Mikael Hartman

Mammographic Density Phenotypes and Risk of Breast Cancer: A Meta-analysis

BACKGROUNDnFibroglandular breast tissue appears dense on mammogram, whereas fat appears nondense. It is unclear whether absolute or percentage dense area more strongly predicts breast cancer risk and whether absolute nondense area is independently associated with risk.nnnMETHODSnWe conducted a meta-analysis of 13 case-control studies providing results from logistic regressions for associations between one standard deviation (SD) increments in mammographic density phenotypes and breast cancer risk. We used random-effects models to calculate pooled odds ratios and 95% confidence intervals (CIs). All tests were two-sided with P less than .05 considered to be statistically significant.nnnRESULTSnAmong premenopausal women (n = 1776 case patients; n = 2834 control subjects), summary odds ratios were 1.37 (95% CI = 1.29 to 1.47) for absolute dense area, 0.78 (95% CI = 0.71 to 0.86) for absolute nondense area, and 1.52 (95% CI = 1.39 to 1.66) for percentage dense area when pooling estimates adjusted for age, body mass index, and parity. Corresponding odds ratios among postmenopausal women (n = 6643 case patients; n = 11187 control subjects) were 1.38 (95% CI = 1.31 to 1.44), 0.79 (95% CI = 0.73 to 0.85), and 1.53 (95% CI = 1.44 to 1.64). After additional adjustment for absolute dense area, associations between absolute nondense area and breast cancer became attenuated or null in several studies and summary odds ratios became 0.82 (95% CI = 0.71 to 0.94; P heterogeneity = .02) for premenopausal and 0.85 (95% CI = 0.75 to 0.96; P heterogeneity < .01) for postmenopausal women.nnnCONCLUSIONSnThe results suggest that percentage dense area is a stronger breast cancer risk factor than absolute dense area. Absolute nondense area was inversely associated with breast cancer risk, but it is unclear whether the association is independent of absolute dense area.

Familial Risk and Heritability of Cancer Among Twins in Nordic Countries

IMPORTANCEnEstimates of familial cancer risk from population-based studies are essential components of cancer risk prediction.nnnOBJECTIVEnTo estimate familial risk and heritability of cancer types in a large twin cohort.nnnDESIGN, SETTING, AND PARTICIPANTSnProspective study of 80,309 monozygotic and 123,382 same-sex dizygotic twin individuals (Nu2009=u2009203,691) within the population-based registers of Denmark, Finland, Norway, and Sweden. Twins were followed up a median of 32 years between 1943 and 2010. There were 50,990 individuals who died of any cause, and 3804 who emigrated and were lost to follow-up.nnnEXPOSURESnShared environmental and heritable risk factors among pairs of twins.nnnMAIN OUTCOMES AND MEASURESnThe main outcome was incident cancer. Time-to-event analyses were used to estimate familial risk (risk of cancer in an individual given a twins development of cancer) and heritability (proportion of variance in cancer risk due to interindividual genetic differences) with follow-up via cancer registries. Statistical models adjusted for age and follow-up time, and accounted for censoring and competing risk of death.nnnRESULTSnA total of 27,156 incident cancers were diagnosed in 23,980 individuals, translating to a cumulative incidence of 32%. Cancer was diagnosed in both twins among 1383 monozygotic (2766 individuals) and 1933 dizygotic (2866 individuals) pairs. Of these, 38% of monozygotic and 26% of dizygotic pairs were diagnosed with the same cancer type. There was an excess cancer risk in twins whose co-twin was diagnosed with cancer, with estimated cumulative risks that were an absolute 5% (95% CI, 4%-6%) higher in dizygotic (37%; 95% CI, 36%-38%) and an absolute 14% (95% CI, 12%-16%) higher in monozygotic twins (46%; 95% CI, 44%-48%) whose twin also developed cancer compared with the cumulative risk in the overall cohort (32%). For most cancer types, there were significant familial risks and the cumulative risks were higher in monozygotic than dizygotic twins. Heritability of cancer overall was 33% (95% CI, 30%-37%). Significant heritability was observed for the cancer types of skin melanoma (58%; 95% CI, 43%-73%), prostate (57%; 95% CI, 51%-63%), nonmelanoma skin (43%; 95% CI, 26%-59%), ovary (39%; 95% CI, 23%-55%), kidney (38%; 95% CI, 21%-55%), breast (31%; 95% CI, 11%-51%), and corpus uteri (27%; 95% CI, 11%-43%).nnnCONCLUSIONS AND RELEVANCEnIn this long-term follow-up study among Nordic twins, there was significant excess familial risk for cancer overall and for specific types of cancer, including prostate, melanoma, breast, ovary, and uterus. This information about hereditary risks of cancers may be helpful in patient education and cancer risk counseling.

Genetic implications of bilateral breast cancer: a population based cohort study

BACKGROUNDnWomen with breast cancer are at high risk of bilateral breast cancer. We aimed to assess the incidence of bilateral breast cancer in relation to age and time since diagnosis of first cancer.nnnMETHODSnWe analysed a population-based cohort of 123757 women with a first primary breast cancer diagnosed in Sweden from 1970 to 2000 for frequency of bilateral breast cancers and deaths by means of record linkage. Second primary breast cancers were categorised as synchronous bilateral breast cancers if diagnosed within 3 months of the first primary cancer or as metachronous if diagnosed more than 3 months after diagnosis of first primary cancer.nnnFINDINGSnWe identified 6550 women who had developed bilateral breast cancer. Age-incidence patterns of synchronous and unilateral breast cancer were similar, although the absolute rates of synchronous bilateral cancer were 50-100 times lower than those of unilateral cancer. A woman aged 80 years or older is at least twice as likely to be diagnosed with synchronous bilateral breast cancer than is a woman younger than 40 years. In the first 20 years after diagnosis of primary breast cancer, incidence of metachronous bilateral cancer decreased from about 800 per 10(5) person-years to 400 per 10(5) person-years in patients diagnosed with primary breast cancer before the age of 45 years, whereas incidence remained at 500-600 per 10(5) person-years in those age 45 years or older at diagnosis. After 30 years follow-up, cumulative risk of metachronous bilateral breast cancer was about 15% irrespective of age at first primary breast cancer.nnnINTERPRETATIONnThe higher than expected risk of synchronous bilateral breast cancer could be explained by non-genetic factors. By contrast, incidence of metachronous bilateral cancer fits neither a model of highly penetrant genes nor aggregation of environmental risk factors.

The Heritability of Prostate Cancer in the Nordic Twin Study of Cancer

Background: Prostate cancer is thought to be the most heritable cancer, although little is known about how this genetic contribution varies across age. Methods: To address this question, we undertook the worlds largest prospective study in the Nordic Twin Study of Cancer cohort, including 18,680 monozygotic (MZ) and 30,054 dizygotic (DZ) same-sex male twin pairs. We incorporated time-to-event analyses to estimate the risk concordance and heritability while accounting for censoring and competing risks of death, essential sources of biases that have not been accounted for in previous twin studies modeling cancer risk and liability. Results: The cumulative risk of prostate cancer was similar to that of the background population. The cumulative risk for twins whose co-twin was diagnosed with prostate cancer was greater for MZ than for DZ twins across all ages. Among concordantly affected pairs, the time between diagnoses was significantly shorter for MZ than DZ pairs (median, 3.8 versus 6.5 years, respectively). Genetic differences contributed substantially to variation in both the risk and the liability [heritability = 58% (95% confidence interval, 52%–63%)] of developing prostate cancer. The relative contribution of genetic factors was constant across age through late life with substantial genetic heterogeneity even when diagnosis and screening procedures vary. Conclusions: Results from the population-based twin cohort indicate a greater genetic contribution to the risk of developing prostate cancer when addressing sources of bias. The role of genetic factors is consistently high across age. Impact: Findings affect the search for genetic and epigenetic markers and frame prevention efforts. Cancer Epidemiol Biomarkers Prev; 23(11); 2303–10. ©2014 AACR.

Familial concordance in cancer survival: a Swedish population-based study

BACKGROUNDnNowadays, the fact that cancers can aggregate in families is generally accepted. The aim of this study was to complete a comprehensive analysis of cancer-survival concordance in parents and their children diagnosed with the same cancer.nnnMETHODSnWe used a population-based Swedish family database, that included about three million families and data for more than a million individuals with cancer. We analysed survival in children in relation to parental survival by use of the Kaplan-Meier method. We then modelled the risk in children in relation to parental survival by use of two multivariate proportional hazard (Cox) models adjusting for possible confounders of survival.nnnFINDINGSnIn our univariate Kaplan-Meier analysis, children with the same cancer as their parent and whose parent had died within 10 years of diagnosis showed significantly worse survival for breast (log rank p=0.01), colorectal (p=0.04), and prostate cancer (p=0.05) than those whose parents were alive at 10 years from diagnosis. By use of Cox modelling, we noted an increased hazard ratio for death from cancer in children with poor parental survival compared with those with good parental survival for colorectal cancer (hazard ratio [HR] 1.44 [95% CI 1.01-2.01]), lung cancer (1.39 [1.00-1.94]), breast cancer (1.75 [1.13-2.71]), ovarian cancer (2.23 [0.78-6.34]), and prostate cancer (2.07 [1.13-3.79]). All hazard-ratio estimates, except for ovarian cancer, were significant, with significant trends of increasing risk of death in children by degree of worsening survival outcome in parents defined in quartiles of survival (ie, good [best quartile], expected [middle two quartiles], or poor [worst quartile]).nnnINTERPRETATIONnOur findings suggest that cancer-specific survival in parents predicts survival from the same cancer in their children. Consequently, data on survival in a parent might have the potential to guide treatment decisions and genetic counselling. Finally, molecular studies to highlight the genetic determinants of cancer survival are now warranted.

Is breast cancer prognosis inherited

IntroductionA genetic component is well established in the etiology of breast cancer. It is not well known, however, whether genetic traits also influence prognostic features of the malignant phenotype.MethodsWe carried out a population-based cohort study in Sweden based on the nationwide Multi-Generation Register. Among all women with breast cancer diagnosed from 1961 to 2001, 2,787 mother-daughter pairs and 831 sister pairs with breast cancer were identified; we achieved complete follow-up and classified 5-year breast cancer-specific prognosis among proband (mother or oldest sister) into tertiles as poor, intermediary, or good. We used Kaplan-Meier estimates of survival proportions and Cox models to calculate relative risks of dying from breast cancer within 5 years depending on the probands outcome.ResultsThe 5-year survival proportion among daughters whose mothers died within 5 years was 87% compared to 91% if the mother was alive (p = 0.03). Among sisters, the corresponding proportions were 70% and 88%, respectively (p = 0.001). After adjustment for potential confounders, daughters and sisters of a proband with poor prognosis had a 60% higher 5-year breast cancer mortality compared to those of a proband with good prognosis (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.2 to 2.2; p for trend 0.002). This association was slightly stronger among sisters (HR, 1.8; 95% CI, 1.0 to 3.4) than among daughters (HR, 1.6; 95% CI, 1.1 to 2.3).ConclusionBreast cancer prognosis of a woman predicts the survival in her first-degree relatives with breast cancer. Our novel findings suggest that breast cancer prognosis might be inherited.

Splenectomy and the risk of sepsis: a population-based cohort study.

Objective:We sought to estimate the long-term risk of sepsis in patients who underwent splenectomy before, during, and after implementation of vaccination. Background:Because patients who have undergone splenectomy are considered at increased risk of bacterial sepsis, they typically receive vaccination, education, and occasionally antibiotic prophylaxis. However, the extent to which these interventions have actually reduced the risk of sepsis remains unclear. Methods:Retrospective cohort study encompassing all patients in the Swedish national inpatient register, who underwent splenectomy in 1970–2009. Patients were followed for hospitalization for or death from sepsis, as identified using national inpatient and cause of death registers. Relative risks, comparing patients to the background population were expressed as standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs). Results:Altogether, 20,132 splenectomized patients were included. The overall SIR for hospitalization for sepsis was 5.7 [95% confidence interval (CI), 5.6–6.0]. However, risks depended on the indication for splenectomy, with SIRs varying from 3.4 (95% CI, 3.0–3.8) for trauma patients to 18 (95% CI, 16–19) for patients with hematologic malignancies. SMRs ranged from 3.1 (95% CI, 2.1–4.3) for trauma to 8.7 (95% CI, 6.8–11) for hematologic disease. In regression analyses adjusting for age at splenectomy, follow-up time, sex, and calendar year of splenectomy, there were no significant risk decreases after implementation of routine vaccination, except for in patients with malignant and non-malignant hematologic disease. Conclusions:The risk of hospitalization or death from sepsis is high in patients who previously underwent splenectomy and depends on the indication for splenectomy. The effectiveness of current vaccination practices warrants further evaluation.

Breast Cancer Onset in Twins and Women With Bilateral Disease

PURPOSEnLittle is known of the onset of breast cancer in high-risk populations. We investigated the risk of breast cancer in twin sisters and in the contralateral breast taking family history into consideration.nnnPATIENTS AND METHODSnWe analyzed a Scandinavian population-based cohort of 2,499 female twin pairs, in which at least one had a diagnosis of breast cancer and estimated the risk of breast cancer in the sister. Using a total of 11 million individuals in Sweden with complete family links, we identified 93,448 women with breast cancer and estimated the risk of a bilateral breast cancer.nnnRESULTSnThe incidence of breast cancer in twin sisters of breast cancer patients was 0.64% per year and 0.42% per year in mono- and dizygotic twin sisters, respectively. In comparison, the risk of familial (affected first-degree relative) and nonfamilial bilateral breast cancer was 1.03% per year and 0.68% per year, respectively. Contrary to the risk of unilateral disease, the risk of cancer in the nonaffected twin and the opposite breast was not affected by age or time since first event. The relative risk of familial bilateral cancer was 52% higher (incidence rate ratio [IRR] = 1.52; 95% CI, 1.42 to 1.64) and the relative risk in the dizygotic twin sister was 25% lower (IRR = 0.75; 95% CI, 0.61 to 0.91) compared with the risk of nonfamilial bilateral cancer.nnnCONCLUSIONnThe elevated risk of breast cancer in high-risk groups is little affected by age and time since diagnosis. Our findings suggest that susceptible groups of women might have already aggregated genetic prerequisites for breast cancer.

Effect of childbirth after treatment on long-term survival from breast cancer

This study quantified long‐term absolute and relative mortality risks of survivors of breast cancer with subsequent childbirth.

Mammographic density and ageing: A collaborative pooled analysis of cross-sectional data from 22 countries worldwide

Background Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. Methods and findings We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35–85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (–0.46 cm [95% CI: −0.53, −0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was −0.24 cm (95% CI: −0.34, −0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (−0.38 cm [95% CI: −0.44, −0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature. Conclusions Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction.