Emily Banks

Epidemiology of breast cancer

Breast cancer is the commonest cause of cancer death in women worldwide. Rates vary about five-fold around the world, but they are increasing in regions that until recently had low rates of the disease. Many of the established risk factors are linked to oestrogens. Risk is increased by early menarche, late menopause, and obesity in postmenopausal women, and prospective studies have shown that high concentrations of endogenous oestradiol are associated with an increase in risk. Childbearing reduces risk, with greater protection for early first birth and a larger number of births; breastfeeding probably has a protective effect. Both oral contraceptives and hormonal therapy for menopause cause a small increase in breast-cancer risk, which appears to diminish once use stops. Alcohol increases risk, whereas physical activity is probably protective. Mutations in certain genes greatly increase breast-cancer risk, but these account for a minority of cases.

Evidence from randomised trials on the long-term effects of hormone replacement therapy

CONTEXT Over the past few decades hormone replacement therapy (HRT) has been used increasingly by post-menopausal women in western countries. The need for objective data on long-term effects prompted the setting up of randomised trials to compare cancer and cardiovascular disease endpoints in HRT users and non-users. With the early termination of part of the Womens Health Initiative trial (JAMA 2002; 288: 321-33), it is timely to review the evidence from such studies. STARTING POINT Four randomised trials including over 20000 women followed up for 4.9 years, on average, have now reported on the effect of HRT for major, potentially fatal, conditions. Overall, HRT users had a significantly increased incidence of breast cancer, stroke, and pulmonary embolism; a significantly reduced incidence of colorectal cancer and fractured neck of femur; but no significant change in endometrial cancer or coronary heart disease.There was no significant variation across the trials in the results for any condition. Three trials had recruited women with previous cardiovascular disease and the fourth, the Womens Health Initiative, had recruited healthy women. Combined oestrogen/progestagen HRT was used in three trials and oestrogen alone in one. Use of HRT over a 5-year period by healthy postmenopausal women in western countries is estimated to cause an extra breast cancer,stroke, or pulmonary embolus in about 6 per 1000 users aged 50-59 and 12 per 1000 aged 60-69. Over the same period, the estimated reduction in incidence of colorectal cancer or fractured neck of femur is 1.7 per 1000 users aged 50-59 and 5.5 per 1000 aged 60-69. The increased incidence of any one of these conditions is greater than any reduction, the estimated net excess over 5 years being 1 per 230 users aged 50-59, and 1 per 150 aged 60-69. WHERE NEXT Substantial new data should soon be available from randomised trials of oestrogen-alone HRT versus placebo, whereas few additional trial data on combined HRT are expected for about a decade. Existing randomised trials are too small to describe reliably the effect of HRT on important but rarer conditions, such as ovarian cancer, or on cause-specific mortality. Nor will they provide information about other types of oestrogen or progestagen. Answers to such questions will require judicious analysis and interpretation of data from observational studies.

Female genital mutilation and obstetric outcome: WHO collaborative prospective study in six African countries.

BACKGROUND Reliable evidence about the effect of female genital mutilation (FGM) on obstetric outcome is scarce. This study examines the effect of different types of FGM on obstetric outcome. METHODS 28 393 women attending for singleton delivery between November, 2001, and March, 2003, at 28 obstetric centres in Burkina Faso, Ghana, Kenya, Nigeria, Senegal, and Sudan were examined before delivery to ascertain whether or not they had undergone FGM, and were classified according to the WHO system: FGM I, removal of the prepuce or clitoris, or both; FGM II, removal of clitoris and labia minora; and FGM III, removal of part or all of the external genitalia with stitching or narrowing of the vaginal opening. Prospective information on demographic, health, and reproductive factors was gathered. Participants and their infants were followed up until maternal discharge from hospital. FINDINGS Compared with women without FGM, the adjusted relative risks of certain obstetric complications were, in women with FGM I, II, and III, respectively: caesarean section 1.03 (95% CI 0.88-1.21), 1.29 (1.09-1.52), 1.31 (1.01-1.70); postpartum haemorrhage 1.03 (0.87-1.21), 1.21 (1.01-1.43), 1.69 (1.34-2.12); extended maternal hospital stay 1.15 (0.97-1.35), 1.51 (1.29-1.76), 1.98 (1.54-2.54); infant resuscitation 1.11 (0.95-1.28), 1.28 (1.10-1.49), 1.66 (1.31-2.10), stillbirth or early neonatal death 1.15 (0.94-1.41), 1.32 (1.08-1.62), 1.55 (1.12-2.16), and low birthweight 0.94 (0.82-1.07), 1.03 (0.89-1.18), 0.91 (0.74-1.11). Parity did not significantly affect these relative risks. FGM is estimated to lead to an extra one to two perinatal deaths per 100 deliveries. INTERPRETATION Women with FGM are significantly more likely than those without FGM to have adverse obstetric outcomes. Risks seem to be greater with more extensive FGM.

Cohort profile: the 45 and up study.

In common with virtually all industrialized countries and many less developed nations, Australia is facing rapid population ageing. Historical patterns of fertility and migration, along with changes in life expectancy, mean that the over 65 age group is likely to increase by around 50% in the next 15–20 years. The further increase in the proportion of people in the very old age groups will result in the ‘ageing of the aged’. The challenges presented by the ageing of the population are far reaching. Discussions have tended to focus on its likely health and economic consequences; however, few aspects of society will remain unaffected by the issue. There is an urgent need for reliable evidence to inform policy to support healthy ageing. The concept of healthy ageing encompasses traditional ideas relating to freedom from disease, as well as broader considerations including independence, quality of life, management of disability, participation in society and the workforce and productivity. A wide range of factors are likely to affect health in later life, including socioeconomic, environmental and cultural variables, cigarette smoking, alcohol consumption, diet, physical activity, reproductive and hormonal factors, infections, availability of healthcare and use of pharmaceutical agents, as well as individuals’ susceptibility to disease. A comprehensive investigation of the determinants of healthy ageing must incorporate assessment of disease risk, quality of life and other indices, in relation to a very wide range of possible exposures, and with consideration of how these exposures might interact with one another. Research needs to be of a sufficient scale to provide specific information on the major diseases and health problems experienced in later life. This is because reliable assessments of risk factor–disease relationships require a substantial degree of pathological homogeneity of outcome and appropriate consideration of confounding. At the same time, research needs to be able to assess the broad risks and benefits of particular exposures, to allow meaningful conclusions to be reached about suitable public health interventions. Finally, it needs to be large and long term enough to track the impact of health interventions and policies at the population level. Australia has some unique characteristics that will impact on healthy ageing and provide particular challenges in delivering health care. For example, it has: a relatively heterogenous population with a large migrant community; an indigenous population with an average life expectancy 17 years less than for nonindigenous Australians; some remote and sparsely populated regions and a mixed health care system with responsibility shared between the national and state governments and delivery in both the public and private sectors. Excellent population-level databases relating to use of health services and medications, and registers of cancers and deaths, are available for statistical linkage with research data sets. There is therefore a need for research that addresses issues specific to the Australian population and makes use of the unique features of the Australian setting, giving the opportunity to provide insights of international relevance. The 45 and Up Study was conceived as a long-term collaborative resource to investigate healthy ageing, in response to the gaps in existing knowledge and the needs of researchers. Initial discussions among interested researchers resulted in the formation of a Scientific Steering Group in 2003 to oversee the development of the Study. The Study is auspiced by the Sax Institute, which also provided funding for its development. The Sax Institute is an independent organization with core funding from the state government of New South Wales, Australia’s most populous state. Its mission is to improve health through facilitating high-quality research and increasing the impact of this research on health policy and services; it has membership from y The Writing Committee is listed at the end of the report. For a list of the 45 and Up Study Collaborators please go to www.45andUp.org.au.

Body-mass index and all-cause mortality: Individual-participant-data meta-analysis of 239 prospective studies in four continents.

Summary Background Overweight and obesity are increasing worldwide. To help assess their relevance to mortality in different populations we conducted individual-participant data meta-analyses of prospective studies of body-mass index (BMI), limiting confounding and reverse causality by restricting analyses to never-smokers and excluding pre-existing disease and the first 5 years of follow-up. Methods Of 10 625 411 participants in Asia, Australia and New Zealand, Europe, and North America from 239 prospective studies (median follow-up 13·7 years, IQR 11·4–14·7), 3 951 455 people in 189 studies were never-smokers without chronic diseases at recruitment who survived 5 years, of whom 385 879 died. The primary analyses are of these deaths, and study, age, and sex adjusted hazard ratios (HRs), relative to BMI 22·5–<25·0 kg/m2. Findings All-cause mortality was minimal at 20·0–25·0 kg/m2 (HR 1·00, 95% CI 0·98–1·02 for BMI 20·0–<22·5 kg/m2; 1·00, 0·99–1·01 for BMI 22·5–<25·0 kg/m2), and increased significantly both just below this range (1·13, 1·09–1·17 for BMI 18·5–<20·0 kg/m2; 1·51, 1·43–1·59 for BMI 15·0–<18·5) and throughout the overweight range (1·07, 1·07–1·08 for BMI 25·0–<27·5 kg/m2; 1·20, 1·18–1·22 for BMI 27·5–<30·0 kg/m2). The HR for obesity grade 1 (BMI 30·0–<35·0 kg/m2) was 1·45, 95% CI 1·41–1·48; the HR for obesity grade 2 (35·0–<40·0 kg/m2) was 1·94, 1·87–2·01; and the HR for obesity grade 3 (40·0–<60·0 kg/m2) was 2·76, 2·60–2·92. For BMI over 25·0 kg/m2, mortality increased approximately log-linearly with BMI; the HR per 5 kg/m2 units higher BMI was 1·39 (1·34–1·43) in Europe, 1·29 (1·26–1·32) in North America, 1·39 (1·34–1·44) in east Asia, and 1·31 (1·27–1·35) in Australia and New Zealand. This HR per 5 kg/m2 units higher BMI (for BMI over 25 kg/m2) was greater in younger than older people (1·52, 95% CI 1·47–1·56, for BMI measured at 35–49 years vs 1·21, 1·17–1·25, for BMI measured at 70–89 years; pheterogeneity<0·0001), greater in men than women (1·51, 1·46–1·56, vs 1·30, 1·26–1·33; pheterogeneity<0·0001), but similar in studies with self-reported and measured BMI. Interpretation The associations of both overweight and obesity with higher all-cause mortality were broadly consistent in four continents. This finding supports strategies to combat the entire spectrum of excess adiposity in many populations. Funding UK Medical Research Council, British Heart Foundation, National Institute for Health Research, US National Institutes of Health.

Investigation of relative risk estimates from studies of the same population with contrasting response rates and designs

BackgroundThere is little empirical evidence regarding the generalisability of relative risk estimates from studies which have relatively low response rates or are of limited representativeness. The aim of this study was to investigate variation in exposure-outcome relationships in studies of the same population with different response rates and designs by comparing estimates from the 45 and Up Study, a population-based cohort study (self-administered postal questionnaire, response rate 18%), and the New South Wales Population Health Survey (PHS) (computer-assisted telephone interview, response rate ~60%).MethodsLogistic regression analysis of questionnaire data from 45 and Up Study participants (n = 101,812) and 2006/2007 PHS participants (n = 14,796) was used to calculate prevalence estimates and odds ratios (ORs) for comparable variables, adjusting for age, sex and remoteness. ORs were compared using Wald tests modelling each study separately, with and without sampling weights.ResultsPrevalence of some outcomes (smoking, private health insurance, diabetes, hypertension, asthma) varied between the two studies. For highly comparable questionnaire items, exposure-outcome relationship patterns were almost identical between the studies and ORs for eight of the ten relationships examined did not differ significantly. For questionnaire items that were only moderately comparable, the nature of the observed relationships did not differ materially between the two studies, although many ORs differed significantly.ConclusionsThese findings show that for a broad range of risk factors, two studies of the same population with varying response rate, sampling frame and mode of questionnaire administration yielded consistent estimates of exposure-outcome relationships. However, ORs varied between the studies where they did not use identical questionnaire items.

Energy balance and cancer: the role of sex hormones

Energy balance can affect the risk for hormone-related cancers by altering sex hormone levels. Energy intake and expenditure are difficult to measure in epidemiological studies, but a chronic excess of intake relative to expenditure leads to a high BMI, which can be accurately measured. In premenopausal women obesity has little effect on the serum concentration of oestradiol, but causes an increase in the frequency of anovular menstrual cycles and thus a reduction in progesterone levels; these changes lead to a large increase in the risk for endometrial cancer. but little change, or a small decrease, in the risk for breast cancer. In post-menopausal women oestradiol levels are not regulated by negative feedback, and obesity causes an increase in the serum concentration of bioavailable oestradiol; this factor causes increases in the risk for both endometrial cancer and breast cancer. The development of ovarian cancer appears to be related more strongly to the frequency of ovulation than to direct effects of circulating levels of sex hormones, and BMI is not clearly associated with the risk for ovarian cancer. In men, increasing BMI has little effect on bioavailable androgen levels, and any effect of obesity on prostate cancer risk is small.

High‐Risk Prescribing and Incidence of Frailty Among Older Community‐Dwelling Men

Evidence about the association between treatment with high–risk medicines and frailty in older individuals is limited. We investigated the relationship between high–risk prescribing and frailty at baseline, as well as 2–year incident frailty, in 1,662 men ≥70 years of age. High–risk prescribing was defined as polypharmacy (≥5 medicines), hyperpolypharmacy (≥10 medicines), and by the Drug Burden Index (DBI), a dose–normalized measure of anticholinergic and sedative medicines. At baseline, frail participants had adjusted odds ratios (ORs) of 2.55 (95% confidence interval, CI: 1.69–3.84) for polypharmacy, 5.80 (95% CI: 2.90–11.61) for hyperpolypharmacy, and 2.33 (95% CI: 1.58–3.45) for DBI exposure, as compared with robust participants. Of the 1,242 men who were robust at baseline, 6.2% developed frailty over two years. Adjusted ORs of incident frailty were 2.45 (95% CI: 1.42–4.23) for polypharmacy, 2.50 (95% CI: 0.76–8.26) for hyperpolypharmacy, and 2.14 (95% CI: 1.25–3.64) for DBI exposure. High–risk prescribing may contribute to frailty in community–dwelling older men.

Comparison of various characteristics of women who do and do not attend for breast cancer screening

BackgroundInformation regarding the characteristics and health of women who do and do not attend for breast cancer screening is limited and representative data are difficult to obtain.MethodsInformation on age, deprivation and prescriptions for various medications was obtained for all women at two UK general practices who were invited to breast cancer screening through the National Health Service Breast Screening Programme. The characteristics of women who attended and did not attend screening were compared.ResultsOf the 1064 women invited to screening from the two practices, 882 (83%) attended screening. Screening attenders were of a similar age to non-attenders but came from significantly less deprived areas (30% of attenders versus 50% of non-attenders came from the most deprived areas, P < 0.0001) and were more likely to have a current prescription for hormone replacement therapy (32% versus 19%, P < 0.0001). No significant differences in recent prescriptions of medication for hypertension, heart disease, hypercholesterolaemia, diabetes mellitus, asthma, thyroid disease or depression/anxiety were observed between attenders and non-attenders.ConclusionWomen who attend the National Health Service Breast Screening Programme come from less deprived areas and are more likely to have a current prescription for hormone replacement therapy than non-attenders, but do not differ in terms of age or recent prescriptions for various other medications.

Variability in vitamin D assays impairs clinical assessment of vitamin D status

Background:  Measuring serum 25(OH)D concentration is common in clinical practice despite the questionable reliability of assays.