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Do Asian breast cancer patients have poorer survival than their western counterparts? A comparison between Singapore and Stockholm
Benita Tan, Gek Lim, Kamila Czene, Per Hall, Kee Chia
Breast Cancer Research , 2009, DOI: 10.1186/bcr2219
Abstract: We compared the survival of 10,287 Singaporean women and 17,090 Swedish women with breast cancer. Relative survival ratios were used to describe the prognosis in the two populations. A Poisson regression model was used to calculate relative risks for different follow-up periods, age groups, time of diagnosis and disease stages.The majority of the Swedish women had local cancer (80%) compared with Singaporean women (51%). The overall 5-year relative survival of the Swedish women appeared better (80%) than that of the Singaporean women (70%). A similar survival pattern was observed, however, between the two countries in a stage-by-stage comparison. Survival improved for all women in Singapore over the two decades, but only in the premenopausal women in Stockholm. In 1980 to 1989, premenopausal Singaporean women had 27% increased risk of death compared with Swedish women, adjusted for stage and year of follow-up, while the postmenopausal women had 48% increased risk. In 1990 to 1999, this risk decreased by 19% and 22% for the premenopausal and postmenopausal Singaporean women compared with the Swedish women.The stage-dependent prognosis was similar for Singaporean women and for Swedish women. Singaporean women, both premenopausal and postmenopausal, had pronounced improvement in prognosis over the calendar periods, probably contributed by marked economic improvement, leading to better medical facilities and management with increased awareness of patients to diagnosis and treatment, as well as improved treatment options. Improvement seen only in the premenopausal women in Stockholm was probably due to improved treatment options.The study of ethnic differences in breast cancer survival is limited except for those between Afro-American women, Asian-American women and Caucasian American women. In the United States, Afro-American women are known to have a worse outcome compared with Caucasian American women. This has been attributed to increased diagnosis of late-stage brea
A constant risk for familial breast cancer? A population-based family study
Kamila Czene, Marie Reilly, Per Hall, Mikael Hartman
Breast Cancer Research , 2009, DOI: 10.1186/bcr2260
Abstract: We analyzed a Swedish population-based cohort with complete family links and calculated incidence rates of breast cancer in mothers of 48,259 daughters diagnosed with breast cancer.The risk for breast cancer in mothers of breast cancer patients is elevated relative to the background population at all ages. Mothers have an overall incidence of 0.34%/year at ages older than a daughter's age at diagnosis. This rate is not affected to any large extent by the daughter's age at diagnosis. A constant incidence rate of 0.40%/year from age 35 years onward is seen in mothers of breast cancer patients diagnosed before 35 years of age. For mothers of daughters diagnosed at age 35 to 44 years the incidence pattern is less clear, with the rate being stable for approximately 20 years after the daughter's age at diagnosis and rising thereafter. Older age at a daughter's diagnosis (≥ 45 years) appears to confer an age-dependent increase in incidence in the mother.Incidence of familial breast cancer in first-degree relatives may increase to a high and constant level by a predetermined age that is specific to each family. This phenomenon appears inconsistent with accepted theories of malignant transformation.Studies of familial aggregation of breast cancer identify a family history of breast cancer as one of the strongest risk factors for the disease [1,2]. Familial risks for female breast cancer have been the subject of numerous epidemiological studies [3-7]. A study that re-analyzed 52 epidemiological studies of familial breast cancer presented summary risk ratios of 1.80 and 2.93 for one and two affected first-degree relatives, respectively [8].Young age at onset of disease within a family has long been regarded as a particularly strong risk factor for breast cancer [9-11]. Several studies have investigated the familial risk for breast cancer in relation to both the proband's age at diagnosis and the age of the person at risk [3,12]. The results are similar, regardless of whether s
The influence of menstrual risk factors on tumor characteristics and survival in postmenopausal breast cancer
Chantal C Orgéas, Per Hall, Lena U Rosenberg, Kamila Czene
Breast Cancer Research , 2008, DOI: 10.1186/bcr2212
Abstract: We used a nationwide, population-based, case-case design of 2,640 Swedish women who were 50 to 74 years old and had postmenopausal breast cancer during 1993 to 1995. Follow-up was conducted until 31 December 2000. We used polytomous multiple logistic regression to investigate the relationships between menstrual factors (age at menarche, cycle length, irregular menstruation, lifetime number of menstrual cycles, and age at menopause), tumor characteristics (size, grade, estrogen receptor and progesterone receptor [PR] status, lymph node involvement, and histology), and Cox proportional hazards modeling for 5-year survival.Younger ages at menarche were significantly associated with grade and lymph node involvement. Women with an age at menarche of 11 years or younger had a more than twofold excess risk of medium-grade (odds ratio [OR] = 2.05; 95% confidence interval [CI] 1.00 to 4.18) and high-grade (OR = 2.04; 95% CI 1.01 to 4.16) tumors. Early menarche significantly increased the risk of lymph node metastases. Survival was poorest in women with the earliest age at menarche, with a 72% increased risk of dying within 5 years after diagnosis (hazard ratio = 1.72; 95% CI 1.02 to 2.89). No significant associations were observed for other menstrual factors with tumor characteristics or survival.Age at menarche has a significant impact on breast cancer prognosis and survival. It remains to be established whether the associations are attributable to age at menarche directly or are associated with the early-life physiological events of breast development and carcinogenesis also taking place during childhood and puberty, as menarche is only the culmination of this series of events.Haenszel [1] hypothesized that factors influencing breast cancer induction also affect prognosis. Estrogen promotes growth in breast cancer cell lines [2], and lower estrogen levels have been correlated with improved disease-free survival in postmenopausal breast cancer [3]. Tumor characteristics are
Is Genetic Background Important in Lung Cancer Survival?
Linda S. Lindstr?m, Per Hall, Mikael Hartman, Fredrik Wiklund, Kamila Czene
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005588
Abstract: Background In lung cancer, a patient's survival is poor with a wide variation in survival within the stage of disease. The aim of this study was to investigate the familial concordance in lung cancer survival by means of analyses of pairs with different degrees of familial relationships. Methods Our population-based Swedish family database included three million families and over 58 100 lung cancer patients. We modelled the proband (parent, sibling, spouse) survival utilizing a multivariate proportional hazard (Cox) model adjusting for possible confounders of survival. Subsequently, the survival in proband's relative (child, sibling, spouse) was analysed with a Cox model. Findings By use of Cox modelling with 5 years follow-up, we noted a decreased hazard ratio for death in children with good parental survival (Hazard Ratio [HR] = 0.71, 95% CI = 0.51 to 0.99), compared to those with poor parental survival. Also for siblings, a very strong protective effect was seen (HR = 0.14, 95% CI = 0.030 to 0.65). Finally, in spouses no correlation in survival was found. Interpretation Our findings suggest that genetic factors are important in lung cancer survival. In a clinical setting, information on prognosis in a relative may be vital in foreseeing the survival in an individual newly diagnosed with lung cancer. Future molecular studies enhancing the understanding of the underlying mechanisms and pathways are needed.
Library Preparation and Multiplex Capture for Massive Parallel Sequencing Applications Made Efficient and Easy
M?rten Neiman, Simon Sundling, Henrik Gr?nberg, Per Hall, Kamila Czene, Johan Lindberg, Daniel Klevebring
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048616
Abstract: During the recent years, rapid development of sequencing technologies and a competitive market has enabled researchers to perform massive sequencing projects at a reasonable cost. As the price for the actual sequencing reactions drops, enabling more samples to be sequenced, the relative price for preparing libraries gets larger and the practical laboratory work becomes complex and tedious. We present a cost-effective strategy for simplified library preparation compatible with both whole genome- and targeted sequencing experiments. An optimized enzyme composition and reaction buffer reduces the number of required clean-up steps and allows for usage of bulk enzymes which makes the whole process cheap, efficient and simple. We also present a two-tagging strategy, which allows for multiplex sequencing of targeted regions. To prove our concept, we have prepared libraries for low-pass sequencing from 100 ng DNA, performed 2-, 4- and 8-plex exome capture and a 96-plex capture of a 500 kb region. In all samples we see a high concordance (>99.4%) of SNP calls when comparing to commercially available SNP-chip platforms.
Breast cancer risk prediction and individualised screening based on common genetic variation and breast density measurement
Hatef Darabi, Kamila Czene, Wanting Zhao, Jianjun Liu, Per Hall, Keith Humphreys
Breast Cancer Research , 2012, DOI: 10.1186/bcr3110
Abstract: We investigate the performance of an up-to-date 18 breast cancer risk single-nucleotide polymorphisms (SNPs), together with mammographic percentage density (PD), body mass index (BMI) and clinical risk factors in predicting absolute risk of breast cancer, empirically, in a well characterised Swedish case-control study of postmenopausal women. We examined the efficiency of various prediction models at a population level for individualised screening by extending a recently proposed analytical approach for estimating number of cases captured.The performance of a risk prediction model based on an initial set of seven breast cancer risk SNPs is improved by additionally including eleven more recently established breast cancer risk SNPs (P = 4.69 × 10-4). Adding mammographic PD, BMI and all 18 SNPs to a Swedish Gail model improved the discriminatory accuracy (the AUC statistic) from 55% to 62%. The net reclassification improvement was used to assess improvement in classification of women into low, intermediate, and high categories of 5-year risk (P = 8.93 × 10-9). For scenarios we considered, we estimated that an individualised screening strategy based on risk models incorporating clinical risk factors, mammographic density and SNPs, captures 10% more cases than a screening strategy using the same resources, based on age alone. Estimates of numbers of cases captured by screening stratified by age provide insight into how individualised screening programs might appear in practice.Taken together, genetic risk factors and mammographic density offer moderate improvements to clinical risk factor models for predicting breast cancer.Breast cancer screening aims to detect the disease early in women and thereby reduce mortality from breast cancer. It may not be cost-effective to screen all women equally often, but rather to allocate resources disproportionately across women at different risks of developing breast cancer. To identify high- and low-risk groups, a model for estimating
High-throughput mammographic-density measurement: a tool for risk prediction of breast cancer
Jingmei Li, Laszlo Szekely, Louise Eriksson, Boel Heddson, Ann Sundbom, Kamila Czene, Per Hall, Keith Humphreys
Breast Cancer Research , 2012, DOI: 10.1186/bcr3238
Abstract: We randomly partitioned our dataset into a training set for model building (733 cases, 748 controls) and a test set for model assessment (765 cases, 747 controls). The Pearson product-moment correlation coefficient (r) was used to compare the MD measurements by Cumulus and our automated measure, which mimics Cumulus. The likelihood ratio test was used to validate the performance of logistic regression models for breast cancer risk, which included our measure capturing additional information in mammographic images.We observed a high correlation between the Cumulus measure and our measure mimicking Cumulus (r = 0.884; 95% CI, 0.872 to 0.894) in an external test set. Adding a variable, which includes extra information to percentage density, significantly improved the fit of the logistic regression model of breast cancer risk (P = 0.0002).Our results demonstrate the potential to facilitate the integration of mammographic density measurements into large-scale research studies and subsequently into clinical practice.Extensive mammographic density (MD) is a strong risk factor for breast cancer. MD refers to the different radiologic patterns of dense and nondense tissue in the breast. Radiologically dense tissue (for example, connective and epithelial tissue) appears light on a mammogram [1]. Nondense tissue is made up mostly of fat, is radiologically lucent, and appears dark on a mammogram. Women with dense tissue in more than 75% of the breast have been consistently reported to be at a four- to sixfold higher risk of developing the disease than are women of similar age with little or no dense tissue [2-4]. A substantial fraction of breast cancers can be attributed to this risk factor. One third of all breast cancers have been found to be diagnosed in women with more than 50% density [5].MD can be evaluated and reported by radiologists on the basis of visual analysis of mammograms. Examples of quantitative and qualitative classification methods based on the visual characte
Is breast cancer prognosis inherited?
Mikael Hartman, Linda Lindstr?m, Paul W Dickman, Hans-Olov Adami, Per Hall, Kamila Czene
Breast Cancer Research , 2007, DOI: 10.1186/bcr1737
Abstract: We 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 proband's outcome.The 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).Breast 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.Breast cancer, the most common female malignancy, has an important genetic contribution estimated to 25% to 28% [1,2]. Mutations in high-penetrant genes such as BRCA1 (breast cancer 1, early onset) and BRCA2 account for only a small proportion of this hereditary component, suggesting an important but yet-to-be-detected role for low-penetrant single nucleotide polymorphisms. Overall, the prognosis of women with a family history of breast cancer has been reported as similar or worse compared to women without a family history [3-6]. A relatively poor outcome ha
Effects of childhood body size on breast cancer tumour characteristics
Jingmei Li, Keith Humphreys, Louise Eriksson, Kamila Czene, Jianjun Liu, Per Hall
Breast Cancer Research , 2010, DOI: 10.1186/bcr2564
Abstract: We studied the relationships between childhood body size and tumour characteristics in a Swedish population-based case-control study consisting of 2,818 breast cancer cases and 3,111 controls. Our classification of childhood body size was derived from a nine-level somatotype. Relative risks were estimated by odds ratios with 95% confidence intervals, derived from fitting unconditional logistic regression models. Association between somatotype at age 7 and tumour characteristics were evaluated in a case-only analysis where P values for heterogeneity were obtained by performing one degree of freedom trend tests.A large somatotype at age 7 was found to be associated with decreased postmenopausal breast cancer risk. Although strongly associated with other risk factors such as age of menarche, adult body mass index and mammographic density, somatotype at age 7 remained a significant protective factor (odds ratio (OR) comparing large to lean somatotype at age 7 = 0.73, 95% confidence interval (CI) = 0.58-0.91, P trend = 0.004) after adjustment. The significant protective effect was observed within all subgroups defined by estrogen receptor (ER) and progesterone receptor (PR) status, with a stronger effect for ER-negative (0.40, 95% CI = 0.21-0.75, P trend = 0.002), than for ER-positive (0.80, 95% CI = 0.62-1.05, P trend = 0.062), tumours (P heterogeneity = 0.046). Somatotype at age 7 was not associated with tumour size, histology, grade or the presence or absence of metastatic nodes.Greater body size at age 7 is associated with a decreased risk of postmenopausal breast cancer, and the associated protective effect is stronger for the ER-negative breast cancer subtype than for the ER-positive subtype.There is considerable evidence that childhood anthropometric measurements are associated with postmenopausal breast cancer risk. It has been consistently shown that variables that approximate body shape and size early in life are inversely associated with breast cancer risk in
Estrogen Receptor Status in Relation to Risk of Contralateral Breast Cancer–A Population-Based Cohort Study
Maria E. C. Sandberg, Per Hall, Mikael Hartman, Anna L. V. Johansson, Sandra Eloranta, Alexander Ploner, Kamila Czene
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046535
Abstract: Background It is unclear whether estrogen receptor (ER)-status of first primary breast cancer is associated with risk of metachronous (non-simultaneous) contralateral breast cancer (CBC), and to what extent endocrine therapy affects this association. Methods We studied the effect of ER-status of the first cancer on the risk of CBC overall, and for different ER-subtypes of CBC, using a large, population-based cohort. The cohort consisted of all women diagnosed with breast cancer in the Stockholm region 1976–2005; 25715 patients, of whom 940 suffered CBC. The relative risk was analyzed mainly using standardized incidence ratios (SIR). Results Women with breast cancer had a doubled risk of CBC compared to the risk of breast cancer in the general female population (SIR: 2.22 [2.08–2.36]), for women with a previous ER-positive cancer: SIR = 2.30 (95% CI:2.11–2.50) and for women with a previous ER-negative cancer: SIR = 2.17 (95% CI:1.82–2.55). The relative risk of ER-positive and ER-negative CBC was very similar for women with ER-positive first cancer (SIR = 2.02 [95%CI: 1.80–2.27] and SIR = 1.89 [95%CI: 1.46–2.41] respectively) while for patients with ER-negative first cancer the relative risk was significantly different (SIR = 1.27 [95% CI:0.94–1.68] for ER-positive CBC and SIR = 4.96 [95%CI:3.67–6.56] for ER-negative CBC). Patients with ER-positive first cancer who received hormone therapy still had a significantly higher risk of CBC than the risk of breast cancer for the general female population (SIR = 1.74 [95% CI:1.47–2.03]). Conclusion The risk of CBC for a breast cancer patient is increased to about two-fold, compared to the risk of breast cancer in the general female population. This excess risk decreases, but does not disappear, with adjuvant endocrine therapy. Patients with ER-positive first cancers have an increased risk for CBC of both ER subtypes, while patients with ER-negative first cancer have a specifically increased risk of ER-negative CBC.
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