Kristjana Einarsdóttir

Risk Factors for Hormone Receptor-Defined Breast Cancer in Postmenopausal Women

The effect of classic breast cancer risk factors on hormone receptor-defined breast cancer is not fully clarified. We explored these associations in a Swedish population-based study. Postmenopausal women ages 50 to 74 years, diagnosed with invasive breast cancer during 1993 to 1995, were compared with 3,065 age frequency-matched controls. We identified 332 estrogen receptor (ER−) and progesterone receptor (PR−) negative, 286 ER+PR−, 71 ER−PR+, 1,165 ER+PR+, and 789 tumors with unknown receptor status. Unconditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI). Women ages ≥30 years, compared with those ages 20 to 24 years at first birth, were at an increased risk of ER+PR+ tumors (OR, 1.5; 95% CI, 1.2-1.8) but not ER−PR− tumors (OR, 1.1; 95% CI, 0.8-1.6). Women who gained ≥30 kg in weight during adulthood had an ∼3-fold increased relative risk of ER+PR+ tumors (OR, 2.7; 95% CI, 1.9-3.8), but no risk increase of ER−PR− tumors (OR, 1.0; 95% CI, 0.5-2.1), compared with women who gained <10 kg. Compared with never users, women who used menopausal estrogen-progestin therapy for at least 5 years were at increased risk of ER+PR+ tumors (OR, 3.0; 95% CI, 2.1-4.1) but not ER−PR− tumors (OR, 1.3; 95% CI, 0.7-2.5). In conclusion, other risk factors were similarly related to breast cancer regardless of receptor status, but high age at first birth, substantial weight gain in adult age, and use of menopausal estrogen-progestin therapy were more strongly related to receptor-positive breast cancer than receptor-negative breast cancer. (Cancer Epidemiol Biomarkers Prev 2006;15(12):2482–8)

Linkage disequilibrium mapping of CHEK2: Common variation and breast cancer risk

Background Checkpoint kinase 2 (CHEK2) averts cancer development by promoting cell cycle arrest and activating DNA repair in genetically damaged cells. Previous investigation has established a role for the CHEK2 gene in breast cancer aetiology, but studies have largely been limited to the rare 1100delC mutation. Whether common polymorphisms in this gene influence breast cancer risk remains unknown. In this study, we aimed to assess the importance of common CHEK2 variants on population risk for breast cancer by capturing the majority of diversity in the gene using haplotype tagging single nucleotide polymorphisms (tagSNPs). Methods and Findings We analyzed 14 common SNPs spanning 52 kilobases (kb) of the CHEK2 gene in 92 Swedish women. Coverage evaluation indicated that these typed SNPs would efficiently convey association signal also from untyped SNPs in the same region. Six of the 14 SNPs predicted well both the haplotypic and single SNP variations within CHEK2. We genotyped these six tagSNPs in 1,577 postmenopausal breast cancer cases and 1,513 population controls, but found no convincing association between any common CHEK2 haplotype and breast cancer risk. The 1100delC mutation was rare in our Swedish population—0.7% in cases and 0.4% in controls—with a corresponding odds ratio for carriers versus noncarriers of 2.26 (95% confidence interval, 0.99–5.15). Estimates of the population frequency and the odds ratio of 1100delC indicate that our sample is representative of a Northern European population. Conclusions Notwithstanding the involvement of the CHEK2 gene in breast cancer aetiology, we show that common polymorphisms do not influence postmenopausal breast cancer risk.

ESR1 and EGF genetic variation in relation to breast cancer risk and survival

IntroductionOestrogen exposure is a central factor in the development of breast cancer. Oestrogen receptor alpha (ESR1) is the main mediator of oestrogen effect in breast epithelia and has also been shown to be activated by epidermal growth factor (EGF). We sought to determine if common genetic variation in the ESR1 and EGF genes affects breast cancer risk, tumour characteristics or breast cancer survival.MethodsWe genotyped 157 single nucleotide polymorphisms (SNPs) in ESR1 and 54 SNPs in EGF in 92 Swedish controls and selected haplotype tagging SNPs (tagSNPs) that could predict both single SNP and haplotype variation in the genes with an R2 of at least 0.8. The tagSNPs were genotyped in 1,590 breast cancer cases and 1,518 controls, and their association with breast cancer risk, tumour characteristics and survival were assessed using unconditional logistic regression models, Cox proportional hazard models and haplotype analysis.ResultsThe single tagSNP analysis did not reveal association evidence for breast cancer risk, tumour characteristics, or survival. A multi-locus analysis of five adjacent tagSNPs suggested a region in ESR1 (between rs3003925 and rs2144025) for association with breast cancer risk (p = 0.001), but the result did not withstand adjustment for multiple comparisons (p = 0.086). A similar region was also implicated by haplotype analyses, but its significance needs to be verified by follow-up analysis.ConclusionOur results do not support a strong association between common variants in the ESR1 and EGF genes and breast cancer risk, tumour characteristics or survival.

Menopausal hormone therapy in relation to breast cancer characteristics and prognosis: a cohort study

IntroductionMenopausal hormone therapy has been reported to increase the risk of certain subtypes of breast cancer and to be associated with a favorable survival. These associations could either be due to an increased mammographic surveillance or to a biological effect. We assessed these associations in a Swedish cohort of postmenopausal breast cancer patients holding information on mammographic examinations, menopausal hormone therapy use, other breast cancer risk factors, and cancer treatment.MethodsWe analyzed 2,660 postmenopausal women aged 50 to 74 years, diagnosed with invasive breast cancer in 1993 to 1995 and followed until the end of 2003 (median follow-up, 9 years and 3 months). We assessed the influence of hormone therapy before diagnosis on tumor characteristics and breast cancer-specific survival. We analyzed hormone therapy before diagnosis by regimen (estrogen–progestin therapy or estrogen alone therapy), recency (current or past), and duration of use (<5 years or ≥ 5 years).ResultsCurrent use, but not past use, compared with never use of hormone therapy before diagnosis seemed to be associated with tumors of low grade and with improved breast cancer-specific survival. The associations were stronger with longer duration, but did not vary significantly by regimen. The favorable survival among current users of hormone therapy was only partly explained by differences in available tumor characteristics and mammographic surveillance.ConclusionsWe conclude that current menopausal hormone therapy, especially long term, is associated with favorable tumor characteristics and survival.

Increase in caesarean deliveries after the Australian Private Health Insurance Incentive policy reforms.

Background The Australian Private Health Insurance Incentive (PHII) policy reforms implemented in 1997–2000 increased PHI membership in Australia by 50%. Given the higher rate of obstetric interventions in privately insured patients, the reforms may have led to an increase in surgical deliveries and deliveries with longer hospital stays. We aimed to investigate the effect of the PHII policy introduction on birth characteristics in Western Australia (WA). Methods and Findings All 230,276 birth admissions from January 1995 to March 2004 were identified from administrative birth and hospital data-systems held by the WA Department of Health. Average quarterly birth rates after the PHII introduction were estimated and compared with expected rates had the reforms not occurred. Rate and percentage differences (including 95% confidence intervals) were estimated separately for public and private patients, by mode of delivery, and by length of stay in hospital following birth. The PHII policy introduction was associated with a 20% (−21.4 to −19.3) decrease in public birth rates, a 51% (45.1 to 56.4) increase in private birth rates, a 5% (−5.3 to −5.1) and 8% (−8.9 to −7.9) decrease in unassisted and assisted vaginal deliveries respectively, a 5% (−5.3 to −5.1) increase in caesarean sections with labour and 10% (8.0 to 11.7) increase in caesarean sections without labour. Similarly, birth rates where the infant stayed 0–3 days in hospital following birth decreased by 20% (−21.5 to −18.5), but rates of births with >3 days in hospital increased by 15% (12.2 to 17.1). Conclusions Following the PHII policy implementation in Australia, births in privately insured patients, caesarean deliveries and births with longer infant hospital stays increased. The reforms may not have been beneficial for quality obstetric care in Australia or the burden of Australian hospitals.

Cancer incidence and mortality trends in Australian adolescents and young adults, 1982-2007

BackgroundIncreasing incidence and lack of survival improvement in adolescents and young adults (AYAs) with cancer have led to increased awareness of the cancer burden in this population. The objective of this study was to describe overall and type-specific cancer incidence and mortality trends among AYAs in Western Australia from 1982–2007.MethodsAge–adjusted incidence and mortality rates were calculated for all malignancies combined and for each of the most common diagnostic groups, using five-year age–specific rates. Joinpoint regression analysis was used to derive annual percentage changes (APC) for incidence and mortality rates.ResultsThe annual incidence rate for all cancers combined increased in males from 1982 until 2000 (APC = 1.5%, 95%CI: 0.9%; 2.1%) and then plateaued, whilst rates for females remained stable across the study period (APC = −0.1%; 95%CI: −0.2%; 0.4%) across the study period. For males, significant incidence rate increases were observed for germ cell tumors, lymphoblastic leukemia and thyroid cancer. In females, the incidence of Hodgkin’s lymphoma, colorectal and breast cancers increased. Significant incidence rate reductions were noted for cervical, central nervous system and lung cancers. Mortality rates for all cancers combined decreased from 1982 to 2005 for both males (APC = −2.6%, 95%CI:−3.3%;−2.0%) and females (APC = −4.6%, 95%CI:−5.1%;−4.1%). With the exception of bone sarcoma and lung cancer in females, mortality rates for specific cancer types decreased significantly for both sexes during the study period.ConclusionsIncidence of certain AYA cancers increased, whilst it decreased for others. Mortality rates decreased for most cancers, with the largest improvement observed for breast carcinomas. Further research is needed to identify the reasons for the increasing incidence of certain cancers.

Comprehensive analysis of the ATM, CHEK2 and ERBB2 genes in relation to breast tumour characteristics and survival: a population-based case-control and follow-up study

BackgroundMutations in the ataxia-telangiectasia mutated (ATM) and checkpoint kinase 2 (CHEK2) genes and amplification of the v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) gene have been suggested to have an important role in breast cancer aetiology. However, whether common variation in these genes has a role in the development of breast cancer or breast cancer survival in humans is still not clear.MethodsWe performed a comprehensive haplotype analysis of the ATM, CHEK2 and ERBB2 genes in a Swedish population-based study, which included 1,579 breast cancer cases and 1,516 controls. We followed the cases for 8.5 years, on average, and retrieved information on the date and cause of death during that period from the nationwide Swedish causes of death registry. We selected seven haplotype-tagging SNPs (tagSNPs) in the ATM gene, six tagSNPs in the CHEK2 gene and seven tagSNPs in the ERBB2 gene that predicted both haplotypic and single locus variations in the respective genes with R2 values ≥ 0.8. These tagSNPs were genotyped in the complete set of cases and controls. We computed expected haplotype dosages of the tagSNP haplotypes and included the dosages as explanatory variables in Cox proportional hazards or logistic regression models.ResultsWe found no association between any genetic variation in the ATM, CHEK2 or ERBB2 genes and breast cancer survival or the risk of developing tumours with certain characteristics.ConclusionOur results indicate that common variants in the ATM, CHEK2 or ERBB2 genes are not involved in modifying breast cancer survival or the risk of tumour-characteristic-defined breast cancer.

Role of public and private funding in the rising caesarean section rate: a cohort study

Objective The caesarean section rates have been rising in the developed world for over two decades. This study assessed the involvement of the public and private health sectors in this increase. Design Population-based, retrospective cohort study. Setting Public and private hospitals in Western Australia. Participants Included in this study were 155 646 births to nulliparous women during 1996–2008. Main outcome measures Caesarean section rates were calculated separately for four patient type groups defined according to mothers’ funding source at the time of birth (public/private) and type of delivery hospital (public/private). The average annual per cent change (AAPC) for the caesarean section rates was calculated using joinpoint regression. Results Overall, there were 45 903 caesarean sections performed (29%) during the study period, 24 803 in-labour and 21 100 prelabour. Until 2005, the rate of caesarean deliveries increased most rapidly on average annually for private patients delivering in private hospitals (AAPC=6.5%) compared with public patients in public hospitals (AAPC=4.3%, p<0.0001). This increase could mostly be attributed to an increase in prelabour caesarean deliveries for this group of women and could not be explained by an increase in breech deliveries, placenta praevia or multiple pregnancies. Conclusions Our results indicate that an increase in the prelabour caesarean delivery rate for private patients in private hospitals has been driving the increase in the caesarean section rate for nulliparous women since 1996. Future research with more detailed information on indication for the prelabour caesarean section is needed to understand the reasons for these findings.

Improved long-term survival in patients on combination therapies following an incident acute myocardial infarction: a longitudinal population-based study

Objective To investigate the single and combined effectiveness of commonly prescribed secondary preventive medications (post-acute myocardial infarction (AMI)) in reducing overall all-cause mortality and by gender. Design Population-based longitudinal cohort study. Setting Western Australia, Australia. Participants 9580 individuals aged 65 years to 84 years who were admitted to hospital with their first AMI diagnosis between 1 January 1995 and 1 January 2006. Main outcome measures Time to death from any cause out to 11 years after first AMI, identified from registry data, was the primary outcome measure. Cardiovascular drugs dispensed within 28 days following hospital discharge were identified as main exposure categories. Results In total, 975 deaths occurred during 1 year follow-up, culminating to 3247 by 11 years. 1-year risk of death was significantly reduced for all drug combinations, but not for drugs dispensed in isolation. Out to 11 years, only combinations of ‘β-blockers and statins’ (with or without ACE inhibitors/angiotensin II receptor blockers (ACEi/ARB)) provided significant reductions in risk of all-cause mortality. In men, the greatest reduction in risk was associated with being dispensed ‘β-blockers and statins’ (HR 0.46, 95% CI 0.36 to 0.58), whereas women benefited most from being dispensed ‘β-blockers, statins and ACEi/ARBs’ (HR 0.77, 95% CI 0.60 to 0.99). Conclusions The combination of ‘β-blockers and statins’ (with or without ACEi/ARB) dispensed within 28 days postdischarge was associated with the greatest long-term survival following an AMI. Our observations of significantly reduced mortality risk in men (compared with women) who were dispensed ‘β-blockers and statins’, or ‘β-blockers and ACEi/ARBs’, warrants further investigation.

Adverse Obstetric and Perinatal Outcomes following Treatment of Adolescent and Young Adult Cancer: A Population-Based Cohort Study

Objective To investigate obstetric and perinatal outcomes among female survivors of adolescent and young adult (AYA) cancers and their offspring. Methods Using multivariate analysis of statewide linked data, outcomes of all first completed pregnancies (n = 1894) in female survivors of AYA cancer diagnosed in Western Australia during the period 1982–2007 were compared with those among females with no cancer history. Comparison pregnancies were matched by maternal age-group, parity and year of delivery. Results Compared with the non-cancer group, female survivors of AYA cancer had an increased risk of threatened abortion (adjusted relative risk 2.09, 95% confidence interval 1.51–2.74), gestational diabetes (2.65, 2.08–3.57), pre-eclampsia (1.32, 1.04–1.87), post-partum hemorrhage (2.83, 1.92–4.67), cesarean delivery (2.62, 2.22–3.04), and maternal postpartum hospitalization>5 days (3.01, 1.72–5.58), but no excess risk of threatened preterm delivery, antepartum hemorrhage, premature rupture of membranes, failure of labor to progress or retained placenta. Their offspring had an increased risk of premature birth (<37 weeks: 1.68, 1.21–2.08), low birth weight (<2500 g: 1.51, 1.23–2.12), fetal growth restriction (3.27, 2.45–4.56), and neonatal distress indicated by low Apgar score (<7) at 1 minute (2.83, 2.28–3.56), need for resuscitation (1.66, 1.27–2.19) or special care nursery admission (1.44, 1.13–1.78). Congenital abnormalities and perinatal deaths (intrauterine or ≤7 days of birth) were not increased among offspring of survivors. Conclusion Female survivors of AYA cancer have moderate excess risks of adverse obstetric and perinatal outcomes arising from subsequent pregnancies that may require additional surveillance or intervention.