Combination of molecular alterations and smoking intensity predicts bladder cancer outcome: a report from the Los Angeles Cancer Surveillance Program.

BACKGROUND: Traditional single-marker and multimarker molecular profiling approaches in bladder cancer do not account for major risk factors and their influence on clinical outcome. This study examined the prognostic value of molecular alterations across all disease stages after accounting for clinicopathological factors and smoking, the most common risk factor for bladder cancer in the developed world, in a population-based cohort. METHODS: Primary bladder tumors from 212 cancer registry patients (median follow-up, 13.2 years) were immunohistochemically profiled for Bax, caspase-3, apoptotic protease-activating factor 1 (Apaf-1), Bcl-2, p53, p21, cyclooxygenase-2, vascular endothelial growth factor, and E-cadherin alterations. "Smoking intensity" quantified the impact of duration and daily frequency of smoking. RESULTS: Age, pathological stage, surgical modality, and adjuvant therapy administration were significantly associated with survival. Increasing smoking intensity was independently associated with worse outcome (P < .001). Apaf-1, E-cadherin, and p53 were prognostic for outcome (P = .005, .014, and .032, respectively); E-cadherin remained prognostic following multivariable analysis (P = .040). Combined alterations in all 9 biomarkers were prognostic by univariable (P < .001) and multivariable (P = .006) analysis. A multivariable model that included all 9 biomarkers and smoking intensity had greater accuracy in predicting prognosis than models composed of standard clinicopathological covariates without or with smoking intensity (P < .001 and P = .018, respectively). CONCLUSIONS: Apaf-1, E-cadherin, and p53 alterations individually predicted survival in bladder cancer patients. Increasing number of biomarker alterations was significantly associated with worsening survival, although markers comprising the panel were not necessarily prognostic individually. Predictive value of the 9-biomarker panel with smoking intensity was significantly higher than that of routine clinicopathological parameters alone.

No association between the SRD5A2 gene A49T missense variant and prostate cancer risk: lessons learned.

The steroid 5-alpha reductase type II gene (SRD5A2) encodes the enzyme which converts testosterone (T) to the more active androgen dihydrotestosterone. A non-synonymous single-nucleotide polymorphism, A49T (rs9282858), in SRD5A2 has been implicated in prostate cancer risk; however, results have been inconsistent. In 1999, we reported a strong association between the A49T variant and prostate cancer risk among African-Americans and Latinos in the Hawaii-Los Angeles Multiethnic Cohort (MEC). We report here an updated analysis of MEC data including the five major ethnic groups of the MEC, an increased sample size, improved genotyping technology and a comprehensive meta-analysis of the published literature. We found a non-statistically significant positive association between prostate cancer risk and carrying either the AT or TT genotype [odds ratio (OR) = 1.16, 95% confidence interval (CI) 0.79-1.69] in the MEC. This finding is in contrast to our previous results of ORs of 3.28 and 2.50 for the association between prostate cancer risk and the variant in African-American and Latino men, respectively; this can be accounted for by genotyping error in our earlier study. Meta-analysis of the published literature, including the current MEC data, shows a summary OR of 1.13 (95% CI 0.95-1.34) for the A49T variant with prostate cancer risk among sporadic, unselected cases. After evaluating more than 6000 cases and 6000 controls, there is little evidence of a role for the SRD5A2 A49T variant in prostate cancer risk. Overall, this report highlights the importance of rigorous genotyping quality control measures and replication efforts in genetic association studies.

Long-term recreational physical activity and risk of invasive and in situ breast cancer: the California teachers study.

BACKGROUND: Long-term physical activity may affect breast cancer risk. Few prospective studies have evaluated in situ or invasive breast cancer risk, or breast cancer receptor subtypes, in relation to long-term activity. METHODS: We examined the association between recreational physical activity and risk of invasive and in situ breast cancer in the California Teachers Study, a cohort of women established in 1995-1996. Of 110 599 women aged 20 to 79 years with no history of breast cancer followed up through December 31, 2002, 2649 were diagnosed as having incident invasive breast cancer and 593 were diagnosed as having in situ breast cancer. Information was collected at cohort entry on participation in strenuous and moderate recreational activities during successive periods from high school through the current age or age 54 years (if older at enrollment) and in the past 3 years. A summary measure of long-term activity up to the current age, or age 54 years if older, was constructed for each woman. RESULTS: Invasive breast cancer risk was inversely associated with long-term strenuous activity (>5 vs 5 vs

Physical activity and colon cancer risk among women in the California Teachers Study.

BACKGROUND: Existing data suggest that physical activity reduces colon cancer risk, but the association is not consistently observed in women. One potential explanation for this inconsistency is that hormone therapy, which is associated with lower colon cancer risk, acts as a modifier of the physical activity/colon cancer relationship. METHODS: Participants in the California Teachers Study (N = 120,147), a prospective cohort of female teachers and administrators residing in California, ages 22 to 84 years at baseline and with no prior history of colon cancer were eligible for study. Between 1996 and 2002, 395 patients were diagnosed with invasive colon cancer. The relative risks (RR) associated with lifetime (high school through age 54 years or current age) and recent (past 3 years) strenuous and moderate recreational physical activity were estimated using Cox proportional hazards regression models. RESULTS: Combined lifetime moderate and strenuous recreational physical activity was only modestly associated with colon cancer risk in the cohort [>or=4 versus or=4 versus

Hormone-related risk factors for breast cancer in women under age 50 years by estrogen and progesterone receptor status: results from a case-control and a case-case comparison.

INTRODUCTION: It has been suggested that hormonal risk factors act predominantly on estrogen receptor and progesterone receptor (ER/PR)-positive breast cancers. However, the data have been inconsistent, especially in younger women. METHODS: We evaluated the impact of age at menarche, pregnancy history, duration of breastfeeding, body mass index, combined oral contraceptive use, and alcohol consumption on breast cancer risk by ER/PR status in 1,725 population-based case patients and 440 control subjects aged 20 to 49 years identified within neighborhoods of case patients. We used multivariable unconditional logistic regression methods to conduct case-control comparisons overall as well as by ER/PR status of the cases, and to compare ER+PR+ with ER-PR- case patients. RESULTS: The number of full-term pregnancies was inversely associated with the risk of ER+PR+ breast cancer (ptrend = 0.005), whereas recent average alcohol consumption was associated with an increased risk of ER+PR+ breast cancer (ptrend = 0.03). Neither of these two factors was associated with the risk of ER- PR- breast cancer. Late age at menarche and a longer duration of breastfeeding were both associated with decreased breast cancer risk, irrespective of receptor status (all ptrend< or = 0.03). CONCLUSION: Our results suggest that the number of full-term pregnancies and recent alcohol consumption affect breast cancer risk in younger women predominantly through estrogen and progesterone mediated by their respective receptors. Late age at menarche and breastfeeding may act through different hormonal mechanisms.

Insulin-like growth factor I, IGF-binding protein 3, and lung cancer risk in a prospective study of men in China.

BACKGROUND: Insulin-like growth factor I (IGF-I) stimulates cell proliferation and inhibits apoptosis in the lung and other tissues by interacting with the IGF-I receptor. The major binding protein for IGF-I, insulin-like growth factor-binding protein 3 (IGFBP-3), modulates the effects of IGF-I but also inhibits cell growth and induces apoptosis independent of IGF-I and its receptor. In a prospective study of men in Shanghai, China, we examined the association between serum levels of IGF-I and IGFBP-3 and the subsequent risk of lung cancer. METHODS: From 1986 to 1989, serum was collected from 18,244 men aged 45-64 years living in Shanghai without a history of cancer. We analyzed IGF-I and IGFBP-3 levels in serum from 230 case patients who developed incident lung cancer during follow-up and from 740 control subjects. RESULTS: Among 230 case patients and 659 matched control subjects, increased IGF-I levels were not associated with increased risk of lung cancer. However, for subjects in the highest quartile relative to the lowest quartile of IGFBP-3, the odds ratio (OR) for lung cancer, adjusted for smoking and IGF-I, was 0.50 (95% confidence interval [CI] = 0.25 to 1.02). When the analysis was restricted to ever smokers (184 case patients and 344 matched control subjects), the OR for lung cancer in men in the highest quartile of IGFBP-3 relative to those in the lowest quartile, adjusted for smoking and IGF-I, was 0.41 (95% CI = 0.18 to 0.92). CONCLUSIONS: In this prospective study of Chinese men, higher serum levels of IGF-I did not increase the risk of lung cancer. However, subjects with higher serum levels of IGFBP-3 were at reduced risk of lung cancer. This finding is consistent with experimental data that indicate that IGFBP-3 can inhibit cellular proliferation and induce apoptosis independent of IGF-I and the IGF-I receptor.

Does menopausal hormone replacement therapy interact with known factors to increase risk of breast cancer?

PURPOSE: We and other investigators have previously shown that postmenopausal combined estrogen and progestin replacement therapy (EPRT) increases the risk of breast cancer and that the risk associated with EPRT is substantially higher than for estrogen replacement therapy (ERT) alone. The present study was conducted to determine whether any particular subgroup of women are at particularly high risk of breast cancer if they use EPRT and whether tumor characteristics in women who develop cancer while on ERT or EPRT are different from those in women not using ERT or EPRT. PATIENTS AND METHODS: We conducted a population-based case-control study in Los Angeles, CA, with patients diagnosed with breast cancer in the late 1980s and early 1990s. Control subjects were matched to patients on age, ethnicity, and neighborhood of residence. We present data on 1,897 postmenopausal patients and 1,637 controls aged 55 to 72 years who had not undergone a simple hysterectomy. RESULTS: Relative risk of breast cancer associated with EPRT use did not vary with body mass index (body mass index at or below v above median [24.6 kg/m(2)]; P =.98), alcohol intake (> or + one v < one drink per week; P =.16), parity (nulliparous v parous; P =.45), history of benign breast disease (yes v no; P =.99), or family history of breast cancer (first degree v none; P =.57). All of these results were compatible with our previously reported estimate of an increased risk of breast cancer of 5% per year of use of EPRT. Hormone users, principally EPRT users, were more likely to have hormone receptor--positive, especially progesterone-positive, tumors. CONCLUSION: We found no evidence that the risk of breast cancer associated with EPRT is limited to subgroups of women with specific cofactors. Tumors in EPRT users are more often hormone receptor--positive, indicating that they may have a better prognosis than breast cancer overall.

Residential mobility in the California Teachers Study: implications for geographic differences in disease rates.

BACKGROUND: Especially for cancers with long latency periods, such as breast cancer, the issue of residential mobility hinders ecologic analyses seeking to examine the role of environmental contaminants in chronic disease etiology. This study describes and evaluates characteristics associated with residential mobility in a sub-sample of the California Teachers Study (CTS) cohort. METHODS: In 2000, lifetime residential histories were collected for a sub-sample of 328 women enrolled in the CTS; women's degree of residential mobility and associated factors were analyzed. RESULTS: While most women moved many times during their lives (average = 8.9), the average number of years at their residence when they enrolled in the study was reasonably long (15.1 years). Age strongly predicted duration at current residence but was not related to the number of lifetime residences. After adjusting for age, California-born women and women living in high socioeconomic status (SES) neighborhoods were significantly more residentially stable. Agreement between self-reported urbanization of recent residences and that based on census data of the geocoded residences was very good (80% concordant). Among women currently living in urban areas, an average of 43.3 years, or 77%, of their lifetimes were spent in urban residences; among women currently living in a rural area, an average of 37.3 years, or 67% of their lifetimes were spent in rural residences. CONCLUSIONS: This suggests that analyses of incidence rates based on current residence, while not capturing a woman's full exposure history, may reasonably reflect some aspect of longer term chronic exposures, especially those related to urbanization, at least in professional women.

Nonsmoking-related arylamine exposure and bladder cancer risk.

Roughly one-half of bladder cancer incidence in the United States can be attributed to known causes, mainly cigarette smoking, and it has been hypothesized that the aromatic amines in tobacco smoke are important etiological agents. Nonsmokers are also exposed, through unknown sources, to many of the same carcinogenic aromatic amines that are present in cigarette smoke. Previous epidemiological studies have not tested whether either of these aromatic amine exposures are associated with cancer risk. We conducted a population-based case-control study in Los Angeles County, California, involving 761 case patients with bladder cancer and 770 individually matched control subjects. In-person interviews provided information on tobacco smoking and other potential risk factors. Quantitative analysis of hemoglobin adducts of 4- and 3-aminobiphenyl (ABP) was used to assess aromatic amine exposure. Adducts of both aminobiphenyls were significantly higher in cases than in controls, independent of cigarette smoking at the time of blood collection and lifetime smoking history. Adjustment for other risk factors as well as for metabolic differences did not materially alter the associations. Our findings strengthen the connection between exposure to aromatic amines in tobacco smoke and cigarette smoking-related bladder cancer and suggest that environmental exposure to arylamines may account for a significant proportion of nonsmoking-related bladder cancer in the general population.

Prediagnostic levels of serum micronutrients in relation to risk of gastric cancer in Shanghai, China.

Data on blood levels of specific carotenoids and vitamins in relation to gastric cancer are scarce. Little is known about the relationship between prediagnostic serum levels of carotenoids other than beta-carotene and risk of gastric cancer especially in non-Western populations. Prediagnostic serum concentrations of alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, lutein/zeaxanthin, retinol, alpha-tocopherol, gamma-tocopherol, and vitamin C were determined on 191 cases and 570 matched controls within a cohort of 18,244 middle-aged or older men in Shanghai, China, with a follow-up of 12 years. High serum levels of alpha-carotene, beta-carotene, and lycopene were significantly associated with reduced risk of developing gastric cancer (all Ps for trend /=3 drinks of alcohol per day; the odds ratios (95% confidence intervals) for the second, third, and fourth quartile categories were 0.69 (0.28-1.70), 0.36 (0.14-0.94), and 0.39 (0.15-0.98), respectively, compared with the lowest quartile of vitamin C (P for trend = 0.02). There were no statistically significant relationships of serum levels of beta-cryptoxanthin, lutein/zeaxanthin, retinol, alpha-tocopherol, and gamma-tocopherol with gastric cancer risk. The present study implicates that dietary carotenes, lycopene, and vitamin C are potential chemopreventive agents for gastric cancer in humans.

Patterns of alcohol consumption and breast cancer risk in the California Teachers Study cohort.

Alcohol consumption of approximately two drinks or more per day has been associated with elevated breast cancer risk in the California Teachers Study cohort as well as in many other populations. The objective of this analysis is to examine effects of age at drinking and drinking patterns and to identify effect modifiers. Of the 103,460 at-risk cohort members, age <85, who resided in California and completed the baseline alcohol assessment, 1,742 were diagnosed with invasive breast cancer after joining the cohort and before January 2001. Incident breast cancers were identified through the California Cancer Registry and follow-up for death and confirmation of continued California residence used various sources. Multivariate Cox proportional hazards regression models were used to estimate relative risks (RRs). Elevated breast cancer risk was most evident for recent drinking [RR = 1.28, 95% confidence interval (CI): 1.06-1.54 for >/=20 g/day versus nondrinkers], with no clear pattern for consumption during earlier periods of life. This elevation in risk was 32% among postmenopausal women (95% CI: 1.06-1.63) and 21% among pre/perimenopausal women (95% CI: 0.76-1.92). Highest risks associated with heavy alcohol consumption were observed among postmenopausal women with a history of biopsy-diagnosed benign breast disease (RR = 1.97, 95% CI: 1.39-2.79 compared to nondrinkers without benign breast disease) or who had used combination hormone replacement therapy (HRT) (RR = 2.24, 95% CI: 1.59-3.14 compared to nondrinkers who never used HRT). Recent alcohol consumption equivalent to two or more drinks per day increases the risk of invasive breast cancer, with the greatest RRs observed among heavy drinkers who are also postmenopausal and have a history of benign breast disease or who use HRT.

A modified reduced-temperature antigen retrieval protocol effective for use with a polyclonal antibody to cyclooxygenase-2 (PG 27).

Antigen retrieval is now a standard procedure in immunohistochemical studies of tissues for diagnosis and research. While the most commonly used protocol (20 minutes at 100 degrees C in citrate buffer pH 6.0) is effective for many antibody/antigen combinations, experience has shown that in some instances, this standard approach fails. Under these circumstances, a successful antigen retrieval protocol may still be established by varying key conditions in the antigen retrieval process. The authors previously have advocated a test battery approach to determine the optimal conditions for antigen retrieval, illustrated here with respect to a polyclonal antibody to cyclooxygenase-2 (PG-27) that failed to give a positive staining result after orthodox antigen retrieval. The key feature of this modified antigen retrieval protocol is heating the deparaffinized tissue sections at a reduced temperature (90 degrees C as opposed to 100 degrees C). For this particular antibody, a boiling condition yields a negative result, a principal reason why previous investigators have used a tyramide signal amplification system to achieve satisfactory immunohistochemical results with this antibody. The optimal antigen retrieval protocol established in the authors' laboratory for this polyclonal antibody to cyclooxygenase-2 (PG-27) was evaluated in a study of formalin-fixed, paraffin-embedded cell lines and 31 bladder cancer tissue blocks using the tissue microarray technique, with side-by-side comparison between the results obtained by a tyramide signal amplification method (without antigen retrieval) and a standard immunohistochemical method with the optimized antigen retrieval protocol. The reduced temperature antigen retrieval protocol yielded a comparable or superior immunostaining for cyclooxygenase-2 both in cell lines and tissue blocks. In conclusion, use of the test battery approach allowed development of a modified antigen retrieval technique that provides a more reliable, much simpler approach for the demonstration of cyclooxygenase-2 in archival tissues.

Correlates of active and passive smoking in the California Teachers Study cohort.

OBJECTIVES: These analyses were designed to describe characteristics associated with active and passive smoking in a large cohort of women in order to identify possible confounders of the relationship between smoking exposures and breast cancer risk. METHODS: Analyses were based on 1995 data collected from the California Teachers Study (CTS) and were restricted to those with complete and usable tobacco data (n = 128,174). Age-adjusted and race-adjusted odds ratios (OR) were generated by unconditional logistic regression. RESULTS: Compared with never smokers, both current and former smokers experienced menarche at an earlier age. Current and former smokers also were more likely than their never smoking counterparts to be nulliparous. Among parous women, current, but not former smokers were less likely than never smokers to have had their first child at an older age. Similarly, among never smokers, those exposed to household passive smoking experienced menarche at an earlier age, were more likely to be nulliparous, and among parous women, were less likely to have had their first child at an older age than never smokers not exposed to passive smoking. Greater alcohol consumption was strongly associated with both active and passive smoking exposures. Compared with never smokers, current smokers were less likely to take antioxidant supplements, whereas former smokers were more likely to take antioxidant supplements. Among never smokers, antioxidant use did not differ depending on passive smoking exposure. A number of other dietary correlates of active and passive smoking were identified. CONCLUSIONS: We identified a number of reproductive and dietary correlates to smoking exposures that underscore the need to adjust for such factors in an analysis of smoking and breast cancer and potentially other disease entities. Furthermore, these findings may suggest potential mechanisms underlying an association between breast cancer and smoking.

Arylamine exposures and bladder cancer risk.

Occupational exposure to arylamines in industrial settings was the first known cause of bladder cancer in humans. In the United States and many developed countries, these industrial dyes have been under strict government control for decades and are believed to contribute minimally to today's population burden of bladder cancer in the West. The two other recognized, and potentially substantial sources of human exposure to arylamines are cigarette smoking and use of hair dyes. This paper reviews the latest epidemiologic findings on the relationships between smoking, hair dye use and bladder cancer risk. Results support the notion that arylamines contained in cigarette smoke and permanent hair dyes are human carcinogens. Furthermore, women may experience higher bladder cancer risk than men from comparable arylamine exposure, possibly due in part to women's higher propensity for arylamine activation relative to men.

Adenomyosis and endometriosis in the California Teachers Study.

OBJECTIVE: To evaluate the reproductive and lifestyle correlates of a surgically confirmed diagnosis of endometriosis or adenomyosis in a large prospective cohort. DESIGN: Collection of surgical diagnoses of endometriosis and adenomyosis during follow-up of women with no prior history of endometriosis and no prior surgery for adenomyosis. SETTING: The California Teachers Study (CTS), an ongoing prospective study of female teachers and school administrators established from the rolls of the California State Teachers Retirement System. PATIENT(S): Women with surgical diagnoses of endometriosis and adenomyosis were identified from California statewide hospital patient discharge records for CTS cohort members with an intact uterus and no prior history of endometriosis. Women with an incident surgical diagnosis of endometriosis (n = 229) or adenomyosis (n = 961) were compared with disease-free women in the same age range (for endometriosis, n = 43,493; for adenomyosis, n = 79,495). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Multivariable logistic regression methods were used to calculate prevalence odds ratios and associated 95% confidence intervals for the associations between self-reported menstrual and reproductive characteristics and either endometriosis or adenomyosis. RESULT(S): Women surgically diagnosed with endometriosis were younger than those surgically diagnosed with adenomyosis. Factors statistically significantly associated with endometriosis were having a mother or sister with endometriosis and nulligravidity. Factors statistically significantly associated with adenomyosis were increasing parity, early menarche (

Beta-cryptoxanthin and lung cancer in Shanghai, China--an examination of potential confounding with cigarette smoking using urinary cotinine as a biomarker for true tobacco exposure.

Diet may be a modifier of smoking-related cancer risk, with protective effects of intake of fruits and vegetables and associated antioxidants found in many observational studies. We previously reported serum beta-cryptoxanthin levels being inversely associated with smoking-related lung cancer incidence in a cohort of Chinese men. We noted, however, that serum beta-cryptoxanthin is negatively correlated with smoking. Since self-reports of smoking intensity undoubtedly contain errors, this negative correlation indicates a potential bias in assessing the effects of beta-cryptoxanthin, due to confounding with the unmeasured (residual) portion of cigarette exposure. We evaluated cotinine levels in pre-diagnostic spot urine samples to attempt to improve smoking assessment. We noted that urinary cotinine levels correlated significantly with cigarette consumption overall and that cotinine was strongly predictive of lung cancer risk. Urinary cotinine, however, was not as strong a predictor of lung cancer risk in current smokers as were self-reports of cigarette consumption and cotinine remained only a marginally significant predictor of lung cancer risk after adjustment for self-reports. An apparent benefit of beta-cryptoxanthin remained evident when including both urinary cotinine and self-reported cigarette consumption and cotinine in the statistical model. However, we conclude that cotinine measured from a single spot urine seems to have only limited value in augmenting self-reports of cigarette consumption so that, at present, the apparent protective effects of beta-cryptoxanthin, as seen in our own study, should continue to be regarded as unproven. We believe that future epidemiological evaluation of the association between beta-cryptoxanthin (and other antioxidants) and reduced lung cancer risk must utilize improved biomarkers to augment smokers' own self-reports of smoking amount.

Alcohol consumption and risk of bladder cancer in Los Angeles County.

The role of alcoholic beverages in bladder carcinogenesis is still unclear, with conflicting evidence from different studies. We investigated the relationship between alcohol consumption and bladder cancer, and the potential interaction between alcohol consumption and other exposures. In a population-based case-control study conducted in Los Angeles County, 1,586 pairs of cases and their matched neighborhood controls were interviewed. Data were analyzed to determine whether bladder cancer risk differs by alcohol consumption, and whether different alcoholic beverages have different effects. The risk of bladder cancer decreased with increasing frequency (p for trend = 0.003) and duration of alcohol consumption (p for trend = 0.017). Subjects who drank more than 4 drinks per day had a 32% lower (odds ratio, 0.68; 95% confidence interval, 0.52-0.90) risk of bladder cancer than those who never drank any alcoholic beverage. Beer (p for trend = 0.002) and wine (p for trend = 0.054) consumption were associated with reduced risk of bladder cancer, while hard liquor was not. The reduction in risk was mostly seen among shorter-term smokers who urinated frequently. Alcohol consumption was strongly associated with a reduced risk of bladder cancer. The effect was modified by the type of alcoholic beverage, cigarette smoking and frequency of urination.

Diet and risk of ovarian cancer in the California Teachers Study cohort.

Dietary phytochemical compounds, including isoflavones and isothiocyanates, may inhibit cancer development but have not yet been examined in prospective epidemiologic studies of ovarian cancer. The authors have investigated the association between consumption of these and other nutrients and ovarian cancer risk in a prospective cohort study. Among 97,275 eligible women in the California Teachers Study cohort who completed the baseline dietary assessment in 1995-1996, 280 women developed invasive or borderline ovarian cancer by December 31, 2003. Multivariable Cox proportional hazards regression, with age as the timescale, was used to estimate relative risks and 95% confidence intervals; all statistical tests were two sided. Intake of isoflavones was associated with lower risk of ovarian cancer. Compared with the risk for women who consumed less than 1 mg of total isoflavones per day, the relative risk of ovarian cancer associated with consumption of more than 3 mg/day was 0.56 (95% confidence interval: 0.33, 0.96). Intake of isothiocyanates or foods high in isothiocyanates was not associated with ovarian cancer risk, nor was intake of macronutrients, antioxidant vitamins, or other micronutrients. Although dietary consumption of isoflavones may be associated with decreased ovarian cancer risk, most dietary factors are unlikely to play a major role in ovarian cancer development.