John M. Hampton

Socioeconomic risk factors for breast cancer: distinguishing individual- and community-level effects.

Background: Women are at higher risk of breast cancer if they have higher socioeconomic status (SES) or live in higher SES or urban communities. We examined whether women living in such communities remained at greater risk of breast cancer after controlling for individual education and other known individual-level risk factors. Methods: Data were from a population-based, breast cancer case-control study conducted in Wisconsin from 1988 to 1995 (n = 14,667). Data on community SES and urbanicity come from the 1990 census, measured at the census tract and zip code levels. We evaluated relationships between individual- and community-level variables and breast cancer risk using multilevel logistic regression models with random community intercepts. Results: After controlling for individual education and other individual-level risk factors (age, mammography use, family history of breast cancer, parity, age at first birth, alcohol intake, body mass index, hormone replacement use, oral contraceptive use, and menopausal status), women living in the highest SES communities had greater odds of having breast cancer than women living in the lowest SES communities (1.20; 95% confidence interval = 1.05–1.37). Similarly, the odds were greater for women in urban versus rural communities (1.17; 1.06–1.28). Conclusions: Community SES and urbanicity are apparently not simply proxies for individual SES. Future research should examine why living in such communities itself is associated with greater risk of breast cancer.

Body mass index before and after breast cancer diagnosis: Associations with all-cause, breast cancer, and cardiovascular disease mortality

Background: Factors related to improving outcomes in breast cancer survivors are of increasing public health significance. We examined postdiagnosis weight change in relation to mortality risk in a cohort of breast cancer survivors. Methods: We analyzed data from a cohort of 3,993 women with ages 20 to 79 years living in New Hampshire, Massachusetts, or Wisconsin with invasive nonmetastatic breast cancers diagnosed in 1988 to 1999 identified through state registries. Participants completed a structured telephone interview 1 to 2 years after diagnosis and returned a mailed follow-up questionnaire in 1998 to 2001 that addressed postdiagnosis weight and other factors. Vital status information was obtained from the National Death Index through December 2005. Hazard ratios and 95% confidence intervals were estimated from Cox proportional hazards models and adjusted for prediagnosis weight, age, stage, smoking, physical activity, and other important covariates. Results: During an average 6.3 years of follow-up from the postdiagnosis questionnaire, we identified 421 total deaths, including 121 deaths from breast cancer and 95 deaths from cardiovascular disease. Increasing postdiagnosis weight gain and weight loss were each associated with greater all-cause mortality. Among women who gained weight after breast cancer diagnosis, each 5-kg gain was associated with a 12% increase in all-cause mortality (P = 0.004), a 13% increase in breast cancer–specific mortality (P = 0.01), and a 19% increase in cardiovascular disease mortality (P = 0.04). Associations with breast cancer mortality were not modified by prediagnosis menopausal status, cigarette smoking, or body mass index. Conclusion: These findings suggest that efforts to minimize weight gain after a breast cancer diagnosis may improve survival. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1403–9)

Bisphosphonates for osteoporosis treatment are associated with reduced breast cancer risk

Background:Bisphosphanates are used primarily for the prevention and treatment of osteoporosis, and are also indicated for osseous complications of malignancy. In addition to their bone resorption properties, the most commonly used nitrogen-containing bisphosphonate compounds also inhibit protein prenylation, and thus may exert anti-tumour properties.Methods:To evaluate whether the use of these drugs may be associated with cancer, specifically breast cancer, we conducted a population-based case–control study in Wisconsin from 2003 to 2006. Participants included 2936 incident invasive breast cancer cases and 2975 population controls aged <70 years. Bisphosphonate use and potential confounders were assessed by interview.Results:Using multivariable logistic regression, the odds ratio for breast cancer in current bisphosphonate users compared with non-users was 0.67 (95% confidence interval 0.51–0.89). Increasing duration of use was associated with a greater reduction in risk (P-trend=0.01). Risk reduction was observed in women who were not obese (P-interaction=0.005).Conclusion:These results are suggestive of an additional benefit of the common use of bisphosphonates, in this instance, the reduction in breast cancer risk.

Obesity, diabetes, and other factors in relation to survival after endometrial cancer diagnosis

Endogenous and exogenous sources of estrogen and characteristics altering these hormone levels have been related to endometrial cancer risk; however, their relationship to survival following diagnosis is less clear. In a population-based study, we examined whether mortality after endometrial cancer diagnosis was affected by prediagnosis obesity, diabetes, smoking, oral contraceptive use, parity, or postmenopausal hormone (PMH) use. Eligible women, aged 40–79 years, diagnosed from 1991–1994 with incident invasive endometrial cancer and identified through the Wisconsin statewide mandatory cancer registry were invited to participate. Of 745 eligible cases, 166 women were deceased after 9.3 years of follow-up, with 43 attributable to endometrial cancer, based upon vital records linkage. Hazard rate ratios (HRR) and 95% confidence intervals were adjusted for age at diagnosis, menopausal status, stage of disease, and other exposures of interest. Obese women (body mass index [BMI] ≥30 kg/m2) prior to endometrial cancer diagnosis had an increased risk of both all-cause (HRR = 1.6, 95% CI 1.0–2.5) and endometrial cancer (HRR = 2.0, 95% CI 0.8–5.1) mortality, compared with nonoverweight women (BMI < 25 kg/m2). Endometrial cancer cases with diabetes also had an increased risk of all-cause mortality compared with nondiabetic women (HRR = 1.7, 95% CI 1.1–2.5), although there was no association with endometrial cancer mortality. There were no associations between PMH use, oral contraceptive use, parity, or smoking and mortality from any cause. The results suggest that history of obesity and diabetes may increase risk of mortality after endometrial cancer diagnosis; modification of these characteristics may improve survival after endometrial cancer diagnosis.

Socioeconomic status and survival after an invasive breast cancer diagnosis.

Women who live in geographic areas with high poverty rates and low levels of education experience poorer survival after a breast cancer diagnosis than women who live in communities with indicators of high socioeconomic status (SES). However, very few studies have examined individual‐level SES in relation to breast cancer survival or have assessed the contextual role of community‐level SES independent of individual‐level SES.

Prevalence of Mammographically Dense Breasts in the United States

BACKGROUND National legislation is under consideration that would require women with mammographically dense breasts to be informed of their breast density and encouraged to discuss supplemental breast cancer screening with their health care providers. The number of US women potentially affected by this legislation is unknown. METHODS We determined the mammographic breast density distribution by age and body mass index (BMI) using data from 1518 599 mammograms conducted from 2007 through 2010 at mammography facilities in the Breast Cancer Surveillance Consortium (BCSC). We applied these breast density distributions to age- and BMI-specific counts of the US female population derived from the 2010 US Census and the National Health and Nutrition Examination Survey (NHANES) to estimate the number of US women with dense breasts. RESULTS Overall, 43.3% (95% confidence interval [CI] = 43.1% to 43.4%) of women 40 to 74 years of age had heterogeneously or extremely dense breasts, and this proportion was inversely associated with age and BMI. Based on the age and BMI distribution of US women, we estimated that 27.6 million women (95% CI = 27.5 to 27.7 million) aged 40 to 74 years in the United States have heterogeneously or extremely dense breasts. Women aged 40 to 49 years (N = 12.3 million) accounted for 44.3% of this group. CONCLUSION The prevalence of dense breasts among US women of common breast cancer screening ages exceeds 25 million. Policymakers and healthcare providers should consider this large prevalence when debating breast density notification legislation and designing strategies to ensure that women who are notified have opportunities to evaluate breast cancer risk and discuss and pursue supplemental screening options if deemed appropriate.

Duration of sleep and breast cancer risk in a large population-based case : control study

One important function of sleep may be its contribution to the maintenance of the immune system and regulation of the circadian rhythms by melatonin. Researchers have speculated that disruption of immune functions involving cortisol levels and natural killer cell activity may increase breast cancer risk whereas increased melatonin exposure may protect against breast cancer. We conducted a multistate population‐based case–control study of 4033 women with invasive breast cancer and 5314 community women without breast cancer in which we inquired about womens sleep habits in the recent past and during adult lifetime. Relative to women who slept 7.0–7.9 h/night, the multivariate odds ratio for developing breast cancer among women who slept an average of 9 h or more per night approximately 2 years prior to interview was 1.13 (95% CI 0.93–1.37). The multivariate‐adjusted odds ratio for the continuous term was 1.06 (95% CI 1.01–1.11), suggesting a 6% increase in risk for every additional hour of sleep. Similar patterns were observed for average lifetime adult sleep duration. We found little evidence that sleeping few hours per night was associated with breast cancer risk. The results of this study suggest that increasing sleep duration is modestly associated with an increased breast cancer risk. In contrast, short duration of sleep (<7 h/night) is not substantially associated with increased risk. Further research in this area is warranted.

Oral Contraceptive Use, Reproductive Factors, and Colorectal Cancer Risk: Findings from Wisconsin

We investigated the association of oral contraceptive (OC) use and reproductive factors with colorectal cancer risk in a large population-based case-control study. Cases were women ages 20 to 74 years, living in Wisconsin, with a new diagnosis of colon (n = 1,122) or rectal (n = 366) cancer. Control participants were randomly selected from population lists of similarly aged female Wisconsin residents (n = 4,297). Risk factor information was collected through structured telephone interviews. Compared with never users, OC users had an odds ratio (OR) of 0.89 [95% confidence interval (95% CI), 0.75-1.06] for colorectal cancer. OC use associations did not differ significantly between colon and rectal cancer sites; however, when compared with never users, recent OC users (<14 years) seemed at reduced risk of rectal cancer (OR, 0.53; 95% CI, 0.28-1.00). Women with age at first birth older than the median (23 years) had 0.83 times the risk of colon cancer compared with women with age at first birth below the median (95% CI, 0.70-0.98). We observed an inverse trend between increasing parity and rectal cancer risk (P = 0.05). Compared with nulliparous women, women with five or more births had 0.66 times the risk of rectal cancer (95% CI, 0.43-1.02). Compared with postmenopausal women, premenopausal women were at reduced risk (OR, 0.67; 95% CI, 0.47-0.97) of colorectal cancer. No significant associations were observed between colorectal cancer risk and age at menarche or age at menopause. These findings suggest differential roles of reproductive factors in colon and rectal cancer etiology.

Proportion of Invasive Breast Cancer Attributable to Risk Factors Modifiable after Menopause

A number of breast cancer risk factors are modifiable later in life, yet the combined impact of the population changes in these risk factors on breast cancer incidence is not known to have been evaluated. The population attributable risk (PAR) associated with individual risk factors and the summary PAR for sets of modifiable and nonmodifiable risk factors were estimated by using data on 3,499 invasive breast cancer cases and 4,213 controls from a population-based study in Wisconsin, Massachusetts, and New Hampshire, conducted from 1997 to 2001. The summary PAR for factors modifiable after menopause, including current postmenopausal hormone use, recent alcohol consumption, adult weight gain, and recent recreational physical activity, was 40.7%. Of the individual modifiable factors, the highest PARs were observed for weight gain (21.3%) and recreational physical activity (15.7%), which together showed a summary PAR of 33.6%. The summary PAR for factors not modifiable after menopause, including family history of breast cancer, personal history of benign breast disease, height at age 25 years, age at menarche, age at menopause, age at first birth, and parity, was 57.3%. These findings suggest that a substantial fraction of postmenopausal breast cancer may be avoided by purposeful changes in lifestyle later in life.

Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk

Breast cancer risk is a polygenic trait. To identify breast cancer modifier alleles that have a high population frequency and low penetrance we used a comparative genomics approach. Quantitative trait loci (QTL) were initially identified by linkage analysis in a rat mammary carcinogenesis model followed by verification in congenic rats carrying the specific QTL allele under study. The Mcs5a locus was identified by fine-mapping Mcs5 in a congenic model. Here we characterize the Mcs5a locus, which when homozygous for the Wky allele, reduces mammary cancer risk by 50%. The Mcs5a locus is a compound QTL with at least two noncoding interacting elements: Mcs5a1 and Mcs5a2. The resistance phenotype is only observed in rats carrying at least one copy of the Wky allele of each element on the same chromosome. Mcs5a1 is located within the ubiquitin ligase Fbxo10, whereas Mcs5a2 includes the 5′ portion of Frmpd1. Resistant congenic rats show a down-regulation of Fbxo10 in the thymus and an up-regulation of Frmpd1 in the spleen. The association of the Mcs5a1 and Mcs5a2 human orthologs with breast cancer was tested in two population-based breast cancer case-control studies (≈12,000 women). The minor alleles of rs6476643 (MCS5A1) and rs2182317 (MCS5A2) were independently associated with breast cancer risk. The minor allele of rs6476643 increases risk, whereas the rs2182317 minor allele decreases risk. Both alleles have a high population frequency and a low penetrance toward breast cancer risk.