Summary To evaluate the feasibility of nipple aspiration and to identify intermediate markers of breast cancer risk, nipple aspirate fluid (NAF) was collected from 177 subjects using a modified breast pump. The first 33 subjects demonstrated that we could obtain NAF quickly, reliably and repeatedly. Specimens from the remaining 144 (Giuliano, 1994). Additional screening tools to identify precancer and early breast cancer are urgently needed.Although the early detection of breast cancer will lead to a higher cure rate, the ideal form of treatment is prevention. The prevention of breast cancer is hindered by the difficulty in identifying an effective agent. Effective agents are difficult to identify in part because of the long period required for breast cancer to develop and, consequently, the requirement for lengthy clinical trials to test the efficacy of the agent, if the end point is the prevention of cancer. One way to shorten the time to finding of an effective agent is the identification of intermediate biomarkers, which are biological alterations in cells or tissue that occur between the time of initiation and tumour invasion. The theory is that an agent that partially or completely reverses the intermediate biomarker back to a normal phenotype may be interrupting carcinogenesis. Validation of the biomarker would require that the agent also decrease the incidence of cancer. Evaluating the effect of the agent requires the analysis of tissue, cells or non-cellular fluid. Nipple

IntroductionThe ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a significant role in the activation of cellular responses to DNA double-strand breaks through subsequent phosphorylation of central players in the DNA damage-response pathway. Recent studies have confirmed that some specific variants in the ATM gene are associated with increased breast cancer (BC) risk. However, the magnitude of risk and the subset of variants that are pathogenic for breast cancer remain unresolved.MethodsTo investigate the role of ATM in BC susceptibility, we studied 76 rare sequence variants in the ATM gene in a case-control family study of 2,570 cases of breast cancer and 1,448 controls. The variants were grouped into three categories based on their likely pathogenicity, as determined by in silico analysis and analyzed by conditional logistic regression. Likely pathogenic sequence variants were genotyped in 129 family members of 27 carrier probands (15 of which carried c.7271T > G), and modified segregation analysis was used to estimate the BC penetrance associated with these rare ATM variants.ResultsIn the case-control analysis, we observed an odds ratio of 2.55 and 95% confidence interval (CI, 0.54 to 12.0) for the most likely deleterious variants. In the family-based analyses, the maximum-likelihood estimate of the increased risk associated with these variants was hazard ratio (HR) = 6.88 (95% CI, 2.33 to 20.3; P = 0.00008), corresponding to a 60% cumulative risk of BC by age 80 years. Analysis of loss of heterozygosity (LOH) in 18 breast tumors from women carrying likely pathogenic rare sequence variants revealed no consistent pattern of loss of the ATM variant.ConclusionsThe risk estimates from this study suggest that women carrying the pathogenic variant, ATM c.7271T > G, or truncating mutations demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2.

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 (OR trend 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. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1863 -70) IntroductionReproductive factors have been consistently associated with breast cancer risk for women unselected for predisposing genetic mutations (1, 2). A first birth is associated with an increased risk of breast cancer in the first 10 years after the birth, but after this time (i.e., after 10 years), if the birth occurs before age 32 years, the birth is associated with a decreased risk and the magnitude of this decrease increases with increasing time since the birth. If the first birth occurs after about age 32, the decreased risk does not occur, and such a woman has a lifelong increased risk compared with a nulliparous woman. Further births have similar effects, so that, for example, a woman with an early first birth and high parity has a much reduced risk if the further births take place at a young age. Women with an early age at menarche and/or a late age at menopause and a greater number of menstrual cycles are all at an increased risk of breast cancer. Taken together, these associations suggest that endogenous steroid hormones play an important role in the etiology of breast cancer. This raises the question of whether use of exogenous steroid hormones, such as oral contraceptives, might also be associated with risk....

Bradbury AR, Patrick‐Miller L, Fetzer D, Egleston B, Cummings SA, Forman A, Bealin L, Peterson C, Corbman M, O’Connell J, Daly MB. Genetic counselor opinions of, and experiences with telephone communication of BRCA1/2 test results. BRCA1/2 test disclosure has, historically, been conducted in‐person by genetics professionals. Given increasing demand for, and access to, genetic testing, interest in telephone and Internet genetic services, including disclosure of test results, has increased. Semi‐structured interviews with genetic counselors were conducted to determine interest in, and experiences with telephone disclosure of BRCA1/2 test results. Descriptive data are summarized with response proportions. One hundred and ninety‐four genetic counselors completed self‐administered surveys via the web. Although 98% had provided BRCA1/2 results by telephone, 77% had never provided pre‐test counseling by telephone. Genetic counselors reported perceived advantages and disadvantages to telephone disclosure. Thirty‐two percent of participants described experiences that made them question this practice. Genetic counselors more frequently reported discomfort with telephone disclosure of a positive result or variant of uncertain significance (p < 0.01) than other results. Overall, 73% of participants reported interest in telephone disclosure. Many genetic counselors have provided telephone disclosure, however, most, infrequently. Genetic counselors identify potential advantages and disadvantages to telephone disclosure, and recognize the potential for testing and patient factors to impact patient outcomes. Further research evaluating the impact of testing and patient factors on cognitive, affective, social and behavioral outcomes of alternative models of communicating genetic information is warranted.

Genomic tests are increasingly complex, less expensive, and more widely available with the advent of next-generation sequencing (NGS). We assessed knowledge and perceptions among genetic counselors pertaining to NGS genomic testing via an online survey. Associations between selected characteristics and perceptions were examined. Recent education on NGS testing was common, but practical experience limited. Perceived understanding of clinical NGS was modest, specifically concerning tumor testing. Greater perceived understanding of clinical NGS testing correlated with more time spent in cancer-related counseling, exposure to NGS testing, and NGS-focused education. Substantial disagreement about the role of counseling for tumor-based testing was seen. Finally, a majority of counselors agreed with the need for more education about clinical NGS testing, supporting this approach to optimizing implementation.