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Purpose: Prenatal DES exposure has been associated with increased risk of breast cancer, but the mechanisms are unknown. Larger bra cup size has also been associated with increased breast cancer risk, although not consistently. We investigated the relation of prenatal DES exposure to mammary gland mass, as estimated by bra cup size., Methods: In 2006, 3,222 DES-exposed and 1,463 unexposed women reported their bra cup size, band size (chest circumference), and weight at age 20. Prevalence ratios (PR) were calculated for DES exposure in relation to large bra cup size, with control for year of birth and study cohort. Primary analyses were carried out among women who reported a chest circumference of no more than 32 inches because their cup size would be less influenced by fat mass., Results: Within this group, DES-exposed women had an estimated 45% increased prevalence (95% CI 0.97-2.18) of large cup size (C or greater) relative to unexposed women. The PR was further increased among women in this group who had a body mass index of < 21 at age 20: PR = 1.83 (95% CI 1.11-3.00). The PR for high-dose DES exposure relative to no exposure was 1.67, 95% CI 1.02-2.73, whereas there was no association of bra cup size with low-dose exposure., Conclusions: These results provide support for the hypothesis that in utero DES exposure may result in greater mammary gland mass. Taken together with previous research on bra size and breast cancer risk, these findings suggest a mechanism for a possible association of in utero DES exposure with increased risk of breast cancer.

Conflicting reports regarding the relationship between breast-feeding and ovarian cancer risk suggest a possible influence of patterns of breast-feeding. We used logistic regression to examine breast-feeding in a large population of parous women who participated in a case-control study of ovarian cancer in New Hampshire and MA, USA. Risk of ovarian cancer was reduced in parous women who ever breast-fed (OR: 0.75; 95% CI: 0.62, 0.92), but evidence was limited for an influence of duration of breast-feeding and the number of children breast-fed. Compared to never breast-feeding, inverse associations were seen for breast-feeding all children (OR: 0.72; 95% CI: 0.58, 0.91) and for breast-feeding some children when the last born child was breast-fed (OR: 0.58; 95% CI: 0.37, 0.91). There was little evidence of reduced risk for those who breast-fed some children when the last born child was not breast-fed (OR: 0.91; 95% CI: 0.66, 1.26). Similar findings were noted in women with exactly two children and in those with two or more children. The protective influence of breast-feeding on ovarian cancer risk may be limited to women who breast-feed their last born child. These findings, which require confirmation by future studies, imply that breast-feeding resets pregnancy-related states that mediate ovarian cancer risk.

Background: The recent decline in US breast cancer incidence rates has been attributed to the marked reduction in use of postmenopausal hormone therapy (HT). An alternative explanation is that women who are not routinely seeking medical care to renew HT prescriptions may be less adherent to recommendations for mammographic screening. To investigate the latter possibility, we compared mammographic intervals according to HT use., Methods: Using data (1995-2007) from the New Hampshire Mammography Network (NHMN), a state-based mammography registry, we assessed mammographic intervals corresponding to HT use or nonuse among postmenopausal women. We used linear mixed effects models to assess whether the length of screening mammogram intervals differed according to HT use., Results: A total of 310,185 mammograms, representing 76,192 postmenopausal women and 319,353 person-years of screening, were included in the analysis. The median screening interval corresponding to HT use overall was 13.0 months (interquartile range: 12.4-15.1) and for nonuse was 13.1 (interquartile range: 12.4-15.8). Virtually, all screening mammograms occurred within a 2-year interval regardless of HT use or nonuse (98.5 and 98.1%, respectively)., Conclusions: Our findings indicate that screening mammography intervals are similar whether or not women are using HT. Thus, reduced utilization of screening mammography is unlikely to account for the decrease in breast cancer incidence seen soon after the WHI report.

Early life exposures, such as being breastfed in infancy, may influence the risk of breast cancer in adulthood. We evaluated the risk of breast cancer in relation to ever having been breastfed in infancy among 9,442 women who participated in a population-based, case-control study. Cases were identified through cancer registries in three states (Massachusetts, New Hampshire, and Wisconsin); controls were identified through statewide drivers' license lists or medicare lists. Data on known and suspected risk factors were obtained through telephone interview. We used unconditional logistic regression to assess the relation of breast cancer with ever having been breastfed and with breastfeeding duration (available for only 19% of breastfed women) in premenopausal women (1,986 cases and 1,760 controls) and postmenopausal women (2,600 cases and 2,493 controls). We found no evidence that ever having been breastfed in infancy was associated with breast cancer risk in either premenopausal women (odds ratio [OR] = 0.96; 95% confidence interval [CI] = 0.83-1.10) or postmenopausal women (OR = 0.98; 95% CI = 0.87-1.10). The association did not differ according to breast cancer stage, mother's history of breast cancer, or any other reproductive factor assessed. Likewise, we found no association between breastfeeding duration and risk of breast cancer. Our results did not support the hypothesis that exposure to breast milk in infancy influences the risk of adult breast cancer.

Objective: To estimate the separate effects of sunlamp and tanning bed device use on melanoma risk., Methods: Population-based case-control study of 423 cases of melanoma and 678 controls in the state of New Hampshire. Exposure data, including sunlamp and tanning bed use, were collected by telephone interview. Associations were evaluated using logistic regression analyses., Results: About 17% of participants ever used a sunlamp, and most use (89%) occurred before 1980. The OR was 1.39 (95% CI 1.00-1.96) for ever using a sunlamp, 1.23 (95% CI 0.81-1.88) for those starting sunlamp use <20 years, and 1.71 (95% CI 1.00-2.92) for those starting >/=20 years. Data suggested increasing risk with number of sunlamp uses and with duration of use (tests of trend p = 0.02). The overall prevalence of tanning bed use was 22% and most use (83%) occurred after 1980. The OR was 1.14 (95% CI 0.80-1.61) for ever using a tanning bed; there was no evidence that risk increased with frequency or duration of use. The OR was 1.96 (95% CI 1.06-3.61) for having used both devices., Conclusion: Results suggest a modest association between sunlamp use and melanoma risk, and increasing risk with greater frequency and duration of use. No association with tanning bed use was found, but sufficient lag time may not have elapsed to assess a potential effect.

Objective: To examine the association between breast density and risk of breast ductal carcinoma in situ (DCIS)., Methods: We assessed breast density in relation to DCIS risk using combined data from statewide mammography registries in NH and VT. The prospective analyses were based on 572 DCIS cases arising in 154,936 women (58,496 premenopausal and 96,440 postmenopausal). Women in the study were followed on average 4.1 years. Breast density was scored by community radiologists using BIRADS categories (fatty, scattered density, heterogeneous density, extreme density)., Results: In premenopausal women, based on 157 cases, the RR for DCIS risk were 0.29 (95% CI: 0.0.04, 2.24) for fatty breasts, 2.06 (95% CI: 1.39, 3.05) for heterogeneous density, and 2.40 (95% CI: 1.47, 3.91) for extreme density, relative to scattered density. In postmenopausal women, based on 369 cases, the RR for DCIS risk were 0.58 (95% CI: 0.37, 0.93) for fatty breasts, 1.41 (95% CI: 1.12, 1.78) for heterogeneous density, and 1.49 (95% CI: 0.93, 2.37) for extreme density, relative to scattered density. The possible interaction between breast density and menopausal status in relation to DCIS risk was not statistically significant., Conclusions: We observed an association between breast density and DCIS risk. Although the association seemed stronger in premenopausal women, there was no evidence of an interaction involving breast density and menopausal status.

Objectives: Evaluate known breast cancer risk factors in relation to breast density., Methods: We examined factors in relation to breast density in 144,018 New Hampshire (NH) women with at least one mammogram recorded in a statewide mammography registry. Mammographic breast density was measured by radiologists using the BI-RADS classification; risk factors of interest were obtained from patient intake forms and questionnaires., Results: Initial analyses showed a strong inverse influence of age and body mass index (BMI) on breast density. In addition, women with late age at menarche, late age at first birth, premenopausal women, and those currently using hormone therapy (HT) tended to have higher breast density, while those with greater parity tended to have less dense breasts. Analyses stratified on age and BMI suggested interactions, which were formally assessed in a multivariable model. The impact of current HT use, relative to nonuse, differed across age groups, with an inverse association in younger women, and a positive association in older women (p < 0.0001 for the interaction). The positive effects of age at menarche and age at first birth, and the inverse influence of parity were less apparent in women with low BMI than in those with high BMI (p = 0.04, p < 0.0001 and p = 0.01, respectively, for the interactions). We also noted stronger positive effects for age at first birth in postmenopausal women (p = 0.004 for the interaction). The multivariable model indicated a slight positive influence of family history of breast cancer., Conclusions: The influence of age at menarche and reproductive factors on breast density is less evident in women with high BMI. Density is reduced in young women using HT, but increased in HT users of age 50 or more.

Objective: To evaluate the potential interaction between N-acetyltransferase 2 (NAT2) and smoking in breast cancer incidence., Methods: The data are derived from a population-based case-control study of women aged 20-69 years who were residents of Massachusetts or Wisconsin during 1997-1998. Incident cases of invasive breast cancer were identified through state tumor registries and age-similar controls were selected at random from population lists. Telephone interviews were conducted to obtain information on known and suspected risk factors including smoking history. Women provided oral mucosal DNA through the mail for genetic studies., Results: A total of 791 cases and 797 controls were included in the analysis. Overall, smoking was modestly associated with breast cancer risk (multivariate odds ratio (OR) for ever smoking: 1.37; 95% confidence interval (CI): 1.12-1.69), and there was a trend in risk for greater pack-years of smoking among postmenopausal women (p for trend = 0.02). Overall, NAT2 was not related to invasive breast cancer (multivariate OR: 1.1 1; 95% CI: 0.90-1.36). Associations of smoking with breast cancer tended to be somewhat stronger among the women with the slow acetylator genotype for NAT2: when compared to those who never smoked and were rapid acetylators, the OR for ever smoking was 1.50 (95% CI: 1.11-2.02) in slow acetylators, and OR: 1.24 (95% CI: 0.91-1.70) in rapid acetylators. However, tests for multiplicative interaction were not significant in case-control comparisons, or in case-only analyses., Conclusion: Results of the study are compatible with the majority of previous studies that indicate little or no association of NAT2, smoking, or their interaction with the occurrence of breast cancer.

Background: A synthetic estrogen, diethylstilbestrol (DES), was widely prescribed to pregnant women during the 1950s and 1960s but was later discovered to be associated with an increased risk of clear-cell carcinoma of the vagina and cervix in female offspring. DES has not been linked to other cancers in female offspring, but studies of other prenatal factors such as twin gestation and pre-eclampsia have indicated that in-utero estrogen levels may influence breast cancer risk. We evaluated the relation of in-utero DES exposure to the risk of adult breast cancer., Methods: A cohort of 4821 exposed women and 2095 unexposed women, most of whom were first identified in the mid-1970s, were followed by mailed questionnaires for an average of 19 years. Reported cancer outcomes were validated by medical record review. Breast cancer incidence in DES-exposed daughters was compared with cancer incidence in unexposed daughters with use of Poisson regression analysis, adjusting for year of birth, age at menarche, age at first birth, and number of births., Findings: The rate ratio for incidence of invasive breast cancer in exposed versus unexposed women was 1.4 (95% confidence interval (CI) = 0.7-2.6). DES exposure was not associated with an increased risk of breast cancer in women under 40 years, but among women aged 40 and older the rate ratio was 2.5 (95% CI = 1.0-6.3). The rate ratio for the association of DES exposure with estrogen receptor-positive tumors was 1.9 (95% CI = 0.8-4.5)., Interpretation: While not statistically significant, the overall 40% excess risk, arising exclusively from the subset of estrogen receptor-positive cases, raises a concern calling for continued investigation.

Objective: The importance of p16 alterations in the pathogenesis of dysplastic nevi and sporadic melanoma remains controversial. The goal of this work was to discover if p16/9p21 alterations occur early in precursor lesions as well as related sporadic melanomas., Methods: DNA was microdissected from 44 cutaneous melanomas, 14 dysplastic nevi, and six nevi without atypia as part of a study of melanoma. Alteration of the p16 region on 9p21 was measured by loss of heterozygosity (LOH) analysis as well as detection of homozygous deletions for p16 exon 2., Results: This analysis revealed that LOH in 9p21 directly surrounding p16 occurred in approximately 40% (17/44) of melanoma tumors representing all Clark levels. LOH was also discovered in 64% (9/14) of dysplastic nevi, and 50% (3/6) of benign nevi. Homozygous deletion of p16 was found in 29% (4/14) of dysplastic nevi but never in benign nevi., Conclusions: These studies reveal that LOH and homozygous deletion can affect 9p21 and the p16 locus early in putative precursor lesions of melanoma, even prior to the establishment of cytologically evident aberrant histology. Comparison of alterations in nevi and melanomas from the same individual revealed a pattern of progressive but heterogeneous events suggesting that systemic processes may affect this region of 9p21 at various times during melanoma progression.

Objective: To elucidate the association between anthropometric measures and ovarian cancer risk., Methods: From a population-based study of 563 cases of ovarian cancer and 523 controls we recorded weight, both at index age and age 18, and height using an in-person questionnaire, and used these to calculate body mass index (BMI). Multivariate logistic regression was used to calculate the exposure odds ratios, adjusted for established risk factors, stratified, in turn, by menopausal status and histologic type of ovarian cancer., Results: Height, weight, and BMI were unrelated to risk for ovarian cancer in the total group of cases and controls. After stratification by menopausal status, weight and BMI were associated positively with risk among premenopausal women, but did not affect risk postmenopausally. High BMI, weight, and height were most strongly related to risk of serous borderline cancer, particularly among premenopausal women. The association did not appear to be confined only to those overweight women with gynecologic problems such as irregular periods or ovarian cysts., Conclusions: Weight and BMI are positively related to premenopausal ovarian cancer risk in this population-based case-control study. This association is particularly noted for serous borderline tumors. This may suggest the importance of endocrine factors, which are altered in overweight women, such as insulin or androgens.

Objective: To clarify the hormonal context of breast cancer etiology we used data from a large, population-based case-control study to investigate the relationship between breast cancer risk and a history of diabetes mellitus, disorders associated with estrogen stimulation (uterine fibroids, endometriosis, gallstones), and disorders associated with androgen stimulation (acne, hirsutism, and polycystic ovaries)., Methods: Breast cancer patients between 50 and 75 years old were identified from state-wide tumor registries in Wisconsin, Massachusetts, and New Hampshire; controls were randomly selected from drivers' license lists (age less than 65) or Medicare enrollment files (age 65-74). Information on reproductive history, medical history, and personal habits was obtained by telephone interview. A total of 5659 cases and 5928 controls were interviewed and provided suitable data., Results: There was no overall association between breast cancer risk and reported history of diabetes mellitus, endometriosis, uterine fibroids, gallstones, or cholecystectomy. However, the disorders with androgenic associations all conferred an increased risk: the overall odds ratio (OR) for a history of acne was 1.4 (95% CI 1.0-1.9), that for hirsutism was 1.2 (95% CI 0.81-1.8), and that for polycystic ovaries 1.6 (95% CI 0.8-3.2). Diabetes mellitus diagnosed before age 35 conferred an odds ratio of 0.52 (95% 0.25-1.1), while diabetes diagnosed at a later age was associated with an increased risk (OR = 1.2, 95% CI 1.0-1.4)., Conclusions: Androgen-related phenomena are likely to be important in the etiology of breast cancer.

Objective: Although many studies have shown that higher weight increases the risk of postmenopausal breast cancer, some aspects of this association are unclear. In order to examine the risk associated with different patterns of weight change, we analyzed data from a large case-control study of postmenopausal breast cancer., Methods: Participants included women aged 50 79 years (n = 5031) who are newly diagnosed with invasive breast cancer in Massachusetts, New Hampshire, and Wisconsin. Similarly-aged population controls (n = 5255) were selected at random from driver's license files and Medicare beneficiary lists. Height, weight, and information on other breast cancer risk factors were ascertained by structured telephone interviews from 1992 to 1995, and logistic regression was used to estimate multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI)., Results: Women in the top quintile groups for height at age 20, recent weight, and recent body mass index had significantly increased risks of breast cancer. Among women who reached their highest adult weight at younger ages (<45 years), increasing weight loss since that age was associated with a reduced risk of postmenopausal breast cancer (OR 0.90, CI 0.84 0.98, per 5 kg). However, weight loss among women whose highest weight occurred after age 45 was not associated with risk (OR 1.00, CI 0.95 1.05, per 5 kg). Weight gain since the lowest adult weight increased risk by 8% for each 5 kg of gain (OR 1.08, CI 1.06-1. 11). Temporary weight cycling (weight loss followed by weight gain) was not associated with increased risk., Conclusions: Weight gain clearly increased risk of postmenopausal breast cancer. These data lend further support to efforts aimed at helping women avoid weight gain as they age.

Objective: Breast size has been hypothesized to predict a woman's risk of breast cancer although studies in the main have not supported an association. In a large, population-based case-control study we examined whether breast size might emerge as a significant risk factor among very lean women in whom breast size might be a truer reflection of the volume of gland mass at risk for malignant change., Methods: The data derive from a population-based case-control study of women aged 50 to 79 years conducted in several New England states and Wisconsin. Incident cases of invasive breast cancer (n = 2015) were identified through state tumor registries and controls (n = 2556) were selected at random within age strata from population lists. Telephone interviews were conducted to obtain information on known and suspected risk factors which included bra dimensions (cup and back size) prior to a first birth, or at the age of 20 for nulliparous women., Results: We observed a significant positive association for cup size which was limited to women who were the most lean as young adults based on chest circumference. Among those reporting a chest size under 34 inches multivariate-adjusted relative risks were 1.34 (95% CI: 1.04 to 1.74) for cup size B, and 1.76 (95% CI: 1.04 to 3.01) for cup size C and larger, compared to a cup size smaller than B, and the trend for increasing cup size was statistically significant (P = 0.005). There was no relation with breast size among women reporting an average or larger back circumference (34 inches or larger)., Conclusion: Breast size before a pregnancy is a positive predictor of postmenopausal breast cancer, but this association is limited to those who were especially lean as young women.

The organochlorines, a diverse group of some 15,000 compounds, have been implicated increasingly as being harmful to humans. Some congeners of DDT and PCB elicit very weak estrogenic responses in animals, while the dioxin TCDD and related compounds have antiestrogenic properties. This review summarizes the evidence regarding whether certain organochlorine compounds, usually as persistent food-chain contaminants, increase the risk of breast and endometrial cancers through their estrogenic potential. In humans, neither ecologic data nor occupational studies provide clear support for an association between organochlorine exposure and the occurrence of these cancers. In our summary analysis of occupational exposure, the rate ratio of breast cancer for exposed cf unexposed women was 0.84 (95 percent confidence interval [CI] = 0.50-1.33) for PCBs and 1.08 (CI = 0.68-1.58) for TCDD. Similarly, effect estimates close to unity were found in summary analysis of breast cancer case-control studies regarding levels of DDE and PCB in adipose tissue or serum. In two recent nested case-control studies using stored specimens, the odds ratio per standard deviation increase in serum p,p'-DDE was 1.27 (CI = 0.95-1.69). Although estrogenic effects of certain organochlorine compounds should be easier to detect on the endometrium, we know of no analytic epidemiologic studies of endometrial cancer published to data. We conclude that available data do not indicate that organochlorines will affect the risk of these two cancers in any but the most unusual situation.