Faculty Publications

Moderate alcohol intake has been consistently associated with a modest (30-50%) increase in breast cancer risk, but it remains unclear if certain individuals have higher susceptibility to the harmful effects of alcohol intake. Individuals differ in their ability to metabolize alcohol through genetic differences in alcohol dehydrogenase (ADH), the enzyme that catalyzes the oxidation of approximately 80% of ethanol to acetaldehyde, a known carcinogen. Using data from the Breast Cancer Family Registry (n = 811 sister sets), we examined whether sisters with breast cancer differ with respect to alcohol consumption and alcohol metabolism (measured by polymorphisms in ADH1B and ADH1C) compared to their sisters without breast cancer. Neither alcohol drinking nor alcohol metabolizing ADH1B and ADH1C genotypes were associated with breast cancer risk. However, only 19% and 42% of sisters were discordant by ADH1B and ADH1C, respectively, and even fewer were discordant by both genotype and alcohol intake, making it difficult to detect differences if they existed.

Background: Understanding the effect of oral contraceptives on risk of breast cancer in BRCA1 or BRCA2 mutation carriers is important because oral contraceptive use is a common, modifiable practice. Methods: We studied 497 BRCA1 and 307 BRCA2 mutation carriers, of whom 195 and 128, respectively, had been diagnosed with breast cancer. Case-control analyses were conducted using unconditional logistic regression with adjustments for family history and familial relationships and were restricted to subjects with a reference age under 50 years. Results: For BRCA1 mutation carriers, there was no significant association between risk of breast cancer and use of oral contraceptives for at least 1 year [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.53-1.12] or duration of oral contraceptive use (P-trend = 0.62). For BRCA2 mutation carriers, there was no association with use of oral contraceptives for at least 1 year (OR, 1.62; 95% CI, 0.90-2.92); however, there was an association of elevated risk with oral contraceptive use for at least 5 years (OR, 2.06; 95% CI, 1.08-3.94) and with duration of use (ORtrend per year of use, 1.08; P = 0.008). Similar results were obtained when we considered only use of oral contraceptives that first started in 1975 or later. Conclusions: We found no evidence overall that use of oral contraceptives for at least 1 year is associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers before age 50. For BRCA2 mutation carriers, use of oral contraceptives may be associated with an increased risk of breast cancer among women who use them for at least 5 years. Further studies reporting results separately for BRCA1 and BRCA2 mutation carriers are needed to resolve this important issue. C1 Univ So Calif, Dept Prevent Med, Calif Keck Sch Med, Los Angeles, CA 90089 USA. Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. No Calif Canc Ctr, Fremont, CA USA. Early Detect Lab, Melbourne, Vic, Australia. Univ Melbourne, Melbourne, Vic, Australia. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Univ Utah, Dept Hematol Oncol, Salt Lake City, UT USA. Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. Mt Sinai Hosp, Canc Care Ontario, Toronto, ON M5G 1X5, Canada. Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. Univ Otago, Dunedin, New Zealand. Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic, Australia. Prince Wales Univ, Hereditary Canc Clin, Sydney, NSW, Australia. Harvard Univ, Sch Med, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. Peter MacCallum Canc Ctr, Melbourne, Vic, Australia.

Background Bilateral prophylactic salpingo-cophorectomy (BPSO) is used widely used to reduce the risk of breast and ovarian cancer in women with BRCA1 and BRCA2 mutations. However, the reduction in mortality after this surgery is unclear. We aimed to assess whether BPSO improves overall mortality or cancer-specific mortality in BRCA1 and BRCA2 mutation carriers. Methods We identified a prospective cohort of 666 women with disease-associated gem-dine mutations in BRCA1 or BRCA2 and no previous cancer diagnosis. in our primary analysis, we compared 155 women who had had BPSO and 271 women matched for age at BPSO who had not had BPSO. In our secondary analysis, we compared 188 women who had had BPSO with 478 women who had not. In both analyses, we compared overall mortality and cancer-specific mortality. All analyses were adjusted for Centre, mutation (BRCA1 vs BRCA2), and birth year. Findings In the primary analysis, mean follow-up from BPSO to censoring was 3.1 years [SD 2(.)4] in the BPSO group and 2(.)1 years [2(.)0] in the non-BPSO group. The hazard ratio (HR) for overall mortality was 0(.)24 (95% CI 0(.)08-0(.)71), for breast-cancer-specific mortality was 0(.)10(0(.)02-0(.)71), and for ovarian-cancer-specific mortality was 0(.)05 (0(.)01-0(.)46) for women who had BPSO compared with those who had not. In secondary analysis, BPSO was associated with reduced overall mortality (HR 0(.)28 [95% Cl 0(.)10-0(.)74]), but not with breast-cancer-specific mortality (0(.)15 [0-02-1-18] or ovarian-cancer-specific mortality (0(.)23 [0(.)02-1(.)87]. When regarded as a time-dependent covariate, BPSO was not associated significantly with mortality. Interpretation if confirmed, the finding that BPSO improves overall survival and cancer-specific survival in women with BRCA mutations will complement our existing knowledge of cancer-risk reduction associated with BPSO. Together, these data could give information to women who are considering genetic testing.

Introduction: Patient preferences are central to the economic appraisal of health services. Cancer genetic services are relatively new, and little is known about clients' preferences. We sought to determine clients' preferences for genetic service delivery, and to identify factors that predict those preferences. Methods: We studied female participants in the Australian Jewish Breast Cancer Study who were offered a test for ancestral mutations in the BRCA1 and BRCA2 genes. Questionnaires, asking respondents to rank their preferences for functions, or attributes, of genetic counselling were received from 256 women (76% response rate). Results: Sixty-two per cent of the respondents gave their highest preference for information on cancer and genetic risk; 19% gave it to breast and ovarian cancer surveillance; 14% gave it to preparation for testing; and, 5% gave it to direction with decision making. Most ranked direction as their least preferred attribute (53%). Women with a stro! ng cancer family history were less likely to give highest preference to information (52%) and more likely to give highest preference to preparation for testing (22%) (P = 0.04; 0.01, respectively). Women with a university degree were less likely to give highest preference to surveillance (15%) (P = 0.04). Conclusion: Most women offered testing had highest preference for information and lowest preference for direction. We have identified factors that predict highest preference for information, preparation, and surveillance attributes. Understanding preferences and their predictors may assist cancer genetic services to provide clients with greater benefits from counselling.

The widespread adoption of screening mammography has resulted in an increased incidence of ductal carcinoma in situ (DCIS), which now accounts for 20% to 30% of new breast cancer diagnoses. Despite treatment with combined lumpectomy and radiation therapy, up to 15% of women will experience an ipsilateral breast recurrence, with 50% of these recurrences containing invasive disease. There is also a 6% incidence of contralateral breast cancers in women treated for DCIS. The recognition that adjuvant tamoxifen reduces local, regional, and distant disease in women diagnosed with invasive breast cancer led to the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 study, which randomized more than 1,800 women undergoing breast-sparing surgery and radiation for DCIS to adjuvant tamoxifen versus placebo for 5 years. At 7 years of follow-up, there was a statistically significant 27% reduction in the annual incidence rate of all breast cancer-related events for those women receiving tamoxifen, including a 48% reduction in invasive breast cancer. The benefit attributable to tamoxifen was confined to those tumors that were estrogen receptor (ER)-positive. However, adverse events, including endometrial cancer, thromboembolic events, and cataracts, are more common in older women. Tamoxifen should be considered as an adjunct to treatment for women undergoing breast-conserving surgery for ER-positive DCIS.

Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of similar to 80%, and following the first diagnosis the 10-year risk of contralateral breast cancer is similar to 30%. It has been shown that both tamoxifen and oophorectomy prevent contralateral breast cancer, but it is not clear whether there is a benefit in giving tamoxifen to women who have previously undergone an oophorectomy. Furthermore, the relative degree of protection in BRCA1 and BRCA2 carriers has not been well evaluated. We studied 285 women with bilateral breast cancer and a BRCA1 or BRCA2 mutation, and 751 control women with unilateral breast cancer and a BRCA1 or BRCA2 mutation in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of breast cancer and had been followed for as long as the case for a second primary breast cancer. The history of tamoxifen use for treating the first breast cancer was compared between bilateral and unilate! ral cases. The multivariate odds ratio for contralateral breast cancer associated with tamoxifen use was 0.50 for carriers of BRCA1 mutations (95% CI, 0.304.85) and was 0.42 for carriers of BRCA2 mutations (95% CI, 0.17-1.02). The protective effect of tamoxifen was not seen among women who had undergone an oophorectomy (OR = 0.83; 95% CI, 0.242.89) but this subgroup was small. In contrast, a strong protective effect of tamoxifen was apparent among women who were premenopausal or who had undergone natural menopause (OR = 0.44; 95% CI, 0.27-0.65). (c) 2005 Wiley-Liss, Inc.

BACKGROUND. New developments in the treatment of patients with metastatic renal cell cancer (MRCC) have suggested a need to reevaluate the role of systemic therapies. The authors convened a panel of medical and urologic oncologists to rate the appropriateness of the main options. METHODS. The authors used the RAND/University of California-Los Angeles Appropriateness Method to evaluate systemic therapy options and cytoreductive nephrectomy. After a comprehensive literature review, an expert panel rated the appropriateness of systemic options (108 permutations) and cytoreductive nephrectomy (24 permutations) for patients with MRCC. RESULTS. The appropriateness evaluation indicated that 27.3% of permutations were rated "appropriate," 46.9% were rated "inappropriate," and 25.8% were rated "uncertain." There was a high rate of agreement (95%). Sunitinib and sorafenib were rated appropriate for patients with low-to-moderate risk regardless of prior treatment. Temsirolimus was rated appropriate for first-line therapy for higher risk patients. Interferon-alpha and low-dose interleukin-2 were rated inappropriate or uncertain. In patients who received prior immunotherapy, cytokines were rated inappropriate. In all permutations for evaluating systemic therapy, enrollment into an investigational trial was considered appropriate, treatment with bevacizumab was uncertain, and thalidomide was inappropriate regardless of risk status or prior therapy. For good surgical risk patients with planned immunotherapy, nephrectomy was rated appropriate in patients who had limited metastatic burden regardless of tumor-related symptoms and in symptomatic patients regardless of metastatic burden. Only the most favorable combination of surgical risk, metastatic burden, and symptoms generated an "appropriate" rating for patients with planned targeted therapy. CONCLUSIONS. The current results begin the process of defining an appropriate role for cytokines, newer targeted therapies, and surgery in the treatment of MRCC. To determine which aspects of breast cancer genetic counselling are important to Ashkenazi Jewish women, a discrete choice experiment was conducted. Participants consisted of 339 Australian Ashkenazi Jewish women who provided a blood sample for research used to test for Ashkenazi Jewish ancestral mutations in the genes BRCA1 and BRCA2, and were offered their genetic test result through a cancer genetics service. Main outcome measures were women's preferences for, and trade-offs between, the genetic counselling aspects of providing cancer, gene, and risk information (information); giving advice about cancer surveillance (surveillance); preparing for genetic testing (preparation); and, assistance with decision-making (direction). Respondents most valued information, about twice as much as advice about surveillance, four times as much as preparation for testing, and nine times as much as assistance with decision-making, which was least valued. Women's preferences were consistent with the major goals of genetic counselling, which include providing information and surveillance advice, and avoiding direction by facilitating autonomous decision-making. There were differences between the women in which aspects they most favoured, suggesting that counselling that elicits and responds to clients' preferences is more likely to meet clients' needs.

The role of acculturation in the breast cancer risk increase among U.S. Chinese women is unclear. We examined the association between acculturation and breast density in a sample of foreign-born, U.S. Chinese women and examined factors that may explain such an association. Between January 2002 and May 2003, 212 Chinese women were recruited from Philadelphia region screening programs. Cranial-caudal mammographic images were classified into one of four categories ranging from "entirely fatty" to "extremely dense." Questionnaires assessed information on sociodemographic, cultural, reproductive, and lifestyle factors. An index of acculturation was created based on self-reported English proficiency and within- and cross-ethnicity social interactions. To estimate odds ratios (OR) for falling into a higher versus lower category for breast density, we conducted logistic regression analysis using proportional odds models for polychotomous outcomes. We found that women in the highest acculturation category had denser breasts [age-adjusted OR, 3.1; 95% confidence interval (95% CI), 1.6-6.0]. They also had fewer live births, higher age at first live birth, and higher dairy food intake, all factors associated with breast density. In 196 women with complete covariate data, only adjustment for number of live births and dairy food intake attenuated the estimate for acculturation by >10%. With adjustment for both simultaneously, the most acculturated women were still more likely to have denser breasts (age- and menopause-adjusted OR, 2.0; 95% CI, 1.0-4.2). These analyses are the first to show breast density differences by level of acculturation among foreign-born, U.S. Chinese women. Despite reproductive and lifestyle differences by level of acculturation, differences in these factors did not explain the acculturation-breast density association. Future longitudinal research will examine whether the association is due to early-life factors, postmigration lifestyle changes, or perimenopausal exposures. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1301-5).

OBJECTIVE: Although perceived control and coping have been studied across various health conditions, these relationships have been less well studied in the context of coping with cancer risk over time. The present study was a longitudinal study of the effects of perceived control and problem-focused coping on changes in psychological adjustment and behavioural outcomes among women at increased risk for ovarian cancer. DESIGN AND METHODS: Eighty women enrolled in a familial cancer risk assessment programme participated in this study. Assessments of problem-focused coping, perceived control and distress were collected upon entry into the programme and again at 3-month follow-up. Behavioural adherence to screening during the 12-month period following programme entry was obtained from clinic records. RESULTS: Using hierarchical regression analysis, we observed a significant interaction between perceived control and problem-focused coping for psychological distress, beta=0.94, p<.05. Specifically, problem-focused coping was associated with increasing distress over time among women who perceived high control. A significant control by coping interaction was also observed for behavioural adherence to pelvic ultrasound and CA125 screening, such that women who perceived high control and utilized problem-focused coping were less likely to undergo screening. CONCLUSIONS: Under conditions of high perceived control, problem-focused coping was associated with increasing distress as well as poorer behavioural adherence. Thus, perceived control and problem-focused coping may not always yield positive psychological or behavioural health outcomes. These findings contribute to a greater understanding of how problem-focused coping and perceived control may influence the course of adjustment to cancer risk over time.

Objectives The objectives of the present study were to examine sociodemographic correlates of soy food consumption among women at increased risk of breast cancer, describe factors influencing soy food consumption or nonconsumption, and identify women's sources of information about soy foods. Design A cross-sectional, self-report survey was used to assess frequency of and factors influencing soy food consumption. Soy food intake was reported for the past year. Subjects/setting Participants were 452 women, with family histories of breast cancer who were enrolled in a cancer risk assessment program. Statistical analyses performed Comparisons between consumers and nonconsumers of soy foods were performed using multivariate logistic regression and chi(2) analyses. Results Thirty-two percent reported soy food consumption. Commonly consumed soy foods were vegetable burgers, tofu, and soymilk. Consumers of soy foods were more likely to have higher levels of education and report eating five or more daily servings of fruits and vegetables. The primary reason for consumption of soy foods was eating a healthful diet, whereas insufficient knowledge about soy food preparation was the primary reason stated for nonconsumption. Both consumers and nonconsumers reported obtaining information about soy foods from magazines, friends, and newspapers. Consumers also indicated using the Internet to seek information. Conclusions These findings contribute to our understanding of the level of soy intake among women at increased risk for breast cancer and highlight potential factors that may influence women's decisions regarding soy food consumption. Women, particularly in this vulnerable population, would benefit from clear messages regarding the health effects of soy.

The development of technology to locate and isolate cancer susceptibility genes has brought together the fields of oncology, cancer control, genetics, and genetic counseling to create a new specialty of cancer risk counseling with the goal to communicate more accurate information about personal cancer risk profiles based on personal and family histories. As cancer risk assessment and counseling services become standard of care in medical practice, their availability is increasingly moving from comprehensive cancer centers and academic institutions to community settings. High-risk cancer genetics clinics in the community face several challenges, including staffing, time commitment, costs, and unique quality control issues. The societal benefits include a more educated public armed with the information needed to make health decisions appropriate for the individual level of risk. [References: 32] IS - 1523-3790 PT - Journal Article PT - Review LG - English ED - 20051215 UP - 20051220

Age at menarche is a strong and consistent predictor of breast cancer risk in the general population, but has not been well studied in women with a family history of breast cancer. We conducted this study to examine whether the presence of a deleterious BRCA1 or BRCA2 mutation influences age at menarche and to investigate whether or not there is an association between age at menarche and the risk of breast cancer in BRCA1 or BRCA2 mutation carriers. The presence of a deleterious BRCA1 or BRCA2 mutation did not appear to influence a woman's age at menarche. A matched case-control study was conducted on 1311 pairs of women who have been identified to be carriers of a deleterious mutation in either the BRCA1 (n = 945 pairs) or the BRCA2 gene (n = 366 pairs). Information about age at menarche was derived from a questionnaire routinely administered to carriers of a mutation in either gene. Among women who carried a deleterious BRCA1 mutation, age at menarche was inversely associa ted with the risk of breast cancer (p trend = 0.0002). This association was not observed among BRCA2 mutation carriers (p trend = 0.49). Compared with BRCA1 carriers whose age at menarche was <= 11 years, women with a menarcheal age between 14 and 15 years old had a 54% reduction in risk (OR = 0.46; 95% CI 0.30-0.69). This study implicates early age at menarche as a determinant of breast cancer among women with a BRCA1 mutation.