Jill A. McDonald

Prevalence and Predictors of BRCA1 and BRCA2 Mutations in a Population-Based Study of Breast Cancer in White and Black American Women Ages 35 to 64 Years

Although well studied in families at high-risk, the roles of mutations in the BRCA1 and BRCA2 genes are poorly understood in breast cancers in the general population, particularly in Black women and in age groups outside of the very young. We examined the prevalence and predictors of BRCA1 and BRCA2 mutations in 1,628 women with breast cancer and 674 women without breast cancer who participated in a multicenter population-based case-control study of Black and White women, 35 to 64 years of age. Among cases, 2.4% and 2.3% carried deleterious mutations in BRCA1 and BRCA2, respectively. BRCA1 mutations were significantly more common in White (2.9%) versus Black (1.4%) cases and in Jewish (10.2%) versus non-Jewish (2.0%) cases; BRCA2 mutations were slightly more frequent in Black (2.6%) versus White (2.1%) cases. Numerous familial and demographic factors were significantly associated with BRCA1 and, to a lesser extent, BRCA2 carrier status, when examined individually. In models considering all predictors together, early onset ages in cases and in relatives, family history of ovarian cancer, and Jewish ancestry remained strongly and significantly predictive of BRCA1 carrier status, whereas BRCA2 predictors were fewer and more modest in magnitude. Both the combinations of predictors and effect sizes varied across racial/ethnic and age groups. These results provide first-time prevalence estimates for BRCA1/BRCA2 in breast cancer cases among understudied racial and age groups and show key predictors of mutation carrier status for both White and Black women and women of a wide age spectrum with breast cancer in the general population.

Hormone replacement therapy regimens and breast cancer risk

OBJECTIVE Hormone replacement therapy (HRT) has increased in the United States over the past 2 decades in response to reports of long‐term health benefits. A relationship between HRT and breast cancer risk has been observed in a number of epidemiological studies. In 2002, the Womens Health Initiative Randomized Controlled Trial reported an association between continuous combined HRT and breast cancer risk. The objective of this study was to examine the association between breast cancer risk and HRT according to regimen and duration and recency of use. METHODS A multicenter, population‐based, case‐control study was conducted in five United States metropolitan areas from 1994 to 1998. Analyzed were data from 3823 postmenopausal white and black women (1870 cases and 1953 controls) aged 35–64 years. Odds ratios (ORs) were calculated as estimates of breast cancer risk using standard, unconditional, multivariable logistic regression analysis. Potential confounders were included in the final model if they altered ORs by 10% or more. Two‐sided P values for trend were computed from the likelihood ratio statistic. RESULTS Continuous combined HRT was associated with increased breast cancer risk among current users of 5 or more years (1.54; 95% confidence interval 1.10, 2.17). Additionally, a statistically significant trend indicating increasing breast cancer risk with longer duration of continuous combined HRT was observed among current users (P = .01). There were no positive associations between breast cancer risk and other HRT regimens. CONCLUSION Our data suggest a positive association between continuous combined HRT and breast cancer risk among current, longer term users. Progestin administered in an uninterrupted regimen may be a contributing factor. Risk dissipates once use is discontinued.

Body mass and mortality after breast cancer diagnosis

Obesity is an established risk factor for some breast cancers, but less is known about its effect on breast cancer prognosis. Understanding this relationship is important, given the increasing number of women diagnosed with breast cancer and the growing prevalence of obesity. We conducted a cohort analysis of 3,924 women ages 20 to 54 with incident breast cancer enrolled between 1980 and 1982 in the Cancer and Steroid Hormone study, a case-control study. Interview data were linked to survival information from the Surveillance, Epidemiology, and End Results Program. We used proportional hazards models to examine the relationship between breast cancer mortality and adult body mass index (BMI; calculated using usual adult weight), BMI at age 18, and weight change from age 18 to adulthood. Hazard ratios (HR) were adjusted for cancer stage and other factors. During a median follow-up of 14.6 years, 1,347 women died of breast cancer. Obese women (adult BMI ≥30.00) were significantly more likely than lean women (BMI ≤22.99) to die of breast cancer [HR, 1.34; 95% confidence interval (CI), 1.09-1.65]. Women with BMIs of 25.00-29.99 (HR, 1.25; 95% CI, 1.08-1.44) or 23.00-24.99 (HR, 1.20; 95% CI, 1.04-1.39) also had higher breast cancer mortality (P for trend <0.0001). BMI at age 18 and weight change were not associated with breast cancer mortality independently of other factors. Obesity could be a preventable risk factor for death among breast cancer patients. Further study is needed to determine how these findings might affect recommendations to reduce breast cancer mortality.

Relation of regimens of combined hormone replacement therapy to lobular, ductal, and other histologic types of breast carcinoma†

The incidence of invasive lobular carcinoma has been increasing among postmenopausal women in some parts of the United States. Part of this may be due to changes in classification over time. However, the use of combined (estrogen and progestin) hormone replacement therapy (CHRT) also has increased during the last decade and may account in part for the increase in invasive lobular breast carcinoma.

The NICHD Women's Contraceptive and Reproductive Experiences Study: Methods and Operational Results

PURPOSE This paper presents methods and operational results of a population-based case-control study examining the effects of oral contraceptive use on breast cancer risk among white and black women aged 35-64 years in five U.S. locations. METHODS Cases were women newly diagnosed with breast cancer during July 1994 through April 1998. Controls were identified through random digit dialing (RDD) using unclustered sampling with automated elimination of nonworking numbers. Sampling was density-based, with oversampling of black women. In-person interviews were conducted from August 1994 through December 1998. Blood samples were obtained from subsets of cases and controls, and tissue samples were obtained from subsets of cases. A computerized system tracked subjects through study activities. Special attention was devoted to minimizing exposure misclassification, because any exposure-disease associations were expected to be small. RESULTS An estimated 82% of households were screened successfully through RDD. Interviews were completed for 4575 cases (2953 whites; 1622 blacks) and 4682 controls (3021 whites; 1661 blacks). Interview response rates for cases and controls were 76.5% and 78.6%, respectively, with lower rates for black women and older women. CONCLUSIONS The methodologic details of this large collaboration may assist researchers conducting similar investigations.

Relationship between Established Breast Cancer Risk Factors and Risk of Seven Different Histologic Types of Invasive Breast Cancer

Background: Important differences in the contributions of certain exposures to the risks of ductal versus lobular breast carcinomas have been observed, but few studies have evaluated the relationships between established breast cancer risk factors and other histologic types. Methods: Information on family history of cancer and reproductive, hormonal, anthropometric, and lifestyle characteristics were collected in a multicenter population-based case-control study consisting of 3,463 ductal, 274 lobular, 261 ductal-lobular, 91 medullary, 77 tubular, 70 comedo, and 61 mucinous invasive breast carcinoma cases (ages 35-64 years, newly diagnosed 1994-1998) and 4,682 controls. Associations between each of these histologic types and various exposures were evaluated using polytomous regression. Results: Heterogeneity in the risks of different histologic types of breast cancer was observed for three exposures: menopausal hormone use, body mass index (BMI), and alcohol consumption. Specifically, current use of unopposed estrogen was associated with a reduced risk of ductal carcinoma and increased risk of comedocarcinoma, and current use of estrogen and progestin was associated with elevated risks of ductal-lobular and tubular carcinomas. Among postmenopausal women, BMI was only inversely related to risk of ductal-lobular carcinoma, and alcohol use was only positively related to risk of lobular carcinoma. Conclusions: Variations in the associations between known breast cancer risk factors and risk of different breast cancer histologies were observed. Although these findings require confirmation, and the analyses of some histologic groups were limited by small sample sizes, they provide some insight into the different etiologies of various histologic subtypes of breast cancer. (Cancer Epidemiol Biomarkers Prev 2006;15(5):946–54)

Reproductive history and mortality after breast cancer diagnosis.

OBJECTIVE: To assess whether reproductive factors are associated with mortality after breast cancer diagnosis. METHODS: We followed up 4,299 U.S. women enrolled between 1980 and 1982 at ages 20–54 years as incident breast cancer cases in a population-based, case-control study, the Cancer and Steroid Hormone Study. Vital status through 1997 for these cases was obtained by linking Cancer and Steroid Hormone Study data to Surveillance, Epidemiology, and End Results files. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for death associated with selected reproductive factors using proportional hazards models. RESULTS: During a median follow-up of 14.5 years, 1,847 deaths occurred. Women aged 20–45 years whose last birth occurred 12 months or less (age-adjusted HR = 1.62, 95% CI 1.10–2.37) and 13–48 months before breast cancer diagnosis (age-adjusted HR = 1.35, 95% CI 1.05–1.75) were at an increased risk for death compared with nulliparous women. After adjusting for additional factors including tumor stage, women whose last birth occurred 12 months or less before diagnosis remained at an increased risk for death (HR = 1.51, 95% CI 1.02–2.23). Fifteen-year survival was 38%, 51%, and 60% among women aged 20–45 years whose last birth was 12 months or less, 13–48 months, and more than 48 months before diagnosis, respectively, compared with 65% among nulliparous women. Mortality risk was not associated with age at first birth, parity, or breastfeeding duration among women aged 20–45 years or among women aged 46–54 years. CONCLUSION: A recent birth may be an adverse prognostic indicator among women diagnosed with breast cancer at ages 20–45 years. LEVEL OF EVIDENCE: II-2

Breast Cancer Risk and Hormone Receptor Status in Older Women by Parity, Age of First Birth, and Breastfeeding: A Case-Control Study

Background: Early age at first birth and multiparity reduce the risk of estrogen receptor-progesterone receptor (ERPR)–positive breast cancer, whereas breastfeeding reduces the risk of both ERPR-positive and ERPR-negative cancers. Methods: We used multivariable logistic regression analysis to investigate whether age at first birth (<25 or ≥25 years) and breastfeeding (ever/never) modify the long-term effect of parity on risk of ERPR-positive and ERPR-negative cancer using 1,457 incident breast cancer cases and 1,455 controls ages ≥55 years who participated in the Womens Contraceptive and Reproductive Experiences Study. Results: Women who gave birth before age 25 years had a 36% reduced risk of breast cancer compared with nulligravida that was not observed for women who started their families at an older age (Pheterogeneity = 0.0007). This protective effect was restricted to ERPR-positive breast cancer (Pheterogeneity = 0.004). Late age at first birth increased the risk of ERPR-negative cancers. Additional births reduced the risk of ERPR-positive cancers among women with an early first birth (Ptrend = 0.0001) and among women who breastfed (Ptrend = 0.004) but not among older mothers or those who never breastfed. In women with a late first birth who never breastfed, multiparity was associated with increased risk of breast cancer. Conclusions: These findings suggest that the effect of parity on a womans long-term risk of breast cancer is modified by age at first full-term pregnancy and possibly by breastfeeding. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1723–30)

Reproductive factors and risk of breast carcinoma in a study of white and African-American women.

Few studies have investigated the association between reproductive factors and the risk of breast carcinoma among African‐American women. The authors assessed whether the number of full‐term pregnancies, age at first full‐term pregnancy, and total duration of breastfeeding were associated with similar relative risk estimates in white and African‐American women in a large multicenter, population‐based case–control study of breast carcinoma.

Infertility drugs and the risk of breast cancer: findings from the National Institute of Child Health and Human Development Women's Contraceptive and Reproductive Experiences Study

Abstract Objective: To determine the association between infertility drug use and invasive breast cancer in a population-based case–control study. Design Multicenter case–control study. Setting Women aged 35 to 64 years in metropolitan Atlanta, Detroit, Los Angeles, Philadelphia, and Seattle. Patient(s) The 4,575 case patients had histologically confirmed primary invasive breast cancer. The 4,682 control subjects were women without breast cancer identified in the same geographic locations using randomized-digit dialing. Intervention(s) A standardized questionnaire focusing on reproductive health and family history as well as use of oral contraceptives and other hormones and infertility drugs was administered to all subjects. Data on the type of breast cancer were also obtained. Main outcome measure(s) Odds ratios examining the association between use of various infertility drugs and invasive breast cancer. Result(s) Overall, a history of infertility drug use was not associated with the risk of developing breast cancer. Compared with women who never used any fertility medication, however, women using human menopausal gonadotropin (hMG) for ≥6 months or for at least six cycles had a relative risk of breast cancer ranging between 2.7 to 3.8. Conclusion(s) Long-term use of certain infertility drugs could adversely affect risk of breast cancer. Additional confirmatory studies are needed.