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Epidemiological studies have examined breast cancer risk in relation to sex hormone concentrations measured by different methods: "extraction" immunoassays (with prior purification by organic solvent extraction, with or without column chromatography), "direct" immunoassays (no prior extraction or column chromatography), and more recently with mass spectrometry-based assays. We describe the associations of estradiol, estrone and testosterone with both body mass index and breast cancer risk in postmenopausal women according to assay method, using data from a collaborative pooled analysis of 18 prospective studies. In general, hormone concentrations were highest in studies that used direct assays and lowest in studies that used mass spectrometry-based assays. Estradiol and estrone were strongly positively associated with body mass index, regardless of the assay method; testosterone was positively associated with body mass index for direct assays, but less clearly for extraction assays, and there were few data for mass spectrometry assays. The correlations of estradiol with body mass index, estrone and testosterone were lower for direct assays than for extraction and mass spectrometry assays, suggesting that the estimates from the direct assays were less precise. For breast cancer risk, all three hormones were strongly positively associated with risk regardless of assay method (except for testosterone by mass spectrometry where there were few data), with no statistically significant differences in the trends, but differences may emerge as new data accumulate. Future epidemiological and clinical research studies should continue to use the most accurate assays that are feasible within the design characteristics of each study., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Associations between circulating concentrations of oestrogens, progesterone, and androgens with breast cancer and related risk factors in premenopausal women are not well understood. We aimed to characterise these associations with a pooled analysis of data from seven studies., Methods: Individual participant data for prediagnostic sex hormone and sex hormone-binding globulin (SHBG) concentrations were contributed from seven prospective studies. We restricted analyses to women who were premenopausal and younger than 50 years at blood collection, and to women with breast cancer diagnosed before age 50 years. We estimated odds ratios (ORs) with 95% CIs for breast cancer associated with hormone concentrations by conditional logistic regression in cases and controls matched for age, date of blood collection, and day of cycle, with stratification by study and further adjustment for cycle phase. We examined associations of hormones with risk factors for breast cancer in control women by comparing geometric mean hormone concentrations in categories of these risk factors, adjusted for study, age, phase of menstrual cycle, and body-mass index (BMI). All statistical tests were two-sided., Findings: We included data for up to 767 women with breast cancer and 1699 controls in the risk analyses. Breast cancer risk was associated with a doubling in concentrations of oestradiol (OR 1·19, 95% CI 1·06-1·35), calculated free oestradiol (1·17, 1·03-1·33), oestrone (1·27, 1·05-1·54), androstenedione (1·30, 1·10-1·55), dehydroepiandrosterone sulphate (1·17, 1·04-1·32), testosterone (1·18, 1·03-1·35), and calculated free testosterone (1·08, 0·97-1·21). Breast cancer risk was not associated with luteal phase progesterone (doubling in concentration OR 1·00, 95% CI 0·92-1·09), and adjustment for other factors had little effect on any of these ORs. Cross-sectional analyses in control women showed several associations of sex hormones with breast cancer risk factors., Interpretation: Circulating oestrogens and androgens are positively associated with the risk for breast cancer in premenopausal women., (Copyright © 2013 Endogenous Hormones and Breast Cancer Collaborative Group. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.)

Objectives: To examine self-reported menopausal-type symptoms among breast cancer patients on aromatase inhibitors (AIs) compared to women of the same age who had not been diagnosed with cancer, and to determine whether the percentage of breast cancer patients experiencing these symptoms changed over the first 6 months of AI treatment., Methods: Data from a 6-month cohort study of 100 breast cancer patients initiating AI therapy and of 200 women of a similar age without a history of cancer were analyzed. At baseline (prior to the initiation of AI therapy among the breast cancer patients), 3 months, and 6 months, a comprehensive questionnaire was administered to participants that ascertained data on the experiencing of specific menopausal-type symptoms., Results: The data showed statistically significant increases in the prevalence of certain symptoms from baseline to either follow-up point among the breast cancer patients; these symptoms included hot flushes, night sweats, pain during intercourse, hair loss, forgetfulness, depression, difficulty falling asleep, and interrupted sleep. Additionally, breast cancer patients were more likely than the women in the comparison group to report the new onset of many of these same symptoms during the follow-up time period., Conclusions: Because bothersome symptoms and side-effects are a major reason for discontinuation and non-adherence to treatment, symptoms should be monitored and addressed by oncologists so that the breast cancer patient can maintain her quality of life and remain adherent to the treatment schedule.

Background: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood., Methods: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies., Results: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer., Conclusion: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Purpose: Ductal lavage, a technique used to sample epithelial cells from breast ducts, has potential use in risk assessment and biomarker evaluation among women at increased risk for breast cancer. However, little is known about the reliability of the procedure., Methods: We evaluated the reliability of nipple aspirate (NAF) and ductal lavage at two time points 6 months apart in women at increased risk for breast cancer. Eligible women had a 5-year Gail risk >or=1.66% or lifetime risk of >20%, and/or a family history or personal history of breast cancer. All ducts that produced NAF were cannulated. The kappa statistic was used to evaluate reliability of NAF production, cellular yield, and cytologic diagnosis., Results: Sixty-nine women (mean age, 47 years) were enrolled over 35 months. Forty-seven returned for a second visit. At baseline, 65% of premenopausal and 41% of postmenopausal women produced NAF (P = 0.05), of which 72% underwent successful lavage of at least one duct. Samples of inadequate cellular material for diagnosis were significantly more likely in postmenopausal women than in premenopausal women (P = 0.04). Of the women who returned for a second visit, 18 of 24 who produced NAF had at least one duct successfully cannulated. Twenty-four ducts in 14 women were lavaged twice. Among these ducts, cellular yield for the two time points was inconsistent (kappa = 0.33 +/- 0.13), and only fair cytologic agreement was observed (kappa = 0.32 +/- 0.15). Ductal lavage was associated with moderate discomfort., Conclusion: Currently, the use of ductal lavage is limited by technical challenges in duct cannulation, inconsistent NAF production, a high rate of inadequate cellular material for diagnosis, fair cytologic reproducibility, and low participant return rates.

Background: The genes mutated in the cancer-prone syndrome, xeroderma pigmentosum (XP genes), have been well studied both biochemically and mechanistically. These genes are important components of the DNA nucleotide excision repair (NER) pathway, which protects against environmentally-induced cancers. XP genes are also downstream of the hereditary breast cancer syndrome gene, BRCA1, suggesting that XP genes may be important to hereditary forms of breast cancer as well. Although mutated XP genes are rare, polymorphic forms with potential functional deficiencies are common, and could pose a significant cancer risk in the general population., Hypothesis: This study tested the hypothesis that common polymorphic variants of XP genes were associated with the risk of breast cancer among a population of women in Washington County, Maryland., Methods: Five single nucleotide polymorphisms (SNPs) among four XP genes (XPC, XPD, XPF and XPG) were genotyped from DNA samples collected at baseline, and then analyzed by conditional logistic regression for association with the incidence of breast cancer. 321 cases were individually matched to 321 controls, by age and menopausal status., Results: No significant associations were found between breast cancer risk and any of the XP genotypes. Odds ratios for all genotypes ranged from 0.61 to 1.14, and none were statistically significant. Adjustment and stratification for family history of breast cancer did not alter the findings., Conclusion: These results suggest that polymorphisms of XP genes are not likely to be significant risk factors for women within the general population. This study did not address, however, risks for subpopulations of women with high exposures to DNA damaging agents.

Family history is a risk factor for breast cancer and could be due to shared environmental factors or polymorphisms of cancer susceptibility genes. Deficient function of DNA repair enzymes may partially explain familial risk as polymorphisms of DNA repair genes have been associated, although inconsistently, with breast cancer. This population based case-control study examined the association between polymorphisms in XPD (Lys751Gln) and XRCC1 (Arg399Gln and Arg194Trp) genes, and breast cancer. Breast cancer cases (n=321) and controls (n=321) were matched on age and menopausal status. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). The analysis was conducted omitting observations with missing data, and by using imputation methods to handle missing data. No significant association was observed between the XPD 751Gln/Lys (OR 1.37, 95% CI 0.96-1.96) and Gln/Gln genotypes (OR 1.08, 95% CI 0.62-1.86) (referent Lys/Lys), XRCC1 399Arg/Gln (OR 1.48, 95% CI 0.92-2.38) and Gln/Gln genotypes (1.11, 95% CI 0.67-1.83) (referent Arg/Arg) or the XRCC1 Arg/Trp and Trp/Trp genotypes (OR 1.12, 95% CI 0.69-1.83) (referent Arg/Arg) and breast cancer. In multivariate analysis, the adjusted odds ratios for the XPD and XRCC1 399 polymorphisms increased and became statistically significant, however, were attenuated when imputation methods were used to handle missing data. There was no interaction with family history. These results indicate that these polymorphisms in XPD and XRCC1 genes are only weakly associated with breast cancer. Without imputation methods for handling missing data, a statistically significant association was observed between the genotypes and breast cancer, illustrating the potential for bias in studies that inadequately handle missing data.

Background: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations., Methods: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided., Results: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk., Conclusion: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.

Catechol-O-methyltransferase (COMT) catalyzes the O-methylation of catechol estrogens (CEs), using S-adenosylmethionine (SAM) as a methyl donor. Several studies have indicated that the val108met COMT polymorphism, which results in a 3-4-fold decrease in activity, is associated with increased breast cancer risk. Folate, whose intake levels have also been associated with breast cancer risk, and other micronutrients in the folate metabolic pathway influence levels of SAM and S-adenosylhomocysteine (SAH), a COMT inhibitor generated by the demethylation of SAM. Because these micronutrients have been shown to alter SAM and SAH levels, we hypothesized that they could also affect COMT-catalyzed CE methylation. Although measurements of SAM and SAH were not initially collected, a secondary analysis of data from two nested case-control studies was performed to examine whether serum levels of folate, vitamin B12 (B12), pyridoxal 5'-phosphate (PLP), cysteine and homocysteine, in conjunction with COMT genotype, were associated with breast cancer risk. COMT(HH) (high activity COMT homozygote) breast cancer cases had statistically significantly lower levels of homocysteine (P = 0.05) and cysteine (P = 0.04) and higher levels of PLP (P = 0.02) than COMT(HH) controls. In contrast, COMT(LL) (low activity COMT homozygote) cases had higher levels of homocysteine than COMT(LL) controls (P = 0.05). No associations were seen between B12, COMT genotype, and breast cancer risk. An increasing number of COMT(L) alleles was significantly associated with increased breast cancer risk in women with below median levels of folate (P(trend) = 0.05) or above median levels of homocysteine (P(trend) = 0.02). These findings are consistent with a role for certain folate pathway micronutrients in mediating the association between COMT genotype and breast cancer risk.

Background: Environmental exposure to organochlorines has been examined as a potential risk factor for breast cancer. In 1993, five large U.S. studies of women located mainly in the northeastern United States were funded to evaluate the association of levels of 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (DDE) and polychlorinated biphenyls (PCBs) in blood plasma or serum with breast cancer risk. We present a combined analysis of these results to increase precision and to maximize statistical power to detect effect modification by other breast cancer risk factors., Methods: We reanalyzed the data from these five studies, consisting of 1400 case patients with breast cancer and 1642 control subjects, by use of a standardized approach to control for confounding and assess effect modification. We calculated pooled odds ratios (ORs) and 95% confidence intervals (CIs) by use of the random-effects model. All statistical tests were two-sided., Results: When we compared women in the fifth quintile of lipid-adjusted values with those in the first quintile, the multivariate pooled OR for breast cancer associated with PCBs was 0.94 (95% CI = 0.73 to 1.21), and that associated with DDE was 0.99 (95% CI = 0.77 to 1.27). Although in the original studies there were suggestions of elevated breast cancer risk associated with PCBs in certain groups of women stratified by parity and lactation, these observations were not evident in the pooled analysis. No statistically significant associations were observed in any other stratified analyses, except for an increased risk with higher levels of PCBs among women in the middle tertile of body mass index (25-29.9 kg/m(2)); however, the risk was statistically nonsignificantly decreased among heavier women., Conclusions: Combined evidence does not support an association of breast cancer risk with plasma/serum concentrations of PCBs or DDE. Exposure to these compounds, as measured in adult women, is unlikely to explain the high rates of breast cancer experienced in the northeastern United States.

Decreases in the incidence of breast cancer have not been achieved, but there is a downward trend in age-adjusted breast cancer mortality rates in the United States. Recent epidemiologic investigations continue to refine our understanding of the role of established breast cancer risk factors, such as reproductive characteristics and body mass index, and in the process advance understanding of the etiology of breast cancer. Important strides are being made in the chemoprevention of breast cancer, but clarifying the potential contributions of factors such as diet, physical activity, and cigarette smoke to the breast cancer burden is a high priority because these lifestyle behaviors also have important implications for primary prevention. The role of both environmental and endogenous exposures in breast carcinogenesis will be more clearly elucidated by studies that account for genetic polymorphisms, some of which may lead to differential susceptibility to harmful agents.

More information is needed about the relative effectiveness of prophylactic surgery, chemoprevention, and surveillance in reducing breast and ovarian cancer risk in women with an inherited susceptibility mutation. We assessed practical and ethical barriers to conducting randomized clinical trials (RCTs) to compare preventive interventions for breast and ovarian cancer. Eighty-seven at-risk women who attended an education and counseling session about BRCA1/2 testing were asked about their willingness to participate in hypothetical research studies for breast and ovarian cancer risk reduction. In addition, 247 Maryland physicians from five specialties completed a mail survey including a question about their likelihood of recommending RCT participation to an at-risk woman. Nineteen percent of at-risk women reported willingness to participate in a hypothetical RCT for breast cancer risk reduction and 17% for ovarian cancer risk reduction. Women with children and women likely to have a prophylactic mastectomy if found to have a susceptibility mutation were significantly more willing to participate in an RCT. A majority of women would be willing to participate in nonrandomized trials or registries. Fifty-two percent of physicians responded that they would be likely to recommend RCT participation to a woman carrying a breast cancer susceptibility mutation. Oncologists were the most likely to recommend an RCT. Although the results of nonrandomized trials may be difficult to interpret because of such issues as selection bias. Greater feasibility combined with fewer ethical concerns make nonrandomized trials a more viable alternative to randomized trials for evaluation of preventive interventions for breast and ovarian cancer when prophylactic surgery is one of the treatments being evaluated.

To evaluate the practice patterns of general and plastic surgeons regarding patients with early-stage breast cancer, all general and plastic surgeons in Quebec and Maryland were mailed self-administered questionnaires evaluating surgeon demographics, practice patterns, treatment preferences, and satisfaction with the results of lumpectomy and radiation therapy or breast reconstruction. Response rates of 38.3 percent and 26.7 percent were obtained for general surgeons in Quebec and Maryland, respectively. The ratio of reported mastectomies to lumpectomies was 1:2 in Maryland and 1:5 in Quebec. All general surgeons considered lumpectomy an important option. Ninety percent of Maryland surgeons versus 44 percent of Quebec surgeons considered mastectomy important. A total of 53.6 percent versus 24.9 percent of general surgeons in Maryland and Quebec, respectively, considered delayed reconstruction an important option. Additionally, 81.3 percent of Maryland surgeons considered immediate reconstruction important, and 79.6 percent discussed it with all stage I or II patients. More than 75 percent of Quebec general surgeons reported discussing immediate or delayed reconstruction with < or =50 percent of these women. Response rates of 53.6 percent and 48.8 percent were obtained for plastic surgeons in Quebec and Maryland, respectively. In one year Quebec plastic surgeons reported that they performed less than half the number of reconstructions performed by Maryland plastic surgeons (7.2 versus 17.3). In Quebec, 82.3 percent of surgeons reported that they frequently discuss delayed reconstruction, 25.1 percent immediate, 62.5 percent pedicled TRAM, and 51.7 percent nonautogenous options. In Maryland, 74.3 percent of plastic surgeons frequently discuss delayed reconstruction, 95.7 percent immediate, 89.9 percent pedicled TRAM, and 85.9 percent nonautogenous options. For women with early-stage breast cancer, regional variations exist in the surgical options discussed and provided.

Objectives: To investigate the association between prediagnostic plasma ascorbic acid concentrations and subsequent breast cancer risk in a nested case-control study., Methods: Female volunteer residents of Washington County, MD, donated 14,625 non-fasting blood samples in 1989. Incident breast cancer cases (n = 115) and controls (n = 115) were matched by age, menopausal status at donation, and date and hour of blood donation., Results: Median ascorbic acid concentrations were similar between cases and controls (1.44 mg/dl vs. 1.39 mg/dl. p = 0.78). There was no evidence for a dose-response relationship between higher plasma ascorbic acid concentrations and breast cancer risk [highest vs. lowest fifths: ORadjusted = 0.90, Ptrend = 0.98)., Conclusions: Findings from this prospective study do not suggest a protective association between prediagnostic plasma ascorbic acid concentrations and breast cancer risk in the subsequent 5 years of follow-up.

Globally, breast cancer is the third most common form of cancer and the most common among women. The age-adjusted incidence rates of breast cancer are 176% higher in developed than in developing nations. Male breast cancer is rare, but important studies provided risk factor information for comparison with studies of female breast cancer. There has been considerable interest in a possible role of organochlorines and polychlorinated biphenyls in the etiology of breast cancer, but the results of several null studies indicate the likelihood of such associations is extremely remote, providing reassuring news for the public. Prophylactic mastectomy was observed to significantly reduce a woman's chances of developing breast cancer, but it does not lower the risk to zero. Tamoxifen was found to be an effective chemopreventive agent in the Breast Cancer Prevention Trial, but this result was not replicated in two randomized trials in Europe. Striking reductions in the risk for breast cancer were observed for raloxifene in a randomized, placebo-controlled trial that had been designed for the prevention of osteoporosis. A large-scale, randomized trial of tamoxifen-verus-raloxifene among women at increased risk for developing breast cancer is now underway.

A nested case-control study was conducted to examine the association between serum concentrations of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), the primary metabolite of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), and polychlorinated biphenyls (PCBs) and the development of breast cancer up to 20 years later. Cases (n = 346) and controls (n = 346) were selected from cohorts of women who donated blood in 1974, 1989, or both, and were matched on age, race, menopausal status, and month and year of blood donation. Analyses were stratified by cohort participation because median DDE and PCB concentrations among the controls were 59 and 147% higher in 1974 than 1989, respectively. Median concentrations of DDE were lower among cases than controls in both time periods [11.7% lower in 1974 (P = 0.06) and 8.6% lower in 1989 (P = 0.41)]. Median concentrations of PCBs were similar among cases and controls [P = 0.21 for 1974 and P = 0.37 for 1989 (Wilcoxon signed rank test)]. The risk of developing breast cancer among women with the highest concentrations of DDE was roughly half that among women with the lowest concentrations, whether based on concentrations in 1974 [odds ratio (OR), 0.50; 95% confidence interval (CI), 0.27-0.89; P(trend) = 0.02] or in 1989 (OR, 0.53; 95% CI, 0.24-1.17; P(trend) = 0.08). The associations between circulating concentrations of PCBs and breast cancer were less pronounced but still in the same direction (1974: OR, 0.68; 95% CI, 0.36-12.9; P(trend) = 0.2; and 1989: OR, 0.73; 95% CI, 0.37-1.46; P(trend) = 0.6). Adjustment for family history of breast cancer, body mass index, age at menarche or first birth, and months of lactation did not materially alter these associations. These associations remained consistent regardless of lactation history and length of the follow-up interval, with the strongest inverse association observed among women diagnosed 16-20 years after blood drawing. Results from this prospective, community-based nested case-control study are reassuring. Even after 20 years of follow-up, exposure to relatively high concentrations of DDE or PCBs showed no evidence of contributing to an increased risk of breast cancer.

To investigate the incidence of breast cancer and prediagnostic serum levels of folate, B12, and pyridoxal 5'-phosphate (B6), we conducted a nested case-control study using resources from the Washington County (Maryland) serum bank. In 1974, 12,450 serum specimens were donated, and in 1989, 14,625 plasma specimens were donated by female residents of Washington County. One hundred ninety-five incident breast cancer cases and 195 controls were matched by age, race, menopausal status at donation, and cohort participation as well as by date of blood donation. In both cohorts and all menopausal subgroups, median B12 concentrations were lower among cases than controls. Differences reached statistical significance only among women who were postmenopausal at donation (1974 cohort, 413 versus 482 pg/ml, P = 0.03; 1989 cohort, 406 versus 452 pg/ml, P = 0.02). Among women postmenopausal at blood donation, observed associations of B12 suggested a threshold effect with increased risk of breast cancer in the lowest one-fifth compared to the higher four-fifths of the control distribution [lowest versus highest fifth: 1974 cohort, matched odds ratio = 4.00 (95% confidence interval = 1.05-15.20); 1989 cohort, matched odds ratio = 2.25 (95% confidence interval = 0.86-5.91)]. We found no evidence for an association between folate, B6, and homocysteine and breast cancer. Findings suggested a threshold effect for serum B12 with an increased risk of breast cancer among postmenopausal women in the lowest one-fifth compared to the higher four-fifths of the control distribution. These results should stimulate further investigations of potentially modifiable risk factors, such as these B-vitamins, for prevention of breast cancer.

The evidence that alcohol consumption increases a woman's chances of getting breast cancer is now more persuasive. Higher blood concentrations of organochlorine compounds were not associated with increased risk of breast cancer in recent studies. The relationship of exogenous estrogen use to breast cancer risk is now clarified: current users of both oral contraceptives and hormone replacement therapy experience a slightly elevated risk that dissipates after cessation of use. Alcohol consumption and hormone replacement therapy are both associated with slightly increased breast cancer risk, but the overall health benefits of hormone replacement therapy and low levels of alcohol consumption appear to outweigh the risks in the general population. These circumstances underscore the complex decisions facing women and the need to consider individual risk factor profiles. For the genes BRCA1 and BRCA2, more data are needed to understand the risks associated with specific mutations, optimal implementation of genetic testing, and prevention and early detection strategies for women who have positive test results. Interesting leads in identifying women at increased risk for breast cancer have been generated via the study of genetic polymorphisms. The results of tamoxifen in the Breast Cancer Prevention Trial have made the possibility of chemoprevention for breast cancer a reality. Raloxifene, another antiestrogen, has emerged as a potential chemopreventive agent. Its efficacy in reducing breast cancer risk will be compared with that of tamoxifen in a randomized trial.

A nested case-control study was conducted to determine whether a genetic polymorphism in the CYP17 gene, which encodes for an enzyme that mediates steroid hormone metabolism, was associated with an increased risk of breast cancer. No association was found between the presence of an A2 allele and the subsequent development of breast cancer [A1/A2 odds ratio, 0.61 (95% confidence interval, 0.33-1.14); A2/A2 odds ratio, 0.89 (95% confidence interval, 0.41-1.95)]. No significant association was observed with risk factors presumed to be surrogates for endogenous estrogen exposure, nor was there an association observed with the stage of disease at diagnosis. Genotype frequencies in this Caucasian population were similar to those reported for African-American, Asian, and Latino women. Additional studies of larger size are needed to achieve a consensus regarding the relevance of CYP17 genotypes to the risk of developing breast cancer.

Purpose: To determine what consumers and providers would want to discuss about breast cancer susceptibility testing (BCST) and their preferred role in testing decisions., Methods: We surveyed 426 at-risk women, 143 nurse practitioners, and 296 physicians in five specialties in Maryland., Results: All groups believe it is important to discuss how the chance of breast cancer can be reduced and what the chances are of getting breast cancer if the test is positive. Both provider groups attributed more importance than consumers to discussing whether cancer can occur if the test is negative. Discussing the risk of depression and anxiety was more important to providers than consumers. Eighty-two percent of women would want their providers to make a recommendation about testing, but only 43% of nurse practitioners and 68% of physicians would do so. Eighteen percent of physicians underestimated the importance of informed consent for testing and 34% of discussing the risk of insurance discrimination. Fewer than 6% of women, if found to have a mutation, would be likely to undergo prophylactic mastectomy, whereas 12% of nurse practitioners and 34% of physicians would be likely to recommend such surgery. One third of respondents in all three groups supported testing a 13-year old daughter of a mutation-carrier., Conclusion: Physicians should place greater value on informed consent and discussing practical aspects of testing, and physicians and nurse practitioners should pay more attention to the limitations of testing children, insurance discrimination, and consumers' desire for provider recommendations. In light of the limited discordance between nurse practitioners and consumers, nurse practitioners can play an increasing role in education and counseling about BCST.

Background: Glutathione S-transferases (GSTs) are encoded by a superfamily of genes and play a role in the detoxification of potential carcinogens. In a nested case-control study, we investigated associations between genetic variability in specific GST genes (GSTM1, GSTT1, and GSTP1) and susceptibility to breast cancer., Methods: In 1989, a total of 32 898 individuals donated blood samples to a research specimen bank established in Washington County, MD. Genotypes of blood specimen DNA were determined for 110 of 115 women with incident cases of breast cancer diagnosed during the period from 1990 through 1995 and up to 113 of 115 control subjects. Associations between specific genotypes and the development of breast cancer were examined by use of logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: The GSTM1 homozygous null genotype was associated with an increased risk of developing breast cancer (OR = 2.10; 95% CI = 1.22-3.64), principally due to an association with postmenopausal breast cancer (OR = 2.50; 95% CI = 1.34-4.65). For GSTP1, the data were suggestive of a trend of increasing risk with higher numbers of codon 105 valine alleles (compared with isoleucine alleles); a 1.97-fold increased risk of breast cancer (95% CI = 0.77-5.02) was associated with valine/valine homozygosity. The risk of breast cancer associated with the GSTT1 homozygous null genotype was 1.50 (95 % CI = 0.76-2.95). The risk of breast cancer increased as the number of putative high-risk genotypes increased (P for trend <.001) (OR = 3.77; 95% CI = 1.10-12.88 for a combined genotype of GSTM1 null, GSTT1 null, and either GSTP1 valine heterozygosity or GSTP1 valine homozygosity)., Conclusions: Our findings suggest that genetic variability in members of the GST gene family may be associated with an increased susceptibility to breast cancer.

Mounting evidence suggests that catechol metabolites of estradiol may contribute to the development of estrogen-induced cancers. O-Methylation, catalyzed by catechol-O-methyltransferase (COMT), inactivates catechol estrogens. COMT is polymorphic in the human population, with 25% of Caucasians being homozygous for a low activity allele of the enzyme (COMT(LL)). We hypothesized that low activity COMT may be a risk factor for human breast cancer and designed a PCR-based RFLP assay to determine COMT genotype in a cohort of 112 matched, nested case-control samples. In the total study population, the odds ratios for the association of breast cancer risk with COMT(HL) and COMT(LL) genotypes were 1.30 [confidence interval (CI), 0.66-2.58] and 1.45 (CI, 0.69-3.07), respectively. Postmenopausal COMT(LL) women had a greater than 2-fold increased risk of developing breast cancer [odds ratio (OR), 2.18; CI, 0.93-5.11]. The association of COMT(LL) with the development of postmenopausal breast cancer was stronger and statistically significant in those women with a body mass index >24.47 kg/m2 (OR, 3.58; CI, 1.07-11.98). When COMT(LL) was combined with either glutathione S-transferase (GST) M1 null or with GSTP1 Ile-105-Val/Val-105-Val (intermediate/low activity, respectively) genotypes, the risk for developing postmenopausal breast cancer was also significantly increased. Our findings suggest that the allele encoding low activity COMT may be an important contributor to the postmenopausal development of breast cancer in certain women.

Breast cancer is a leading women's health issue. Continued advances in understanding the temporal sequencing of relevant exposures promises to shed light on the continuum of breast carcinogenesis. Oral contraceptive use and the transient increase in risk following childbirth are exposures that affect the near-term risk of breast cancer. The availability of commercial testing for inherited susceptibility to breast cancer has accelerated the need for data to develop sound policy for implementing gene testing. The risks associated with BRCA1 and BRCA2 mutations may be less than previously estimated. Antiestrogens with lesser risks than tamoxifen hold promise for chemoprevention, but await testing. Not enough is known to formulate primary prevention strategies based on lifestyle interventions. Further understanding lifestyle factors that may be involved in the etiology of breast cancer and are amenable to preventive intervention thus remains a top priority, with diet and physical activity of greatest interest.

Breast cancer is the most common cancer among women worldwide. Genetic, environmental, and gene-environment interactions are discussed in relation to breast cancer etiology. A major advance in the study of inherited forms of breast cancer occurred with the identification of two genes, BRCA1 and BRCA2, that may account for a majority of inherited forms of breast cancer cases. Hypotheses have been formulated concerning the importance of timing of exposures to environmental agents and a possible role of "xenogenetics" in relation to breast cancer risk. With respect to early detection, regular mammography screening for women aged 50 years and older is clearly associated with a significant reduction in breast cancer mortality, but mammography among women aged 40 to 49 remains controversial. Concerning chemoprevention, the risks and benefits of tamoxifen continue to be clarified, retinoids hold promise, and monoterpenes have emerged as a possible chemopreventive agent.

Background: A study of system delay, the time between the initial medical consultation and the establishment of a diagnosis, in breast cancer patients revealed that almost 40% of women reported delays of at least 4 weeks. The objective of this study was to explore the reasons for these prolonged intervals between initial medical consultation and establishment of a diagnosis., Methods: A total of 367 female breast cancer patients from the National Cancer Institute's Black/White Cancer Survival Study were studied. Medical systems involved in the diagnosis and treatment of these women included hospital outpatient and emergency room, private clinic, public clinic, private doctor, and health maintenance organization., Results: In about 25% of the cases, the delay was attributed by the woman to the patient herself, and the most common reason she gave was that she felt that the problem was not important. In about 45% of the cases, the provider and the health care system were said to be responsible for the delay through difficulties in scheduling or physician inaction, while in another 17% both the patient and the system were responsible., Conclusions: This study looked at the issue of how the behaviors of women and their providers contribute to the timing of breast cancer diagnosis. It is one of the only studies to examine the woman's role in delay. It is clear from this study that additional work is needed to look at this question. However, the results of this study suggest that efforts must be made to reduce the time needed to get an appointment with a physician or a diagnostic test, as well as to educate physicians and the women themselves regarding the importance of breast symptoms and the value of prompt evaluation, diagnosis, and treatment.

The exact nature of the association between hormones and the development of breast cancer remains uncertain. Studies of endogenous hormone levels and breast cancer suggest a possible role of estrogens and androgens in the cause of breast cancer. Numerous studies have been conducted to assess the risk of breast cancer among women exposed to exogenous hormones. Several studies of women who have used oral contraceptives have shown a twofold increase in risk for the onset of breast cancer at an early age associated with 10 years of oral contraceptive use. One of the largest studies, the Cancer and Steroid Hormone Study, found no association between breast cancer and oral contraceptive use for women up to the age of 54. A meta-analysis combining the results of 31 published studies of the association between hormone replacement therapy and breast cancer revealed no increased risk of breast cancer associated with ever-use (risk ratio [RR], 1.02; 95% confidence interval [CI], 0.93-1.12). Use of oral contraceptives for more than 10 years was associated with a small increased risk (RR, 1.23; 95% CI, 1.08-1.40), but few studies have examined very long term use. A recent study of pregnancy and breast cancer outcome found no adverse influence of pregnancy shortly before or after diagnosis of breast cancer on prognosis. The results of a wide range of studies should be considered when weighing the benefits and risks of hormone use among women at increased risk of breast cancer or with a history of breast cancer.

Purpose: To determine the prevalence and severity of vasomotor, gynecologic, and other symptoms among breast cancer patients, their health concerns, beliefs about estrogen replacement therapy (ERT), and willingness to take estrogen under medical supervision., Materials and Methods: A questionnaire was mailed to 320 women aged 40 to 65 years and diagnosed with in situ or invasive locoregional breast cancer in the years 1988 to 1992., Results: Of 222 eligible respondents, 190 were postmenopausal. The prevalence of symptoms among the postmenopausal women was as follows: hot flashes, 65%; night sweats, 44%; vaginal dryness, 48%; dyspareunia, 26%; difficulty sleeping, 44%; and feeling depressed, 44%. The latter two symptoms increased in frequency with increasing severity of vasomotor symptoms (P for trend < or = .001). Forty-one percent of menopausal women perceived that they had experienced, since their breast cancer diagnosis, a physical or emotional problem related to menopause. Of these women, 50% felt they needed treatment. Overall, 31% of postmenopausal women would consider taking estrogen. Those who perceived that they had experienced a menopausal problem were more likely to consider estrogen than those who did not (42% v 22%, P = .003). The proportions willing to take estrogen increased with increasing severity of symptoms, particularly feelings of depression and sleep disturbance (P for trend = .008 and .007, respectively). Awareness that estrogen decreases the risks of heart disease and osteoporosis was not associated with an increased willingness to take it. However, beliefs that estrogen increases the risks of recurrent breast cancer and uterine cancer were associated with a decreased willingness to take it (P = .003 and .08, respectively)., Conclusion: Vasomotor symptoms have a significant impact on the quality of life of breast cancer patients. Clinical trials to determine the safest and the most effective ways to relieve these symptoms are needed.

Studies of the etiology, early detection, and prevention of breast cancer reported in the past year are reviewed in this paper. Studies of the etiology of breast cancer include reports on genetic and environmental factors. A major advance in the study of inherited forms of breast and ovarian cancer occurred with the identification of the BRCA1 gene. A second breast cancer susceptibility gene, the BRCA2 gene, was localized to chromosome 13q12-13. Multiple mutations in the BRCA1 gene have been identified, presenting a challenge for the development of predictive testing. Controversy continues over the association between hormone replacement therapy and the development of breast cancer. A study of exercise suggests a strong protective effect against the development of early onset breast cancer. Recent studies have failed to find a strong link between dietary fat intake and the development of breast cancer. A meta-analysis of studies of the efficacy of screening for the prevention of breast cancer mortality demonstrates a significant reduction in mortality among women 50 years of age and older. A lowering of breast cancer mortality for women aged 40 to 49 was only demonstrated after 10 to 12 years of follow-up. The risks and benefits of tamoxifen therapy, a potential breast cancer chemoprevention agent, continue to be clarified. Adverse effects on the endometrium, including an increased risk of endometrial cancer, have been reported. Beneficial effects include an improved cardiovascular risk profile and preservation of bone mineral density among postmenopausal women.

Survival differences have been noted between black women and white women with breast cancer. It is hypothesized that a prolonged interval between initial medical consultation and establishment of a diagnosis (system delay), resulting in a more advanced stage of disease at diagnosis, might explain part of this survival difference. This study was performed to determine whether system delay differs between black and white breast cancer patients, and to examine predictors of delay in blacks and whites. The study population consisted of 996 female breast cancer patients from the National Cancer Institute's Black/White Cancer Survival Study, a cohort study carried out in 1985-1986 in the metropolitan areas of Atlanta, Georgia, New Orleans, Louisiana, and San Francisco/Oakland, California. The median system delay was slightly longer for blacks than for whites--2.7 weeks versus 2.1 weeks--but this difference was not statistically significant. Having a palpable lump at diagnosis was associated with reduced system delay in both races, while use of a public clinic increased system delay for blacks. Older women were less likely to be subject to longer system delay than younger women, and this effect was somewhat more pronounced in whites. Survival differences between blacks and whites are probably not due to differences in system delay. However, many women had delays of at least 3 months. Given that younger age and the absence of a palpable lump were the factors most predictive of significant system delay, interventions should be targeted specifically toward reducing system delay in younger women who present without the classical painless lump.

Background: Women with a first-degree relative with breast cancer are at increased risk of developing this disease. The optimal medical management of these women is unclear, with options including close breast cancer screening, bilateral prophylactic mastectomy, or participation in chemoprevention trials. Among women who undergo prophylactic bilateral mastectomy, very little is known about satisfaction with this surgery. Also, we know very little about variables related to prophylactic mastectomy decision making., Methods: Participants were women at increased risk of breast cancer due to family history. These women were categorized by self-report as not interested in prophylactic mastectomy (n = 58), interested but deciding against surgery (n = 92), or subsequently having a bilateral prophylactic mastectomy (n = 14). Information on screening practices, risk perception, level of depression, and cancer-related worry was collected. Women completing prophylactic mastectomy reported on their satisfaction with the surgery and breast reconstruction., Results: Women selecting surgery reported more breast cancer worry. The group expressing no interest in surgery reported fewer biopsies and lower risk estimates. Women completing surgery were satisfied with their decision, although satisfaction with reconstruction was mixed., Conclusion: Factors influencing surgical decision making may include breast-cancer-related worry, biopsy history, and subjective breast cancer risk.

Objectives: Bilateral prophylactic mastectomy is a drastic breast cancer preventive option for which indications are not standardized and efficacy has not been proven. To estimate the magnitude of this controversial practice, surgeons were surveyed on their recommendations about and performance of prophylactic mastectomy., Methods: A cross-sectional survey was sent to general surgeons (n = 522), plastic surgeons (n = 80), and gynecologists (n = 801) licensed to practice in Maryland in 1992. Proportions responding were 41.9%, 66.3%, and 54.9%, respectively. In addition, there were 30 respondents who identified "other" as their specialty. The respondents were asked about the role of bilateral prophylactic mastectomy and the number of times they had recommended and performed it in a year., Results: Seven hundred forty-two surgeons responded (51.8%). More plastic surgeons (84.6%) than general surgeons (47.0%) and gynecologists (38.3%) agreed that bilateral prophylactic mastectomy has a role in the care of high-risk women. Eighty-one percent of plastic surgeons had recommended the procedure, compared with 38.8% of general surgeons and 17.7% of gynecologists., Conclusions: Indications and practice patterns reveal heterogeneity of medical opinion and practice of prophylactic mastectomy. This study raises the need for better evaluation of the efficacy and appropriateness of prophylactic mastectomy.

The capacity of peripheral blood lymphocytes to repair X-ray-induced DNA damage, manifest as chromatid damage 30-90 min after G2-phase X-irradiation, was measured among available members of a family exhibiting a cluster of breast-cancer cases occurring in one generation. The cancer patients had been exposed to repeated chest fluoroscopic examinations during early childhood and adolescence. The development of breast cancer was correlated with DNA repair proficiency and history of radiation exposure. The results of the family study provide preliminary support for the hypothesis that a deficiency in repair of X-irradiation DNA damage may be a susceptibility factor for the development of breast cancer. This hypothesis, however, requires confirmation in a larger study. Studying the combined effect of susceptibility factors and environmental exposures may enhance our knowledge of the etiology of breast cancer and provide leads for effective prevention strategies aimed at reducing exposures or altering susceptibility to unavoidable exposures.

Advances in the past year in understanding the etiology, early detection, and prevention of breast cancer are reviewed. Reports suggest that exogenous hormone therapy is associated with only moderate or no excess risk of breast cancer. Studies examining the association between exposure to organochlorine compounds and the risk of breast cancer are inconsistent and further investigations are required. The report by the International Workshop of Screening for Breast Cancer emphasizes the benefit in reducing breast cancer mortality to be gained by regular screening among women aged 50 years and older. Age is the strongest predictor of breast cancer risk, yet screening rates tend to diminish with age. Chemoprevention trials for the primary prevention of breast cancer are underway in North America and Europe. Agents under investigation include tamoxifen and fenretinide. The risks and benefits of tamoxifen therapy continue to be clarified with reports from a pilot prevention trial and follow-up of participants of prior adjuvant treatment trials. A beneficial effect in reducing cardiac morbidity has been observed among women taking 40 mg/d of tamoxifen for at least 2 years. Several studies demonstrated the increased risk of endometrial pathologic changes, including endometrial cancer associated with tamoxifen therapy. Because of the uncertainty of net risks and benefits, close monitoring for adverse side effects should be incorporated into ongoing prevention trials.

To examine the association prospectively between endogenous hormones and breast cancer, a population-based, nested case-control study was conducted using serum collected in 1974. Serum hormone levels among 51 women, who subsequently developed breast cancer, were compared with controls matched on age and time since last menstrual period. The levels of estrogens, progesterone, sex-hormone binding globulin, and androstenedione were compared between cases and controls. No statistically significant differences in endogenous hormones levels were observed between women who subsequently developed breast cancer and controls. Despite the fact that risk factors for breast cancer implicated endogenous hormones, especially estrogen, in the etiology of this disease, our study failed to demonstrate a statistically significant association between endogenous hormones and the risk of breast cancer. If there is an association between endogenous hormones and breast cancer, the magnitude of the effect is weak.

Major advances in the past year in the etiology, early detection, and prevention of breast cancer are reviewed. Progress has been made in the genetic epidemiology of breast cancer. A major gene locus has been identified among cancer families with predominantly breast or ovarian cancer, or both. Hormonal factors associated with breast cancer continue to be studied. Recent reports suggested that exogenous hormone therapy is associated with only moderate or no excess risk of breast cancer. With respect to early detection, controversy arose regarding the benefit of screening for women younger than 50 years of age. The Canadian National Breast Screening Study showed no decrease in breast cancer mortality for women 40 to 49 years old who were screened annually compared with women who had a baseline breast examination. An international workshop was convened to review results of breast cancer screening trials with emphasis on women younger than 50 years of age. Chemoprevention trials for the primary prevention of breast cancer are underway in North America and Europe. Agents under investigation include tamoxifen and fenretinide. Prevention of breast cancer will also be examined in two trials with multiple disease end points; one is an intervention with low dietary fat, and the other is an intervention with specific micronutrients.

This paper has reviewed the rationale for and design of the NSABP Breast Cancer Prevention Trial and has provided a brief critique of the philosophy of chemoprevention of breast cancer and of certain practical aspects of the trial design. If the assumptions and estimates from the trial protocol are correct, the net benefit of the trial will be moderately large and positive (50 to 77 events prevented). However, over 500 women per year will be treated with tamoxifen unnecessarily. Recalculation of the net-benefit table using another set of reasonable assumptions regarding risks and the trial assumptions regarding benefits shows a negative effect to a small positive effect overall (-17 to 8 events). If the probability of adverse ocular events is included in the net-benefit equations, it appears that more harm than good will result from the intervention. In the face of the uncertainty regarding the net benefit of the trial, ranges of these risks and benefits should be provided to both potential and enrolled participants. The lack of significant benefit to participants seen with the recalculations may raise the question of whether the trial should continue as designed. One option would be to limit trial participation to postmenopausal women only, since 1) breast cancer is more common in postmenopausal women, 2) tamoxifen is more effective in postmenopausal women, 3) cardiovascular disease is more common in postmenopausal women, and 4) reductions in cholesterol levels and preservation of bone mass have only been documented in postmenopausal women (11, 27). Even in this case, however, the fundamental philosophical question of whether large numbers of healthy women should be "treated" with a toxic drug for the primary prevention of a rare event remains.

Delay in seeking medical attention for breast cancer symptoms, as well as delay in the diagnosing of and delivery of effective treatments for breast cancer may result in advanced states of disease, thereby contributing to breast cancer mortality. Our knowledge of the scope and characteristics of delay in breast cancer is limited. Delay can be divided into two components, patient and system delay. Patient delay is the time it takes for a women to seek help once she has discovered a breast symptom. System delay is the time it takes for a woman to be evaluated, diagnosed, and treated once she has sought help. Most of the studies have dealt with patient delay, with few studies being performed on system delay, especially in the United States. It is evident that patient and system delays of 2-3 months apiece do occur in a small percentage of cases. However, there is not a clear picture of the factors associated with these long delays. Studies have had conflicting results and have often been difficult to compare because of inconsistent definitions of delay. This review critically examines the available literature on delay in breast cancer. Given the lack of a complete understanding regarding the factors associated with long delay, and the fact that the earlier a breast cancer is diagnosed and treated, the greater the likelihood of long-term survival, it is especially important to do further work to determine the factors associated with long delay so that interventions can be designed to minimize delay and thus permit earlier diagnoses and treatments of breast cancers.

Dehydroepiandrosterone and dehydroepiandrosterone sulfate are steroids which may be associated with the development of breast cancer. To examine the association between serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate and the risk of developing premenopausal breast cancer, we measured hormone levels in 15 women who donated blood to a community-based serum bank in 1974 and who subsequently developed premenopausal breast cancer and in 29 matched controls from the same group of volunteers. The mean serum level of dehydroepiandrosterone among cases was 10% lower than among controls. The risk of developing breast cancer for women in the highest tertile compared with the lowest tertile of serum dehydroepiandrosterone was 0.40 with a suggestion of a dose-response trend with increasing levels. No consistent association between dehydroepiandrosterone sulfate and the risk of premenopausal breast cancer was evident. In contrast to postmenopausal breast cancer, a protective effect of dehydroepiandrosterone against premenopausal breast cancer is suggested, but because of the small sample size, the results of this study need to be replicated by others.

Dehydroepiandrosterone and dehydroepiandrosterone sulfate are endogenous steroids that are produced in the adrenal cortex. A number of studies have suggested that circulating levels of these hormones are related in some way to the risk of developing breast cancer. We measured serum levels of these steroids in 30 postmenopausal women who donated blood in 1974 for a community-based serum bank and who subsequently, at least 9 years later, developed breast cancer and in 59 matched controls from the same group of volunteers. Significantly elevated serum levels of dehydroepiandrosterone were found among cases prior to diagnosis compared to controls; serum levels of dehydroepiandrosterone sulfate were slightly increased among cases. In controls, current cigarette use was associated with increased serum levels of these steroids, and levels of both steroids decreased with age.