Treatment-related side effects among Hispanic and non-Hispanic white long-term breast cancer survivors by tamoxifen use and duration.

PURPOSE: To determine the associations between ethnicity, age at diagnosis, obesity, multimorbidity, and odds of experiencing breast cancer (BC) treatment-related side effects among long-term Hispanic and non-Hispanic white (NHW) survivors from New Mexico and explore differences by tamoxifen use. METHODS: Lifestyle and clinical information including self-reported tamoxifen use and presence of treatment- related side effects were collected at follow-up interviews (12-15 years) for 194 BC survivors. Multivariable logistic regression models were used to examine associations between predictors and odds of experiencing side effects overall and by tamoxifen use. RESULTS: Women ranged in age at diagnosis (30-74, M = 49.3, SD = 9.37), most were NHW (65.4%) and had in-situ or localized BC (63.4%). Less than half reportedly used tamoxifen (44.3%), of which 59.3% reported using > 5 years. Overall, survivors who were overweight/obese at follow-up were 5.42 times more likely to experience treatment-related pain (95% CI 1.40-21.0) compared to normal weight survivors. Survivors with multimorbidity, compared to survivors without, were more likely to report treatment-related sexual health issues (aOR 6.90, 95% CI 1.43-33.2) and poorer mental health (aOR 4.51, 95% CI 1.06-19.1). The statistical interactions between ethnicity and overweight/obese with tamoxifen use were significant (p-interaction < 0.05) for treatment-related sexual health issues. CONCLUSION: Our results demonstrate that survivors with overweightness/obesity or multimorbidity may be more likely to experience BC treatment-related side effects. Tamoxifen use modifies associations between ethnicity, being overweight/obese, and sexual health issues following treatment. The likelihood of experiencing treatment-related side effects were more favorable for those on tamoxifen or those who had used tamoxifen for longer durations. These findings highlight the importance of fostering side effect awareness and applying appropriate interventions to assist with disease management throughout BC survivorship care.

Cumulative menstrual months and breast cancer risk by hormone receptor status and ethnicity: The Breast Cancer Etiology in Minorities Study.

Reproductive and hormonal factors may influence breast cancer risk via endogenous estrogen exposure. Cumulative menstrual months (CMM) can be used as a surrogate measure of this exposure. Using harmonized data from four population-based breast cancer studies (7284 cases and 7242 controls), we examined ethnicity-specific associations between CMM and breast cancer risk using logistic regression, adjusting for menopausal status and other risk factors. Higher CMM was associated with increased breast cancer risk in non-Hispanic Whites, Hispanics and Asian Americans regardless of menopausal status (all FDR adjusted P trends = .0004), but not in African Americans. In premenopausal African Americans, there was a suggestive trend of lower risk with higher CMM. Stratification by body mass index (BMI) among premenopausal African American women showed a nonsignificant positive association with CMM in nonobese (BMI <30 kg/m2 ) women and a significant inverse association in obese women (OR per 50 CMM = 0.56, 95% CI 0.37-0.87, Ptrend  = .03). Risk patterns were similar for hormone receptor positive (HR+; ER+ or PR+) breast cancer; a positive association was found in all premenopausal and postmenopausal ethnic groups except in African Americans. HR- (ER- and PR-) breast cancer was not associated with CMM in all groups combined, except for a suggestive positive association among premenopausal Asian Americans (OR per 50 CMM = 1.33, P = .07). In summary, these results add to the accumulating evidence that established reproductive and hormonal factors impact breast cancer risk differently in African American women compared to other ethnic groups, and also differently for HR- breast cancer than HR+ breast cancer.

Physical activity, ethnicity, and quality of life among breast cancer survivors and population-based controls: the long-term quality of life follow-up study.

PURPOSE: To explore the relationship between physical activity (PA) and quality of life (QOL) among Hispanic and non-Hispanic white breast cancer (BC) cases and population-based controls from the New Mexico 'Long-Term Quality of Life Study'. METHODS: Self-reported PA (low, moderate, vigorous MET hours/week) at baseline and follow-up interviews (12-15 years) were available for 391 cases and controls and modeled using multiple linear regressions with SF-36 mean composite scores for physical and mental health. The change in PA from baseline to follow-up and interactions with ethnicity were also examined. Models were adjusted for age at diagnosis/baseline interview, education, comorbidities, body mass index, and change in PA. RESULTS: PA intensities at each timepoint did not differ by case/control status; however, the change in vigorous PA was lower among cases (p = 0.03). At follow-up, low intensity PA increased mental health QOL scores among cases; however, the interaction between low intensity PA and ethnicity was statistically significant among controls indicating decreased mental health among Hispanics (p = 0.02). Change in moderate PA was associated with increased physical and mental health among cases (physical: ß = 0.186, p = 0.008; mental: ß = 0.225, p = 0.001) and controls (physical: ß = 0.220, p < 0.0001; mental: ß = 0.193, p = 0.002), when controlling for confounders. CONCLUSION: Our results demonstrate that all levels of PA are important for mental health among BC cases, while activities of higher intensity are important for physical health among women overall. The statistical interaction observed between ethnicity and low intensity PA among controls for mental health warrants further research to provide a meaningful interpretation.

Menstrual and reproductive characteristics and breast cancer risk by hormone receptor status and ethnicity: The Breast Cancer Etiology in Minorities study.

We pooled multiethnic data from four population-based studies and examined associations of menstrual and reproductive characteristics with breast cancer (BC) risk by tumor hormone receptor (HR) status [defined by estrogen receptor (ER) and progesterone receptor (PR)]. We estimated odds ratios and 95% confidence intervals using multivariable logistic regression, stratified by age (<50, ≥50 years) and ethnicity, for 5,186 HR+ (ER+ or PR+) cases, 1,365 HR- (ER- and PR-) cases and 7,480 controls. For HR+ BC, later menarche and earlier menopause were associated with lower risk in non-Hispanic whites (NHWs) and Hispanics, and higher parity and longer breast-feeding were associated with lower risk in Hispanics and Asian Americans, and suggestively in NHWs. Positive associations with later first full-term pregnancy (FTP), longer interval between menarche and first FTP and shorter time since last FTP were limited to younger Hispanics and Asian Americans. Except for nulliparity, reproductive characteristics were not associated with risk in African Americans. For HR- BC, lower risk was associated with later menarche, except in African Americans and older Asian Americans and with longer breast-feeding in Hispanics and Asian Americans only. In younger African Americans, HR- BC risk associated with higher parity (≥3 vs. 1 FTP) was increased fourfold in women who never breast-fed, but not in those with a breast-feeding history, suggesting that breast-feeding may mitigate the adverse effect of higher parity in younger African American women. Further work needs to evaluate why menstrual and reproductive risk factors vary in importance according to age and ethnicity.

A Pooled Analysis of Breastfeeding and Breast Cancer Risk by Hormone Receptor Status in Parous Hispanic Women.

BACKGROUND: Data on breastfeeding and breast cancer risk are sparse and inconsistent for Hispanic women. METHODS: Pooling data for nearly 6,000 parous Hispanic women from four population-based studies conducted between 1995 and 2007 in the United States and Mexico, we examined the association of breastfeeding with risk of breast cancer overall and subtypes defined by estrogen receptor (ER) and progesterone receptor (PR) status, and the joint effects of breastfeeding, parity, and age at first birth. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. RESULTS: Among parous Hispanic women, older age at first birth was associated with increased breast cancer risk, whereas parity was associated with reduced risk. These associations were found for hormone receptor positive (HR+) breast cancer only and limited to premenopausal women. Age at first birth and parity were not associated with risk of ER- and PR- breast cancer. Increasing duration of breastfeeding was associated with decreasing breast cancer risk (≥25 vs. 0 months: OR = 0.73; 95% CI = 0.60, 0.89; Ptrend = 0.03), with no heterogeneity by menopausal status or subtype. At each parity level, breastfeeding further reduced HR+ breast cancer risk. Additionally, breastfeeding attenuated the increase in risk of HR+ breast cancer associated with older age at first birth. CONCLUSIONS: Our findings suggest that breastfeeding is associated with reduced risk of both HR+ and ER- and PR- breast cancer among Hispanic women, as reported for other populations, and may attenuate the increased risk in women with a first pregnancy at older ages.

Reproductive history, breast-feeding and risk of triple negative breast cancer: The Breast Cancer Etiology in Minorities (BEM) study.

Few risk factors have been identified for triple negative breast cancer (TNBC) which lacks expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). This more aggressive subtype disproportionately affects some racial/ethnic minorities and is associated with lower survival. We pooled data from three population-based studies (558 TNBC and 5,111 controls) and examined associations of TNBC risk with reproductive history and breast-feeding. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression. For younger women, aged <50 years, TNBC risk was increased two-fold for parous women who never breast-fed compared to nulliparous women (OR = 2.02, 95% CI = 1.12-3.63). For younger parous women, longer duration of lifetime breast-feeding was associated with a borderline reduced risk (≥24 vs. 0 months: OR = 0.52, 95% CI = 0.26-1.04, Ptrend = 0.06). Considering the joint effect of parity and breast-feeding, risk was increased two-fold for women with ≥3 full-term pregnancies (FTPs) and no or short-term (<12 months) breast-feeding compared to women with 1-2 FTPs and breast-feeding ≥12 months (OR = 2.56, 95% CI = 1.22-5.35). None of these associations were observed among older women (≥50 years). Differences in reproductive patterns possibly contribute to the ethnic differences in TNBC incidence. Among controls aged <50 years, the prevalence of no or short-term breast-feeding and ≥3 FTPs was highest for Hispanics (22%), followed by African Americans (18%), Asian Americans (15%) and non-Hispanic whites (6%). Breast-feeding is a modifiable behavioral factor that may lower TNBC risk and mitigate the effect of FTPs in women under age 50 years.

Healthy lifestyle impact on breast cancer-specific and all-cause mortality.

PURPOSE: While several studies have evaluated the association of combined lifestyle factors on breast cancer-specific mortality, few have included Hispanic women. We constructed a "healthy behavior index" (HBI) and evaluated its associations with mortality in non-Hispanic White (NHW) and Hispanic women diagnosed with breast cancer from the southwestern U.S. METHODS: Diet and lifestyle questionnaires were analyzed for 837 women diagnosed with invasive breast cancer (1999-2004) in New Mexico as part of the 4-Corners Women's Health Study. An HBI score ranging from 0 to 12 was based on dietary pattern, physical activity, smoking, alcohol consumption, and body size and shape, with increasing scores representing less healthy characteristics. Hazard ratios for mortality over 14 years of follow-up were estimated for HBI quartiles using Cox proportional hazards models adjusting for education and stratified by ethnicity and stage at diagnosis. RESULTS: A significant increasing trend was observed across HBI quartiles among all women, NHW women, and those diagnosed with localized or regional/distant stage of disease for all-cause (AC) mortality (p-trend = 0.006, 0.002, 0.03, respectively). AC mortality was increased >2-fold for all women and NHW women in HBI Q4 versus Q1 (HR = 2.18, 2.65, respectively). The association was stronger in women with regional/distant than localized stage of disease (HR = 2.62, 1.94, respectively). Associations for Hispanics or breast cancer-specific mortality were not significant. CONCLUSIONS: These findings indicate the associations between the HBI and AC mortality, which appear to differ by ethnicity and stage at diagnosis. Interventions for breast cancer survivors should address the combination of lifestyle factors on prognosis.

Genetic variation in TNFα, PPARγ, and IRS-1 genes, and their association with breast-cancer survival in the HEAL cohort.

PURPOSE: Tumor necrosis factor-α (TNF-α), peroxisome proliferator-activated receptor-γ (PPARγ), and insulin receptor substrate-1 (IRS-1) are associated with obesity, insulin resistance, and inflammation. Few data exist on associations between polymorphisms in these genes and mortality in breast cancer survivors. METHODS: We investigated associations between TNF-α -308G > A (rs1800629); PPARγ Pro12Ala (rs1801282); and IRS-1 Gly972Arg (rs1801278) polymorphisms and anthropometric variables, circulating levels of previously measured biomarkers, and tumor characteristics in 553 women enrolled in the Health, Eating, Activity, and Lifestyle Study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer between 1995 and 1999 (median follow-up 14.7 years).  Using Cox proportional hazards models adjusted for possible confounders, we evaluated associations between these polymorphisms and mortality. RESULTS: Carriers of the PPARγ variant allele had statistically significantly lower rates of type 2 diabetes (P = 0.04), lower BMI (P = 0.01), and HOMA scores [P = 0.004; non-Hispanic White (NHWs) only]; carriers of the TNF-α variant A allele had higher serum glucose (P = 0.004, NHW only); and the IRS-1 variant was associated with higher leptin levels (P = 0.003, Hispanics only). There were no associations between any of the polymorphisms and tumor characteristics. Among 141 deaths, 62 were due to breast cancer. Carriers of the TNF-α-variant A allele had a decreased risk of breast-cancer-specific mortality [hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.10-0.83] and all-cause mortality (HR 0.51; 95% CI 0.28-0.91). CONCLUSIONS: Neither the PPARγ nor the IRS-1 polymorphism was associated with mortality outcome. The TNF-α -308 G > A polymorphism was associated with reduced breast-cancer-specific and all-cause mortality.

Associations between ALDH1A1 polymorphisms, alcohol consumption, and mortality among Hispanic and non-Hispanic white women diagnosed with breast cancer: the Breast Cancer Health Disparities Study.

PURPOSE: ALDH1A1, one of the main isotopes of aldehyde dehydrogenase-1 is involved in the differentiation and protection of normal hematopoietic stem cells and functions in alcohol sensitivity and dependence. We evaluated the associations between ALDH1A1 polymorphisms, alcohol consumption, and mortality among Hispanic and non-Hispanic white (NHW) breast cancer (BC) cases from the Breast Cancer Health Disparities Study. METHODS: Nine SNPs in ALDH1A1 were evaluated in 920 Hispanic and 1372 NHW women diagnosed with incident invasive BC. Adjusted Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Models were stratified by Native American (NA) ancestry and alcohol consumption. RESULTS: A total of 443 deaths occurred over a median follow-up time of 11 years. After adjusting all results for multiple comparisons, rs7027604 was significantly associated with all-cause mortality (HRAA = 1.40; 95% CI 1.13-1.73, P adj = 0.018). The rs1424482 CC genotype (HRCC = 1.69; 95% CI 1.20-2.37, P adj = 0.027) and the rs7027604 AA genotype (HRAA = 1.65; 95% CI 1.21-2.26, P adj = 0.018) were positively associated with non-BC mortality. Among long-term light drinkers, rs1888202 was associated with decreased all-cause mortality (HRCG/GG = 0.36; 95% CI 0.20-0.64), while associations were not significant among non-drinkers or moderate/heavy drinkers (P interation = 0.218). The increased risk of all-cause mortality associated with rs63319 was limited to women with low NA ancestry (HRAA = 1.53; 95% CI 1.19-1.97). CONCLUSIONS: Multiple SNPs in ALDH1A1 were associated with increased risk of mortality after BC. Future BC studies examining the relationship between ALDH1A1 and mortality should consider the modifying effects of alcohol consumption and NA ancestry.

Pre-diagnostic breastfeeding, adiposity, and mortality among parous Hispanic and non-Hispanic white women with invasive breast cancer: the Breast Cancer Health Disparities Study.

BACKGROUND: U.S. Hispanic women have high rates of parity, breastfeeding, and obesity. It is unclear whether these reproductive factors are associated with breast cancer (BC) mortality. We examined the associations between breastfeeding, parity, adiposity and BC-specific and overall mortality in Hispanic and non-Hispanic white (NHW) BC cases. METHODS: The study population included 2921 parous women (1477 Hispanics, 1444 NHWs) from the Breast Cancer Health Disparities Study with invasive BC diagnosed between 1995 and 2004. Information on reproductive history and lifestyle factors was collected by in-person interview. Overall and stratified Cox proportional hazard regression models by ethnicity, parity, and body mass index (BMI) at age 30 years were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: After a median follow-up time of 11.2 years, a total of 679 deaths occurred. Pre-diagnostic breastfeeding was associated with a 16% reduction in mortality (HR 0.84; 95% 0.72-0.99) irrespective of ethnicity. Parity significantly modified the association between breastfeeding duration and mortality (p interaction = 0.05), with longer breastfeeding duration associated with lower risk among women who had ≤2 births (p trend = 0.02). Breastfeeding duration was associated with reduced risk of both BC-specific and overall mortality among women with BMI <25 kg/m2, while positive associations were observed among women with BMI ≥25 kg/m2 (p interactions <0.01). CONCLUSION: Pre-diagnostic breastfeeding was inversely associated with risk of mortality after BC, particularly in women of low parity or normal BMI. These results provide another reason to encourage breastfeeding and weight management among young women.

Associations of sex steroid hormones with mortality in women with breast cancer.

Epidemiological studies have demonstrated associations between circulating levels of sex steroid hormones and risk of breast cancer in postmenopausal women. However, data on associations with breast cancer survival are limited. We measured levels of estradiol, estrone, testosterone, and sex hormone-binding globulin (SHBG), in serum collected on average 30 months after diagnosis from 358 postmenopausal women diagnosed with stage I-IIIA breast cancer between 1995 and 1998 who participated in a multiethnic, prospective cohort study. Women were followed through December, 2012. We evaluated associations between log-transformed analytes and breast cancer-specific and all-cause mortality fitting multivariable Cox proportional hazards models. Over a median of 14.5 years of follow-up, 102 deaths occurred; 43 of these were due to breast cancer. In models adjusted for ethnicity/study site, age, body mass index, and tumor stage, increased levels of log-transformed SHBG were associated with reduced risk of both breast cancer-specific mortality (hazard ratio, HR 0.48; 95 % confidence interval, CI 0.26-0.89) and all-cause mortality (HR 0.64, 95 % CI 0.43-0.97). There were no associations between levels of estradiol, estrone, or testosterone for either endpoint. In subgroup analyses, after correction for multiple testing, increased estrone was significantly associated with reduced risk for breast cancer-specific mortality among participants with ER-negative tumors (HR 0.16, 95 % CI 0.05-0.63) but not among participants with ER-positive tumors. Increased serum levels of SHBG were associated with decreased risk of breast cancer-specific and all-cause mortality in women with breast cancer. These results should be confirmed in larger breast cancer survivor cohorts.

Ethnic differences in the relationships between diabetes, early age adiposity and mortality among breast cancer survivors: the Breast Cancer Health Disparities Study.

The contribution of type 2 diabetes and obesity on mortality in breast cancer (BC) patients has not been well studied among Hispanic women, in whom these exposures are highly prevalent. In a multi-center population-based study, we examined the associations between diabetes, multiple obesity measures, and mortality in 1180 Hispanic and 1298 non-Hispanic white (NHW) women who were diagnosed with incident invasive BC from the San Francisco Bay Area, New Mexico, Utah, Colorado, and Arizona. Adjusted hazard ratios (HR) and 95 % confidence intervals (CI) were calculated using Cox proportional hazards regression models. The median follow-up time from BC diagnosis to death was 10.8 years. In ethnic-stratified results, the association for BC-specific mortality among Hispanics was significantly increased (HR 1.85 95 % CI 1.11, 3.09), but the ethnic interaction was not statistically significant. In contrast, obesity at age 30 increased BC-specific mortality risk in NHW women (HR 2.33 95 % CI 1.36, 3.97) but not Hispanics (p-interaction = 0.045). Although there were no ethnic differences for all-cause mortality, diabetes, obesity at age 30, and post-diagnostic waist-hip ratio were significantly associated with all-cause mortality in all women. This study provides evidence that diabetes and adiposity, both modifiable, are prognostic factors among Hispanic and NHW BC patients.

Use of complementary and alternative medicine and breast cancer survival in the Health, Eating, Activity, and Lifestyle Study.

PURPOSE: Use of complementary and alternative medicine (CAM) is common among breast cancer patients, but less is known about whether CAM influences breast cancer survival. METHODS: Health Eating, Activity, and Lifestyle (HEAL) Study participants (n = 707) were diagnosed with stage I-IIIA breast cancer. Participants completed a 30-month post-diagnosis interview including questions on CAM use (natural products such as dietary and botanical supplements, alternative health practices, and alternative medical systems), weight, physical activity, and comorbidities. Outcomes were breast cancer-specific and total mortality, which were ascertained from the Surveillance Epidemiology and End Results registries in Western Washington, Los Angeles County, and New Mexico. Cox proportional hazards regression models were fit to data to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for mortality. Models were adjusted for potential confounding by sociodemographic, health, and cancer-related factors. RESULTS: Among 707 participants, 70 breast cancer-specific deaths and 149 total deaths were reported. 60.2 % of participants reported CAM use post-diagnosis. The most common CAM were natural products (51 %) including plant-based estrogenic supplements (42 %). Manipulative and body-based practices and alternative medical systems were used by 27 and 13 % of participants, respectively. No associations were observed between CAM use and breast cancer-specific (HR 1.04, 95 % CI 0.61-1.76) or total mortality (HR 0.91, 95 % CI 0.63-1.29). CONCLUSION: Complementary and alternative medicine use was not associated with breast cancer-specific mortality or total mortality. Randomized controlled trials may be needed to definitively test whether there is harm or benefit from the types of CAM assessed in HEAL in relation to mortality outcomes in breast cancer survivors.

Obesity, ethnicity, and quality of life among breast cancer survivors and women without breast cancer: the long-term quality of life follow-up study.

PURPOSE: The purpose of this study was to examine the relationship between obesity and quality of life (QOL) among Hispanic and non-Hispanic white breast cancer survivors and population-based controls from the 'Long-Term Quality of Life Study'--a 12- to 15-year follow-up study of breast cancer cases/survivors and controls from New Mexico (n = 451). METHODS: Using multiple linear regressions, obesity measures [body mass index (BMI) ≥ 30 kg/m(2)] at baseline and follow-up interview were modeled with composite scores for physical and mental health from the SF-36 Quality of Life Survey. Interaction between ethnicity and BMI and change in BMI were evaluated. All models were adjusted for age, ethnicity, Charlson Index, depression, fatigue, and physical activity. RESULTS: Baseline obesity (ß = -6.58, p = 0.04) was significantly associated with decreased mental health among survivors, but not among controls. Obesity at baseline and follow-up were significantly associated with decreased physical health among survivors (baseline ß = -10.51, p = 0.004; follow-up ß = -7.16, p = 0.02) and controls (baseline ß = -11.07, p < 0.001; follow-up ß = -5.18, p = 0.04). No significant interactions between ethnicity and BMI were observed. CONCLUSIONS: Our findings provide unique information about a diverse population of breast cancer survivors and controls and the impact of obesity on the mental and physical aspects of QOL.

Red meat, poultry, and fish intake and breast cancer risk among Hispanic and Non-Hispanic white women: The Breast Cancer Health Disparities Study.

PURPOSE: There is suggestive but limited evidence for a relationship between meat intake and breast cancer (BC) risk. Few studies included Hispanic women. We investigated the association between meats and fish intake and BC risk among Hispanic and NHW women. METHODS: The study included NHW (1,982 cases and 2,218 controls) and the US Hispanics (1,777 cases and 2,218 controls) from two population-based case-control studies. Analyses considered menopausal status and percent Native American ancestry. We estimated pooled ORs combining harmonized data from both studies, and study- and race-/ethnicity-specific ORs that were combined using fixed or random effects models, depending on heterogeneity levels. RESULTS: When comparing highest versus lowest tertile of intake, among NHW we observed an association between tuna intake and BC risk (pooled OR 1.25; 95 % CI 1.05-1.50; trend p = 0.006). Among Hispanics, we observed an association between BC risk and processed meat intake (pooled OR 1.42; 95% CI 1.18-1.71; trend p < 0.001), and between white meat (OR 0.80; 95% CI 0.67-0.95; trend p = 0.01) and BC risk, driven by poultry. All these findings were supported by meta-analysis using fixed or random effect models and were restricted to estrogen receptor-positive tumors. Processed meats and poultry were not associated with BC risk among NHW women; red meat and fish were not associated with BC risk in either race/ethnic groups. CONCLUSIONS: Our results suggest the presence of ethnic differences in associations between meat and BC risk that may contribute to BC disparities.

Associations between ALOX, COX, and CRP polymorphisms and breast cancer among Hispanic and non-Hispanic white women: The breast cancer health disparities study.

Chronic inflammation is suggested to be associated with specific cancer sites, including breast cancer. Recent research has focused on the roles of genes involved in the leukotriene/lipoxygenase and prostaglandin/cyclooxygenase pathways in breast cancer etiology. We hypothesized that genes in ALOX/COX pathways and CRP polymorphisms would be associated with breast cancer risk and mortality in our sample of Hispanic/Native American (NA) (1430 cases, 1599 controls) and non-Hispanic white (NHW) (2093 cases, 2610 controls) women. A total of 104 Ancestral Informative Markers was used to distinguish European and NA ancestry. The adaptive rank truncated product (ARTP) method was used to determine the significance of associations for each gene and the inflammation pathway with breast cancer risk and by NA ancestry. Overall, the pathway was associated with breast cancer risk (PARTP = 0.01). Two-way interactions with NA ancestry (P(adj) < 0.05) were observed for ALOX12 (rs2292350, rs2271316) and PTGS1 (rs10306194). We observed increases in breast cancer risk in stratified analyses by tertiles of polyunsaturated fat intake for ALOX12 polymorphisms; the largest increase in risk was among women in the highest tertile with ALOX12 rs9904779CC (Odds Ratio (OR), 1.49; 95% Confidence Interval (CI) 1.14-1.94, P(adj) = 0.01). In a sub-analysis stratified by NSAIDs use, two-way interactions with NSAIDs use were found for ALOX12 rs9904779 (P(adj) = 0.02), rs434473 (P(adj ) = 0.02), and rs1126667 (P(adj) = 0.01); ORs for ALOX12 polymorphisms ranged from 1.55 to 1.64 among regular users. Associations were not observed with breast cancer mortality. These findings could support advances in the discovery of new pathways related to inflammation for breast cancer treatment.

MAPK genes interact with diet and lifestyle factors to alter risk of breast cancer: the Breast Cancer Health Disparities Study.

Mitogen-activated protein kinases (MAPK) are integration points for multiple biochemical signals. We evaluated 13 MAPK genes with breast cancer risk and determined if diet and lifestyle factors mediated risk. Data from 3 population-based case-control studies conducted in Southwestern United States, California, and Mexico included 4183 controls and 3592 cases. Percent Indigenous American (IA) ancestry was determined from 104 ancestry informative markers. The adaptive rank truncated product (ARTP) was used to determine the significance of each gene and the pathway with breast cancer risk, by menopausal status, genetic ancestry level, and estrogen receptor (ER)/progesterone receptor (PR) strata. MAP3K9 was associated with breast cancer overall (P(ARTP) = 0.02) with strongest association among women with the highest IA ancestry (P(ARTP) = 0.04). Several SNPs in MAP3K9 were associated with ER+/PR+ tumors and interacted with dietary oxidative balance score (DOBS), dietary folate, body mass index (BMI), alcohol consumption, cigarette smoking, and a history of diabetes. DUSP4 and MAPK8 interacted with calories to alter breast cancer risk; MAPK1 interacted with DOBS, dietary fiber, folate, and BMI; MAP3K2 interacted with dietary fat; and MAPK14 interacted with dietary folate and BMI. The patterns of association across diet and lifestyle factors with similar biological properties for the same SNPs within genes provide support for associations.

Genetic variants in interleukin genes are associated with breast cancer risk and survival in a genetically admixed population: the Breast Cancer Health Disparities Study.

Interleukins (ILs) are key regulators of immune response. Genetic variation in IL genes may influence breast cancer risk and mortality given their role in cell growth, angiogenesis and regulation of inflammatory process. We examined 16 IL genes with breast cancer risk and mortality in an admixed population of Hispanic/Native American (NA) (2111 cases and 2597 controls) and non-Hispanic white (NHW) (1481 cases and 1585 controls) women. Adaptive Rank Truncated Product (ARTP) analysis was conducted to determine gene significance and lasso (least absolute shrinkage and selection operator) was used to identify potential gene by gene and gene by lifestyle interactions. The pathway was statistically significant for breast cancer risk overall (P ARTP = 0.0006), for women with low NA ancestry (P(ARTP) = 0.01), for premenopausal women (P(ARTP) = 0.02), for estrogen receptor (ER)+/progesterone receptor (PR)+ tumors (P(ARTP) = 0.03) and ER-/PR- tumors (P(ARTP) = 0.02). Eight of the 16 genes evaluated were associated with breast cancer risk (IL1A, IL1B, IL1RN, IL2, IL2RA, IL4, IL6 and IL10); four genes were associated with breast cancer risk among women with low NA ancestry (IL1B, IL6, IL6R and IL10), two were associated with breast cancer risk among women with high NA ancestry (IL2 and IL2RA) and four genes were associated with premenopausal breast cancer risk (IL1A, IL1B, IL2 and IL3). IL4, IL6R, IL8 and IL17A were associated with breast cancer-specific mortality. We confirmed associations with several functional polymorphisms previously associated with breast cancer risk and provide support that their combined effect influences the carcinogenic process.

Risk factors for self-reported arm lymphedema among female breast cancer survivors: a prospective cohort study.

INTRODUCTION: Lymphedema is a potentially debilitating condition that occurs among breast cancer survivors. This study examines the incidence of self-reported lymphedema, timing of lymphedema onset, and associations between sociodemographic, clinical and lifestyle factors and lymphedema risk across racial-ethnic groups using data from a multicenter, multiethnic prospective cohort study of breast cancer survivors, the Health, Eating, Activity and Lifestyle Study. METHODS: A total of 666 women diagnosed with breast cancer staged as in situ, localized or regional disease at ages 35 to 64 years were recruited through the Surveillance, Epidemiology, and End Results registries in New Mexico (non-Hispanic white and Hispanic white), Los Angeles County (black), and Western Washington (non-Hispanic white) and followed for a median of 10.2 years. We evaluated sociodemographic factors, breast cancer- and treatment-related factors, comorbidities, body mass index (BMI), hormonal factors, and lifestyle factors in relation to self-reported lymphedema by fitting Cox proportional hazards models, estimating hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Over the follow-up period, 190 women (29%) reported lymphedema. The median time from breast cancer diagnosis to onset of lymphedema was 10.5 months (range: 0.5 to 134.9 months). Factors independently associated with lymphedema were total/modified radical mastectomy (versus partial/less than total mastectomy; HR = 1.37, 95% CI: 1.01 to 1.85), chemotherapy (versus no chemotherapy; HR = 1.48, 95% CI: 1.09 to 2.02), no lymph nodes removed (versus ≥10 lymph nodes removed; HR = 0.17, 95% CI: 0.08 to 0.33), pre-diagnostic BMI ≥30 kg/m2 (versus BMI <25 kg/m2; HR = 1.59, 95% CI: 1.09 to 2.31), and hypertension (versus no hypertension; HR = 1.49, 95% CI: 1.06 to 2.10). After adjusting for demographics and breast cancer- and treatment-related factors, no significant difference in lymphedema risk was observed across racial/ethnic groups. Analyses stratified by race/ethnicity showed that hypertension and chemotherapy were lymphedema risk factors only for black women. CONCLUSIONS: Breast cancer patients who have undergone extensive surgery or extensive lymph node dissection, or who have a higher BMI should be closely monitored for detection and treatment of lymphedema. Further studies are needed to understand the roles of chemotherapy and hypertension in the development of lymphedema.

Angiogenesis genes, dietary oxidative balance and breast cancer risk and progression: the Breast Cancer Health Disparities Study.

Angiogenesis is essential for tumor development and progression. Genetic variation in angiogenesis-related genes may influence breast carcinogenesis. We evaluated dietary factors associated with oxidative balance, DDIT4 (one SNP), FLT1 (35 SNPs), HIF1A (four SNPs), KDR (19 SNPs), MPO (one SNP), NOS2A (15 SNPs), TEK (40 SNPs) and VEGFA (eight SNPs) and breast cancer risk among Hispanic (2,111 cases and 2,597 controls) and non-Hispanic white (1,481 cases and 1,586 controls) women in the Breast Cancer Health Disparities Study. Adaptive rank truncated product (ARTP) analysis was used to determine gene and pathway significance with breast cancer. TEK was associated with breast cancer overall (pARTP = 0.03) and with breast cancer survival (pARTP = 0.01). KDR was of borderline significance overall (pARTP = 0.07), although significantly associated with breast cancer in both low and intermediate Native American (NA) ancestry groups (pARTP = 0.02) and estrogen receptor (ER)+/progesterone receptor (PR)- tumor phenotype (pARTP = 0.008). Both VEGFA and NOS2A were associated with ER-/PR- tumor phenotype (pARTP = 0.01 and pARTP = 0.04, respectively). FLT1 was associated with breast cancer survival among those with low NA ancestry (pARTP = 0.009). With respect to diet, having a higher dietary oxidative balance score (DOBS) was significantly associated with lower breast cancer risk [odds ratio (OR) 0.74, 95% confidence interval (CI) 0.64-0.84], with the strongest associations observed for women with the highest NA ancestry (OR 0.44, 95% CI 0.30-0.65). We observed few interactions between DOBS and angiogenesis-related genes. Our data suggest that dietary factors and genetic variation in angiogenesis-related genes contribute to breast cancer carcinogenesis.