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The in utero origins of breast cancer are an increasing focus of research. However, the long time period between exposure and disease diagnosis, and the lack of standardized perinatal data collection makes this research challenging. We assessed perinatal factors, as proxies for in utero exposures, and breast cancer risk using pooled, population-based birth and cancer registry data. Birth registries provided information on perinatal exposures. Cases were females born in Norway, Sweden or Denmark who were subsequently diagnosed with primary, invasive breast cancer (n = 1419). Ten controls for each case were selected from the birth registries matched on country and birth year (n = 14,190). Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using unconditional regression models. Breast cancer risk rose 7% (95% CI 2-13%) with every 500 g (roughly 1 s.d.) increase in birth weight and 7% for every 1 s.d. increase in birth length (95% CI 1-14%). The association with birth length was attenuated after adjustment for birth weight, while the increase in risk with birth weight remained with adjustment for birth length. Ponderal index and small- and large-for-gestational-age status were not better predictors of risk than either weight or length alone. Risk was not associated with maternal education or age, gestational duration, delivery type or birth order, or with several pregnancy complications, including preeclampsia. These data confirm the positive association between birth weight and breast cancer risk. Other pregnancy characteristics, including complications such as preeclampsia, do not appear to be involved in later breast carcinogenesis in young women.

Background: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer., Methods: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC)., Results: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139)., Conclusion: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

Context: Sex steroids play a central role in breast cancer development., Objective: This study aimed to relate polymorphic variants in 36 candidate genes in the sex steroid pathway to serum concentrations of sex steroid hormones and SHBG., Design: Data on 700 genetic polymorphisms were combined with existing hormone assays and data on breast cancer incidence, within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nurses' Health Study (NHS) cohorts; significant findings were reanalyzed in the Multiethnic Cohort (MEC)., Setting and Participants: We analyzed data from a pooled sample of 3852 pre- and postmenopausal Caucasian women from EPIC and NHS and 454 postmenopausal women from MEC., Main Outcome Measures: Outcome measures were SHBG, testosterone, dehydroepiandrosterone (DHEAS), androstenedione, estrone (E1), and estradiol (E2) as well as breast cancer risk., Results: Globally significant associations were found among pre- and postmenopausal women combined between levels of SHBG and the SHBG gene and between DHEAS and the FSHR and AKR1C3 genes. Among postmenopausal women, serum E1 and E2 were significantly associated with the genes CYP19 and FSHR, and E1 was associated with ESR1. None of the variants related to serum hormone levels showed any significant association with breast cancer risk., Conclusions: We confirmed associations between serum levels of SHBG and the SHBG gene and of E1 and E2 and the CYP19 and ESR1 genes. Novel associations were observed between FSHR and DHEAS, E1, and E2 and between AKR1C3 and DHEAS.

Among older mothers, preeclampsia in the first pregnancy was associated with a reduction in maternal breast cancer risk that was significantly more pronounced in women bearing male than female infants. Androgen concentrations in male, preeclamptic pregnancies were consistent with the hypothesis that elevated pregnancy androgens might mediate this apparent modifying effect of fetal gender.

Exploring whether the positive association between birth weight and breast cancer risk differs by other breast cancer risk factors may help inform speculation about biological mechanism. In these data, high birth weight was associated with breast cancer risk in younger and in more educated women, but was not associated overall.

In 1983-87, we conducted a population-based case-control study of breast cancer in Asian women living in California and Hawaii, in which migration history (a composite of the subject's place of birth, usual residence in Asia (urban/rural), length of time living in the West, and grandparents' place of birth) was associated with a six-fold risk gradient that paralleled the historical differences in incidence rates between the US and Asian countries. This provided the opportunity to determine whether endogenous hormones vary with migration history in Asian-American women. Plasma obtained from 316 premenopausal and 177 naturally premenopausal study controls was measured for levels of estrone (E1), estradiol (E2), estrone sulphate (E1S), androstenedione (A), testosterone (T), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), progesterone (PROG) and sex hormone-binding globulin (SHBG). Levels of the oestrogens and sex hormone-binding globulin did not differ significantly between Asian- and Western-born women, although among premenopausal women, those least westernised had the lowest levels of E1, E2, and E1S. Androgen levels, particularly DHEA, were lower in women born in the West. Among premenopausal women, age-adjusted geometric mean levels of DHEA were 16.5 and 13.8 nmol l(-1) in Asian- and Western-born women respectively; in postmenopausal women these values were 11.8 and 9.2 nmol l(-1), (P<0.001) respectively. Among postmenopausal women, androgens tended to be highest among the least westernised women and declined as the degree of westernisation increased. Our findings suggest that aspects of hormone metabolism play a role in population differences in breast cancer incidence., (Copyright 2002 Cancer Research UK)

From 1940 through the 1960s, diethylstilbestrol (DES), a synthetic oestrogen, was given to pregnant women to prevent pregnancy complications and losses. Subsequent studies showed increased risks of reproductive tract abnormalities, particularly vaginal adenocarcinoma, in exposed daughters. An increased risk of breast cancer in the DES-exposed mothers was also found in some studies. In this report, we present further follow-up and a combined analysis of two cohorts of women who were exposed to DES during pregnancy. The purpose of our study was to evaluate maternal DES exposure in relation to risk of cancer, particularly tumours with a hormonal aetiology. DES exposure status was determined by a review of medical records of the Mothers Study cohort or clinical trial records of the Dieckmann Study. Poisson regression analyses were used to estimate relative risks (RR) and 95% confidence intervals (CI) for the relationship between DES and cancer occurrence. The study results demonstrated a modest association between DES exposure and breast cancer risk, RR = 1.27 (95% CI = 1.07-1.52). The increased risk was not exacerbated by a family history of breast cancer, or by use of oral contraceptives or hormone replacement therapy. We found no evidence that DES was associated with risk of ovarian, endometrial or other cancer., (Copyright 2001 Cancer Research Campaign.)

Objective: Although clinical reports have raised concern that breast implants may either increase the risk of breast cancer or delay its diagnosis, epidemiologic studies have generally shown implant recipients to be at a reduced risk of subsequent breast cancer. A large retrospective cohort study was undertaken to clarify effects of cosmetic breast implantation., Methods: Medical records of 13,488 women receiving cosmetic implants at 18 plastic surgery practices and a group of 3936 patients who received other types of plastic surgery at the same practices were reviewed and information abstracted. Questionnaires were sent to all subjects located as alive, with 71% being completed. Attempts were made to obtain medical verification for all reported cancers and to obtain death certificates for deceased subjects., Results: A total of 136 breast cancers were observed among the breast implant patients. External analyses, using general population rates from the Surveillance, Epidemiology and End Results (SEER) program, resulted in 152.2 cases expected and a standardized incidence ratio (SIR) of 0.9 (95% CI 0.8-1.1). A comparable SIR was found for the other plastic surgery patients (SIR =1.0, 95% CI 0.7-1.2). Internal analyses, directly comparing the implant patients with the other plastic surgery patients, showed a RR of 0.8 (95% CI 0.6-1.1). In neither the external nor internal analyses was there any systematic variation in risk by age or calendar year of initial implant. Risk also did not vary by years of follow-up or by type of implant. Risk was not affected by exclusion of patients who received their implants following surgery for benign breast disease. Although breast tumors tended to be detected at a somewhat later stage among the breast implant than the comparison patients, the difference was not statistically significant, nor was there any significant difference in breast cancer mortality between the two groups., Conclusions: Breast implants do not appear to alter the risk of subsequent breast cancer.

Although it has been demonstrated in previous studies that tubal ligation can have widespread effects on ovarian function, including a decrease in the risk of subsequent ovarian cancer, few studies have evaluated effects on breast cancer risk. In a population-based case-control study of breast cancer among women 20-54 years of age conducted in three geographic areas, previous tubal ligations were reported by 25.3% of the 2173 cases and 25.8% of the 1990 controls. Initially it appeared that tubal ligations might impart a slight reduction in risk, particularly among women undergoing the procedure at young ages (<25 years). However, women were more likely to have had the procedure if they were black, less educated, young when they bore their first child, or multiparous. After accounting for these factors, tubal ligations were unrelated to breast cancer risk (relative risk (RR) = 1.09, 95% confidence interval (CI) 0.9-1.3), with no variation in risk by age at, interval since, or calendar year of the procedure. The relationship of tubal ligations to risk did not vary according to the presence of a number of other risk factors, including menopausal status or screening history. Furthermore, effects of tubal ligation were similar for all stages at breast cancer diagnosis. Further studies would be worthwhile given the biologic plausibility of an association. However, future investigations should include information on type of procedure performed (since this may relate to biologic effects) as well as other breast cancer risk factors.

Breast cancer incidence has historically been 4-7 times higher in the United States than in Asia. A previous study by the authors in Asian-American women demonstrated a substantial increase in breast cancer risk in women who migrated from Asia to the United States, with the risk almost doubling during the first decade after migration. Increased use of oral contraceptives soon after migration to the United States could possibly explain this rapid rise in risk. In a population-based case-control study of Chinese, Filipino, and Japanese-American women, aged 20-55 years, who lived in San Francisco-Oakland, California; Los Angeles, California; and Oahu, Hawaii during 1983-1987, 597 cases (70% of those eligible) and 966 controls (75%) were interviewed. Controls were matched to cases on age, ethnicity, and area of residence. Oral contraceptive (OC) use increased with time since migration; 15.0% of Asian-born women who had been in the West <8 years, 33.4% of Asian-born women who had been in the West > or =8 years, and 49.6% of Asian women born in the West had ever used OCs. However, duration of OC use (adjusted for age, ethnicity, study area, years since migration, education, family history of breast cancer and age at first full-term birth) was not associated with increased risk of breast cancer. Moreover, neither OC use before age 25 years nor before first full-term birth was associated with increased risk. Results were unchanged when restricted to women under age 45 years or under age 40 years. After adjustment for duration of OC use, women who had been in the United States > or =8 years were still at almost twice the risk of breast cancer compared with women who had been in the United States 2-7 years. This study suggests that OC use cannot explain the elevated risk observed in Asian women who migrated to the United States > or =7 years ago.

The reproducibility of RIAs of circulating sex hormones has been evaluated as part of recent epidemiological investigations, but none seem to have addressed the reproducibility or validity of RIAs for urinary hormones or their metabolites. As part of a case-control study of breast cancer in Asian-American women, 12-h overnight urine samples were obtained, and a methodological study was conducted to identify laboratories capable of assaying urinary hormones. For the reproducibility component of this study, two laboratories with extensive experience in hormone assays measured urinary estrone, estradiol, estriol, pregnanediol glucuronide, and estrone glucuronide using samples from 15 women (5 midfollicular, 5 midluteal, and 5 postmenopausal). Variance estimates from these measurements were used to calculate the laboratory variability (coefficient of variation) and to assess the magnitude of the biological variability among the women in relation to the total variability (intraclass correlation coefficient). For the validity component, urinary estrone, estradiol, and estriol levels were measured in the same samples by gas chromatography-mass spectroscopy in the laboratory of Dr. Herman Adlercreutz (University of Helsinki, Helsinki, Finland). We found that the degree of assay reproducibility differed between the laboratories, but that laboratory variability was usually low compared with the range of hormone values among women, particularly for the estrogens. Values for estrone and estradiol were well correlated among all of the laboratories. For estriol, the RIAs tended to overestimate levels compared with gas chromatography-mass spectroscopy. In one laboratory, assays for pregnanediol glucuronide and estrone glucuronide were consistently reproduced; in the other, the reproducibility of the RIA for pregnanediol glucuronide was problematic, and estrone glucuronide was not measured. Despite some limitations, urinary hormones and their metabolites can be reliably measured by current RIAs in large investigations attempting to link hormone level to disease risk and may be particularly advantageous for studies of postmenopausal women, where serum concentrations of estrone and estradiol are low and assay measurements are not as dependable.

Background: Hormone replacement therapy has been associated in some studies with reductions in breast cancer mortality among women who develop this disease. It is unclear whether this association reflects the biologic activity of the hormones or the earlier detection of tumors among hormone users. We examined breast cancer mortality among women who were diagnosed with axillary lymph node-negative and node-positive breast cancer according to the currency of estrogen use at diagnosis., Methods: Vital status through June 1995 was determined for 2614 patients with postmenopausal breast cancer diagnosed during the period from 1973 to January 1981. We estimated adjusted hazard-rate ratios (adjusting for tumor size, age, race, Quetelet [body mass] index, and number of positive lymph nodes in women with node-positive disease) and unadjusted cumulative probabilities of breast cancer death over time since diagnosis., Results: Among patients with node-negative disease, rate ratios for breast cancer mortality associated with current use compared with nonuse at diagnosis were 0.5 (95% confidence interval [CI] = 0.3-0.8) until 144 months after diagnosis and 2.2 (95% CI = 0.9-5.2) thereafter. Mortality was not statistically significantly lower in past users. The cumulative probabilities of breast cancer mortality at the end of follow-up were 0.14, 0.14, and 0.09 in nonusers, past users, and current users, respectively. Among women with node-positive disease, the rate ratios associated with current and past use were both 0.5 until 48 months after diagnosis (95% CI = 0.3-0.8 for current users; 95% CI = 0.3-0.9 for past users) and were 1.1 (95% CI = 0.7-1.7) and 1.8 (95% CI = 1.2-2.7), respectively, thereafter. The cumulative probabilities of breast cancer mortality were 0.32, 0.39, and 0.27 in nonusers, past users, and current users, respectively., Conclusions: Patients with breast cancer who were using replacement estrogens at the time of diagnosis experienced reductions in breast cancer mortality, which waned with the time since diagnosis.

Evidence from case-control studies suggests, although not entirely consistently, that soy intake may protect against breast cancer. The designs and findings of studies conducted in Asian women living in Japan, Singapore, China, and the United States are reviewed. Because of the considerably higher intake of soy by native Asians than by Asian Americans living in California and Hawaii, these studies investigated different segments of the dose-response relation between soy intake and breast cancer risk. Data are not sufficient to determine the amount or frequency of soy intake effective in protecting against breast cancer. Of concern is that soy intake may be homogeneously high in Asia, making it difficult to identify differences in breast cancer risk between high and moderate daily consumers. In studies conducted in Asian Americans, it is difficult to be certain that soy intake is not a marker of other factors related to Western lifestyle that are causally associated with risk of breast cancer. Additional studies assessing the role of soy and breast cancer are needed. These studies should assess intake of all food sources of soy, considering portion size as well as other dietary and nondietary factors that may confound the soy-breast cancer association. A better understanding of the mechanisms whereby soy intake may influence the risk of breast cancer is also needed. Dietary intervention studies with soy will provide information on the acute effects of soy on endogenous hormone concentrations. Cross-sectional and longitudinal studies are necessary to investigate the longer-term relations between hormone concentrations and soy intake in women.

In a population-based case-control study of parous women less than 45 years of age, we evaluated the relations of various pregnancy characteristics to maternal breast cancer risk. Cases (N = 1,239) diagnosed with in situ or invasive breast cancer from 1990 to 1992 in Atlanta, GA, Seattle/Puget Sound, WA, and five counties in central New Jersey, and population controls (N = 1,166) identified by random-digit dialing, were interviewed regarding the details of their pregnancies. We used logistic regression to estimate relative risks (RR) and 95% confidence intervals (CI) and to adjust for breast cancer risk factors. Women who reported nausea or vomiting in their first pregnancy had a slightly lower risk of breast cancer (RR = 0.87; 95% CI = 0.72-1.0). We found no strong or consistent associations for maternal risk related to gestational length, pregnancy weight gain, gestational diabetes, pregnancy hypertension, or gender of the offspring, although we found some evidence for reductions in risk for toxemia (RR = 0.81; 95% CI = 0.61-1.1) and specific sex (RR for female twins vs singletons = 0.48; 95% CI = 0.20-1.3) and timing characteristics of twinning. Overall, these data provide little support for the hypothesis that pregnancy hormone levels are associated with subsequent maternal risk of breast cancer in young women.

Objectives: Endogenous sex hormones are thought to be involved in breast and endometrial cancers, but few studies have evaluated the relationships between hormones and risk factors for these diseases., Methods: We related serum hormone and sex-hormone binding globulin (SHBG) levels to reproductive and lifestyle risk factors in a cross-sectional study of 125 postmenopausal women in five geographic regions of the United States., Results: The estrogens were associated positively, while SHBG was associated negatively with body mass index (wt/ht2). Estrone, (E1), estrone sulfate, and bioavailable estradiol (BioE2) were inversely associated with height. Androstenedione was positively associated with age at menopause, while androstenedione, E1, estradiol, and BioE2 were inversely associated with age at menarche. Weekly alcohol drinkers had higher hormone levels, and lower SHBG levels than those who abstained. Androstenedione and E1 decreased with increasing levels of nonrecreational activity., Conclusions: Several of these findings support the hypothesis that breast and endometrial cancer risk factors are mediated, in part, through increased endogenous hormone levels. The androstenedione findings are of interest in light of studies relating androstenedione to endometrial and possibly breast cancer. An association of age at menarche with E2, independent of androstenedione, may reflect increased aromatase activity in women with earlier menarche.

Background: A variety of breast cancer risk factors pertain to a woman's adolescence and may be related to nutritional influences. We assessed risk of early-onset breast cancer related to diet during adolescence in a case-control study., Methods: Study participants were accrued from the following three geographical regions covered by cancer registries: Atlanta, GA; Seattle/Puget Sound, WA; and central New Jersey. Case patients (n = 1647) were newly diagnosed with breast cancer, and control subjects (n = 1501) were identified by random-digit-dialing techniques. In an interview, each subject was asked to recall the frequency of consumption and portion size of 29 key food items at ages 12-13 years. Mothers of a subset of respondents completed questionnaires, and food groups were recalculated after removal of foods with poor agreement between mother and daughter. Logistic regression analyses were used to calculate odds ratios and 95% confidence intervals., Results: When high versus low quartiles of consumption were compared, there was a suggestion of a reduced risk associated with high consumption of fruits and vegetables, although this finding was not statistically significant. Slight increases (of borderline statistical significance) in risk of breast cancer were found for intake of chicken or high-fat meat. Intake of animal fat, high-fat foods, high-fat snacks and desserts, or dairy products during adolescence had no apparent influence on breast cancer risk. Removal of foods suspected to be poorly recalled by the daughters did not change any of the risk estimates., Conclusion: These data do not provide evidence for a strong influence of dietary intakes during adolescence on risk of early-onset breast cancer.

In a population-based case-control study of women younger than 45 years of age, we obtained a detailed lifetime history of alcohol use to evaluate the effects of drinking during different periods of life in relation to breast cancer risk. This analysis focused on interviews obtained from 1,645 cases and 1,497 controls. Breast cancer risk was not influenced by drinking during the teenage years or early adulthood. Contemporary drinking (that is, average intake during the recent 5-year interval) was directly associated with risk, but the adverse effect of recent drinking was restricted to women who consumed > or = 14 drinks per week [relative risk (RR) = 1.7; 95% confidence interval (CI) = 1.2-2.5]. The effect of alcohol was most pronounced among women with advanced disease. Compared with nondrinkers, the risk estimate associated with recent consumption of > or = 14 drinks per week was 2.4 (95% CI = 1.6-3.8) for women with regional/distant disease. Our data add support to the accumulating evidence that alcohol consumption is associated with increased risk of breast cancer and further indicate that alcohol acts at a late stage in breast carcinogenesis.

Breast cancer rates among Asian-Americans are lower than those of US whites but considerably higher than rates prevailing in Asia. It is suspected that migration to the US brings about a change in endocrine function among Asian women, although reasons for this change remain obscure. The high intake of soy in Asia and its reduced intake among Asian-Americans has been suggested to partly explain the increase of breast cancer rates in Asian-Americans. We conducted a population-based case-control study of breast cancer among Chinese-, Japanese-, and Filipino-American women in Los Angeles County MSA, San Francisco Oakland MSA, and Oahu, Hawaii. Using a common questionnaire which assessed frequency of intake of some 90 food items, 597 Asian-American women (70% of those eligible) diagnosed with incident, primary breast cancer during 1983-1987 and 966 population-based controls (75% of those eligible) were interviewed. Controls were matched to cases on age, ethnicity, and area of residence. This analysis compares usual adult intake of soy (estimated primarily from tofu intake) among breast cancer cases and control women. After adjustment for age, ethnicity and study area, intake of tofu was more than twice as high among Asian-American women born in Asia (62 times per year) compared to those born in the US (30 times per year). Among migrants, intake of tofu decreased with years of residence in the US. Risk of breast cancer decreased with increasing frequency of intake of tofu after adjustment for age, study area, ethnicity, and migration history; the adjusted OR associated with each additional serving per week was 0.85 (95% CI = 0.74-0.99). The protective effect of high tofu intake was observed in pre- and postmenopausal women. This association remained after adjustment for selected dietary factors and menstrual and reproductive factors. However, this study was not designed specifically to investigate the role of soy intake and our assessment of soy intake may be incomplete. We cannot discount the possibility that soy intake is a marker of other protective aspects of Asian diet and/or Asian lifestyle.

Background: Breast cancer incidence rates have historically been four to seven times higher in the United States than in China or Japan, although the reasons remain elusive. When Chinese, Japanese, or Filipino women migrate to the United States, their breast cancer risk rises over several generations and reaches that for white women in the United States, indicating that modifiable exposures are involved. In a previous report on this case-control study of breast cancer in Asian-American women, designed to take advantage of their diversity in risk and lifestyle, we demonstrated a sixfold gradient in risk by migration history, comparable to the international differences in breast cancer incidence rates., Purpose: In this analysis, we have examined the roles of adult height, adiposity, and weight change in breast cancer etiology., Methods: A population-based, case-control study of breast cancer was conducted among women of Chinese, Japanese, and Filipino ethnicities, aged 20-55 years, living in San Francisco-Oakland (CA), Los Angeles (CA), and Oahu (HI) during the period from April 1, 1983, through June 30, 1987. We successfully interviewed 597 (70%) of 852 eligible case subjects and 966 (75%) of 1287 eligible control subjects from August 1985 through February 1989. Subjects were asked about current height, usual adult weight, and usual weight in each decade of life, excluding the most recent 3 years and any periods of pregnancy., Results: Height, recent adiposity (weight in the current decade of life/height 1.5), and recent weight change (between the current and preceding decades of life) were strong predictors of breast cancer risk after adjustment was made for accepted breast cancer risk factors. Risk doubled (relative risk [RR] = 2.01; 95% confidence interval [CI] = 1.16-3.49) over the 7-inch (17.8-cm) range in height (two-sided P for trend = .003), with comparable effects in both premenopausal and postmenopausal women. Except for reduced risk in the heavy, younger women (weight/height 1.5 > 29 kg/m 1.5 and < 40 years old), risk was positively associated with usual adult adiposity. Trends in risk became more striking as adiposity in each succeeding decade of adult life was considered. Women in their 50s and in the top quintile for their age group had twice the breast cancer risk (RR = 2.13; 95% CI = 1.17-3.87) of women in the bottom quintile (two-sided P for trend = .004). Women in their 50s, above the median adiposity for their age group, and with a recent gain of more than 10 pounds had three times the risk (RR = 3.01; 95% CI = 1.45-6.25) of women below the median adiposity and with no recent weight change. Recent weight loss was consistently associated with reduced risk (RRs of approximately 0.7) relative to no recent weight change., Conclusions: Adult adiposity, weight change, and height are critical determinants of breast cancer risk. Increased adiposity and weight gain in the decade preceding diagnosis are especially influential, suggesting that excess weight may function as a late stage promoter., Implications: Weight maintenance and/or reduction as an adult, possibly accompanied by specific changes in diet and physical activity, may have a significant and rapid impact on breast cancer risk.

We conducted a population-based case-control study of breast cancer among Chinese-, Japanese- and Filipino-American women in Los Angeles County Metropolitan Statistical Area (MSA), San Francisco-Oakland MSA and Oahu, Hawaii. One objective of the study was to quantify breast cancer risks in relation to menstrual and reproductive histories in migrant and US-born Asian-Americans and to establish whether the gradient of risk in Asian-Americans can be explained by these factors. Using a common study design and questionnaire in the three study areas, we successfully conducted in-person interviews with 597 Asian-American women diagnosed with incident, primary breast cancer during the period 1983-87 (70% of those eligible) and 966 population-based controls (75% of those eligible). Controls were matched to cases on age, ethnicity and area of residence. In the present analysis, which included 492 cases and 768 controls, we observed a statistically non-significant 4% reduction in risk of breast cancer with each year delay in onset of menstruation. Independent of age at menarche risk of breast cancer was lower (odds ratio; OR=0.77) among women with menstrual cycles greater than 29 days. Parous Asian-American women showed a significantly lower risk of breast cancer then nulliparous women (OR=0.54). An increasing number of livebirths and a decreasing age at first livebirth were both associated with a lower risk of breast cancer, although the effect of number of livebirths was no longer significant after adjustment for age at first livebirth. Women with a pregnancy (spontaneous or induced abortions) but no livebirth had a statistically non-significant increased risk (OR=1.84), but there was no evidence that one type of abortion was particularly harmful. A positive history of breastfeeding was associated with non-significantly lower risk of breast cancer (OR=.78). There are several notable differences in the menstrual and reproductive factors between Asian-Americans in this study and published data on US whites. US-born Asian Americans had an average age at menarche of 12.12 years-no older than has been found in comparable studies of US whites, but 1.4 years earlier than Asian women who migrated to the US. Asian-American women, particularly those born in the US and those who migrated before age 36, also had a later age at first birth and fewer livebirths than US whites. A slightly higher proportion of Asian-American women breastfed, compared with US whites. The duration of breastfeeding was similar in US-born Asians and US whites, but was longer in Asian migrants, especially those who migrated at a later age. Menstrual and reproductive factors in Asian-American women are consistent with their breast cancer rates being at least as high as in US whites, and they are. However, the effects of these menstrual and reproductive factors were small and the ORs for migration variables changed only slightly after adjustment for these menstrual and reproductive factors. These results suggest that the lower rates of breast cancer in Asians must be largely as a result of other environmental/lifestyle factors.

Background: For several decades, mortality from breast cancer has been higher in the northeastern part of the United States than in other regions, particularly the South. Rates have also been somewhat higher in the Midwest and West than in the South, especially among older women. The reasons for these geographic variations are not well understood., Purpose: The objective of this study was to evaluate geographic differences in U.S. breast cancer mortality rates in 1987, after taking into account regional differences in the distribution of recognized breast cancer risk factors (e.g., late age at first live birth) and certain prognostic factors (e.g., mammography use)., Methods: The 1987 breast cancer mortality rates for four regions of the country were obtained from the National Center for Health Statistics. Regional data on the distribution of breast cancer risk factors were obtained from 1987 National Health Interview Cancer Epidemiology Supplement interviews with 9778 white women aged 20-79 years. Regional data on the distribution of mammography use were obtained from 1987 National Health Interview Cancer Control Supplement interviews with 3795 white women aged 50-79 years., Results: Age-adjusted mortality ratios (MRs) among women 50 years and older were 1.15, 1.18, and 1.30 in the West, Midwest, and Northeast, respectively, compared with the South. Corresponding MRs among women 20-49 years old were 1.01, 1.08, and 1.07 in the West, Midwest, and Northeast, respectively, compared with the South. After adjustment for recognized risk factors and certain prognostic factors, MRs among older women were 1.13 (95% confidence interval [CI] = 1.04-1.23), 1.08 (95% CI = 1.01-1.16), and 1.13 (95% CI = 1.04-1.23) in the West, Midwest, and Northeast, respectively, compared with the South. Corresponding MRs among younger women were 0.94 (95% CI = 0.76-1.16), 1.05 (95% CI = 0.92-1.18), and 0.99 (95% CI = 0.86-1.14), respectively., Conclusion: Before adjustment for regional differences in recognized risk factors and prognostic factors, mortality excesses among younger women in the Northeast, Midwest, and West were less than 10% compared with the South. After adjustment, MRs were near unity for all regions. Among older women, the excess mortality was more substantial before adjustment for relevant factors, ranging from 15% in the West to 30% in the Northeast. Approximately 50% of the excesses in the Northeast and Midwest and 10% of the excess in the West could be explained on the basis of regional differences in the prevalence of recognized breast cancer risk factors and prognostic factors. After adjustment for these factors, the magnitude of excess in breast cancer mortality in the Northeast (13%) was comparable to that in the West (13%) but still slightly higher than that in the Midwest (8%).

Background: Few estimates of the fraction of cases of breast cancer attributable to recognized risk factors have been published. All estimates are based on selected groups, making their generalizability to the U.S. population uncertain., Purpose: Our goal was to estimate the fraction of breast cancer cases in the United States attributable to well-established risk factors (i.e., later age at first birth, nulliparity, higher family income, and first-degree family history of breast cancer), using data from the first National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study (NHEFS), the survey and follow-up of a probability sample of the U.S. population., Methods: From a cohort of 7508 female participants surveyed in the early 1970s, and followed up between 1982 and 1984 and again in 1987, 193 breast cancer cases were accrued for study. We calculated incidence rates, relative risks (RRs), and population attributable risks (PARs) for breast cancer risk factors and extended our results to the U.S. female population by using sample weights from the NHANES I survey., Results: Our PAR estimates suggest that later age at first birth and nulliparity accounted for a large fraction of U.S. breast cancer cases, 29.5% (95% confidence interval [CI] = 5.6%-53.3%); higher income contributed 18.9% (95% CI = -4.3% to 42.1%), and family history of breast cancer accounted for 9.1% (95% CI = 3.0%-15.2%). Taken together, these well-established risk factors accounted for approximately 47% (95% CI = 17%-77%) of breast cancer cases in the NHEFS cohort and about 41% (95% CI = 2%-80%) in the U.S. population., Conclusions: The RRs for most of these risk factors were modest, but their prevalence as a group was high, leading to estimates that suggest that a substantial proportion of breast cancer cases in the United States are explained by well-established risk factors., Implications: Elucidation of the determinants underlying recognized factors and study of other factors that may confer risk or protection are needed in efforts to advance understanding of breast cancer etiology and to aid in devising strategies for prevention.

It has been suggested that cancers of the testis and breast are associated with exposure to estrogens and other hormones in utero. Twin pregnancies have higher levels of pregnancy-associated hormones than singleton pregnancies, and these levels may be higher in dizygotic than in monozygotic twin pregnancies. Through a large population-based study of twins, we assessed the hypothesis that levels of pregnancy-associated hormones have etiologic importance for cancers of the testis, breast, and other sites. The incidence of all cancers among 46,767 members of the Swedish Twin Registry was compared with the incidence among the Swedish general population. We found testicular cancer excess among dizygotic twins (observed/expected[O/E ratio = 2.3, CI = 1.1-4.2) compared with older men (O/E ratio = 1.2, CI = 0.5-2.4). In addition, a substantially elevated incidence of breast cancer was observed in dizygotic twin women aged 20 to 29 years (O/E = 6.7, CI = 2.9-13.1). None of the other age or zygosity groups showed notable elevations in incidence of testicular, breast, or other cancers. We conclude that dizygotic twinship may be associated with cancer of the breast and testis among young adults. These findings support the concept that pregnancy hormones are associated with risk of testicular and breast cancer, although non-hormonal aspects of twin pregnancy that vary with respect to zygosity cannot be excluded as explanatory factors.

Background: Several studies have suggested a link between oral contraceptive use and breast cancer in younger women, but it is possible that chance or bias, including selective screening of contraceptive users, contributed to the putative association., Purpose: Given that oral contraceptives were first marketed in the United States in the early 1960s, we conducted a population-based case-control study to examine the relationship between use of oral contraceptives and breast cancer among women in a recently assembled cohort, focusing on women younger than 45 years of age who had the opportunity for exposure throughout their entire reproductive years., Methods: Breast cancer patients and healthy control subjects were identified, the latter group by random-digit dialing, in Atlanta, Ga., Seattle/Puget Sound, Wash., and central New Jersey. In Seattle and New Jersey, the study was confined to women 20 through 44 years of age; in Atlanta the age range was extended through 54 years. Patients included women with in situ or invasive breast cancer newly diagnosed during the period of May 1, 1990, through December 31, 1992. In-person interviews were completed by 2203 (86.4%) of 2551 eligible patients and 2009 (78.1%) of 2571 eligible control subjects. Analyses focused on women younger than 45 years of age (1648 patients and 1505 control subjects) to maximize opportunities for extended exposure. Logistic regression analyses were used to obtain maximum likelihood estimates of relative risks (RRs) and their 95% confidence intervals (CIs)., Results: Among women younger than 45 years, oral contraceptive use for 6 months or longer was associated with an RR for breast cancer of 1.3 (95% CI = 1.1-1.5). Risks were enhanced for breast cancers occurring prior to age 35 years (RR = 1.7; 95% CI = 1.2-2.6), with the RR rising to 2.2 (95% CI = 1.2-4.1) for users of 10 or more years. The RR for breast cancer for those whose oral contraceptive use began early (before age 18 years) and continued long-term (> 10 years) was even higher (RR = 3.1; 95% CI = 1.4-6.7). The RRs observed for those who used oral contraceptives within 5 years of cancer diagnosis were higher than for those who had not, with the effect most marked for women younger than age 35 years (RR = 2.0; 95% CI = 1.3-3.1). Oral contraceptive associations were also strongest for cancers diagnosed at advanced stages. Evaluation of screening histories and methods of diagnosis failed to support the speculation that associations could be due to selective screening. Among women 45 years of age and older, no associations of risk with use of oral contraceptives were noted., Conclusions: The relationship between oral contraceptives and breast cancer in young women appears to have a biologic basis rather than to be an artifact or the result of bias.

This study examines the relationship between menopausal estrogen and estrogen-progestin replacement therapy and risk of breast cancer, focusing on whether associations differ according to whether the tumors are in situ or invasive. Data are from a prospective study conducted 1980-89 on 49,017 selected participants in the Breast Cancer Detection Demonstration Project, a five-year screening program conducted between 1973 and 1980 in the United States. Overall, the rate ratio for estrogen-only use compared with no-hormone use was 1.0, and that for the estrogen-progestin combination was 1.2 (95 percent confidence interval [CI] = 1.0-1.6). However, the associations differed according to whether the tumors were in situ or invasive. The rate ratios of in situ breast cancer associated with use of estrogens alone and the combination regimen were 1.4 (CI = 1.0-2.0) and 2.3 (CI = 1.3-3.9), respectively. Duration of estrogen-only use also was associated with risk of in situ tumors, with users for 10 or more years at twice the risk of nonusers (P-value for trend test = 0.02). Duration of use was not associated with risk of invasive cancer. Our results are consistent with the hypothesis that hormone replacement therapy is related to earlier-stage breast cancer; however, the possibility that the results reflect increased breast cancer surveillance among those taking hormones cannot be ruled out.

Background: Breast cancer incidence rates have historically been 4-7 times higher in the United States than in China or Japan, although the reasons remain elusive. When Chinese, Japanese, or Filipino women migrate to the United States, breast cancer risk rises over several generations and approaches that among U.S. Whites., Purpose: Our objective was to quantify breast cancer risks associated with the various migration patterns of Asian-American women., Methods: A population-based, case-control study of breast cancer among women of Chinese, Japanese, and Filipino ethnicities, aged 20-55 years, was conducted during 1983-1987 in San Francisco-Oakland, California, Los Angeles, California, and Oahu, Hawaii. We successfully interviewed 597 case subjects (70% of those eligible) and 966 control subjects (75%)., Results: A sixfold gradient in breast cancer risk by migration patterns was observed. Asian-American women born in the West had a breast cancer risk 60% higher than Asian-American women born in the East. Among those born in the West, risk was determined by whether their grandparents, especially grandmothers, were born in the East or the West. Asian-American women with three or four grandparents born in the West had a risk 50% higher than those with all grandparents born in the East. Among the Asian-American women born in the East, breast cancer risk was determined by whether their communities prior to migration were rural or urban and by the number of years subsequently lived in the West. Migrants from urban areas had a risk 30% higher than migrants from rural areas. Migrants who had lived in the West for a decade or longer had a risk 80% higher than more recent migrants. Risk was unrelated to age at migration for women migrating at ages less than 36 years. Ethnic-specific incidence rates of breast cancer in the migrating generation were clearly elevated above those in the countries of origin, while rates in Asian-Americans born in the West approximated the U.S. White rate., Conclusions: Exposure to Western lifestyles had a substantial impact on breast cancer risk in Asian migrants to the United States during their lifetime. There was no direct evidence of an especially susceptible period, during either menarche or early reproductive life., Implications: Because heterogeneity in breast cancer risk in these ethnic populations is similar to that in international comparisons and because analytic epidemiologic studies offer the opportunity to disentangle correlated exposures, this study should provide new insights into the etiology of breast cancer.

The relationship of breast size both to breast cancer risk and to the laterality of the tumor was studied among 261 women diagnosed with breast cancer and 291 control subjects who were enrolled in the United States' Breast Cancer Detection and Demonstration Project from 1973 to 1980. Standardized measures of breast area were obtained by applying planimetry to bilateral screening mammograms taken four years before breast cancer was diagnosed in case subjects. The left breast was larger in 53 percent of women with breast cancer and in 60 percent of women in the control group; the difference in breast area by laterality was significant only among controls (P = 0.01). To assess breast cancer risk, breast area was categorized by quartiles, with the lowest quartile being the referent group. Risk was increased minimally among women with the largest breast area (odds ratios = 0.9, 0.9, 1.2); however, the point estimates were not statistically significant and there was no evidence of a linear trend. Left-sided diseased was diagnosed in 51 percent of women in the case group. Although the mean area of the breast with the malignancy did not differ significantly from the opposite breast, cancer developed in the larger breast of 57 percent of women with left- and 46 percent of women with right-sided disease. Breast size was associated with cancer of the left breast but not the right. However, these size differences were small since the area of the larger breast was less than 10 percent greater than the smaller breast among half of the case subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Few studies have evaluated the late effects of adjuvant chemotherapy for breast cancer. Moreover, the relation between the risk of leukemia and the amount of drug given and the interaction of chemotherapy with radiotherapy have not been described in detail., Methods: We conducted a case-control study in a cohort of 82,700 women given a diagnosis of breast cancer from 1973 to 1985 in five areas of the United States. Detailed information about therapy was obtained for 90 patients with leukemia and 264 matched controls. The dose of radiation to the active marrow was estimated from individual radiotherapy records (mean dose, 7.5 Gy)., Results: The risk of acute nonlymphocytic leukemia was significantly increased after regional radiotherapy alone (relative risk, 2.4), alkylating agents alone (relative risk, 10.0), and combined radiation and drug therapy (relative risk, 17.4). Dose-dependent risks were observed after radiotherapy and treatment with melphalan and cyclophosphamide. Melphalan was 10 times more leukemogenic than cyclophosphamide (relative risk, 31.4 vs. 3.1). There was little increase in the risk associated with total cyclophosphamide doses of less than 20,000 mg., Conclusions: Although leukemia occurs in few patients with breast cancer, significantly elevated risks were linked to treatments with regional radiation and alkylating agents. Melphalan is a more potent leukemogen than cyclophosphamide or radiotherapy. Low risks were associated with the levels of cyclophosphamide in common use today. Systemic drug therapy combined with radiotherapy that delivers high doses to the marrow appears to enhance the risk of leukemia.

To determine the relation of mammographic densities to subsequent breast cancer risk, a case-control study was undertaken using prediagnostic mammograms of screening program participants. Mammograms of cases (n = 266) and controls (n = 301) were blindly assessed for mammographic densities, which were measured by planimetry. The odds of breast cancer increased steadily with increasing breast density (test for trend, P less than 0.0001). Breast cancer odds was 1.7 for densities between 5% and 24.9%, 2.5 for 25% through 44.9%, 3.8 for 45% through 64%, and 4.3 for densities of 65% and greater (referent = less than 5% densities). Odds ratios also increased with increasing densities among women with the P2 and DY mammographic patterns. These findings suggest that the percentage of mammographic densities in the breast can predict breast cancer risk more accurately than a qualitative assessment of mammographic patterns.

We used the population-based tumor registry of Kaiser Permanente in the United States (Portland, OR) to analyze breast cancer incidence from 1960 to 1985. Overall, incidence rose 45% during this period. The largest increases occurred in women 60 years of age or older (74%) and in those 45-59 (36%). The rate in women aged 20-44 has remained essentially unchanged. Localized and regional disease showed similar increases. Review of medical records revealed that only a small portion of this increase was likely to result from increased screening activities. From the increased availability of receptor assays in a large proportion of cases since the mid-1970s, we observed that incidence of estrogen receptor-negative cancers rose 22%-27% between the mid-1970s and the mid-1980s. In contrast, incidence of estrogen receptor-positive tumors increased an average of 131% in the same period, perhaps implicating hormonal factors in the rising incidence of breast cancer.

We investigated the relation between alcohol consumption and breast cancer in the Epidemiologic Follow-up Study of the first National Health and Nutrition Examination Survey, a cohort study based on sample of the U.S. population. A total of 7188 women 25 to 74 years of age who were examined during the period 1971 through 1975 were included in the analysis. Information about alcohol consumption was obtained during the base-line interview. The median follow-up period for this cohort was 10 years. One hundred twenty-one cases of breast cancer that developed after the baseline examination were identified through hospital records or death certificates. The relative-risk estimate for any amount of drinking relative to no drinking was 1.5 (95 percent confidence interval, 1.1 to 2.2). The estimates for three levels of consumption, from the lowest to the highest, were 1.4 (confidence interval, 0.9 to 2.3), 1.5 (0.9 to 2.6), and 1.6 (1.0 to 2.7), in comparison to no drinking at all. These relative-risk estimates were not materially affected by adjustment for known risk factors for breast cancer or for several dietary factors. The results of this study, consistent with those of two other cohort studies and a number of case-control studies, suggest that moderate alcohol consumption is associated with an elevation in the risk of breast cancer of 50 to 100 percent.

In 1984-1985, estrogen and androgen levels in blood sera were measured in 320 women who had been treated for cervical cancer in the early 1960s. Study subjects were from US clinics in Baltimore, Maryland; Boston and Norfolk, Massachusetts; Buffalo, New York; Houston, Texas; and San Juan, Puerto Rico. These clinics had participated in a larger international follow-up study of cervical cancer in which a 20-30% reduction in breast cancer risk was linked to prior pelvic irradiation, even when treatment occurred after menopause. Overall, the 203 irradiated and 117 nonirradiated women had similar mean levels of estradiol, estrone, androstenedione, and testosterone. However, there appeared to be negative, albeit inconsistent, trends for androstenedione, testosterone, and estrone, suggesting that the irradiated women had lower levels of these hormones when compared with the nonirradiated women. These differences did not reach the level of statistical significance. While chance could partially explain these findings, it is plausible that the frequently observed protective association of breast cancer with pelvic irradiation could be due in part to a decrease in steroid hormones that is secondary, perhaps, to adrenal irradiation.

Mammographic parenchymal patterns have been suggested as indicators of breast cancer risk. However, few well-controlled studies have used prediagnostic mammograms to determine the pattern classification. The authors studied 266 cases of breast cancer and 301 controls from 25 screening centers of the Breast Cancer Detection and Demonstration Project, a nationwide screening program conducted between 1973 and 1980 to evaluate the risk associated with mammographic patterns using mammograms taken four years before the detection of breast cancer. Mammograms of the cancerous breast of cases and of the ipsilateral breast in the control matched to each case were blindly assessed by one of the investigators (J.N.W.), originator of the mammographic pattern classification. The breast cancer odds ratio among women with the combined P2 + DY patterns, compared with women with the N1 pattern, was 2.8 (95% confidence interval (CI): 1.6-5.1). This estimate of relative risk was comparable with the risk associated with other recognized breast cancer risk factors. The odds ratio among P2 + DY women with a first-degree family history of breast cancer was 5.5 (95% CI: 2.6-11.8) compared with N1 women without a family history. These data provide additional evidence that mammographic patterns are indicators for subsequent development of breast cancer, particularly among women with a first-degree family history of this malignancy.

We investigated the relationship between methylxanthine consumption and breast cancer using data from a case-control study which included 1,510 cases and 1,882 controls identified through a nation-wide breast cancer screening program. There was no evidence of a positive association between methylxanthine consumption and risk of breast cancer. In fact, there was some suggestion of a negative association, particularly in women diagnosed after age 50. In addition, there was no evidence of increased risk with past or recent methylxanthine consumption, or with the consumption of caffeine or specific beverages, most notably brewed or instant caffeinated coffee and tea.

The relationship between oral contraceptives and breast cancer was evaluated among 2,022 cases and 2,183 controls participating in a multicentre breast cancer screening programme. Ever use of oral contraceptives was not related to breast cancer risk (RR = 1.0, 95% CI 0.9-1.2), and no overall patterns of increasing or decreasing risks were observed according to the duration of use, or time since first or most recent use. Although we had no women with extended periods of oral contraceptive use early in life, no evidence of adverse effects attributable to short-term use before age 25, before first live birth or during the perimenopausal period were observed. Further, oral contraceptives did not interact with other breast cancer risk factors, except among those with a history of two or more breast biopsies (RR = 2.0). Analyses by stage of disease revealed that risk was related to the duration of oral contraceptive use: greater than or equal to 5 years use was associated with reduced risk for in situ cancer (RR = 0.59) and increased risks for invasive cancers (RR = 1.5 and 1.4 respectively for small and large lesions). These data suggest that oral contraceptive effects may vary by stage of disease, but provide no overall evidence of an association between oral contraceptives and breast cancer.

A population-based case-control study was conducted to examine whether tumor estrogen receptor status differentiated risk factor patterns for breast cancer. From December 1980 to December 1982, 458 women with newly diagnosed breast cancer and 568 control women, aged 20-54 years, from the Atlanta, Georgia, metropolitan area were interviewed. On the basis of tumor estrogen receptor results, cases were classified as receptor-positive or receptor-negative. Intercase analysis showed that age was positively and significantly associated with estrogen receptor-positive breast cancer (p = 0.001); the relative risk for an estrogen receptor-positive as opposed to an estrogen receptor-negative tumor was elevated threefold among women aged 50-54 years compared with those aged less than 35 years. In the case-control analysis, race was the only individual factor that demonstrated a significant difference in the risk for estrogen receptor-positive versus estrogen receptor-negative cancer (p less than 0.05), with blacks being at a 25% excess risk for estrogen receptor-negative cancer compared with whites. Although a history of benign breast disease was a risk factor for both positive and negative tumors, the association was stronger for the estrogen receptor-positive tumors. Postmenopausal women were at a lower risk for both cancer subtypes compared with premenopausal women. Compared with non-users, women who had ever taken oral contraceptives had a 16% decrease in the risk for receptor-positive cancer and a 22% increase in the risk for receptor-negative cancer. These results are consistent with the notion that certain exposure variables may relate to hormonal status, possibly by augmentation or suppression of estrogen receptor activity.

The association between alcohol consumption and breast cancer was investigated in a case-control study involving 1,524 cases and 1,896 controls identified through a nationwide screening program. Ever drinking alcohol was not associated with any substantial increase in risk [odds ratio (OR) = 1.1; 95% confidence interval (Cl) = 1.0-1.3], but there was a significant trend in risk with increasing average weekly intake (P less than .04). Women who had one or fewer drinks daily (83% of all drinkers) did not experience any excess risk compared to nondrinkers, but significant excess risks were observed among those who drank from 1 to 2 (OR = 1.3; 95% Cl = 1.0-1.7) or more than 2 (OR = 1.7; 95% Cl = 1.2-2.4) drinks a day. An increased risk associated with alcohol consumption was evident only for those who drank at younger ages (less than 30 yr), regardless of current consumption. Alcohol effects were adjusted for a variety of factors, including reproductive history, were adjusted for a variety of factors, including reproductive history, socioeconomic indicators, and obesity, but none exerted any appreciable confounding influence. The results support an association between moderate alcohol consumption in early life and subsequent breast cancer risk, although interpretation should be cautious in the absence of dietary information.

A case control study of 2,908 breast cancer cases and 3,180 controls, derived from a nationwide screening program, enabled evaluation of the relationship of breast cancer risk to a variety of menstrual factors. Risk was significantly inversely related to age at menarche, with women who first menstruated at age 15 or later having a 23% lower risk than those with menarche prior to the age of 12. There was a higher relative risk (1.3) for premenopausal than menopausal women. In contrast to previous studies, there was only a slight increase in risk associated with a late age at natural menopause, possibly owing to errors in recall. Bilateral oophorectomy at an early age exerted a protective influence on breast cancer risk, with effects manifested approximately 10 to 15 years after oophorectomy. Women who had both ovaries removed prior to the age of 40 had a 45% reduced risk compared to women with a natural menopause at ages 50 to 54. In addition, bilateral oophorectomy at an early age was associated with a lowered risk relative to natural menopause at a comparable age, which may reflect the more pronounced and sudden decline in endogenous hormones associated with the surgery. Although these results were based on patient reports regarding the types of surgical menopause experienced, validation against medical records showed close correspondence regarding the number of ovaries removed.

To assess the relationship of menopausal estrogens to breast cancer risk, the authors conducted a case-control study among 881 cases and 863 controls identified through the Breast Cancer Detection Demonstration Project (BCDDP). Use of estrogens was associated with a relative risk (RR) of 1.24 (95% C.I. 1.0-1.5), with higher risks observed among users of high-dose preparations. Hormone effects predominated among women who received them following bilateral oophorectomy (RR = 1.54), obliterating the protective effect normally associated with the operation. In this group, risk increased with years of estrogen use, reaching risks of 2-3 for users of ten or more years. High risks were also observed among oophorectomized women who used hormones in the presence of other risk factors, including nulliparity, family history of breast cancer, and benign breast disease. These results suggest a possible, although complex, relationship between estrogen use and risk of breast cancer.

To investigate the relationship of smoking to breast cancer risk, the authors conducted a case-control study involving 1,547 patients and 1,930 controls identified between 1973 and 1980 through a nationwide screening program. There was no evidence that smoking affected risk (relative risk (RR) = 1.2), nor were there any apparent relationships with more detailed exposure measures. No substantial variations in risk were noted by menopausal status; in particular, there was no support for the notion that smoking is associated with a reduced risk among naturally menopausal women (RR = 1.1). In addition, the data provided no general evidence that smokers experience an earlier menopause than nonsmokers, even when heavy smoking was considered. Evaluation of a number of sources of confounding and effect modification failed to alter the conclusion that smoking status does not appear to alter breast cancer risk among this population.

The risk of second primary cancer was evaluated in more than 25,000 women with cancer of the genital organs diagnosed between 1935 and 1982 in Connecticut. Significant excesses of subsequent cancers were observed following cancers of the cervix (35%, n = 656), uterine corpus (16%, n = 1,060), and ovary (58%, n = 366). When observed and expected second cancers of the female genital tract were excluded, these excesses became 40%, 30%, and 59% after cervix, uterine corpus, and ovary, respectively. Among women with either cancer of the cervix or uterine corpus, the risk of developing a second cancer rose with increasing duration of follow-up, reaching an excess of 61 and 34%, respectively, after 20 years. In contrast, among patients with ovarian cancer, the second cancer risk decreased over time to 41% after 10 years. Cancers related to smoking, i.e., oral cavity and pharynx, esophagus, and respiratory system, were notably increased among cervical cancer patients. The twofold to threefold risks observed for these second cancers are consistent with recent evidence linking cervical cancer to cigarette smoking and seem too large to be artifacts of confounding by low socioeconomic status. An increased incidence of second cancer of the abdominal organs (colon, rectum, kidney, bladder, ovaries) was generally observed for each gynecologic site. However, only rectal cancer was consistently linked with radiation treatment for the first primary cancer. Leukemia occurred in excess after cancers of the uterine corpus and ovary, but not after cervical cancer. The predominant cell type was acute nonlymphocytic leukemia, and the excess was associated with radiotherapy for uterine corpus cancer and with chemotherapy for ovarian cancer. Cancers of the breast and colon were increased following uterine corpus and ovarian cancer and vice versa, which supports the notion that these sites share a common etiology, perhaps related to dietary or hormonal factors. Cervical cancer patients experienced a deficit of subsequent breast cancer, possibly due to ovarian removal or ablation by radiation. Investigators need to explore further the association between the smoking-related cancer sites and cervical cancer, to clarify the role of radiotherapy and chemotherapy in relation to excess cancers, and to define more fully the etiologic factors that link cancers of the breast, colon, uterine corpus, and ovary.

Breast cancer risk among 1,362 cases and 1,250 controls participating in a large multicenter screening program was examined in relation to hypertension and the use of rauwolfia derivatives. A previous diagnosis of hypertension, reported by 22% of the cases and 23% of the controls, was not associated with an increased risk of breast cancer [odds ratio (OR) = 0.9]; nor was there any excess risk for long-term hypertensives. In addition, there was no significant increase in risk associated with use of either rauwolfia derivatives (OR = 1.2), thiazide preparations (OR = 1.2), or methyldopa (OR = 1.1). However, there were significant excess risks among long-term users and those with extended intervals since first use of rauwolfia. Rauwolfia users of 10 or more years' duration or those whose initial use occurred greater than or equal to 10 years before diagnosis had risk ratios of 4.5 (95% Cl, 1.2-19.8) and 3.8 (95% Cl, 2.3-11.6), respectively. These results suggest that women exposed to long-term rauwolfia use have an elevated risk of developing breast cancer, although the results fail to support previous observations of a generalized adverse effect.