Faculty Bibliography

It is well known that early-onset breast cancer may be due to an inherited predisposition. When evaluating women diagnosed with breast cancer under age 30, two important syndromes are typically considered: Hereditary Breast and Ovarian Cancer Syndrome and Li-Fraumeni syndrome. Many women are offered genetic testing for mutations in the BRCA1 and BRCA2 genes; however, few are offered genetic testing for mutations in the TP53 gene. There is a concern that overly restrictive testing of TP53 may fail to recognize families with Li-Fraumeni syndrome. We reviewed the genetic test results and family histories of all women with early-onset breast cancer who had genetic testing of the TP53 gene at the Toronto Hospital for Sick Children. Of the 28 women tested, six (33.3 %) had a mutation in the TP53 gene; a mutation was found in 7.7 % of women who did not meet current criteria for Li-Fraumeni syndrome. By reviewing similar data published between 2000 and 2011, we estimate that 5-8 % of women diagnosed with early-onset breast cancer, and who have a negative family history, may have a mutation in the TP53 gene. Given the potential benefits versus harms of this testing, we discuss the option of simultaneous testing of all three genes (BRCA1, BRCA2, and TP53) for women diagnosed with breast cancer before age 30.

BACKGROUND: To evaluate the effect of the cumulative number of ovulatory cycles and its contributing components on the risk of breast cancer among BRCA mutation carriers. METHODS: We conducted a matched case-control study on 2,854 pairs of women with a BRCA1 or BRCA2 mutation. Conditional logistic regression was used to estimate the association between the number of ovulatory cycles and various exposures and the risk of breast cancer. Information from a subset of these women enrolled in a prospective cohort study was used to calculate age-specific breast cancer rates. RESULTS: The annual risk of breast cancer decreased with the number of ovulatory cycles experienced (rho = -0.69; P = 0.03). Age at menarche and duration of breastfeeding were inversely related with risk of breast cancer among BRCA1 (P(trend) < 0.0001) but not among BRCA2 (P(trend) >/= 0.28) mutation carriers. The reduction in breast cancer risk associated with surgical menopause [OR, 0.52; 95% confidence interval (CI), 0.40-0.66; P(trend) < 0.0001] was greater than that associated with natural menopause (OR, 0.81; 95% CI, 0.62-1.07; P(trend) = 0.14). There was a highly significant reduction in breast cancer risk among women who had an oophorectomy after natural menopause (OR, 0.13; 95% CI, 0.02-0.54; P = 0.006). CONCLUSIONS: These data challenge the hypothesis that breast cancer risk can be predicted by the lifetime number of ovulatory cycles in women with a BRCA mutation. Both pre- and postmenopausal oophorectomy protect against breast cancer. IMPACT: Understanding the basis for the protective effect of oophorectomy has important implications for chemoprevention.

INTRODUCTION: Breastfeeding has been inversely related to breast cancer risk in the general population. Clarifying the role of breastfeeding among women with a BRCA1 or BRCA2 mutation may be helpful for risk assessment and for recommendations regarding prevention. We present an updated analysis of breastfeeding and risk of breast cancer using a large matched sample of BRCA mutation carriers. METHODS: We conducted a case-control study of 1,665 pairs of women with a deleterious mutation in either BRCA1 (n = 1,243 pairs) or BRCA2 (n = 422 pairs). Breast cancer cases and unaffected controls were matched on year of birth, mutation status, country of residence and parity. Information about reproductive factors, including breastfeeding for each live birth, was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the association between ever having breastfed, as well as total duration of breastfeeding, and the risk of breast cancer. RESULTS: Among BRCA1 mutation carriers, breastfeeding for at least one year was associated with a 32% reduction in risk (OR = 0.68; 95% CI 0.52 to 0.91; P = 0.008); breastfeeding for two or more years conferred a greater reduction in risk (OR = 0.51; 95% CI 0.35 to 0.74). Among BRCA2 mutation carriers, there was no significant association between breastfeeding for at least one year and breast cancer risk (OR = 0.83; 95% CI 0.53 to 1.31; P = 0.43). CONCLUSIONS: These data extend our previous findings that breastfeeding protects against BRCA1-, but not BRCA2-associated breast cancer. BRCA mutation carriers should be advised of the benefit of breastfeeding in terms of reducing breast cancer risk.

BACKGROUND: Breast cancer prevention with tamoxifen in high-risk women is limited due to concerns of endometrial cancer and thromboembolism. We report the risk of endometrial cancer, deep vein thrombosis and pulmonary embolism in women <50 years given tamoxifen for breast cancer prevention. METHODS: We searched the Cochrane Central Register of Controlled Trials and National Library of Medicine for published data from January 1970 to December 2010. We contacted principal investigators of clinical trials, and searched Grey literature and conference proceedings for unpublished data. We reviewed three breast cancer prevention trials comparing tamoxifen (20mg per day) with placebo for five years in high-risk women <50 years. The absolute risk and relative risk (RR) for each outcome were estimated. RESULTS: The RR for endometrial cancer in women <50 years given tamoxifen is 1.19 (95% CI, 0.53-2.65; p=0.6) as compared to the placebo. The RR for deep vein thrombosis with tamoxifen is 2.30 (95% CI, 1.23-4.31; p=0.009) in the active phase of treatment. The risk decreases to 1.00 (95% CI, 0.38-2.67; p=0.9) in the follow-up phase. The RR for pulmonary embolism with tamoxifen is 1.16 (95% CI, 0.55-2.43; p=0.6). INTERPRETATION: The risk of endometrial cancer, deep vein thrombosis and pulmonary embolism is low in women <50 years who take tamoxifen for breast cancer prevention. The risk decreases from the active to follow-up phase of treatment. Education and counseling are the cornerstones of breast cancer chemoprevention.

Despite benefits of screening mammography, many South Asian (SA) immigrant women in Canada remain under screened. We aimed to elicit their experiences and beliefs about barriers to mammography and possible solutions. SA immigrant women aged 50 years or over were eligible if they never had a mammogram or had one more than 3 years ago. We employed the participatory mixed-method approach of Concept Mapping. Sixty women participated with a mean age of 58 years. Participants brainstormed 150 items which were consolidated into 67 items. After sorting and rating, cluster analysis revealed eight clusters of barriers on knowledge, fear, language and transportation, access to mammogram center, access to doctor, beliefs and practices, self-care, and family dependence. Participants discussed possible solutions, and emphasized out-reach models to address knowledge gaps and issues of language and transportation. One example was a community-based shuttle bus to screening centres, hosted by trained co-ethnic workers. The results are discussed to enhance the socio-cultural sensitivity of breast screening programs.

BACKGROUND: The problems of cancer are increasing in low- and middle-income countries (LMCs), which now have significant majorities of the global case and mortality burdens. The professional oncology community is being increasingly called upon to define pragmatic and realistic approaches to these problems. PATIENTS AND METHODS: Focusing on mortality and case burden outcomes defines public health oncology or population-affecting cancer medicine. We use this focus to consider practical approaches. RESULTS: The greatest cancer burdens are in Asia. A public health oncology perspective mandates: first, addressing the major and social challenges of cancer medicine for populations: human rights, health systems, corruption, and our limited knowledge base for value-conscious interventions. Second, adoption of evolving concepts and models for sustainable development in LMCs. Third, clear and realistic statements of action and inaction affecting populations, grounded in our best cancer science, and attention to these. Finally, framing the goals and challenges for population-affecting cancer medicine requires a change in paradigm from historical top-down models of technology transfer, to one which is community-grounded and local-evidence based. CONCLUSION: Public health oncology perspectives define clear focus for much needed research on country-specific practical approaches to cancer control.

Women in low- and middle-income countries (LMICs) have yet to benefit from recent advances in breast cancer diagnosis and treatment now experienced in high-income countries. Their unique sociocultural and health system circumstances warrant a different approach to breast cancer management than that applied to women in high-income countries. Here, we present experience from the last five years working in rural Bangladesh. Case and consecutive series data, focus group and individual interviews, and clinical care experience provide the basis for this paper. These data illustrate a complex web of sociocultural, economic, and health system conditions which affect womens' choices to seek and accept care and successful treatment. We conclude that health system, human rights, and governance issues underlie high mortality from this relatively rare disease in Bangladesh.

BACKGROUND: Hyperinsulinemia and the metabolic syndrome are both risk factors for breast cancer. It is not clear if diabetes is associated with the risk of breast cancer in women with a BRCA1 or BRCA2 mutation. METHODS: The authors reviewed the medical histories of 6052 women with a BRCA1 or BRCA2 mutation, half of whom had been diagnosed with breast cancer. They estimated the odds ratio for breast cancer, given a self-report of diabetes. They then estimated the hazard ratio for a new diagnosis of diabetes associated with a history of breast cancer. RESULTS: There was no excess of diabetes in the period before the diagnosis of breast cancer, compared with controls with no diagnosis of breast cancer. The risk of diabetes was doubled among BRCA carriers in the 15-year period after the diagnosis of breast cancer (relative risk, 2.0; 95% confidence interval [CI], 1.4-2.8; P = .0001), compared with carriers without cancer. The risk was particularly high for women with a body mass index (BMI) >25.0 kg/m(2) (odds ratio, 5.8; 95% CI, 4.0-8.6; P = .0001). CONCLUSIONS: After a diagnosis of breast cancer, women with a BRCA1 or BRCA2 mutation face a 2-fold increase in the risk of diabetes, which is exacerbated by a high BMI.

Recent progress with declines in mortality in some high-income countries has obscured the fact that for the majority of women worldwide who are newly diagnosed, breast cancer is a neglected disease in the context of other numerically more frequent health problems. For this growing majority, it is also an orphan disease, in that detailed knowledge about tumor characteristics and relevant host biology necessary to provide even basic care is absent. With the possible exception of nutritional recommendations, current international cancer policy and planning initiatives are irrelevant to breast cancer. The progress that has occurred in high-income countries has come at extraordinary fiscal expense and patient toxicity, which of themselves suggest nonrelevance to women and healthcare practitioners in middle- and low-income countries. The implications of these circumstances appear clear: if the promise of the now 60-year-old Declaration of Human Rights that the fruits of medical science accrue to all mankind is to be realized with respect to breast cancer, a basic and translational global research initiative should be launched.