Search

Background Current or recent use of combined oral contraceptives (containing oestrogen+progestagen) has been associated with a small increase in breast cancer risk. Progestagen-only contraceptive use is increasing, but information on associated risks is limited. We aimed to assess breast cancer risk associated with current or recent use of different types of hormonal contraceptives in premenopausal women, with particular emphasis on progestagen-only preparations. Methods and findings Hormonal contraceptive prescriptions recorded prospectively in a UK primary care database (Clinical Practice Research Datalink [CPRD]) were compared in a nested case–control study for 9,498 women aged Overall, 44% (4,195/9,498) of women with breast cancer and 39% (7,092/18,171) of matched controls had a hormonal contraceptive prescription an average of 3.1 (SD 3.7) years before breast cancer diagnosis (or equivalent date for controls). About half the prescriptions were for progestagen-only preparations. Breast cancer ORs were similarly and significantly raised if the last hormonal contraceptive prescription was for oral combined, oral progestagen-only, injected progestagen, or progestagen-releasing intrauterine devices (IUDs): ORs = 1.23 (95% CI [1.14 to 1.32]; p < 0.001), 1.26 (95% CI [1.16 to 1.37]; p < 0.001), 1.25 (95% CI [1.07 to 1.45]; p = 0.004), and 1.32 (95% CI [1.17 to 1.49]; p < 0.001), respectively. Our meta-analyses yielded significantly raised relative risks (RRs) for current or recent use of progestagen-only contraceptives: oral = 1.29 (95% CI [1.21 to 1.37]; heterogeneity χ25 = 6.7; p = 0.2), injected = 1.18 (95% CI [1.07 to 1.30]; heterogeneity χ28 = 22.5; p = 0.004), implanted = 1.28 (95% CI [1.08 to 1.51]; heterogeneity χ23 = 7.3; p = 0.06), and IUDs = 1.21 (95% CI [1.14 to 1.28]; heterogeneity χ24 = 7.9; p = 0.1). When the CPRD results were combined with those from previous published findings (which included women from a wider age range), the resulting 15-year absolute excess risk associated with 5 years use of oral combined or progestagen-only contraceptives in high-income countries was estimated at: 8 per 100,000 users from age 16 to 20 years and 265 per 100,000 users from age 35 to 39 years. The main limitation of the study design was that, due to the nature of the CPRD data and most other prescription databases, information on contraceptive use was recorded during a defined period only, with information before entry into the database generally being unavailable. This means that although our findings provide evidence about the short-term associations between hormonal contraceptives and breast cancer risk, they do not provide information regarding longer-term associations, or the impact of total duration of contraceptive use on breast cancer risk. Conclusions This study provides important new evidence that current or recent use of progestagen-only contraceptives is associated with a slight increase in breast cancer risk, which does not appear to vary by mode of delivery, and is similar in magnitude to that associated with combined hormonal contraceptives. Given that the underlying risk of breast cancer increases with advancing age, the absolute excess risk associated with use of either type of oral contraceptive is estimated to be smaller in women who use it at younger rather than at older ages. Such risks need be balanced against the benefits of using contraceptives during the childbearing years.

Background In 2006, the Bowel Cancer Screening Programme (BCSP) in England began offering biennial faecal occult blood testing (FOBt) at ages 60–69 years. Although FOBt is aimed at detecting colorectal neoplasms, other conditions can affect the result. In a large UK prospective study, we examined associations, both before and after screening, between FOBt positivity and 10 conditions that are often associated with gastrointestinal bleeding. Methods By electronically linking BCSP and Million Women Study records, we identified 604 495 women without previous colorectal cancer who participated in their first routine FOBt screening between 2006 and 2012. Regression models, using linked national hospital admission records, yielded adjusted relative risks (RRs) in FOBt-positive versus FOBt-negative women for colorectal cancer, adenoma, diverticular disease, inflammatory bowel disease, haemorrhoids, upper gastrointestinal cancer, oesophagitis, peptic ulcer, anaemia and other haematological disorders. Results RRs in FOBt-positive versus FOBt-negative women were 201.3 (95% CI 173.8–233.2) for colorectal cancer and 197.9 (95% CI 180.6–216.8) for adenoma within 12 months after screening and 3.49 (95% CI 2.31–5.26) and 4.88 (95% CI 3.80–6.26), respectively, 12–24 months after screening; P

Reported associations between coffee consumption and an increased risk of pancreatic cancer could be due to residual confounding by smoking and/or biased recall of coffee consumption in retrospective studies. Studying associations prospectively in never smokers should minimise these problems, but thus far such studies have included relatively small numbers of cases. In this study, 309,797 never‐smoking women self‐reported typical daily coffee consumption at a mean age of 59.5 years (SD 5.0 years) and were followed up for a median of 13.7 years (IQR: 12.2‐14.9) through record linkage to national health cancer and death registries. During this period, 962 incident cases of pancreatic cancers were registered. Cox regression was used to calculate adjusted relative risks [RRs] of incident pancreatic cancer with 95% confidence intervals [CIs] in relation to coffee consumption at baseline. After adjustment for potential confounding factors, including body mass index and alcohol consumption, RRs of pancreatic cancer in never‐smokers who reported usually consuming 1‐2, 3‐4, and ≥5 cups of coffee daily, compared to non‐drinkers of coffee, were 1.02 (CI 0.83–1.26), 0.96 (0.76–1.22), and 0.87 (0.64–1.18), respectively (trend p=0.2). A meta‐analysis of results from this cohort and 3 smaller prospective studies found little or no statistically significant association between coffee consumption and pancreatic cancer risk in never smokers (summary RR=1.00, CI 0.86‐1.17 for ≥2 versus zero cups of coffee per day).

Background The role of diet in breast cancer aetiology is unclear; recent studies have suggested associations may differ by estrogen receptor status. Methods Baseline diet was assessed in 2000–04 using a validated questionnaire in 691 571 postmenopausal UK women without previous cancer, who had not changed their diet recently. They were followed by record linkage to national cancer and death databases. Cox regression yielded adjusted relative risks for breast cancer for 10 food items and eight macronutrients, subdivided mostly into five categories of baseline intake. Trends in risk across the baseline categories were calculated, assigning re-measured intakes to allow for measurement error and changes in intake over time; P-values allowed for multiple testing. Results Women aged 59.9 (standard deviation (SD 4.9)) years at baseline were followed for 12 (SD 3) years; 29 005 were diagnosed with invasive breast cancer. Alcohol intake had the strongest association with breast cancer incidence: relative risk (RR) 1.08 [99% confidence interval (CI) 1.05–1.11] per 10 g/day higher intake, P = 5.8 × 10−14. There were inverse associations with fruit: RR 0.94 (99% CI 0.92–0.97) per 100 g/day higher intake, P = 1.1 × 10−6, and dietary fibre: RR 0.91 (99% CI 0.87–0.96) per 5 g/day increase, P = 1.1 × 10−4. Fruit and fibre intakes were correlated (ρ = 0.62) and were greater among women who were not overweight, so residual confounding cannot be excluded. There was no heterogeneity for any association by estrogen receptor status. Conclusions By far the strongest association was between alcohol intake and an increased risk of breast cancer. Of the other 17 intakes examined, higher intakes of fruit and fibre were associated with lower risks of breast cancer, but it is unclear whether or not these associations are causal.

Introduction Published findings on the associations between smoking and the incidence of cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are inconsistent. We aimed to generate prospective evidence on these relationships, overall and by anatomical site. Methods We followed 1,223,626 women without prior cancer by electronic linkage to national cancer registration data. Questionnaire information about smoking and other factors was recorded at recruitment (1996-2001) and every 3-5 years subsequently. Cox regression yielded adjusted relative risks (RRs) comparing smokers versus never-smokers. Results After 14 (SD4) years follow-up per woman, 6699 had a first registered cutaneous SCC and 48,666 a first BCC. In current versus never-smokers, SCC incidence was increased (RR=1.22, 95%CI 1.15-1.31) but BCC incidence was decreased (RR=0.80, 0.78-0.82). RRs varied substantially by anatomical site; for the limbs, current smoking was associated with an increased incidence of SCC (1.55, 1.41-1.71) and a decreased incidence of BCC (0.72, 0.66-0.79), but for facial lesions there was little association of current smoking with either SCC (0.93, 0.82-1.06) or BCC (0.92, 0.88-0.96). Findings in meta-analyses of results from this and 7 other prospective studies were largely dominated by the findings in this study. Conclusion Smoking-associated risks for cutaneous SCC and BCC are opposite to each other, and may vary by anatomical site.

Objective: To compare associations of behavioural and related factors for incident subarachnoid and intracerebral haemorrhage and ischaemic stroke. Methods: 712,433 Million Women Study participants without prior stroke, heart disease or cancer reported behavioural and related factors at baseline (1999-2007) and were followed by record linkage to national hospital admission and death databases. Cox regression yielded adjusted relative risks (RRs) by type of stroke. Heterogeneity was assessed using chi-squared tests. Where appropriate, meta-analyses were done of published prospective studies. Results: After 12.9 (SD 2.6) years follow-up, 8128 women had an incident ischaemic stroke, 2032 intracerebral haemorrhage and 1536 subarachnoid haemorrhage. In women with diabetes, risk of ischaemic stroke was substantially increased (RR=2.01; 95% CI 1.84-2.20), intracerebral haemorrhage slightly increased (RR=1.31; 1.04-1.65) but subarachnoid haemorrhage reduced (RR=0.43; 0.26-0.69) (heterogeneity by stroke type, pConclusions: Classic risk factors for stroke have considerably different effects on the three main pathological types of stroke.

Ovarian cancer risk is known to be reduced amongst women who have had children, but reported associations with breastfeeding are varied. Few studies have had sufficient power to explore reliably these associations by tumour histotype. In a prospective study of 1.1 million UK women, 8719 developed ovarian cancer during follow-up. Cox regression yielded adjusted relative risks (RRs) overall and by tumour histotype amongst women with different childbearing patterns. Nulliparous women had a 24% greater ovarian cancer risk than women with one child, with significant heterogeneity by histotype (p=0.01). There was no significant increase in serous tumours, a modest increase in mucinous tumours, but a substantial increase in endometrioid (RR=1.49, 95% CI: 1.18-1.89) and clear-cell tumours (RR=1.68, 1.29-2.20). Among parous women, each additional birth was associated with an overall 6% reduction in ovarian cancer risk; this association also varied by histotype (p=0.0006), with the largest reduction in risk for clear-cell tumours (RR per birth=0.75, 0.65-0.85, p In this large prospective study, ovarian cancer risk associated with parity varied substantially by tumour histotype. Nulliparity was associated with a substantially greater overall risk than expected from the effect of a single birth, especially for clear cell and endometrioid tumours, perhaps suggesting that infertility is associated with these histotypes.

BACKGROUND: Some carcinogenic viruses are known to be transmissible by blood transfusion. Intensive viral screening of transfused blood now exists in most countries. In the UK, high-sensitivity nucleic acid amplification tests for hepatitis C virus were introduced in 1999 and it was thought that this would reduce, and possibly eliminate, transfusion-related liver cancer. We aimed to investigate cancer risk in recipients of blood transfusion in 2000 or after. METHODS: A total of 1.3 million UK women recruited in 1998 on average were followed for hospital records of blood transfusion and for cancer registrations. After excluding women with cancer or precancerous conditions before or at the time of transfusion, Cox regression yielded adjusted relative risks of 11 site-specific cancers for women with compared to without prior blood transfusion. RESULTS: During follow up, 11 274 (0.9%) women had a first recorded transfusion in 2000 or after, and 1648 (14.6%) of them were subsequently diagnosed with cancer, a mean 6.8 years after the transfusion. In the first 5 years after transfusion there were significant excesses for most site-specific cancers examined, presumably because some had preclinical cancer. However, 5 or more years (mean 8 years) after blood transfusion, there were significant excess risks only for liver cancer (adjusted relative risk = 2.63, 95%CI 1.45-4.78) and for non-Hodgkin lymphoma (adjusted relative risk = 1.74, 1.21-2.51). When analyses were restricted to those undergoing hip or knee replacement surgery, the commonest procedure associated with transfusion, these relative risks were not materially altered. CONCLUSIONS: In a large cohort of UK women, transfusions in the 21st century were associated with long-term increased risks of liver cancer and non-Hodgkin lymphoma. Some of these malignancies may have been caused by carcinogenic agents that are not currently screened for in transfused blood.

Background: Some viruses are known to be transmissible by blood transfusion. Intensive viral screening of transfused blood now exists in most countries. In the UK, high-sensitivity nucleic acid amplification tests for hepatitis C virus were introduced in 1999 and it was thought that this would reduce, and possibly eliminate, transfusion-related liver cancer. We aimed to investigate cancer risk in recipient of blood transfusion in 2000 or after. Methods: 1.3 million UK women recruited in 1998, on average, were followed for hospital records of blood transfusion and for cancer registrations. After excluding women with cancer or precancerous conditions before or at the time of transfusion, Cox regression yielded adjusted relative risks of 11 site-specific cancers for women with compared to without prior blood transfusion. Results: During follow up, 11,274 (0.9%) women had a first recorded transfusion in 2000 or after, and 1648 (14.6%) of them were subsequently diagnosed with cancer, a mean 6.8 years after the transfusion. In the first 5 years after transfusion there were, as expected, significant excesses for most site-specific cancers examined, presumably because some had preclinical cancer. However, 5 or more years (mean 8 years) after blood transfusion there were significant excess risks only for liver cancer (relative risk=2.63, 95%CI 1.45-4.78) and for non-Hodgkin lymphoma (relative risk=1.74, 1.21-2.51). When analyses were restricted to those undergoing hip or knee replacement surgery, the commonest procedure associated with transfusion, these risks were not materially altered. Conclusions: In a large cohort of UK women, 21st century transfusions were associated with long-term increased risks of liver cancer and non-Hodgkin lymphoma. These findings suggest that some cases of liver cancer and non-Hodgkin lymphoma are caused by carcinogenic agents that are not currently screened for in transfused blood.

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 the prospective studies of body mass index (BMI), limiting confounding and reverse causality by restricting analyses to never-smokers and excluding prior disease and the first 5 years of follow- up. Methods: Of 10,625,411 participants in Asia, Australia/New Zealand, Europe, and North America from 239 prospective studies (median follow-up 13·7 [IQR: 11·4-14·7] years), 3,951,455 in 189 studies were never-smokers without specific chronic diseases at recruitment who survived 5 years, of whom 385,879 died. The primary analyses are of these deaths, using age and sex-adjusted hazard ratios (HRs). Findings: All-cause mortality was minimal (HR=1) at BMI (kg/m2) 20-25, and increased significantly both just below this range (BMI 18·5-25, mortality increased approximately log-linearly with BMI; HR per 5 units higher BMI was 1·31 (1·29-1·33) in all regions; 1·39 (1·35-1·43) 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/New Zealand. This HR per 5 units higher BMI (for BMI>25) was greater in younger than older people (1.52 at 35–49 years vs 1·21 at 70-89 years; PheterogeneityInterpretation: The associations of both overweight and obesity with higher all-cause mortality were broadly consistent in four continents. This supports strategies to combat the entire spectrum of excess adiposity in many populations.

Objective: To determine whether transdermal compared with oral use of hormone replacement therapy reduces the risk of gallbladder disease in postmenopausal women. Design: Prospective cohort study (Million Women Study). Setting: Women registered with the National Health Service (NHS) in England and Scotland. Participants: 1 001 391 postmenopausal women (mean age 56) recruited between 1996 and 2001 from NHS breast screening centres and followed by record linkage to routinely collected NHS hospital admission data for gallbladder disease. Main outcome measures: Adjusted relative risk and standardised incidence rates of hospital admission for gallbladder disease or cholecystectomy according to use of hormone replacement therapy. Results: During follow-up 19 889 women were admitted for gallbladder disease; 17 190 (86%) had a cholecystectomy. Compared with never users of hormone replacement therapy, current users were more likely to be admitted for gallbladder disease (relative risk 1.64, 95% confidence interval 1.58 to 1.69) but risks were substantially lower with transdermal therapy than with oral therapy (relative risk 1.17, 1.10 to 1.24 v 1.74, 1.68 to 1.80; heterogeneity P0.625 mg, 1.91 (1.78 to 2.04) v ≤0.625 mg, 1.76 (1.68 to 1.84); heterogeneity P=0.02; estradiol >1 mg, 1.68 (1.59 to 1.77) v

Objective: To identify risk factors for cataracts treated surgically in post-menopausal women. Design: Population-based, prospective cohort study. Participants: A total of 1,312,051 post-menopausal women in the UK Million Women Study, aged 56 years on average (SD 4.8), without previous cataract surgery, hospital admission with cataracts or cancer at baseline, were followed for cataracts treated surgically. Methods: Cox regression was used to calculate adjusted relative risks (RRs) for cataract surgery by lifestyle factors, treatment for diabetes, reproductive history and use of hormonal therapies. Main outcome measures: Cataract surgery identified by linkage to central National Health Service records for in-patient and day-patient admissions (Hospital Episode Statistics for England and Scottish Morbidity Records in Scotland). Results: Overall, 89,343 women underwent cataract surgery during an average of 11 (SD 3) years of follow-up. Women with diabetes were at greatest risk (diabetes vs no diabetes RR = 2.90, 95% CI 2.82-2.97). Other factors associated with an increased risk of cataract surgery were: current smoking (current smokers of >=15 cigarettes/day vs never smokers RR = 1.26, 95% CI 1.23-1.30) and obesity (BMI >=30 vs Conclusions: Diabetes, smoking and obesity were risk factors for cataract surgery. Alcohol use, physical activity, reproductive history and use of hormonal therapies had little, if any, association with cataract surgery risk.

Histopathological and molecular studies suggest that different histological subtypes (histotypes) of ovarian cancer have different aetiologies. Few studies have been large enough to explore reliably the effect of tubal ligation (sterilization), which has been associated with a reduced overall risk of ovarian cancer, on different tumour histotypes. In a prospective study of 1.1 million UK women without prior cancer or bilateral oophorectomy, 8,035 ovarian cancers occurred during mean follow‐up of 13.8 years. Using a Cox proportional hazards model, we estimated adjusted relative risks of ovarian cancer associated with tubal ligation. Overall, there was substantial heterogeneity in tumour risk associated with tubal ligation for the four main histotypes, serous, endometrioid, mucinous and clear cell (heterogeneity: p