Background: Breast cancer is the most frequent female cancer in both developed and developing world which comprising 16% of all female cancer according to WHO GLOBOCAN 2008. The statistic from Hong Kong Cancer Registry reported that breast cancer is the third commonest cause of female death in Hong Kong. Breast cancer incidence varies remarkably among developed countries. The high dietary consumption of soy isoflavones has been hypothesized to explain the lower breast cancer incidence among women in Asian countries in observational studies, but whether soy isoflavones exert estrogenic or anti-estrogenic in breast tissue remains uncertain. Objective: This systematic review was to assess the effects of isoflavone-rich soy consumption on breast cancer risk in pre- and post-menopausal women Methods: Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for conducting and reporting randomized controlled trials were followed. Data sources: A systematic review of randomized controlled trials was conducted through searching databases: MEDLINE, PubMed and Cochrane Library (2002 until March 2012). Keywords for electronic searches included: [(soy OR isoflavones) AND (breast cancer OR breast neoplasms)] limited study types to human & randomized controlled studies. Study selection: RCTs of the effects of isoflavones or supplement versus placebo or control diet among pre- and post-menopausal participants who were currently free from breast cancer. Outcome measurements: serum sex hormones and IGF profile, mammographic density and menstruation cycle length Results: 15 RCTs (1527 women) compared isoflavones with placebo or control diet for study duration ranged from 2 months to 2 years. No significant effect was found on serum sex hormones, IGF profile, mammographic density or menstrual cycle length. The effect of menstrual cycle on mammographic densities was noticed. Conclusion: The results of the systematic review did not support the hypothesis that short-term isoflavones exposure has an effect on modulating breast cancer risk. The effect of menstrual cycle on mammographic densities probably reflects the effect of hormonal changes. Null results did not necessarily contradict the inverse association between soy intake and breast cancer risk from the results of epidemiologic studies. The absence of conclusive data on the effects might be attributable to the insufficient exposure duration in the RCTs. Longer duration of soy exposure and early life exposure might be a scope for future research. / published_or_final_version / Public Health / Master / Master of Public Health

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Breast cancer is the most common cancer and the second most common cause of cancer death in women. In 2008 there were 182,460 women diagnosed with breast cancer, and 40,480 women died of this disease. Breast cancer can be prevented by medical (tamoxifen or raloxifene) or surgical approaches (bilateral mastectomy or oophorectomy). Prevention is only recommended for women at high risk for developing breast cancer; therefore, proper risk calculation is essential in identifying women that may benefit from prevention measures. There is an easy-to-use and easily accessible risk calculation tool for determining a woman's risk of developing breast cancer and need for referral for counseling, gene testing, and possibly preventive therapy. This article reviews the components of risk assessment, the most frequently used risk calculation tool, and approaches to breast cancer risk reduction including medical and surgical therapies. The use of these therapies results in a risk reduction of 50-90%.

A pilot study was conducted to evaluate whether premenstrual syndrome was a risk factor for breast cancer among premenopausal women. As subjects, 54 women between the ages of 26 and 46 years, each diagnosed with breast cancer, were compared to three separate control groups, consisting of 193 female patients seen in medical offices for routine physical exams, 51 female nursing students, and 559 female graduate students. Each eligible subject was either mailed or personally given a survey questionnaire probing premenstrual and menstrual symptomatology and general descriptive characteristics. An association between premenstrual syndrome and breast cancer was evaluated by estimating exposure odds ratios and associated confidence intervals. Analysis of the data suggested that premenstrual syndrome did not pose a breast cancer risk among premenopausal women. / Graduation date: 1993

Introduction: Despite intense research efforts and improvements to mortality rates, breast cancer remains the leading cause of premature cancer death for women. Identifying women at highest risk is vitally important for screening decisions that may have a critical impact on diagnosis and prognosis. A family history of breast cancer is a well-established risk factor, but it can be unreliable. An easily measured and accurate biomarker of breast cancer risk would be a significant advancement to public health by allowing targeted screening of women who would benefit most. It may also reveal underlying molecular mechanism that could illuminate pathways to prevention. Incidence rates of breast cancer have remained unmoved owing to the lack of known modifiable risk factors. This may be due in part because most breast cancer research has focused on behaviors and exposures in, or recalled from, adulthood. The studies detailed in this dissertation seek to investigate the associations between oxidative stress and breast cancer risk in both adult women and adolescent girls with a family history of breast cancer. Methods: To determine the relationship between oxidative stress and breast cancer risk in adult women with a family history of breast cancer we measured and compared urinary levels of 8-OxodG and F2-Isoprostane in a prospective matched case control study nested within the New York Breast Cancer Family Registry. Cases (N=73) were individually matched with 2 controls on age, year of urine donation, menopausal status, and race. Conditional logistic regression methods were used to determine the odds of breast cancer from oxidative stress controlling for other risk factors for breast cancer and potential confounders. To better understand how oxidative stress levels change during puberty in girls and if such change is modified by a family history of breast cancer, we measured and compared levels of those same urinary biomarkers of oxidative stress in adolescent girls with and without a family history of breast cancer from the New York site of the Lessons in Epidemiology and Genetics of Adult Cancer from Youth cohort (LEGACY). Oxidative stress levels were measured both cross-sectionally at baseline and longitudinally every 6-months for up to 18-months. Linear regression was used for the cross-sectional analysis and repeated measures analysis using mixed models was employed for the longitudinal analysis. In both studies, biomarker levels were measured using well-established ELISA methods and adjusted for hydration status using specific gravity. Results: In the case control study of adult women we found that both 8-OxodG and F2-Isoprostane levels were significantly associated with a reduced risk of breast cancer after adjusting for BRCA1/2 mutation status, time between menarche and parity or menopause, and BMI (8-OxodG: β10-unit= -0.14, OR=0.87, p=0.03; F2-Isoprostane: β10-unit = -0.53, OR=0.59 , p=0.03). This inverse association was strongest among women under 50 and in women with a BMI below 25 for both biomarkers, and among women who reached menarche before age 14 for F2-Isoprostane. Overall, women in the highest tertile of either oxidative stress biomarker had approximately 50% reduced odds of breast cancer diagnosis. In our cross-sectional study of adolescent girls, we found that there was no significant difference in either oxidative stress biomarker in girls based on their family history of breast cancer. F2-Isoprostane levels were significantly associated with breast development measured by Tanner stage even after adjusting for age, age-specific BMI category and race (β=0.28, p=0.01). 8-OxodG levels were not significantly associated with age, BMI, race or Tanner stage at baseline but they were significantly associated with overweight/obese BMI but only among girls with a breast cancer family history (β=0.47, p=0.01). Change in 8-OxodG levels was significantly higher over the follow-up period in girls with a family history of breast cancer. This result remained significant after categorical measures of age, BMI, Tanner breast stage and race were added to the longitudinal model. F2-Isoprostane levels significantly increased in all girls over follow-up but this increase did not differ by family history of breast cancer, and the change was no longer significant our multivariate longitudinal analysis. Discussion: In both adult women and adolescent girls we found significant associations between oxidative stress and breast cancer risk. In adult women, low levels of urinary biomarkers of oxidative stress may promote cancer progression. During adolescence, girls with a family history of breast cancer may be exposed to higher rates of DNA oxidation that could result in genetic mutations. The relationships between oxidative stress, breast development, family history, and BMI should be the focus of future investigations.

Advancements in medicine and technology have led to an increasing number of cancer survivors. The development of a second primary cancer is one of the most severe sequelae of a cancer diagnosis, particularly for cancers that lack an effective screening tool as with ovarian cancer. Breast and ovarian cancer are major causes of morbidity and mortality in women; in the U.S., breast cancer has the highest incidence in women and ovarian cancer is the most fatal of gynecological cancers. Further, these two cancers have been found to co-occur. Along with possible treatment effects of the first cancer, shared risk factors, shared genetics, and interactions between these two have been hypothesized to contribute to their co-occurrence. Research on shared risk factors for second cancers is lacking and being able to identify potentially modifiable factors associated with second primary cancer could improve clinical recommendations for cancer survivors. Therefore, this dissertation examined risk factors for the development of double primary breast and ovarian cancer (DPBOC) in three parts 1) a comprehensive review of the literature to identify studies assessing risk factors for DPBOC, 2) a case-control study assessing the association between three potentially-modifiable risk factors (oral contraceptive (OC) use, parity, and breastfeeding), and risk of second primary ovarian cancer following breast cancer (BR-OV), second primary breast cancer following ovarian cancer (OV-BR), single primary ovarian cancer (OV), and single primary breast cancer (BR), and 3) a cohort study assessing OC use, parity, and breastfeeding and risk of BR-OV, OV, and BR. The comprehensive review identified few studies assessing epidemiologic risk factors for the development of DPBOC and most of the findings were not statistically significant. The majority of studies focused on treatment of breast cancer and risk of second primary ovarian cancer. While most of the findings on chemotherapy, radiotherapy, and Tamoxifen were heterogeneous and lacked statistical significance, hormone therapy for breast cancer may be associated with an increased risk of second primary ovarian cancer. The majority of studies on genetic risk factors for DPBOC looked at BRCA1/2 mutations or a crude measure of family history. Both BRCA1/2 and family history were consistently associated with risk of DPBOC, but studies varied on the extent of this risk due to differences in study design, exposure and outcome definition, and statistical power. No studies were identified examining DNA methylation and risk of DPBOC. The case-control study used data from the three clinic-based sites of the Breast Cancer Family Registry (BCFR) which consisted of women from breast and ovarian cancer families. We observed an inverse association with both OC use (OR=0.38, 95% CI: 0.22, 0.60) and breastfeeding (OR=0.52, 95% CI: 0.31, 0.87) and risk of DPBOC, but a positive association with parity (≥2 full-term pregnancies: OR=5.78, 95% CI: 2.82, 14.58), regardless of diagnosis order (BR-OV or OV-BR). We found similar associations for our OV and BR outcomes as well. When we examined differences between high and average risk women (using BRCA1/2 mutation status and predicted lifetime risk of breast or ovarian cancer), the inverse association with OC use only remained in women at average risk while the inverse association with breastfeeding only remained in women at high risk. As the positive association with parity and all of our outcomes disagreed with our hypothesis we conducted several sensitivity analyses to explore this finding. Survivor bias may have influenced our results as we observed differences in our findings between cases diagnosed ≤2 or ≤5 years before the baseline interview (pseudo-incident) and cases diagnosed >2 or >5 years before the baseline interview (prevalent). Specifically, the inverse association with OC use and all of our outcomes, and the positive association with parity and all of our outcomes were attenuated in the pseudo-incident group. To address concerns of selection and information bias in our case-control study, we conducted a cohort study using data from The Breast Cancer Prospective Family Study Cohort (ProF-SC). In contrast to our case-control findings, we observed a suggestive positive association between OC use and risk of BR-OV (HR=1.62, 95% CI: 0.91, 2.90) which became stronger in women at high risk, and an inverse association between having two or more full-term pregnancies compared to nulliparous and risk of BR-OV (HR=0.47, 95% CI: 0.22, 0.97) which did not vary by underlying risk of breast and ovarian cancer. However, our BR-OV results may have similarly been influenced by survivor bias as we observed differences in our results between our pseudo-incident and prevalent BR-OV cases; the association between OC use and BR-OV only remained in the prevalent cases. In summary, the results of this dissertation highlight the methodological challenges in the study of second primary cancers and the importance of considering survivor bias in a cohort of cancer survivors being followed for second cancers. Further, our results are suggestive of a discordant effect of OC use on first primary versus second primary ovarian cancer which should be explored in future studies.

Striking differences exist between countries in the incidence of breast cancer, with rates higher in the West than in Asian countries. The causes of these differences are unknown, but because incidence rates change in migrants, they are thought to be due to lifestyle rather than genetic differences. The objective of this thesis was to compare established breast cancer risk factors, physical activity, and diet in three groups of postmenopausal women at substantially different risks of developing breast cancer – Caucasians (N = 413), Chinese born in the West or who migrated to the West before age 21 (N = 216), and recent Chinese migrants, 99% of whom coming from urban China (N = 421). In this cross-sectional study, information on risk factors and diet were collected by telephone, and physical activity and anthropometric data were obtained at a home visit. Compared to Caucasians, recent Chinese migrants weighed on average 14 kg less, were 6 cm shorter, had menarche a year later, were more often parous, and less often had a family history of breast cancer or a benign breast biopsy. Estimating 5-year absolute breast cancer risks using the Gail Model showed that risk estimates in Caucasians would be reduced by only 11% if they had the risk factor profile of recent Chinese migrants for the variables in the Gail Model. Compared to Caucasians, recent Chinese migrants had lower average total physical activity over lifetime, and also spent less time on moderate- and vigorous-intensity activity. Compared to Caucasians, recent Chinese migrants consumed per day on average 175 fewer calories, 6 more grams of energy-adjusted protein, 16 more grams of energy-adjusted carbohydrates, and 5 fewer grams of energy-adjusted fat. Also, recent Chinese migrants consumed higher amounts of grains, fruits, vegetables, fish, and soy products, and lower amounts of alcohol, meat, dairy products, and sweets than Caucasians. Western born Chinese and early Chinese migrants had values intermediate between the other two groups for most of the variables. These results suggest that in addition to the established risk factors, some dietary factors may also contribute to the lower breast cancer risk in urban Chinese women.

Striking differences exist between countries in the incidence of breast cancer, with rates higher in the West than in Asian countries. The causes of these differences are unknown, but because incidence rates change in migrants, they are thought to be due to lifestyle rather than genetic differences. The objective of this thesis was to compare established breast cancer risk factors, physical activity, and diet in three groups of postmenopausal women at substantially different risks of developing breast cancer – Caucasians (N = 413), Chinese born in the West or who migrated to the West before age 21 (N = 216), and recent Chinese migrants, 99% of whom coming from urban China (N = 421). In this cross-sectional study, information on risk factors and diet were collected by telephone, and physical activity and anthropometric data were obtained at a home visit. Compared to Caucasians, recent Chinese migrants weighed on average 14 kg less, were 6 cm shorter, had menarche a year later, were more often parous, and less often had a family history of breast cancer or a benign breast biopsy. Estimating 5-year absolute breast cancer risks using the Gail Model showed that risk estimates in Caucasians would be reduced by only 11% if they had the risk factor profile of recent Chinese migrants for the variables in the Gail Model. Compared to Caucasians, recent Chinese migrants had lower average total physical activity over lifetime, and also spent less time on moderate- and vigorous-intensity activity. Compared to Caucasians, recent Chinese migrants consumed per day on average 175 fewer calories, 6 more grams of energy-adjusted protein, 16 more grams of energy-adjusted carbohydrates, and 5 fewer grams of energy-adjusted fat. Also, recent Chinese migrants consumed higher amounts of grains, fruits, vegetables, fish, and soy products, and lower amounts of alcohol, meat, dairy products, and sweets than Caucasians. Western born Chinese and early Chinese migrants had values intermediate between the other two groups for most of the variables. These results suggest that in addition to the established risk factors, some dietary factors may also contribute to the lower breast cancer risk in urban Chinese women.

Background Night shift work is inevitable for maintaining continuous services in different sectors e.g. healthcare, financial, transport and service sectors. Night shift work increases exposure of light at night. Exposure of light at night suppresses production of a neurohormone melatonin. Melatonin has shown potential cancer protective action in animal experiments. Melatonin deficiency is suggested to be related to the development of various cancer especially breast cancer. Breast cancer incidence in Hong Kong is rising. Particular concern about association between night shift work and breast cancer is raised. Objective To collect evidence from studies of other countries with study populations of different professions and to evaluate the relationship between night shift work and breast cancer Method MEDLINE was searched to identify publications, limited to English articles, from 1973 to May 2011. Search terms include (circadian rhythm or night work or night shift or shift work or work schedule tolerance) and (cancer or neoplasm or neoplasia) and (risk or rate or incidence). No restriction was set to the publication type. Results Altogether 343 titles retrieved from MEDLINE search. Finally, 8 primary observational studies that met inclusion criteria were identified for this review. Of these, two were prospective cohort studies, one was retrospective cohort study, two were nested case-control studies and three were case-control studies. Most of the study had crude exposure assessment of night shift work, in which four studies relied on group level of exposure probability instead of individual exposure information. Six of eight studies showed positive results on the association of night shift work and breast cancer in women. Three studies found that risk of breast cancer was increased significantly for those who had engaged in night shift work in a long duration i.e. more than 20-30 years, but they were all conducted in populations of same occupational group i.e. nurse and only a moderate increase of breast cancer risk was found. The results were subject to confounding and bias. No consistent results were found for effect of shorter duration of night shift work on risk of breast cancer. Conclusion Based on the studies included, there is suggestive evidence of an association of night shift work and breast cancer. Further studies on this are needed. Involvement of population of different occupational groups, controlling confounder of hormone use and conducting exposure assessment with high reliability using individual information instead of that from group are suggested. / published_or_final_version / Community Medicine / Master / Master of Public Health

Introduction: Breast density is an important independent risk factor for breast cancer and is negatively associated with diagnostic sensitivity of mammography. Measurement of breast density can be used to identify women at increased risk of developing breast cancer and those who would benefit from additional imaging. However, measurement techniques are generally subjective and do not reflect the true three-dimensional nature of the breast and its component tissues.Method: A semi-automated method for determining the volume of glandular tissue from digitised mammograms has been developed in Manchester. It requires a calibration device (stepwedge) to be imaged alongside the breast during mammography, with magnification markers on the compression paddle to accurately determine breast thickness. Improvements to the design of the stepwedge and markers have enabled the method to be applied to the screening population for the first time. 1,289 women had their volumetric breast density measured using this method and additionally completed a questionnaire on breast cancer risk factors.Results: The method has demonstrated excellent intra- and inter-observer agreement. The median percentage breast density in the study cohort was 8.4% (interquartile range 4.9 – 14.2%). There was no significant difference between left and right breasts; the difference between MLO and CC views was significant (CC view was denser), but values were closely correlated (r = 0.92, p < 0.001). The median glandular volume was 60.1cm3 and exhibited no significant variation between left/right breasts or CC/MLO views. A number of breast cancer risk factors were found to be significantly correlated with glandular volume and percentage breast density, including age, weight, BMI, parity, current HRT use and current smoking. The strength of correlation was equal to or greater than that of visually assessed mammographic density. Glandular volume and percentage breast density measurements demonstrated strong relationships with visually assessed mammographic density, which has been shown to be highly correlated with risk.Conclusions: These findings are promising and suggest that volumetric breast density measured using this method should be associated with breast cancer risk. However, further work is required to establish this relationship directly. The method will be used in a large study, known as PROCAS (Predicting Risk Of Cancer At Screening) which aims to develop individualised breast cancer risk prediction models; these have the potential to form the basis of tailored screening intervals. Preliminary work has been undertaken to adapt the method for full field digital mammography, which suggests that it is possible to use the integrated digital detector as the calibration device.