopausal women, when compared to never-users of other HC., Conclusions: Observed association between HR IUD use and risk of BC in postmenopausal women is worrying and deserves further attention. Selection bias seemed not to explain this result. Considering the increasing popularity of HR IUD use in, e.g., USA, impact of possible adverse effects in public health could be significant.

Background: Prolonged steroid hormone therapy increases the risk of breast cancer, especially the risk of lobular cancer, but the effect of the levonorgestrel-releasing intrauterine system (LNG-IUS) use is controversial. In this study we aimed to test the hypothesis that risk for lobular breast cancer is elevated among LNG-IUS users., Material and Methods: We identified from the national Medical Reimbursement Registry of Finland the women aged 30-49 who had used LNG-IUS for the treatment or prevention of menorrhagia in 1994-2007, and from the Finnish Cancer Registry breast cancers diagnosed before the age of 55 and by the end of 2012., Results: A total of 2015 women had breast cancer diagnosed in a cohort of 93 843 LNG-IUS users during follow-up consisting of 1 032 767 women-years. The LNG-IUS users had an increased risk for both ductal breast cancer [standardized incidence ratio (SIR) 1.20, 95% confidence interval (CI) 1.14-1.25] and for lobular breast cancer (SIR 1.33, 95% CI 1.20-1.46), as compared with the general female population. The highest risk was found in LNG-IUS users who purchased the device at least twice, whose SIR for lobular cancer was 1.73 (95% CI 1.37-2.15)., Conclusions: The results imply that intrauterine administration of levonorgestrel is not only related to an excess risk of lobular breast cancer but also, in contrary to previous assumptions, to an excess risk of ductal breast cancer.

Background: Family history is an established risk factor for breast cancer. Although some important genetic factors have been identified, the extent to which familial risk can be attributed to genetic factors versus common environment remains unclear., Methods: We estimated the familial concordance and heritability of breast cancer among 21,054 monozygotic and 30,939 dizygotic female twin pairs from the Nordic Twin Study of Cancer, the largest twin study of cancer in the world. We accounted for left-censoring, right-censoring, as well as the competing risk of death., Results: From 1943 through 2010, 3,933 twins were diagnosed with breast cancer. The cumulative lifetime incidence of breast cancer taking competing risk of death into account was 8.1% for both zygosities, although the cumulative risk for twins whose co-twins had breast cancer was 28% among monozygotic and 20% among dizygotic twins. The heritability of liability to breast cancer was 31% [95% confidence interval (CI), 10%-51%] and the common environmental component was 16% (95% CI, 10%-32%). For premenopausal breast cancer these estimates were 27% and 12%, respectively, and for postmenopausal breast cancer 22% and 16%, respectively. The relative contributions of genetic and environmental factors were constant between ages 50 and 96. Our results are compatible with the Peto-Mack hypothesis., Conclusion: Our findings indicate that familial factors explain almost half of the variation in liability to develop breast cancer, and results were similar for pre- and postmenopausal breast cancer, Impact: We estimate heritability of breast cancer, taking until now ignored sources of bias into account., (©2015 American Association for Cancer Research.)

Pregnancy, parity, and circulating steroid hormone levels are associated with risk of breast cancer, but little is known about hormone concentrations during pregnancy and subsequent breast cancer risk. We evaluated early pregnancy (<140 days gestation) serum estradiol, estrone, progesterone, and testosterone and breast cancer risk in a nested case-control study in the Finnish Maternity Cohort. The cohort includes 98% of pregnancies registered in Finland since 1983. Individuals with samples collected in the first pregnancy leading to a live birth were eligible. Breast cancer cases (n = 1,199) were identified through linkage with the Finnish Cancer Registry; 2,281 matched controls were selected using incidence density sampling. ORs were calculated using conditional logistic regression. Hormone concentrations were not associated with breast cancer overall. Estradiol was positively associated with risk of breast cancer diagnosed age <40 [4th vs. 1st quartile OR 1.60 (1.07-2.39); Ptrend = 0.01], and inversely associated with breast cancer diagnosed at age ≥40 [4th vs. 1st quartile OR 0.71 (0.51-1.00); Ptrend = 0.02]. Elevated concentrations of the steroid hormones were associated with increased risk of estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors in women age <40 at diagnosis. We observed no association between steroid hormones and ER(+)/PR(+) disease. These data suggest a positive association between high concentrations of early pregnancy steroid hormones and risk of ER(-)/PR(-) breast cancer in women diagnosed age <40, and an inverse association for overall breast cancer diagnosed age ≥40. Further research on pregnancy hormones and risk of steroid receptor-negative cancers is needed to further characterize this association., (©2014 American Association for Cancer Research.)

Recent studies have suggested that statins, an established drug group in the prevention of cardiovascular mortality, could delay or prevent breast cancer recurrence but the effect on disease-specific mortality remains unclear. We evaluated risk of breast cancer death among statin users in a population-based cohort of breast cancer patients. The study cohort included all newly diagnosed breast cancer patients in Finland during 1995-2003 (31,236 cases), identified from the Finnish Cancer Registry. Information on statin use before and after the diagnosis was obtained from a national prescription database. We used the Cox proportional hazards regression method to estimate mortality among statin users with statin use as time-dependent variable. A total of 4,151 participants had used statins. During the median follow-up of 3.25 years after the diagnosis (range 0.08-9.0 years) 6,011 participants died, of which 3,619 (60.2%) was due to breast cancer. After adjustment for age, tumor characteristics, and treatment selection, both post-diagnostic and pre-diagnostic statin use were associated with lowered risk of breast cancer death (HR 0.46, 95% CI 0.38-0.55 and HR 0.54, 95% CI 0.44-0.67, respectively). The risk decrease by post-diagnostic statin use was likely affected by healthy adherer bias; that is, the greater likelihood of dying cancer patients to discontinue statin use as the association was not clearly dose-dependent and observed already at low-dose/short-term use. The dose- and time-dependence of the survival benefit among pre-diagnostic statin users suggests a possible causal effect that should be evaluated further in a clinical trial testing statins' effect on survival in breast cancer patients.

Pregnancy reduces maternal risk of breast cancer in the long term, but the biological determinants of the protection are unknown. Animal experiments suggest that estrogens and progesterone could be involved, but direct human evidence is scant. A case-control study (536 cases and 1,049 controls) was nested within the Finnish Maternity Cohort. Eligible were primiparous women who delivered at term a singleton offspring before age 40. For each case, two individually matched controls by age (± 6 months) and date of sampling (± 3 months) were selected. Estradiol, estrone and progesterone in first-trimester serum were measured by high-performance liquid chromatography tandem mass spectrometry and sex-hormone binding globulin (SHBG) by immunoassay. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. In the whole study population there was no association of breast cancer with any of the studied hormones. In analyses stratified by age at diagnosis, however, estradiol concentrations were positively associated with risk of breast cancer before age 40 (upper quartile OR, 1.81; CI, 1.08-3.06), but inversely associated with risk in women who were diagnosed ≥ age 40 (upper quartile OR, 0.64; CI, 0.40-1.04), p(interaction) 0.004. Risk estimates for estrone mirrored those for estradiol but were less pronounced. Progesterone was not associated with risk of subsequent breast cancer. Our results provide initial evidence that concentrations of estrogens during the early parts of a primiparous pregnancy are associated with maternal risk of breast cancer and suggest that the effect may differ for tumors diagnosed before and after age 40., (Copyright © 2011 UICC.)

Objective: A short interval between the first and second birth was associated with an increased risk of advanced ductal breast cancer among women with 5+ childbirths in our previous study. We now evaluated the significance of this risk factor and its relation to the age at first birth among mothers with 2-4 children., Methods: The cohort of 190,949 Finnish women with 2-4 children comprised 3,834 women with ductal breast cancer diagnosed before 2009. Conditional logistic regression for case-control design nested within the cohort was used to estimate proportional hazard ratios (HR) associated with the birth interval. Controls were matched for age and number of children. Age at the first birth and the interval from the last birth to cancer were co-variables., Results: Among women with the first birth <30 years, the HR of advanced ductal breast cancer at 50+ years for a short (<1.5 years) versus long (>3 years) interval between the first and second birth was 0.48 (95% Confidence Interval 0.33-0.70). Among women with the first birth at 30+ years, the HR of this cancer type diagnosed before the age of 50 years for a short versus long interval between the first and second birth was 5.83 (95% CI 2.30-14.8)., Conclusion: The interval between first and second birth strongly influences the risk of ductal breast cancer. Because second pregnancy soon after the first one decreased the risk of ductal breast cancer in young primiparas but increased the risk in older primiparas, it is likely that in such circumstances second pregnancy continues the actions initiated by the first pregnancy/breast-feeding.

Background: Elevated serum concentrations of insulin-like growth factor (IGF)-I have been associated with increased risk of developing breast cancer. Previously, we reported a similar association in samples obtained during pregnancy. This study was conducted to further characterize the association of IGF-I during pregnancy with maternal breast cancer risk., Methods: A case-control study was nested within the Finnish Maternity Cohort. The study was limited to primiparous women younger than 40 years, who donated blood samples during early (median, 12 weeks) pregnancy and delivered a single child at term. Seven hundred nineteen women with invasive breast cancer were eligible. Two controls (n = 1,434) were matched with each case on age and date at blood donation. Serum IGF-I concentration was measured using an Immulite 2000 analyzer. Conditional logistic regression was used to estimate ORs and 95% CIs., Results: No significant associations were observed between serum IGF-I concentrations and breast cancer risk in both the overall analysis (OR, 1.08; 95% CI, 0.80-1.47) and in analyses stratified by histologic subtype, lag time to cancer diagnosis, age at pregnancy, or age at diagnosis., Conclusion: There was no association between IGF-I and maternal breast cancer risk during early pregnancy in this large nested case-control study., Impact: Serum IGF-I concentrations during early pregnancy may not be related to maternal risk of developing breast cancer., (©2011 AACR.)

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.)

Background: Few studies have evaluated the role of the ubiquitous Epstein-Barr virus (EBV) infection, together with levels of the immunomodulator, vitamin D, in different breast cancer entities. We studied, prospectively, the association of EBV and vitamin D status with the risk of pregnancy-associated breast cancer (PABC), breast cancer diagnosed during pregnancy or 1 year post-partum, using a nested case-control study., Methods: Serum vitamin D and antibodies to EBV were measured for 108 PABC cases of the Finnish Maternity Cohort, and 208 controls matched for date of birth, date of sampling and parity. The joint effect of vitamin D and EBV on the risk of PABC was evaluated., Results: EBV seropositivity was generally not associated with the risk of PABC. Among individuals with sufficient (≥75 nmol/l) levels of vitamin D, we, however, found similar increased risk estimates for PABC associated with serum immunoglobulin G (IgG) antibodies to EBV early antigens [odds ratio (OR)=7.7, 95% (confidence interval) CI 1.4-42.3] and the viral reactivator protein, ZEBRA (OR=7.8, 95% CI 1.1-61.2)., Conclusion: Immunological markers of EBV reactivation status among individuals with sufficient vitamin D levels were consistently associated with increased risk of the disease. This suggests that EBV reactivation may be an indicator of the progression of breast cancer occurring soon after pregnancy, while the virus probably is not the aetiological agent., (Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.)

We examined the associations between various doses and routes of administration of norethisterone acetate (NETA) in estrogen-progestagen therapy (EPT) and the risk of breast cancer in Finland. All Finnish women with first invasive breast cancer diagnosed between the ages of 50-62 during 1995-2007 (n = 9,956) were identified from the Finnish Cancer Registry. For each case, 3 controls of the same age were retrieved from the Finnish Population Register. The use of estradiol+NETA-therapy by the cases and controls was traced from the national Medical Reimbursement Registry. The data were analyzed with multivariate conditional logistic regression, adjusting for parity, age at the first birth, and health care district. The continuous mode of NETA use tended to be associated with a higher rate ratio for breast cancer than the sequential use. The use of continuous "low" dose (NETA 0.5 mg + estradiol 1.0 mg) was associated with an increased rate ratio of breast cancer already in less than 3 years of use (odds ratio 1.94; 95% confidence interval 1.39-2.70) while a risk elevation for "high" dose (NETA 1.0 mg + estradiol 2.0 mg) was seen after 3 years use (1.71; 1.51-2.54). Oral and transdermal use of NETA were accompanied with comparable risks for breast cancer. In conclusion, the dose or route of administration of NETA in EPT do not modify the risks for breast cancer.

Background: Several laboratory and epidemiological studies have inversely linked endogenous vitamin D and the risk of breast cancer. The acquisition of vitamin D over time on the relative risk (RR) of the disease development is not known. In a longitudinal study, we evaluated the association between vitamin D levels at pregnancy over time with the risk of breast cancer, and pregnancy-associated breast cancer., Method: The risk for subsequent development of breast cancer associated with serum 25-hydroxyvitamin (25-OHD) levels was assessed for consecutive (1st and 2nd pregnancy) samples of 100 cases, with mean lag times (micro(t)) of 7.4 and 4.6 years between sampling and the diagnosis, and matched (parity, age, year, season) controls. Pregnancy-associated breast cancer (PABC, 111 case-control pairs, micro(t)=1 year) risk was also studied. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using the lowest quintile as the reference., Results: Serum 25-OHD level was not associated with an increased risk neither at the 1st nor at the 2nd pregnancy samples (OR=1.4, 95%CI 0.6-3.4; OR 1.4, 95%CI 0.7-2.8, respectively), but was associated with an increased risk of PABC (OR=2.7, 95%CI 1.04-6.7)., Conclusion: Generally, vitamin D may not be related to breast cancer risk but the increased PABC risk fits the association of vitamin D with the most aggressive cancers, and warrants caution with vitamin D supplementation during pregnancy., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

Background: The interval between successive births (birth interval) may affect breast cancer risk, whereas interval from last birth to cancer onset may modify its behaviour., Methods: The study cohort consisted of 29 488 Finnish grand multiparous (GM) women, including 628 women with breast cancer. Conditional logistic regression for case-control design nested within the cohort was used to estimate proportional hazards (referred as relative risks, RR). Age at first birth and parity were co-variables., Results: Short interval (<1 year) between first and second birth increased the risk of advanced ductal breast cancer at ages < 50 years (RR=5.29; 95% CI 2.00-14.0) as compared to interval 3+ years. The risk of advanced ductal cancer was also large (RR = 4.00; 95% CI 1.19-13.4) shortly (<3 years) after last birth as compared with the period 15+ years., Conclusions: Short birth interval-associated excess breast cancer risk may be related to stimulatory effects of female steroid hormones produced during two closely connected pregnancies, or defective breast maturation owing to failures in breastfeeding.

Objective: To estimate the risk for breast cancer in Finnish women using postmenopausal estradiol (E2)-progestogen therapy., Methods: All Finnish women over 50 years using E2-progestogen therapy for at least 6 months in 1994-2005 (N=221,551) were identified from the national medical reimbursement register and followed up for breast cancer incidence (n=6,211 cases) through the Finnish Cancer Registry to the end of 2005. The risk for breast cancer in E2-progestogen therapy users was compared with that in the general population., Results: The standardized incidence ratio for all types of breast cancer was not elevated within the first 3 years of use, but it rose to 1.31 (95% confidence interval 1.20-1.42) for the use from 3-5 years and to 2.07 (1.84-2.30) with 10 or more years of use. Exposure to sequential progestogen for 5 years or more was accompanied with a lower risk elevation (1.78, 1.64-1.90) than exposure to continuous use (2.44, 2.17-2.72). Oral and transdermal use of E2-progestogen therapy was associated with comparable risk elevations for breast cancer. The use of norethisterone acetate was accompanied with a higher risk after 5 years of use (2.03, 1.88-2.18) than that of medroxyprogesterone acetate (1.64, 1.49-1.79). The risk of lobular breast cancer increased sooner than that for ductal cancer and was detectable for E2-progestogen therapy use less than 3 years (1.35, 1.18-1.53). There was no excess risk of breast cancer with distant metastases among E2-progestogen therapy users., Conclusion: The use of E2-progestogen therapy is associated with an increased risk for breast cancer after 3 years of use. The risk is lower for sequential than for continuous use, but comparable for oral and transdermal use. The risk elevation may not be uniform for all progestogens., Level of Evidence: II.

The breast cancer incidence in the Philippines is among the highest in Asia. Age-standardized incidence rates (ASR) in Metro Manila and Rizal Province derived from the Philippine Cancer Society-Manila Cancer Registry and the Department of Health-Rizal Cancer Registry showed increase from 1980 to 2002, and were significantly higher in 7 cities in Metro Manila and significantly lower in 14 cities/municipalities mostly in Rizal Province. The AJCC Clinical Stage did not change from 1993 to 2002 among incident cases, the average distribution being: I= 5%, IIA= 20%, IIB= 18%, IIIA= 9%, IIIB= 10%, IV= 11%, Unknown= 28%. The International Agency for Research on Cancer attempted to run a randomized screening trial in 1995-1997 in the Philippines based on clinical breast examination by trained nurses and midwives. Unfortunately, even after home visits by a team equipped to perform needle biopsy, only 35% of screen-positive cases eventually had a diagnostic test. The estimated prevalence of BRCA mutations among unselected patients in the Philippine General Hospital (PGH) in 1998 was 5.1%, with a prevalence of 4.1% for BRCA2 mutations alone. There is a continuing effort at improving IHC hormone receptor testing at PGH, particularly on early fixation in buffered formalin. It was observed that hormone receptor-positive proportions tended to be higher in core needle biopsy specimens (72%) compared to mastectomy specimens (65%). During the years 1991, 1994 and 1997, 97% of incident cases of early breast cancer underwent modified radical mastectomy, 18% had postoperative radiotherapy, 51% had adjuvant hormone treatment and 47% received adjuvant chemotherapy. Survival of incident cases in 1993 to 2002 was compared to that of Filipino-Americans and Caucasians in the SEER 13 database. The age-adjusted 5-year relative survival, using period analysis, of Metro Manila residents, Filipino-Americans and Caucasians were 58.6%, 89.6% and 88.3% respectively.

Objectives: The purpose of this study was to utilize the variation in the level and timing of the change in postmenopausal hormone therapy (HT) use between the Nordic countries to assess the population-level impact of decline in HT use on the breast and colon cancer incidences., Methods: Nationwide HT-sales data in defined daily doses (DDDs) per 1000 inhabitant in 1995-2005 in Finland, Iceland, Norway and Sweden were obtained from drug control authorities. Breast and colon cancer incidence data by 5-year age-groups were obtained from the National Cancer Registers. By time series analysis we estimated in each age-group and country how much a change in HT-sales changes cancer incidence., Results: The decline of HT-sales varied; the decline from the highest sales was 61% in Sweden, 51% in Norway, 43% in Iceland and 25% in Finland. With the exception of Finland, the breast cancer incidence increased from 1995 to the year following the year with maximum HT-sales and decreased after that year. In the model combining countries and years, changes in HT-sales predicted the change in breast cancer incidence, an average 7% for each 10 DDD units of HT-sales. No clear association between HT-sales and colon cancer incidence was found., Conclusions: The time and country specific data suggest, that on the population level, a notable drop from high level of HT use somewhat decreases breast cancer incidence or breaks its increasing trends. The suggested protective effect of HT for colon cancer was not seen.

Background: Breast cancer incidence continuous to increase. We examined at population level the association between the relative excess risk of breast cancer and previous age of mother at first birth., Method: Incidence of breast cancer in 34 industrialized countries was obtained from the GLOBOCAN 2002 and SEER databases. Data on age of mother at first birth was collected through national statistics offices. National relative excess risk (RER) was calculated by subtracting the lowest age-specific incidence rate from the rate in each population, and dividing the difference by the latter., Results: The national RER in 2002 correlated closely with a higher average age at first birth in 1972, 1982, 1992 and also 2002, Pearson correlation [r] being 0.83, 0.79, 0.72 and 0.61, respectively; P < 0.0001. RER of breast cancer in 2002 for those aged 15-44 years correlated closely with the mean age at first birth in 1982 and 1992 (r: 0.81 and 0.75; P < 0.0001), whereas RER for those aged 45-54 years correlated strongly with age at first birth in 1972 and 1982 (r: 0.81 and 0.76; P < 0.0001), and for those aged 55-64 years with age at first birth in 1972 (r: 0.77; P < 0.0001)., Conclusions: The rising age at first childbirth of mothers has been followed by marked increases in breast cancer incidence. Later age at first birth seems to characterize secular diffusion of 'modern' lifestyles with a potentially large impact on increased breast cancer risk, and hence should be accompanied by greater opportunities for prevention through modifiable risk factors.

Breast cancer survivors are at increased risk of treatment-related second cancers. This study is the first to examine risk 30 or more years after diagnosis and to present absolute risks of second cancer which accounts for competing mortality. We identified 23,158 second non-hematological malignancies excluding breast in a population-based cohort of 376,825 one-year survivors of breast cancer diagnosed from 1943 to 2002 and reported to four Scandinavian cancer registries. We calculated standardized incidence ratios (SIR) and utilized a competing-risk model to calculate absolute risk of developing second cancers. The overall SIR for second cancers was 1.15 (95% confidence interval [CI] = 1.14-1.17). The SIR for potentially radiotherapy-associated cancers 30 or more years after breast cancer diagnosis was 2.19 (95% CI = 1.87-2.55). However, the largest SIRs were observed for women aged <40 years followed for 1-9 years. At 20 years after breast cancer diagnosis, the absolute risk of developing a second cancer ranged from 0.6 to 10.3%, depending on stage and age; the difference in the absolute risk compared to the background population was greatest for women aged <40 years with localized disease, 2.3%. At 30 years post breast cancer diagnosis, this difference reached 3.2%. These risks were small compared to the corresponding risk of dying from breast cancer. Although the absolute risks were small, we found persistent risks of second non-hematological malignancies excluding breast 30 or more years after breast cancer diagnosis, particularly for women diagnosed at young ages with localized disease.

Purpose: To quantify long-term temporal trends in the excess absolute risk (EAR) of secondary leukemia among breast cancer (BC) survivors, using multivariate analyses to evaluate the effects of subtype, age at BC diagnosis, attained age, and calendar year., Patients and Methods: We identified 376,825 1-year survivors of BC within 4 nationwide, population-based cancer registries in Sweden, Denmark, Finland, and Norway (1943-2001). Estimates of EAR (per 100,000 person-years) were modeled using Poisson regression methods and cumulative risks calculated using a competing risk model., Results: A total of 687 non-chronic lymphocytic leukemias (EAR = 9.05; 95% confidence interval (CI) = 7.5-10.7) was reported. Significantly elevated risks were observed for the first time for chronic myeloid leukemia (CML) (EAR = 2.06; 95% CI = 1.3-2.9) and acute lymphoblastic leukemia (ALL) (EAR = 0.62; 95% CI = 0.2-1.1), in addition to acute myeloid leukemia (AML) (EAR = 5.00; 95% CI = 3.9-6.2). Excesses of CML, ALL, AML and all leukemias combined persisted over 25 years after BC diagnosis. For all leukemias, EAR decreased with increasing calendar year (P = 0.04) of BC diagnosis. Risk for all leukemia and AML by calendar year of BC diagnosis depended on age at diagnosis. For women diagnosed with BC after 1985, the 10-year cumulative risk of leukemia for those diagnosed before and after age 50 was small, 0.10% and 0.14%, respectively., Conclusions: Although secondary leukemia is a rare event, BC survivors experience statistically significant excesses for at least 25 years after diagnosis, including CML and ALL. Decreasing leukemia risks in recent calendar years likely reflect changes in treatment.

Elevated blood pressure has been proposed to be a risk factor for breast cancer but the results remain controversial. In this study, the incidence of breast cancer among 9,112 postmenopausal, hypertensive women included in the community-based hypertension register of the North Karelia project was assessed through the Finnish Cancer Registry. The mean follow-up time was 27 years. The incidence of breast cancer in hypertensive women in our cohort was similar to the age and period specific population-based rates for Eastern Finland [the standardised incidence ratio 0.96 (95% confidence interval 0.86-1.05)]. In the Cox regression analysis, there was no association between blood pressure levels, or use of antihypertensive (AH) drugs, and breast cancer incidence, when all women were considered. There was a statistically significant interaction of the use of AH drugs at baseline and the diastolic blood pressure (DBP). Among women who were not using AH drugs at baseline, the DBP level was positively associated with the subsequent risk of breast cancer (hazard ratio 1.26/10 mm Hg, 95% confidence interval 1.06-1.46). In women with AH drugs at baseline, the DBP had an opposite effect of borderline significance (hazard ratio 0.90/10 mm Hg, 95% confidence interval 0.78-1.01). In conclusion, breast cancer incidence among postmenopausal hypertensive patients in general does not differ from that of general population. Elevated DBP levels may be associated with an increased breast cancer risk among nonpharmacologically treated women.

Objective: To evaluate whether the risk of estrogen-only therapy on breast cancer varies by dose, constituent, and route of administration., Methods: All Finnish women older than age 50 years using oral or transdermal estradiol (n=84,729), oral estriol (n=7,941), or vaginal estrogens (n=18,314) for at least 6 months during 1994-2001 were identified from the national medical reimbursement register. They were followed for breast cancer with the aid of the Finnish Cancer Registry to the end of 2002., Results: Altogether, 2,171 women with breast cancer were identified. The standardized incidence ratio of breast cancer with systemic estradiol for less than 5 years was 0.93 (95% confidence interval 0.80-1.04), and for estradiol use for 5 years or more, 1.44 (1.29-1.59). Oral and transdermal estradiol was accompanied by a similar risk of breast cancer. The risk was most prominent with the dose greater than 1.9 mg/d orally; whereas the risk associated with transdermal route was not dose-dependent. The standardized incidence ratio for the lobular type of breast cancer (1.58) was slightly higher than that for the ductal type (1.36). The use of estradiol was associated with both localized breast cancer (1.45; 1.26-1.66) and cancer spread to regional nodes (1.35; 1.09-1.65). The incidence of carcinoma in situ (n=32) was increased (2.43; 1.66-3.42) among estradiol users., Conclusion: Estradiol for 5 years or more, either orally or transdermally, means 2-3 extra cases of breast cancer per 1,000 women who are followed for 10 years. Oral estradiol use for less than 5 years, oral estriol, or vaginal estrogens were not associated with a risk of breast cancer., Level of Evidence: II-2.

Few studies have examined long-term suicide risk among breast cancer survivors, and there are no data for women in the United States. We quantified suicide risk through 2002 among 723,810 1-year breast cancer survivors diagnosed between January 1, 1953, and December 31, 2001, and reported to 16 population-based cancer registries in the United States and Scandinavia. Among breast cancer survivors, we calculated standardized mortality ratios (SMRs) and excess absolute risks (EARs) compared with the general population, and the probability of suicide. We used Poisson regression likelihood ratio tests to assess heterogeneity in SMRs; all statistical tests were two-sided, with a .05 cutoff for statistical significance. In total 836 breast cancer patients committed suicide (SMR = 1.37, 95% confidence interval [CI] = 1.28 to 1.47; EAR = 4.1 per 100,000 person-years). Although SMRs ranged from 1.25 to 1.53 among registries, with 245 deaths among the sample of US women (SMR = 1.49, 95% CI = 1.32 to 1.70), differences among registries were not statistically significant (P for heterogeneity = .19). Risk was elevated throughout follow-up, including for 25 or more years after diagnosis (SMR = 1.35, 95% CI = 0.82 to 2.12), and was highest among black women (SMR = 2.88, 95% CI = 1.44 to 5.17) (P for heterogeneity = .06). Risk increased with increasing stage of breast cancer (P for heterogeneity = .08) and remained elevated among women diagnosed between 1990 and 2001 (SMR = 1.36, 95% CI = 1.18 to 1.57). The cumulative probability of suicide was 0.20% 30 years after breast cancer diagnosis.

An increase in breast cancer incidence has been reported in areas of Belarus and Ukraine contaminated by the Chernobyl accident and has become an issue of public concern. The authors carried out an ecological epidemiological study to describe the spatial and temporal trends in breast cancer incidence in the most contaminated regions of Belarus and Ukraine, and to evaluate whether increases seen since 1986 correlate to radiation exposure from the Chernobyl accident. The authors investigated the trends through age-cohort-period-region analyses of district-specific incidence rates of breast cancer for Gomel and Mogilev regions of Belarus and Chernigiv, Kyiv and Zhytomir regions of Ukraine. Dose-response analyses were based on Poisson regression, using average district-specific whole body doses accumulated since the accident from external exposure and ingestion of long-lived radionuclides. The study demonstrated increases in breast cancer incidence in all areas following the Chernobyl accident, reflecting improvements in cancer diagnosis and registration. In addition, a significant 2-fold increase in risk was observed, during the period 1997-2001, in the most contaminated districts (average cumulative dose of 40.0 mSv or more) compared with the least contaminated districts (relative risk [RR] in Belarus 2.24, 95% confidence interval [CI] 1.51-3.32 and in Ukraine 1.78, 95% CI=1.08-2.93). The increase, though based on a relatively small number of cases, appeared approximately 10 years after the accident, was highest among women who were younger at the time of exposure and was observed for both localised and metastatic diseases. It is unlikely that this excess could be entirely due to the increased diagnostic activity in these areas., (Copyright (c) 2006 Wiley-Liss, Inc.)

Purpose: To assess the risk of esophageal cancer as second cancer among breast-cancer patients treated with radiotherapy., Methods and Materials: The records of the Finnish Cancer Registry from 1953 to 2000 were used to assess the risk of esophageal cancer as second cancer among 75,849 breast-cancer patients. Patients were treated with surgery (n = 33,672), radiotherapy (n = 35,057), chemotherapy and radiotherapy (n = 4673), or chemotherapy (n = 2,447). The risk of a new primary cancer was expressed as standardized incidence ratio (SIR), defined as the ratio of observed to expected cases., Results: By the end of 2000, the number of observed cases esophageal cancers was 80 vs. 72 expected cases (standardized incidence ratio (SIR) = 1.1, 95% Confidence Interval (CI) = 0.9 to 1.5). Among patients followed for 15 years and treated with radiotherapy, the SIR for esophageal cancer was 2.3 (95% CI = 1.4 to 5.4). No increase in risk was seen for patients treated without radiotherapy. The risk of esophageal cancer was increased among patients diagnosed during 1953 to 1974, although age at the treatment did not have marked effect on the risk estimate., Conclusion: Increased risk of second cancer in the esophagus was observed for breast-cancer patients in Finland, especially among patients with over 15 years of follow-up and treated in the earliest period, which may relate to the type of radiotherapy.

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.)

Objective: The issue of light at night and cancer continuously attracts discussion. The major hypotheses are that melatonin may decrease risk of hormone-related cancers, particularly breast cancer, or even act as a potent antioxidant and thus have a protective effect against cancer development in general., Methods: We tested the hypothesis that blind persons are at lower risk of cancer in a follow-up study linking a cohort of 17,557 persons with visual impairment identified from the Finnish Register of Visual Impairment with cancer incidence data of the Finnish Cancer Registry for years 1983-2003., Results: Breast cancer risk in females decreased by degree of visual impairment, and a similar but less consistent trend was observed for prostate cancer in males. The incidence for the remaining cancers among nearly to totally blind persons was significantly higher than in average Finnish population., Conclusions: Our findings add to the suggestive epidemiological evidence for a decreased risk of hormone-related cancers in people with visual impairment and, consequently, a relationship between visible light at night and breast cancer risk. The result is strongly against the hypothesis of a systemic protective effect related lack of visible light.

The importance of genetic and other risk factors in the development of breast cancer after radiotherapy (RT) for Hodgkin lymphoma (HL) has not been determined. We analyzed data from a breast cancer case-control study (105 patients, 266 control subjects) conducted among 3 817 survivors of HL diagnosed at age 30 years or younger in 6 population-based cancer registries. Odds ratios (ORs) and excess relative risks (ERRs) were calculated using conditional regression. Women who received RT exposure (> or = 5 Gy radiation dose to the breast) had a 2.7-fold increased breast cancer risk (95% confidence interval (CI) 1.4-5.2), compared with those given less than 5 Gy. RT exposure (> or = 5 Gy) was associated with an OR of 0.8 (95% CI, 0.2-3.4) among women with a first- or second-degree family history of breast or ovarian cancer, and 5.8 (95% CI, 2.1-16.3) among all other women (interaction P = .03). History of a live birth appeared to increase the breast cancer risk associated with RT among women not treated with ovarian-damaging therapies. Breast cancer risk following RT varied little according to other factors. The additional increased relative risk of breast cancer after RT for HL is unlikely to be larger among women with a family history of breast or ovarian cancer than among other women.

Background: Many women develop breast cancer after treatment for Hodgkin lymphoma (HL) at a young age. We estimated this future risk, taking into account age and calendar year of HL diagnosis, HL treatment information, population breast cancer incidence rates, and competing causes of death., Methods: Relative risks of breast cancer for categories defined by radiation dose to the chest (0, 20- < 40 Gy, or > or = 40 Gy) and use of alkylating agents (yes or no) were estimated from a case-control study conducted within an international population-based cohort of 3817 female 1-year survivors of HL diagnosed at age 30 years or younger from January 1, 1965, through December 31, 1994. To compute cumulative absolute risks of breast cancer, we used modified standardized incidence ratios to relate cohort breast cancer risks to those in the general population, enabling application of population-based breast cancer rates, and we allowed for competing risks by using population-based mortality rates in female HL survivors., Results: Cumulative absolute risks of breast cancer increased with age at end of follow-up, time since HL diagnosis, and radiation dose. For an HL survivor who was treated at age 25 years with a chest radiation dose of at least 40 Gy without alkylating agents, estimated cumulative absolute risks of breast cancer by age 35, 45, and 55 years were 1.4% (95% confidence interval [CI] = 0.9% to 2.1%), 11.1% (95% CI = 7.4% to 16.3%), and 29.0% (95% CI = 20.2% to 40.1%), respectively. Cumulative absolute risks were lower in women treated with alkylating agents., Conclusions: Breast cancer projections varied considerably by type of HL therapy, time since HL diagnosis, and age at end of follow-up. These estimates are applicable to HL survivors treated with regimens of the past and can be used to counsel such patients and plan management and preventive strategies. Projections should be used with caution, however, in patients treated with more recent approaches, including limited-field radiotherapy and/or ovary-sparing chemotherapy.

Background: Belief that depression and other psychological factors predict breast cancer is common, but there have been few prospective epidemiological studies on this relationship., Method: The relationship between depression, personality traits, illness attitudes, life events and health history, and breast cancer risk was studied in a prospective, 6-9 year follow-up of a cohort study of 10892 Finnish women of 48-50 years of age at the baseline. Cancer cases were obtained from the Cancer Registry of Finland. Multivariate logistic regression analysis was performed controlling for socioeconomic factors, family history of cancer, parity, and health behaviours., Results: Breast cancer incidence in the cohort was 1.15 times the average in age group 50-59. There was no evidence of depression, trait anxiety, cynical distrust, or coping being significant predictors of breast cancer incidence., Conclusion: In this cohort study with the 6-9 year follow-up, psychological factors such as depression, trait anxiety, cynical distrust, or coping did not increase breast cancer risk.

The association between occupations that involve night shift work (a surrogate for exposure to light at night with subsequent melatonin suppression) and breast cancer risk is uncertain. We therefore conducted a systematic review and meta-analysis of observational studies to assess the effects of night work on breast cancer risk. Data sources were MEDLINE from January 1960 to January 2005, experts in the field, bibliographies, and abstracts. Search terms included night work terms, flight personnel terms, cancer terms, and risk terms. Independent data extraction by two authors using standardised forms was performed. The method of DerSimonian and Laird was used to derive combined estimates and Egger's; and Begg and Mazumdar's tests for publication bias were conducted. Based on 13 studies, including seven studies of airline cabin crew and six studies of other night shift workers, the aggregate estimate for all studies combined was 1.48 (95% CI, 1.36-1.61), with a similar significant elevation of breast cancer risk among female airline cabin crew (standardised incidence ratio (SIR), 1.44; 95% CI, 1.26-1.65), and female night workers (relative risk (RR), 1.51; 95% CI, 1.36-1.68) separately. We found some evidence suggesting confounding due to incomplete adjustment for breast cancer risk factors, with smaller effects in the studies that more completely adjusted for reproductive history and other confounding factors. Egger's and Begg and Mazumdar's tests for publication bias showed no significant asymmetry (P>0.05). Studies on night shift work and breast cancer risk collectively show an increased breast cancer risk among women. Publication bias is unlikely to have influenced the results.

Background: Earlier studies have found increased breast cancer risk among female cabin crew. This has been suggested to reflect lifestyle factors (for example, age at first birth), other confounding factors (for example, age at menarche), or occupational factors such as exposure to cosmic radiation and circadian rhythm alterations due to repeated jet lag., Aims: To assess the contribution of occupational versus lifestyle and other factors to breast cancer risk among cabin attendants in Finland., Methods: A standardised self-administered questionnaire on demographic, occupational, and lifestyle factors was given to 1041 cabin attendants. A total of 27 breast cancer cases and 517 non-cases completed the questionnaire. Breast cancer diagnoses were confirmed through the Finnish Cancer Registry. Exposure to cosmic radiation was estimated based on self-reported flight history and timetables. A conditional logistic regression model was used for analysis., Results: In the univariate analysis, family history of breast cancer (OR = 2.67, 95% CI: 1.00 to 7.08) was the strongest determinant of breast cancer. Of occupational exposures, sleep rhythm disruptions (OR = 1.72, 95% CI: 0.70 to 4.27) were positively related and disruption of menstrual cycles (OR = 0.71, 95% CI: 0.26 to 1.96) negatively related to breast cancer. However, both associations were statistically non-significant. Cumulative radiation dose (OR = 0.99, 95% CI: 0.83 to 1.19) showed no effect on breast cancer., Conclusions: Results suggest that breast cancer risk among Finnish cabin attendants is related to well established risk factors of breast cancer, such as family history of breast cancer. There was no clear evidence that the three occupational factors studied affected breast cancer risk among Finnish flight attendants.

The cohort consisted of 1,489 Finnish female physical education and 8,560 language teachers born after 1920 and alive in 1967. The 2 study populations were similar in social class and way of living and clearly discordant in physical activity both during their university studies and later in life. The incidence of breast cancer among these teachers up to the year 2000 was assessed through a record linkage with the Finnish Cancer Registry. The number of breast cancer cases among physical education teachers was 61 in 32,862 person-years and among language teachers was 404 in 177,188 person-years. In Poisson-regression analysis, the incidence rate ratio--adjusted for age, calendar time, number of children and age at first birth--for physical education vs. language teachers was overall 0.83 (95% confidence interval 0.63-1.09). This relative rate was 0.79 (0.46-1.36) in ages <50 years and 0.86 (0.62-1.18) in ages > or =50 years. Our study is concordant with the hypothesis that life-long physical activity may reduce the risk of breast cancer., (Copyright 2003 Wiley-Liss, Inc.)

Context: Second cancer is the leading cause of death in long-term survivors of Hodgkin disease (HD), with exceptionally high risks of breast cancer among women treated at a young age. Quantitative associations between radiotherapy dose delivered to the breast and administered chemotherapy have not been reported to date in large series, nor has the influence of ovarian exposures on subsequent risk., Objective: To quantify the long-term risk of breast cancer associated with use of radiotherapy and chemotherapy to treat young women with HD., Design, Setting, and Subjects: Matched case-control study of breast cancer within a cohort of 3817 female 1-year survivors of HD diagnosed at age 30 years or younger, between January 1, 1965, and December 31, 1994, and within 6 population-based cancer registries. The study was conducted March 1, 1996, through September 30, 1998., Main Outcome Measures: Relative risk (RR) of breast cancer associated with radiation dose delivered to site of breast cancer or to ovaries and with cumulative dose of alkylating agents., Results: Breast cancer occurred in 105 patients with HD who were matched to 266 patients with HD but without breast cancer. A radiation dose of 4 Gy or more delivered to the breast was associated with a 3.2-fold (95% confidence interval [CI], 1.4-8.2) increased risk, compared with the risk in patients who received lower doses and no alkylating agents. Risk increased to 8-fold (95% CI, 2.6-26.4) with a dose of more than 40 Gy (P<.001 for trend). Radiation risk did not vary appreciably by age at exposure or reproductive history. Increased risks persisted for 25 or more years following radiotherapy (RR, 2.3; 95% CI, 0.5-16.5; P =.03 for trend with dose). Treatment with alkylating agents alone resulted in a reduced risk (RR, 0.6; 95% CI, 0.2-2.0) of breast cancer, and combined alkylating agents and radiotherapy in a 1.4-fold (95% CI, 0.6-3.5) increased risk. Risk of breast cancer decreased with increasing number of alkylating agent cycles (P =.003 for trend). Risk also was low (RR, 0.4; 95% CI, 0.1-1.1) among women who received 5 Gy or more delivered to ovaries compared with those who received lower doses., Conclusions: Hormonal stimulation appears important for the development of radiation-induced breast cancer, as evidenced by the reduced risk associated with ovarian damage from alkylating agents or radiation. The high radiation-related risk, which did not diminish at the highest doses or the longest follow-up, however, suggests the need for lifetime surveillance and programs of patient and public awareness.

A population-based case-control study was performed to evaluate the risk of endometrial cancer related to tamoxifen or toremifene treatment. All patients with breast cancer diagnosis since 1980 in Finland who subsequently developed an endometrial cancer by the end of 1995 and 3 matched controls were identified among the 38,000 breast cancer patients of the Finnish Cancer Registry database. Detailed information on treatment of breast cancer and potential confounders was collected from hospital records. The OR for tamoxifen treatment (59 cases), adjusted for significant cofactors (increased risk associated with obesity, low parity and PR positivity) was 2.9 (95% CI 1.8-4.7). The OR for toremifene (3 cases) was 0.9 (95% CI 0.3-3.9). The OR related to adjuvant tamoxifen treatment reached its maximum 2-5 years after the beginning of treatment (OR 5.1, 95% CI 2.1-13), while the OR for tamoxifen used for palliative treatment of advanced breast cancer was especially high after a lag of over 5 years (OR 9.5, 95% CI 2.5-36). The risk increase due to tamoxifen was slightly higher if the age at initiation was below 55, and risk was more pronounced among patients with well-differentiated endometrial cancer than patients with cancers of clinical grades 2 or 3. According to our results, treatment with tamoxifen increases the risk of endometrial cancer. Due to the rare use of toremifene up to the mid-1990s, the risk assessment concerning it was inconclusive., (Copyright 2002 Wiley-Liss, Inc.)

Objectives: The association between the risk of breast cancer and the physical load of work was studied because physical activity may reduce breast cancer risk via hormonal mechanisms., Methods: Occupational physical activity was estimated from a self-determined rating [scale 1 (low)-5 (high)] of occupational physical load for 1800 randomly selected women born in 1930-1969. The medians of the ratings were used as occupation-specific indices of occupational physical activity. All 65 occupations with at least 5 ratings, covering 75% of the economically active female population in Finland, were included in further analyses. The occupation-specific numbers of observed and expected cases of breast cancer during 1971-1995 among women born in 1906-1945 (17,986 cases) were grouped according to the index for occupational physical activity. Expected rates were calculated with the social-class-specific population and the entire Finnish female population as reference populations. The relative risks (RR) of breast cancer for categories 3-5, in comparison with categories 1-2 were calculated using Poisson regression models. The occupation-specific mean number of children and mean age at first childbirth were adjusted for., Results: The RR was lower for occupations in category 5 than for those in categories 1-4, especially in the youngest (25-39 years) age group (RR 0.51, 95% confidence interval 0.44-0.58). Adjustment for social class and reproductive factors raised the RR (95% confidence interval 0.56-0.74) for category 5 in different age strata, all the RR values still being statistically significant., Conclusions: The results support the hypothesis that occupational physical activity, if high enough, markedly reduces breast cancer risk.