Association of parity and ovarian cancer risk by family history of breast or ovarian cancer in a population-based study of postmenopausal women.

Although parity is associated with a decreased risk of ovarian cancer in the general population, this association among women with a family history is less clear. We examined this question in a prospective cohort of 31,377 Iowa women 55-69 years of age at baseline. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated through Cox regression. We identified 181 incident epithelial ovarian cancers through 13 years of follow-up. At baseline, 14% of the women reported breast or ovarian cancer in a first-degree relative, and an additional 12% reported a family history in a second-degree relative. Among women without a family history of breast or ovarian cancer in a first-degree relative, nulliparous women were at slightly increased risk of ovarian cancer (RR = 1.4, 95% CI = 0.9-2.4) compared with parous women, whereas among women with a family history, nulliparous women were at a much higher risk (RR = 2.7, 95% CI = 1.1-6.6) than parous women. Similar results were seen when family history included first- or second-degree relatives with breast or ovarian cancer or a first- or second-degree relative with ovarian cancer only. Nulliparity may be more strongly associated with an increased risk of ovarian cancer among women with a family history of breast or ovarian cancer, compared with women who do not have a family history of those cancers.     

Risk of breast cancer classified by joint estrogen receptor and progesterone receptor status among women 20-44 years of age

To gain insight into whether breast cancer tumors jointly classified by estrogen receptor (ER) and progesterone receptor (PR) status represent diseases with differing etiologies, data from a population-based case-control study of US women 20-44 years of age were analyzed. Cases included 1,556 women diagnosed between 1990 and 1992. Age- and geographic-frequency-matched controls included 1,397 women identified by random digit dialing. Heterogeneity between ER+PR+ and ER-PR- tumors was most pronounced in relation to age, race, and recreational exercise at 12-13 years of age. Multivariate-adjusted odds ratios for ER+PR+ tumors were 0.64 (95% confidence interval (CI): 0.47, 0.89) for 30-34 versus 40-44 years of age, 0.89 (95% CI: 0.63, 1.25) for Black versus White race, and 0.84 (95% CI: 0.68, 1.03) for exercise at 12-13 years of age above versus at or below the median. Corresponding odds ratios for ER-PR- tumors were 1.24 (95% CI: 0.86, 1.77), 1.51 (95% CI: 1.07, 2.14), and 1.15 (95% CI: 0.90, 1.48). Risk of ER-PR- cancer in relation to menstrual and reproductive (parity and lactation) characteristics, alcohol consumption, and family history of breast cancer was similar to that observed for ER+PR+ tumors. These findings only modestly support the hypothesis that hormonally related risk factors have differing relations with ER+PR+ versus ER-PR- tumors among younger women.     

Hormone-related factors and risk of breast cancer in relation to estrogen receptor and progesterone receptor status

Risk factors were examined for subgroups of breast cancer characterized by estrogen receptor (ER) and progesterone receptor (PR) status. Data from the Carolina Breast Cancer Study, a population-based, North Carolina case-control study of 862 breast cancer cases aged 20-74 years diagnosed during 1993-1996 and 790 controls frequency matched on race and age, were obtained by personal interview. ER and PR status was retrieved from medical records (80%) or was determined in the authors' laboratory (11%) but was missing for 9% of cases. The receptor status distribution was as follows: 53% ER+PR+, 11% ER+PR-, 8% ER-PR+, and 28% ER-PR-. Several hormone-related factors were associated with stronger increased risks for ER+PR+ than for ER-PR- breast cancer: the elevated odds ratios were strongest for ER+PR+ breast cancer among postmenopausal women who had an early age at menarche (odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.4), nulliparity/late age at first full-term pregnancy (OR = 1.7, 95% CI: 0.9, 3.2 and OR = 1.6, 95% CI: 1.0, 2.7, respectively), or a high body mass index (OR = 1.6, 95% CI: 0.9, 3.0) and among pre-/perimenopausal women who had a high waist-hip ratio (OR = 1.9, 95% CI: 1.2, 3.1). In contrast, family history of breast or ovarian cancer and medical radiation exposure to the chest produced higher odds ratios for ER-PR- than for ER+PR+ breast cancer, especially among pre-/perimenopausal women.     

Food Sources of Fat and Sex Hormone Receptor Status of Invasive Breast Tumors in Women of the Malmö Diet and Cancer Cohort

We examined associations between food intakes and incident breast cancer, defined by estrogen receptor (ER) and progesterone receptor (PR) status in the Malmö Diet and Cancer cohort (～17,000 women aged 45–73 yr). The hazard ratios (HRs) of ER+PR+ (n = 270), ER+PR? (n = 87), and ER?PR? (n = 61) tumors and all cancer (n = 544) were estimated after 10 yr of follow-up. In multivariate analysis of ER+PR+ tumors, a protective linear risk trend, indicating change between adjoining food categories, was seen with yogurt (HR = 0.89, 95% CI = 0.80–0.99), but increased risks with eggs (HR = 1.10, 95% CI = 1.01–1.20) and dried soups/sauces (HR = 1.10, 95% CI = 1.00–1.22). In ER?PR? tumors, vegetable-oil-based margarine (HR = 1.31, 95% CI = 1.09–1.59) and dried soups/sauces (HR = 1.31 95% CI = 1.05–1.64) showed increased risks. Heterogeneity was observed between ER+PR+ and ER?PR? tumors for vegetable-oil-based margarine (P < 0.01). Regular milk showed decreased, and dried soups/sauces increased, risk with all breast cancer. The study suggests that fat-containing food may contribute both to hormonal and nonhormonal mechanisms in breast tumor development and supports observations of positive associations between characteristics of Westernized diets and postmenopausal breast cancer.     

Alcohol consumption and breast cancer risk in the Women's Health Study

The authors assessed the association between moderate alcohol consumption and breast cancer risk in the Women's Health Study (United States, 1992-2004). During an average of 10 years of follow-up, 1,484 cases of total breast cancer (1,190 invasive and 294 in situ) were documented among 38,454 women who, at baseline, were free of cancer and cardiovascular disease and provided detailed dietary information, including alcohol consumption, for the preceding 12 months. Higher alcohol consumption was associated with a modest increase in breast cancer risk; the multivariable relative risks for > or =30 g/day of alcohol vs. none were 1.32 (95% confidence interval (CI): 0.96, 1.82) for total breast cancer and 1.43 (95% CI: 1.02, 2.02) for invasive breast cancer. An increased risk was limited to estrogen receptor (ER)- and progesterone receptor (PR)-positive tumors; the multivariable relative risks for an increment of 10 g/day of alcohol were 1.11 (95% CI: 1.03, 1.20) for ER+PR+ tumors (804 cases), 1.00 (95% CI: 0.81, 1.24) for ER+PR- tumors (125 cases), and 0.99 (95% CI: 0.82, 1.20) for ER-PR- tumors (167 cases). The association also seemed strongest among those taking postmenopausal hormones currently, but the test for interaction was not significant. The findings from this prospective study suggest that moderate alcohol consumption increases breast cancer risk.     

Family history of cancer and incidence of acute leukemia in adults

Family history of cancer may represent shared genetic and environmental risk factors for leukemia. The authors examined associations of first-degree family history of cancer with adult acute leukemia incidence by using data on 811 patients (or their proxies) identified at diagnosis and 637 population-based controls in the United States and Canada during 1986-1990. For proxy-interviewed patients, relative risks were elevated for family history of any cancer (relative risk = 1.7, 95% confidence interval (CI): 1.3, 2.4), hematopoietic cancer (relative risk = 1.8, 95% CI: 1.1, 3.0), leukemia (relative risk = 2.4, 95% CI: 1.3, 4.6), and breast cancer (relative risk = 1.7, 95% CI: 1.0, 3.0) but not for colorectal, prostate, or lung cancer. For self-interviewed patients, family history of hematopoietic cancer was inversely associated with leukemia incidence (relative risk = 0.6, 95% CI: 0.4, 1.1). Regardless of patient interview type, history of breast cancer in sisters was positively associated with adult acute leukemia, whereas history of breast cancer in mothers was not. The role of family history of cancer in leukemia etiology is unclear because of differential reporting by patients and proxies. Specifically, self-interviewed patients may underreport cancer in their first-degree relatives. Associations between family history of breast cancer and leukemia incidence may be the result of unmeasured, shared etiologies specific to these cancers.     

The genetic epidemiology of second primary breast cancer.

It is well established that women with a family history of breast cancer run a higher risk of breast cancer than do women without a family history. The evidence, however, is less clear regarding a possible association between a family history of breast cancer and risk of second primaries. The purpose of this prospective study was to estimate the risk for second primary breast cancer associated with having a family history of breast, endometrial, and ovarian cancers. A cohort of 4,660 women with a first primary breast cancer diagnosed between 1980 and 1982 were interviewed as part of the Cancer and Steroid Hormone Study, a multi-center population-based case-control study, and followed through eight Surveillance, Epidemiology, and End Results (SEER) program registries for 4 to 6 years. Of these women, 136 developed a second primary breast cancer in the contralateral breast at least 6 months after diagnosis of the first primary. Cox proportional hazards modeling techniques were used to model the time to onset of second primary breast cancer while adjusting for multiple predictors. The risk of contralateral breast cancer was elevated among cohort members who reported a history of breast cancer in a first-degree relative (multivariable-adjusted rate ratio (RR) = 1.91, 95% confidence interval (CI) = 1.22-2.99). Early age at onset (< 46 years) in the relative further increased the risk of developing contralateral breast cancer (sister: multivariable-adjusted RR = 3.36, 95% CI 1.62-6.98; mother: multivariable-adjusted RR = 2.35, 95% CI 1.02-5.43). Bilateral breast cancer in mothers was also associated with more than a two and a half-fold increase in risk (multivariable-adjusted RR = 2.55, 95% CI 1.02-6.35). The association between family history of breast cancer and risk of contralateral breast cancer did not vary substantially according to age at onset of the first primary breast cancer. The age-adjusted rate ratio for development of a second primary breast cancer among women with a first-degree relative with endometrial cancer was 2.13 (95% CI 1.04-4.35), while the corresponding rate ratio among women with a family history of ovarian cancer was 1.69 (95% CI 0.42-6.83). There was little evidence that age at onset among the relatives with endometrial or ovarian cancer affected the risk. Some of these findings have not been previously reported and need replication in future studies.     

Increased cancer risk among relatives of nonsmoking lung cancer cases

Lung cancer has been shown to aggregate in families of nonsmoking lung cancer cases with an earlier age at onset. The current study evaluates whether relatives of nonsmoking lung cancer cases are at increased risk of cancers at sites other than lung. Families were identified through 257 population‐based, nonsmoking lung cancer cases and 277 population‐based, nonsmoking controls residing in metropolitan Detroit. Data were collected for 2,252 relatives of cases and 2,408 relatives of controls. First‐degree relatives of nonsmoking lung cancer cases were at 1.52‐fold (95% CI, 1.02–2.27) increased risk of cancer of the digestive system after adjustment for each relative's age, race, sex, and smoking status. Relative risk estimates also were elevated, but not significantly, for tobacco‐related cancers (RR = 1.39) and breast cancer (RR = 1.72). Among first‐degree relatives of younger probands (age 40–59), risk was non‐significantly increased 72% (95% CI 0.95–3.10) for all cancers combined and 3.14‐fold for cancers of the digestive system (95% CI 0.76–12.9). Nonsmoking relatives of cases were at increased risk of all cancer sites combined (RR = 1.32; 95% CI 1.003–1.73), cancers other than lung (RR = 1.37; 95% CI 1.03–1.82), and digestive system cancers (RR = 2.01; 95% CI 1.20–3.37). These findings of moderate familial aggregation for cancers of the lung, digestive system, breast, and tobacco‐related sites suggest that common susceptibility genes may act to increase risk for a variety of cancers in families. Genet. Epidemiol. 17:1–15, 1999. © 1999 Wiley‐Liss, Inc.     

Familial aggregation of breast cancer with early onset lung cancer.

Site-specific familial aggregation and evidence supporting Mendelian codominant inheritance have been shown in lung cancer. In characterizing lung cancer families, a number of other cancers have been observed. The current study evaluates whether first-degree relatives of early onset lung cancer cases are at increased risk of breast cancer. Families were identified through population-based lung cancer cases and controls under 40 years of age. Cases were ascertained through the Metropolitan Detroit SEER registry; controls through random-digit dialing. Data were available for 384 female relatives of 118 cases and 465 female relatives of 161 controls. Breast cancer in relatives was evaluated after adjusting for age, race, sex, and smoking status of each family member and the sex and age of the probands. A positive family history of early onset lung cancer increased breast cancer risk among first-degree relatives 5. 1-fold (95% CI, 1.7-15.1). Relatives of cases with adenocarcinoma of the lung were at highest risk (RR = 6.3, 95% CI 2.0-20). Mean age of breast cancer diagnosis among relatives of cases was 52.2 years and not statistically different from relatives of controls. Three case families also reported early ovarian cancers (mean age of diagnosis of 35 years). These findings suggest that shared susceptibility genes may act to increase risk of early onset lung and breast cancer in families.     

Aggregation of ovarian cancer with breast, ovarian, colorectal, and prostate cancer in first-degree relatives

Epidemiologic studies have demonstrated a tendency for common cancers to aggregate in families. The authors investigated the effects of family history of cancer at multiple sites, including the breast, ovary, colorectum, and prostate, on ovarian cancer risk among 607 controls and 558 ovarian cases in Hawaii and Los Angeles, California, in 1993-1999. A family history of cancer of the breast, ovary, colorectum, or prostate in first-degree relatives was associated with an increased risk of ovarian cancer (odds ratio (OR)=1.7, 95% confidence interval (CI): 1.1, 2.6; OR=3.2, 95% CI: 1.3, 7.9; OR=1.5, 95% CI: 0.9, 2.5; and OR=1.6, 95% CI: 1.0, 2.8, respectively). A greater risk of ovarian cancer was observed for women with parents rather than siblings with a history of breast or prostate cancer and for women with parental colorectal cancer diagnosed at an early age, suggesting a genetic predisposition among these women. The risk of nonmucinous tumors, but not mucinous tumors, was positively associated with a family history of cancer. No significant interaction effects on risk existed between oral contraceptive pill use or pregnancy and family history of breast and/or ovarian cancer. Study findings suggest that ovarian cancer aggregates with several common cancers in family members.     

The HER2 I655V polymorphism and breast cancer risk in Ashkenazim

SUMMARY: BACKGROUND Over-expression of the human epidermal growth factor receptor 2 (Her2) protooncogene is associated with poor prognosis among female patients with breast cancer. A polymorphism in the HER2 gene (I655V) has been associated with an elevated risk of breast cancer in some ethnic groups.METHODS Subjects from a community-based study of 5318 Ashkenazim from the Washington, DC area were selected for analysis of the I655V HER2 germline polymorphism. We estimated age-specific breast cancer risk from HER2 I655V based on the family history data, using the female first-degree relatives of the study participants and a novel extension of the kin cohort method.RESULTS The estimated cumulative risk of breast cancer to age 70 was approximately 30% higher among HER2 I655V carriers than noncarriers (RR = 1.33; 95% confidence interval [CI] = 1.03-1.83). The effect of the allele seems stronger at younger ages (among women younger than 50 years, RR = 2.11; CI = 1.39-3.28) and especially among younger women with a family history of breast cancer (RR = 8.9; CI = 1.9-19.7). Increased risk of breast cancer associated with the I655V allele was also observed among BRCA1/2 mutation carriers, although these results are based on small numbers.CONCLUSION These analyses suggest that the HER2 valine allele might be associated with increased risk of breast cancer, especially in young women and in women with a family history of the disease.     

Fruit, vegetable, and animal food intake and breast cancer risk by hormone receptor status

The effects of diet on breast cancer are controversial and whether the effects vary with hormone receptor status has not been well investigated. This study evaluated the associations of dietary factors with risk for breast cancer overall and by the hormone receptor status of tumors among Chinese women. The Shanghai Breast Cancer Study, a large, population-based, case-control study, enrolled 3,443 cases and 3,474 controls in 1996-1998 (phase I) and 2002-2005 (phase II); 2676 cases had estrogen receptor (ER) and progesterone receptor (PR) data. Dietary intake was assessed using a validated, quantitative, food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (95% CI) were derived from multivariate, polychotomous, unconditional logistic regression models. Total vegetable intake was inversely related to breast cancer risk, with an adjusted OR for the highest quintile of 0.80 (95% CI = 0.67-0.95; P trend = 0.02). Reduced risk was also related to high intake of allium vegetables (P trend = 0.01) and fresh legumes (P trend = 0.0008). High intake of citrus fruits and rosaceae fruits were inversely associated with breast cancer risk (P trend = 0.003 and 0.004, respectively), although no consistent association was seen for total fruit intake. Elevated risk was observed for all types of meat and fish intake (all P trend < 0.05), whereas intakes of eggs and milk were associated with a decreased risk of breast cancer (both P trend <0.05). There was little evidence that associations with dietary intakes varied across the 4 tumor subtypes or between ER+/PR+ and ER-/PR- tumors (P for heterogeneity >0.05). Our results suggest that high intake of total vegetables, certain fruits, milk, and eggs may reduce the risk of breast cancer, whereas high consumption of animal-source foods may increase risk. The dietary associations did not appear to vary by ER/PR status.     

Selected antioxidants and risk of hormone receptor-defined invasive breast cancers among postmenopausal women in the Women's Health Initiative Observational Study

BACKGROUND: Few studies have evaluated carotenoids and vitamins C and E in association with the risk of breast cancers defined by estrogen receptor (ER) and progesterone receptor (PR) status. OBJECTIVE: We examined the associations between dietary and supplemental intakes of these nutrients and risk of breast cancers jointly defined by both ER and PR status among postmenopausal women. DESIGN: Our investigation was conducted in the Women's Health Initiative Observational Study. After following 84 805 women for an average of 7.6 y, 2879 incident invasive breast cancer cases had been ascertained, of whom 2509 had receptor data. We used Cox proportional hazards models to assess the associations of interest. RESULTS: Dietary alpha-carotene (highest versus lowest quintile: RR = 0.83; 95% CL = 0.70, 0.99; P for trend = 0.019), beta-carotene (highest versus lowest quintile: RR = 0.78; 95% CL = 0.66, 0.94; P for trend = 0.021), and lycopene (highest versus lowest quintile: RR = 0.85; 95% CL = 0.73, 1.00; P for trend = 0.064) were inversely associated with risk of ER+PR+breast cancer, but not with other breast cancer groups jointly defined by ER and PR status. Total or supplemental beta-carotene and dietary intakes of lutein+zeaxanthin and beta-cryptoxanthin were not associated with breast cancers defined by ER and PR status. Vitamin E (regardless of source) and dietary vitamin C were not associated with breast cancer. However, total and supplemental vitamin C intake had weak positive associations with breast cancer overall. CONCLUSION: Dietary intake of certain carotenoids might be differentially associated with risk of invasive breast cancers jointly defined by ER and PR status among postmenopausal women.     

Cancer risk assessment: quality and impact of the family history interview

BACKGROUND: Identification of individuals at high risk for colon and breast cancer requires an adequate family history assessment and can influence cancer screening and genetic testing decisions. Little data exist that evaluate the completeness of the family history interview in primary care. METHODS: Retrospective chart review of 995 new patient visits to 28 primary care physicians evaluating the completeness of the family cancer history for colon or breast cancer. Family history information was evaluated for inclusion of age at diagnosis, degree of kinship, and specification of disease of interest. RESULTS: Family history information on cancer diagnoses was collected on 679 (68%) of the patients. Specific information regarding the individual affected and the cancer diagnosis was present in 414 (61%) of the records. Affected first-degree relatives were more likely to have their age of cancer diagnosis recorded than second-degree relatives (39%, 95% confidence interval [CI]=34%-44% vs 16%, 95% CI=12%-20%). Age at diagnosis of cancer in first-degree relatives was documented in 51% of colon cancers, 38% of breast cancers, and 27% of ovarian cancers. Only 17% of individuals who meet criteria for early-onset breast cancer genetic testing were referred for genetic services. CONCLUSIONS: Adequate cancer risk assessment using family history information requires age at cancer diagnosis and specification of a cancer diagnosis. Age at diagnosis was frequently missing from family history assessments, which could have a potential impact on identification of high-risk individuals. When family history information does identify high-risk individuals, only the minority are referred for genetic services.     

Environmental tobacco smoke and breast cancer incidence

To evaluate whether environmental tobacco smoke (ETS) influences breast cancer incidence, data from a population-based case-control study were analyzed. Respondents with available ETS information assessed by in-person questionnaires included 1356 newly diagnosed cases and 1383 controls. Relative to nonsmokers who reported no residential ETS exposure throughout the life course, the odds ratios (OR) for breast cancer were not substantially elevated in relation to ETS exposure, active smoking, or a joint measure of active and passive smoking (OR, 1.15, 95% CI, 0.90, 1.48). An increased OR, however, was noted among nonsmokers who lived with a smoking spouse for over 27 years (2.10, 95% CI, 1.47, 3.02), although no dose-response was evident. Also, among women with hormone-receptor-positive tumors only, the OR for both active and passive smoking was increased (1.42 for ER+ PR+, 95% CI, 1.00, 2.00). Our data suggest that if there is an effect for ETS on breast cancer, that effect is restricted to selected subgroups of women, such as those with long-term exposure from a smoking spouse.     

Dietary Mushroom Intake and the Risk of Breast Cancer Based on Hormone Receptor Status

Although many studies have documented the antitumor activities of mushrooms, the association between mushroom intake and breast cancer, defined by hormone receptor status, has received minimal empirical investigation. This study evaluated the association between mushroom intake and the risk of breast cancer according to hormone receptor status among Korean women. Mushroom intake and breast cancer risk were examined among 358 breast cancer patients and 360 cancer-free controls. Intake of mushrooms was assessed using a quantitative food frequency questionnaire. Greater mushroom intake was related to lower risk of breast cancers among premenopausal women (odds ratio [OR] = 0.35, 95% confidence interval [CI] = 0.13–0.91 for the highest vs. the lowest quartile intake). The association was stronger for premenopausal women with estrogen receptor (ER)+/progesterone receptor (PR) + tumors (OR = 0.30, 95% CI = 0.11–0.79 for the highest vs. the lowest quartile intake) than those with ER–/PR– tumors. Our results suggest that high consumption of mushrooms might be related to lower risks for breast cancers among premenopausal women; this association may be more robust among women with hormone receptor positive tumors.     

Long-term Dietary Acrylamide Intake and Breast Cancer Risk in a Prospective Cohort of Swedish Women

The association between dietary acrylamide intake and the incidenceof invasive breast cancer was examined among 61,433 Swedishwomen who were cancer free and completed a food frequency questionnairein 1987–1990 and again in 1997. During a mean follow-upof 17.4 years, a total of 2,952 incident cases of breast cancerwere diagnosed in the cohort. In multivariate analyses controllingfor breast cancer risk factors, no statistically significantassociation was observed between long-term acrylamide intake(assessed at baseline and in 1997) and the risk of breast cancer,overall or by estrogen receptor (ER) and progesterone receptor(PR) status. The multivariate rate ratios comparing extremequartiles of acrylamide intake were 0.91 (95% confidence interval(CI): 0.80, 1.02) for overall breast cancer, 0.89 (95% CI: 0.74,1.08) for ER+PR+ tumors, 1.17 (95% CI: 0.84, 1.64) for ER+PR–tumors, and 0.91 (95% CI: 0.61, 1.38) for ER–PR–tumors. The association between acrylamide intake and breastcancer risk did not differ by smoking status. These findingsfor Swedish women do not support the hypothesis that dietaryacrylamide is positively associated with risk of breast cancer,at least not within the ranges of acrylamide consumed by thispopulation. acrylamide; breast neoplasms; cohort studies; diet; prospective studies     

Breast cancer incidence in women with abnormal cytology in nipple aspirates of breast fluid.

This is a prospective study of breast cancer risk in relation to nipple aspirate fluid cytology in 2,701 volunteer white women from the San Francisco Bay Area first enrolled between 1973 and 1980. The women were not pregnant or lactating and were free of breast cancer within 6 months of entry into the study. The breast cancer status of this cohort was determined between June 1988 and April 1991. Follow-up was complete for 87% (n = 2,343) of the cohort, representing 29,961 person-years and an average of 12.7 years of follow-up. The overall breast cancer incidence was 4.4% (104 of 2,343) and rose with fluid cytology findings as follows: no fluid obtained, 2.6% (9 of 352); unsatisfactory specimen, 4.8% (15 of 315); normal cytology, 4.3% (56 of 1,291); epithelial hyperplasia, 5.5% (18 of 327); and atypical hyperplasia, 10.3% (6 of 58). Relative risks for breast cancer and their 95% confidence intervals were estimated by Cox regression, adjusting for age and year of entry. Compared with the relative risk for women who yielded no fluid, relative risks were: unsatisfactory specimen, relative risk (RR) = 1.4 (95% confidence interval (CI) 0.6-3.3); normal cytology, RR = 1.8 (95% CI 0.9-3.6); epithelial hyperplasia, RR = 2.5 (95% CI 1.1-5.5); and atypical hyperplasia, RR = 4.9 (95% CI 1.7-13.9). These findings were strongest for and were mainly confined to women aged 25-54 years. Women with atypical hyperplasia and a first-degree family history of breast cancer were six times more likely to develop breast cancer than were women with atypical hyperplasia but without a family history of breast cancer (95% CI 1.0-30.2). These findings provide strong support for our hypothesis that hyperplasia and atypical hyperplasia diagnosed in nipple aspirates of breast fluid are associated with an increased risk of breast cancer.