Reproductive factors and specific histological types of breast cancer: prospective study and meta-analysis

Little is known about how reproductive factors affect the risk of breast cancers of different histology. In an analysis of prospective data on 1.2 million middle-aged UK women, we used proportional hazards models to estimate the relative risks of six histological types in relation to menarche, childbearing and menopause. During 8.7 million person-years of follow-up, 17 923 ductal, 3332 lobular, 1062 tubular, 944 mixed ductal lobular, 330 mucinous and 117 medullary cancers were diagnosed. The effect of both age at menarche and age at first birth was greatest for lobular tumours; relative risks per 5-year increase in age at menarche for ductal, lobular, and tubular cancers were 0.93 (0.87–0.99), 0.65 (0.56–0.76), and 0.75 (0.57–0.98), respectively (P-value for heterogeneity=0.0001); and the relative risks per 5-year increase in age at first birth were 1.10 (1.07–1.12), 1.23 (1.17–1.29), and 1.13 (1.03–1.23), respectively (P-value for heterogeneity=0.0006). Increasing parity reduced the risk of each tumour type, except medullary cancers, but the reduction in risk was greater for mucinous cancers than for any other subtype considered (P<0.05 for comparison with each other subtype in turn). The effect of menopause did not vary significantly by tumour histology. Meta-analysis of published results on the effects of age at menarche and age at first birth on ductal and lobular cancers were in keeping with our findings

Breast cancer histological classification: agreement between the Office for National Statistics and the National Health Service Breast Screening Programme

INTRODUCTION: Epidemiological studies rely on data supplied by central cancer registration sources to be timely, accurate and complete. Validation studies of such data at a national level are limited. Data collected for the Million Women Study was used to compare the level of agreement between the Office for National Statistics (ONS) and the National Health Service Breast Screening Programme (NHSBSP) in the recording of incident screen-detected breast cancer histology between 1996 and 2001. METHODS: 1.3 million women aged 50 to 64 years were recruited into the Million Women Study cohort via the NHSBSP. Incident screen-detected breast cancer histologies were notified separately by the ONS and NHSBSP. ICD-10 and ICD-02 ONS codes and NHSBSP histology data were similarly coded to allow for comparison in terms of cancer invasiveness and morphology. The statistical outcome measures are percentage agreement and the kappa statistic. RESULTS: A total of 5,886 incident screen-detected breast cancers were available for analysis. Of the 5,886 screen-detected cancers reported by the ONS and NHSBSP, 5,684 (96.6%, κ = 0.9) agreed in terms of the degree of invasiveness. Of the 5,458 cancers that had been assigned a specific morphology code, there was exact agreement between the ONS and the NHSBSP in 4,922 cases (90.2%, κ = 0.8). CONCLUSION: There is an excellent level of agreement between the ONS and NHSBSP in the recording of the histology of screen-detected breast cancer. From these results it is not possible to comment on which source of data is the more or less accurate, although the differences are very small

Recent declines in breast cancer incidence: mounting evidence that reduced use of menopausal hormones is largely responsible

Substantial reductions in breast cancer incidence in women 50 years old or older have been observed recently in many developed countries, and falling use of menopausal hormone therapy (HT) remains the most plausible explanation. In keeping with recent observations from the Women's Health Initiative, a report from the California Teachers Study cohort in this issue of Breast Cancer Research adds to this growing evidence. The investigators found a 26% reduction in invasive breast cancer in the cohort from 2000-2002 to 2003-2005, which accompanied an estimated 64% drop in HT use between 2000-2001 and 2005-2006. By collating individual data on the use of HT and breast cancer incidence, they also demonstrated that the decline in incidence was concentrated in women who had ceased HT use. The decline reflected a decrease predominantly in oestrogen receptor-positive tumours in the context of stable screening patterns over the study period. Millions of women continue to use HT, and these findings support carefully targeted short duration use as an important ongoing strategy to minimise breast cancer risk

Breast cancer risk associated with different HRT formulations: a register-based case-control study

BACKGROUND: Previous epidemiological studies have inconsistently shown a modestly increased breast cancer risk associated with hormone replacement therapy (HRT). Limited information is available about different formulations – particularly concerning different progestins. METHODS: A case-control study was performed within Germany in collaboration with regional cancer registries and tumor centers. Up to 5 controls were matched breast cancer cases. Conditional logistic regression analysis was applied to estimate crude and adjusted odds ratios (OR) and 95% confidence intervals (95% CI). Stratified analyses were performed to compare the risk of different estrogens, progestins, and combinations. RESULTS: A total of 3593 cases of breast cancer were identified and compared with 9098 controls. The adjusted overall risk estimate for breast cancer (BC) associated with current or past use of HRT was 1.2 (1.1–1.3), and almost identical for lag times from 6 months to 6 years prior to diagnosis. No significant trend of increasing BC risk was found with increasing duration of HRT use, or time since first or last use in aggregate. Many established BC risk factors significantly modified the effect of HRT on BC risk, particularly first-degree family history of BC, higher age, lower education, higher body mass index (BMI), and never having used oral contraceptives (OCs) during lifetime. Whereas the overall risk estimates were stable, the numbers in many of the sub-analyses of HRT formulation groups (estrogens, progestins, and combinations) were too small for strong conclusions. Nevertheless, the BC risk seems not to vary much across HRT formulation subgroups. In particular, no substantial difference in BC risk was observed between HRT containing conjugated equine estrogens (CEE) or medroxyprogesterone acetate (MPA) and other formulations more common in Europe. CONCLUSION: The BC risk of HRT use is rather small. Low risk estimates for BC and a high potential for residual confounding and bias in this observational study do not permit causal conclusions. Apparently, there is not much variation of the BC risk across HRT formulations (estrogens, progestins). However, the small numbers and the overlapping nature of some of the subgroups suggest cautious interpretation

The Women's international study of long-duration oestrogen after menopause (WISDOM): a randomised controlled trial

BACKGROUND: At the time of feasibility work and final design of the trial there was no randomised control trial evidence for the long-term risks and benefits of hormone replacement therapy. Observational studies had suggested that long term use of estrogen was likely to be associated, amongst other things, with reduced risks of osteoporosis and ischaemic heart disease and increased risks of breast and endometrial cancer. Concomitant use of progestogens had been shown to protect against endometrial cancer, but there were few data showing how progestogen might affect estrogen actions on other conditions. Disease specific risks from observational studies suggested that, overall, long-term HRT was likely to be beneficial. Several studies showed that mortality from all causes was lower in HRT users than in non-users. Some secondary cardiovascular prevention trials were ongoing but evidence was also required for a range of outcomes in healthy women. The WISDOM trial was designed to compare combined estrogen and progestogen versus placebo, and estrogen alone versus combined estrogen and progestogen. During the development of WISDOM the Women's Health Initiative trial was designed, funded and started in the US. DESIGN: Randomised, placebo, controlled, trial. METHODS: The trial was set in general practices in the UK (384), Australia (94), and New Zealand (24). In these practices 284175 women aged 50–69 years were registered with 226282 potentially eligible. We sought to randomise 22300 postmenopausal women aged 50 – 69 and treat for ten years. The interventions were: conjugated equine estrogens, 0.625 mg orally daily; conjugated equine estrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily; matched placebo. Primary outcome measures were: major cardiovascular disease, osteoporotic fractures, breast cancer and dementia. Secondary outcomes were: other cancers, all cause death, venous thromboembolism and cerebro-vascular disease. RESULTS: The trial was prematurely closed during recruitment following publication of early results from the Women's Health Initiative. At the time of closure, 56583 had been screened, 8980 entered run-in, and 5694 (26% of target of 22,300) randomised. Those women randomised had received a mean of one year of therapy, mean age was 62.8 years and total follow-up time was 6491 person years. DISCUSSION: The WISDOM experience leads to some simple messages. The larger a trial is the more simple it needs to be to ensure cost effective and timely delivery. When a trial is very costly and beyond the resources of one country, funders and investigators should make every effort to develop international collaboration with joint funding

Lifetime body size and reproductive factors: comparisons of data recorded prospectively with self reports in middle age

<p>Abstract</p> <p>Background</p> <p>Data on lifetime exposures are often self-reported in epidemiologic studies, sometimes many years after the relevant age. Validity of self-reported data is usually inferred from their agreement with measured values, but few studies directly quantify the likely effects of reporting errors in body size and reproductive history variables on estimates of disease-exposure associations.</p> <p>Methods</p> <p>The MRC National Survey of Health and Development (NSHD) and the Million Women Study (MWS) are UK population-based prospective cohorts. The NSHD recruited participants at birth in 1946 and has followed them at regular intervals since then, whereas the MWS recruited women in middle age. For 541 women who were participants in both studies, we used statistical measures of association and agreement to compare self-reported MWS data on body size throughout life and reproductive history, obtained in middle age, to NSHD data measured or reported close to the relevant ages. Likely attenuation of estimates of linear disease-exposure associations due to the combined effects of random and systematic errors was quantified using regression dilution ratios (RDRs).</p> <p>Results</p> <p>Data from the two studies were very strongly correlated for current height, weight and body mass index, and age at menopause (Pearson r = 0.91-0.95), strongly correlated for birth weight, parental heights, current waist and hip circumferences and waist-to-height ratio (r = 0.67-0.80), and moderately correlated for age at menarche and waist-to-hip ratio (r = 0.52-0.57). Self-reported categorical body size and clothes size data for various ages were moderately to strongly associated with anthropometry collected at the relevant times (Spearman correlations 0.51-0.79). Overall agreement between the studies was also good for most quantitative variables, although all exhibited both random and systematic reporting error. RDRs ranged from 0.66 to 0.86 for most variables (slight to moderate attenuation), except weight and body mass index (1.02 and 1.04, respectively; little or no attenuation), and age at menarche, birth weight and waist-to-hip ratio (0.44, 0.59 and 0.50, respectively; substantial attenuation).</p> <p>Conclusions</p> <p>This study provides some evidence that self-reported data on certain anthropometric and reproductive factors may be adequate for describing disease-exposure associations in large epidemiological studies, provided that the effects of reporting errors are quantified and the results are interpreted with caution.</p

Body mass index and use and costs of primary care services among women aged 55-79 years in England: a cohort and linked data study.

BACKGROUND: Excess weight is associated with poor health and increased healthcare costs. There are no reliable data describing the association between BMI and the use and costs of primary care services in the United Kingdom. METHODS: Among 69,440 participants in the Million Women Study with primary care records in the Clinical Practice Research Datalink between April 2006 (mean age 64 years) and March 2014, the annual rates and costs of their primary care consultations, prescription medications, and diagnostic and monitoring tests were estimated in relation to their self-reported body mass index (BMI) at recruitment in 1996-2001 (mean age 56 years). Associations of BMI with annual costs were projected to all women in England aged 55-79 years in 2013. RESULTS: Over an average follow-up of 6.0 years, annual rates and mean costs were lowest for women with a BMI of 20 to <22.5 kg/m2 for consultations (7.0 consultations, 99% CI 6.8-7.1; £288, £280-£295) and prescription medications (27.0 prescribed items, 26.0-27.9; £227, £216-£237). Above 20 kg/m2, a 2 kg/m2 higher BMI (a 5 kg change in weight for a woman of average height) was associated with 5.2% (4.8-5.6) and 9.9% (9.2-10.6) higher mean annual consultation and prescription medication costs, respectively. Annual rates and mean costs of diagnostic and monitoring tests were similar for women with different BMIs. Among all women aged 55-79 years in England, excess weight accounted for an estimated 11% (£229 million/£2.2 billion) of all consultation costs and 20% (£384 million/£1.9 billion) of all prescription medication costs, of which 27% were for diabetes drugs, 19% for circulatory system drugs, and 13% for analgesics. CONCLUSIONS: Excess body weight is associated with higher use and costs of primary care services among women in England. Reducing the prevalence of excess weight could improve the health of women and reduce pressures on primary care.Cancer Research UK (grant C570/A16491); Medical Research Council (grant MR/K02700X/1)