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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.

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

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Recent research shows that cancer survivors are at greater risk of developing cancer than the general population. Knowledge of the magnitude of second cancer risk and cancer-specific deaths among cancer survivors, factors that influence their second cancer risk, cancer survivors’ perceptions of second cancer risk and current practices and existing gaps in follow-up care is urgently needed if we hope to prepare survivors and their healthcare providers as to how best to monitor their long-term health. An exploratory mixed method study, guided by Kaplan and colleagues (2000) multilevel approach to the health determinants, was conducted to provide a detailed understanding of second cancer risks among cancer survivors. Data collection methods included: (1) qualitative survey of current practices in the follow-up care offered for cancer survivors across Canada, (2) population-based health databases (cancer registry and health insurance databases), and (3) qualitative interviews on cancer survivors’ perceptions of second cancer risks. Coordinated follow-up services are not universally available across Canada. Yet, cancer survivors have a 4-7-fold increased risk of developing cancer compared to the general population in Nova Scotia and Manitoba. Second cancer risks varied by demographic and disease-related factors such as age at first cancer diagnosis, cancer type, treatment era, and time since diagnosis. Second cancer risk does not exist only as an epidemiological calculation. Second cancer risk, from the perspective of cancer survivors, is shaped by more intuitive conceptual models than statistical models of risk. The theme, Life After Cancer – Living with Risk, described survivors’ sense that second cancer risk is now a part of their everyday lives.

For patients receiving radiation therapy, there is a risk of developing radiation induced carcinomas, especially if they have a long life expectancy. However, radiotherapy is not the only contributor of radiation exposure to healthy tissue. With the introduction of highly conformal treatment techniques comes the increase in pretreatment imaging necessary to accurately target tumour volumes and consequently, radiation exposure to healthy tissue. In this work the radiation dose delivered to radiosensitive organs from a number of treatment planning techniques was evaluated and the risk of radiation induced cancer was assessed. MOSFET detectors and Gafchromic film were used to measure the accumulative concomitant dose to the thyroid and contralateral breast from early stage breast carcinoma radiotherapy and to the contralateral testis from seminoma radiotherapy, with dose contributions from CT imaging for treatment planning, pretreatment imaging (CBCT) and treatment delivery peripheral dose. To the author's knowledge this is the first work investigating the total concomitant treatment related dose and associated risk to these treatment sites. Peripheral dose contributed the largest concomitant dose to the healthy tissue, measuring up to 0.7, 1.0 and 5.0 Gy to the testis, thyroid and contralateral breast, respectively. The highest testicular, thyroid and contralateral breast carcinoma risk was found to be 0.4, 0.2 and 1.4%, respectively. In conclusion, the risk of radiation induced carcinoma to the assessed radiosensitive tissues was found to be minimal, however, when considering treatment techniques and/or introducing pretreatment imaging protocols, the dose to the normal tissue should be kept as low as reasonably achievable.

Recent research shows that cancer survivors are at greater risk of developing cancer than the general population. Knowledge of the magnitude of second cancer risk and cancer-specific deaths among cancer survivors, factors that influence their second cancer risk, cancer survivors’ perceptions of second cancer risk and current practices and existing gaps in follow-up care is urgently needed if we hope to prepare survivors and their healthcare providers as to how best to monitor their long-term health. An exploratory mixed method study, guided by Kaplan and colleagues (2000) multilevel approach to the health determinants, was conducted to provide a detailed understanding of second cancer risks among cancer survivors. Data collection methods included: (1) qualitative survey of current practices in the follow-up care offered for cancer survivors across Canada, (2) population-based health databases (cancer registry and health insurance databases), and (3) qualitative interviews on cancer survivors’ perceptions of second cancer risks. Coordinated follow-up services are not universally available across Canada. Yet, cancer survivors have a 4-7-fold increased risk of developing cancer compared to the general population in Nova Scotia and Manitoba. Second cancer risks varied by demographic and disease-related factors such as age at first cancer diagnosis, cancer type, treatment era, and time since diagnosis. Second cancer risk does not exist only as an epidemiological calculation. Second cancer risk, from the perspective of cancer survivors, is shaped by more intuitive conceptual models than statistical models of risk. The theme, Life After Cancer – Living with Risk, described survivors’ sense that second cancer risk is now a part of their everyday lives.