HRT: a reappraisal of the risks and benefits

The document attached has been archived with permission from the editor of the Medical Journal of Australia. An external link to the publisher’s copy is included.In 2002, when results of the Women's Health Initiative (WHI) randomised controlled trial of hormone replacement therapy (HRT) showed an increased occurrence of breast cancer and thromboembolism, up to two-thirds of women taking HRT stopped the therapy, often without medical consultation. Recent analyses of the WHI data and other randomised controlled trials suggest that, although there are potential side effects and risks involved in taking HRT, these may be reduced by: using lower HRT doses; minimising or eliminating systemic progestogens; using non-oral routes in some women; and initiating HRT in symptomatic women near menopause. When HRT is initiated near menopause for symptom control, there may be additional benefits (reduced fracture and cardiovascular risk) that outweigh the risks (which are not significantly raised in women under age 60 years). Older women with continuing symptoms should not be denied HRT if their therapy and risks are assessed on an individual basis and each patient is aware of the risks.Alastair H MacLenna

Association between Common Variation in 120 Candidate Genes and Breast Cancer Risk

Association studies in candidate genes have been widely used to search for common low penetrance susceptibility alleles, but few definite associations have been established. We have conducted association studies in breast cancer using an empirical single nucleotide polymorphism (SNP) tagging approach to capture common genetic variation in genes that are candidates for breast cancer based on their known function. We genotyped 710 SNPs in 120 candidate genes in up to 4,400 breast cancer cases and 4,400 controls using a staged design. Correction for population stratification was done using the genomic control method, on the basis of data from 280 genomic control SNPs. Evidence for association with each SNP was assessed using a Cochran–Armitage trend test (p-trend) and a two-degrees of freedom χ(2) test for heterogeneity (p-het). The most significant single SNP (p-trend = 8 × 10(−5)) was not significant at a nominal 5% level after adjusting for population stratification and multiple testing. To evaluate the overall evidence for an excess of positive associations over the proportion expected by chance, we applied two global tests: the admixture maximum likelihood (AML) test and the rank truncated product (RTP) test corrected for population stratification. The admixture maximum likelihood experiment-wise test for association was significant for both the heterogeneity test (p = 0.0031) and the trend test (p = 0.017), but no association was observed using the rank truncated product method for either the heterogeneity test or the trend test (p = 0.12 and p = 0.24, respectively). Genes in the cell-cycle control pathway and genes involved in steroid hormone metabolism and signalling were the main contributors to the association. These results suggest that a proportion of SNPs in these candidate genes are associated with breast cancer risk, but that the effects of individual SNPs is likely to be small. Large sample sizes from multicentre collaboration will be needed to identify associated SNPs with certainty

Active and passive smoking and the risk of breast cancer in women aged 36–45 years: a population based case–control study in the UK

Active smoking has little or no effect on breast cancer risk but some investigators have suggested that passive smoking and its interaction with active smoking may be associated with an increased risk. In a population based case–control study of breast cancer in women aged 36–45 years at diagnosis, information on active smoking, passive smoking in the home, and other factors, was collected at interview from 639 cases and 640 controls. Women were categorised jointly by their active and passive smoking exposure. Among never smoking controls, women who also reported no passive smoking exposure were significantly more likely to be nulliparous and to be recent users of oral contraceptives. Among those never exposed to passive smoking, there was no significant association between active smoking and breast cancer, relative risk (RR) of 1.12 (95% confidence interval (CI) 0.72–1.73) for past smokers and RR of 1.19 (95% CI 0.72–1.95) for current smokers, nor was there an association with age started, duration or intensity of active smoking. Compared with women who were never active nor passive smokers, there was no significant association between passive smoking in the home and breast cancer risk in never smokers, RR of 0.89 (95% CI 0.64–1.25), in past smokers, RR of 1.09 (95% CI 0.75–1.56), or in current smokers, RR of 0.93 (95% CI 0.67–1.30). There was no trend with increasing duration of passive smoking and there was no heterogeneity among any of the subgroups examined. In this study, there was no evidence of an association between either active smoking or passive smoking in the home and risk of breast cancer

An investigation of breast cancer risk factors in Cyprus: a case control study

Background: Breast cancer is the most common form of malignancy affecting women worldwide. It is also the leading cancer in females in Cyprus, with approximately 400 new cases diagnosed annually. It is well recognized that genetic variation as well as environmental factors modulate breast cancer risk. The main aim of this study was to assess the strength of associations between recognized risk factors and breast cancer among Cypriot women. This is the first epidemiological investigation on risk factors of breast cancer among the Cypriot female population.Methods: We carried out a case-control study, involving 1,109 breast cancer patients and a group of 1,177 controls who were recruited while participating in the National screening programme for breast cancer. Information on demographic characteristics and potential risk factors were collected from both groups during a standardized interview. Logistic regression analysis was used to assess the strength of the association between each risk factor and breast cancer risk, before and after adjusting for the possible confounding effect of other factors.Results: In multivariable models, family history of breast cancer (OR 1.64, 95% CI 1.23, 2.19) was the strongest predictor of breast cancer risk in the Cypriot population. Late menarche (OR 0.64, 95% CI 0.45, 0.92 among women reaching menarche after the age of 15 vs. before the age of 12) and breastfeeding (OR 0.74, 95% CI 0.59, 0.92) exhibited a strong protective effect. In the case of breastfeeding, the observed effect appeared stronger than the effect of pregnancy alone. Surprisingly, we also observed an inverse association between hormone replacement therapy (HRT) although this may be a product of the retrospective nature of this study.Conclusion: Overall the findings of our study corroborate with the results of previous investigations on descriptive epidemiology of risk factors for breast cancer. This investigation provides important background information for designing detailed studies that aim to improve our understanding of the epidemiology of breast cancer in the Cypriot population, including the study of gene-environment interactions. Furthermore, our study provides the first scientific evidence for formulating targeted campaigns for prevention and early diagnosis of breast cancer in Cyprus

Oral contraceptive use before first birth and risk of breast cancer: a case control study

BACKGROUND: The aim of this study was first, to investigate whether women starting oral contraceptive (OC) use at a young age and before first birth have an increased risk for breast cancer and second, to report difficulties encountered in studying long-term health impacts of medical technologies. METHODS: Breast cancers occurring up until 1997 among 37153 Helsinki students born between 1946 and 1960 were identified by record linkage from the Finnish Cancer Registry; for each cancer case, five age-matched random controls were picked from the same student population. Those who had used the Helsinki Student Health Service (HSHS) at least three times (150 cases and 316 controls) form the final study subjects. Data on OC use and background characteristics were collected from patient records, and data on live births were derived from the population register. Odds ratios (OR) were adjusted for number of births, smoking and sports activity. RESULTS: Compared to the few non-users, OC users had a higher risk of breast cancer: the adjusted OR was 2.1 (95% confidence interval 1.1–4.2). Among OC users, no statistically significant differences in risk of breast cancer were found in regard to starting age or first birth, but small numbers made confidence intervals wide. Even though we had chosen students to be our study group, the population turned out to be unsuitable to answer our research question: most women had started their OC use old (at the age of 20 or later) and there were very few unexposed (almost all had used OC and before their first birth). CONCLUSIONS: Because adoption of the modern pattern of OC use was not common among students, it is unlikely that the impact of early and extended OC use can be studied before 2010, when women born in the 1960s are 40 to 50 years old

Estimates of heritable and environmental components of familial breast cancer using family history information

Using the Swedish Family-Cancer Database, the increased risk of breast cancer in women with relatives with the disease did not vary with paternal/maternal lineage. Familial breast cancer heritable component was 73% and the environmental proportion 27%. Familial aggregation of breast cancer in women below age 51 years is mainly due to heritable causes