Faculty Publications

Women with mutations of the genes BRCA1 or BRCA2 are at increased risk of ovarian cancer. Oral contraceptives protect against ovarian cancer in general, but it is not known whether they protect against the disease in carriers of these mutations. We obtained self-reported lifetime histories of oral contraceptive use from 451 women who carried mutations of BRCA1 or BRCA2. We used conditional logistic regression to estimate the odds ratios associated with oral contraceptive use, comparing the histories of 147 women with ovarian cancer ( cases) to those of 304 women without ovarian cancer ( controls) who were matched to cases on year of birth, country of residence and gene ( BRCA1 vs BRCA2). Reference ages for controls had to exceed the ages at diagnosis of their matched cases. After adjusting for parity, the odds-ratio for ovarian cancer associated with use of oral contraceptives for at least 1 year was 0.85 ( 95 percent confidence interval, 0.53 - 1.36). The risk decreased by 5% ( 1 - 9%) with each year of use ( P for trend = 0.01). Use for 6 or more years was associated with an odds-ratio of 0.62 ( 0.35 - 1.09). These data support the hypothesis that long-term oral contraceptive use reduces the risk of ovarian cancer among women who carry mutations of BRCA1 or BRCA2.

Family-based research is essential to understanding the genetic and environmental etiology of human disease. The success of family-based research often depends on investigators' ability to identify, recruit, and achieve a high participation rate among eligible family members. However, recruitment of family members raises ethical concerns due to the tension between protecting participants' privacy and promoting research quality, and guidelines for these activities are not well established. The Cancer Genetics Network Bioethics Committee assembled a multidisciplinary group to explore the scientific and ethical issues that arise in the process of family-based recruitment. The group used a literature review as well as expert opinion to develop recommendations about appropriate approaches to identifying, contacting, and recruiting family members. We conclude that there is no single correct approach, but recommend a balanced approach that takes into account the nature of the parti cular study as well as its recruitment goals. Recruitment of family members should be viewed as part of the research protocol and should require appropriate informed consent of the already-enrolled participant. Investigators should inform prospective participants why they are being contacted, how information about them was obtained, and what will happen to that information if they decide not to participate. The recruitment process should also be sensitive to the fact that some individuals from families at increased genetic risk will have no prior knowledge of their risk status. These recommendations are put forward to promote further discussion about the advantages and disadvantages of various approaches to family-based recruitment. They suggest a framework for considering alternative recruitment strategies and their implications, as well as highlight areas in need of further empirical research. (C) 2004 Wiley-Liss, Inc.

Purpose Data on the efficacy of bilateral prophylactic mastectomy for breast cancer risk reduction in women with BRCA1 and BRCA2 (BRCA1/2) mutations are limited, despite the clinical use of this risk-management strategy. Thus, we estimated the degree of breast cancer risk reduction after surgery in women who carry these mutations. Patients and Methods Four hundred eighty-three women with disease-associated germline BRCA1/2 mutations were studied for the occurrence of breast cancer. Cases were mutation carriers who underwent bilateral prophylactic mastectomy and who were followed prospectively from the time of their center ascertainment and their surgery, with analyses performed for both follow-up periods. Controls were BRCA1/2 mutation carriers with no history of bilateral prophylactic mastectomy matched to cases on gene, center, and year of birth, Both cases and controls were excluded for previous or concurrent diagnosis of breast cancer. Analyses were adjusted for duration of endogenous ovarian hormone exposure, including age at bilateral prophylactic oophorectomy if applicable. Results Breast cancer was diagnosed in two (1.9%) of 105 women who had bilateral prophylactic mastectomy and in 184 (48.7%) of 378 matched controls who did not have the procedure, with a mean follow-up of 6.4 years. Bilateral prophylactic mastectomy reduced the risk of breast cancer by approximately 95% in women with prior or concurrent bilateral prophylactic oophorectomy and by approximately 90% in women with intact ovaries. Conclusion Bilateral prophylactic mastectomy reduces the risk of breast cancer in women with BRCA1/2 mutations by approximately 90%. (C) 2004 by American Society of Clinical Oncology.

A new mechanism for the chemopreventive activity of cyclooxygenase-2 (Cox-2) inhibitors in epithelial cancers, related to the integrity of the epithelial basement membrane is proposed. A recent study showed that the degrdn. and removal of mammary epithelial basement membrane by transgenic expression of matrilysin (MMP-7) promotes mammary tumorigenicity of the transgenic mice. In the absence of an intact basement membrane, the surface epithelium represents a precursor lesion, and subsequent genetic and epigenetic changes will lead to overt neoplastic transformation and tumorigenicity. The frequent placement of the surface epithelium in such a precursor state by repeated gonadotropin stimulation and subsequent Cox-2 induced changes would increase the risk of subpopulation (the cancer prone cells that have accumulated genetic mutations) to transform. The implication of this mechanism provides support for the use of Cox-2 inhibitors in preventing ovarian cancer. By inhibiting Cox-2, the loss of the basement membrane of the ovarian surface epithelium may be lessened, and neoplastic transformation of the ovarian surface epithelial cells may be reduced. [on SciFinder (R)]

Background: Several studies have reported that the risk of breast cancer decreases with increasing duration of breast-feeding. Whether breast-feeding is associated with a reduced risk of hereditary breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations is currently unknown. Methods: We conducted a case-control study of women with deleterious mutations in either the BRCA1 or the BRCA2 gene. Study participants, drawn from an international cohort, were matched on the basis of BRCA mutation (BRCA1 [n = 685] or BRCA2 [n = 2801), year of birth ( 2 years), and country of residence. The study involved 965 case subjects diagnosed with breast cancer and 965 control subjects who had no history of breast or ovarian cancer. Information on pregnancies and breast-feeding practices was derived from a questionnaire administered to the women during the course of genetic counseling. Conditional logistic regression analyses were used to estimate odds ratios (ORs) for the risk of breast cancer. All statistical tests were two-sided. Results: Among women with BRCA1 mutations, the mean total duration of breast-feeding was statistically significantly shorter for case subjects than for control subjects (6.0 versus 8.7 months, respectively; mean difference = 2.7 months, 95% confidence interval [CI] = 1.4 to 4.0; P<.001). The total duration of breast-feeding was associated with a reduced risk of breast cancer (for each month of breast-feeding, OR = 0.98, 95% CI = 0.97 to 0.99; P-trend <.001)- Women with BRCA1 mutations who breast-fed for more than 1year were less likely to have breast cancer than those who never breast-fed (OR = 0.55, 95% CI = 0.38 to 0.80; P =.001), although no such association was seen for BRCA2 (OR = 0.95, 95% CI = 0.56 to 1.59; P =.83). Conclusions: Women with deleterious BRCA1mutations who breast-fed for a cumulative total of more than 1year had a statistically significantly reduced risk of breast cancer.