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1.  Quality of life outcomes from the Exercise and Nutrition Enhance Recovery and Good Health for You (ENERGY)-randomized weight loss trial among breast cancer survivors 
Obesity is a poor prognostic factor and is negatively related to quality of life (QOL) in breast cancer survivors. Exercise and Nutrition to Enhance Recovery and Good Health for You is the largest weight loss trial completed among cancer survivors. Percent losses in body weight with an intensive group-based intervention versus an attention control were 6.0 versus 1.5 % (p < 0.0001) and 3.7 versus 1.3 % (p<0.0001) at 12 and 24 months, respectively. ENERGY also was designed to answer the research question: Does weight loss significantly improve vitality and physical function (key components of QOL)? 692 breast cancer survivors (BMI: 25–45 kg/m2) at 4 US sites were randomized to a year-long intensive intervention of 52 group sessions and telephone counseling contacts versus a non-intensive (control) of two in-person counseling sessions. Weight, self-reported QOL, and symptoms were measured semi-annually for two years. Significant decreases in physical function and increases in symptoms were observed among controls from baseline to 6 months, but not in the intervention arm, −3.45 (95 % Confidence Interval [CI] −6.10, –0.79, p = 0.0109) and 0.10 (95 %CI 0.04, 0.16, p = 0.0021), respectively. Improvements in vitality were seen in both arms but trended toward greater improvement in the intervention arm −2.72 (95 % CI −5.45, 0.01, p = 0.0508). These differences diminished over time; however, depressive symptoms increased in the intervention versus control arms and became significant at 24 months, −1.64 (95 % CI −3.13, –0.15, p = 0.0308). Increased QOL has been reported in shorter term diet and exercise trials among cancer survivors. These longer term data suggest that diet and exercise interventions improve some aspects of QOL, but these benefits may diminish over time.
PMCID: PMC4654570  PMID: 26518022
Obesity; Breast cancer; Weight loss; Quality of life; Physical function; Symptoms
2.  Results of the Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) Trial: A Behavioral Weight Loss Intervention in Overweight or Obese Breast Cancer Survivors 
Journal of Clinical Oncology  2015;33(28):3169-3176.
Obesity increases risk for all-cause and breast cancer mortality and comorbidities in women who have been diagnosed and treated for breast cancer. The Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) study is the largest weight loss intervention trial among survivors of breast cancer to date.
In this multicenter trial, 692 overweight/obese women who were, on average, 2 years since primary treatment for early-stage breast cancer were randomly assigned to either a group-based behavioral intervention, supplemented with telephone counseling and tailored newsletters, to support weight loss or a less intensive control intervention and observed for 2 years. Weight and blood pressure were measured at 6, 12, 18, and 24 months. Longitudinal mixed models were used to analyze change over time.
At 12 months, mean weight loss was 6.0% of initial weight in the intervention group and 1.5% in the control group (P < .001). At 24 months, mean weight loss in the intervention and control groups was 3.7% and 1.3%, respectively (P < .001). Favorable effects of the intervention on physical activity and blood pressure were observed. The weight loss intervention was more effective among women older than 55 years than among younger women.
A behavioral weight loss intervention can lead to clinically meaningful weight loss in overweight/obese survivors of breast cancer. These findings support the need to conduct additional studies to test methods that support sustained weight loss and to examine the potential benefit of intentional weight loss on breast cancer recurrence and survival.
PMCID: PMC4582146  PMID: 26282657
3.  Macronutrient Composition Influence on Breast Cancer Risk in Hispanic and Non-Hispanic White Women: The 4-Corners Breast Cancer Study 
Nutrition and cancer  2011;63(2):185-195.
The association of dietary macronutrient composition with risk of breast cancer is not well understood. We investigated the macronutrient composition of diet in the 4-Corners Breast Cancer Study. Logistic regression models were used for case-control comparisons adjusted for age, center, education, smoking, total activity, calories, dietary fiber, dietary calcium, height, parity, recent hormone exposure, reference year body mass index (BMI), and the interaction of BMI and recent hormone exposure. Breast cancer risk declined with increasing dietary fat and increased with carbohydrates similarly across ethnicity and menopausal status. Associations of carbohydrate (direct) and fat (inverse), particularly saturated and monounsaturated fat, with breast cancer were present among normal and overweight postmenopausal women and absent among obese postmenopausal women. No substantive differences were noted in the association of macronutrients with risk of breast cancer between non-Hispanic white and Hispanic women. Associations of the macronutrients carbohydrate and fat with breast cancer risk were attenuated among postmenopausal obese women.
PMCID: PMC4700927  PMID: 21271459
4.  Differential expression of prognostic biomarkers between interval and screen-detected breast cancers: does age or family history matter? 
The aim of this study was to compare tumor expression of prognostic biomarkers between interval breast cancers and screen-detected breast cancers overall, and according to age at diagnosis and familial risk. Tissue micro-arrays were constructed from 98 breast cancers (47 interval and 51 screen-detected) diagnosed in women in the Cancer Genetics Network. Arrays were immuno-stained to compare protein expression of six biomarkers including estrogen and progesterone receptor (ER/PR), Her2/neu, EGFR, cytokeratin 5/6, and Ki67. Fisher’s Exact test was used to compare expression between interval and screen-detected cancers. Interval cancers were larger (P = 0.04), higher stage (P < 0.001), and more likely to have lobular histology (P = 0.01) than screen-detected cancers. Overall, interval cancers more often over-expressed EGFR (P = 0.01) and were somewhat more likely to be ER− (55% vs. 43%, P = 0.3), and triple negative (ER−/PR−/Her2−) (21 vs. 12%, P = 0.26). A greater difference in the proportion of interval versus screen-detected tumors that were ER− (53 vs. 35%; P = 0.29), PR− (35 vs. 21%; P = 0.25) and EGFR+ (17 vs. 0%; P = 0.02) was evident among women over 50. There was a trend toward differential expression among women with familial risk for PR− (P = 0.005) and triple negative status (P = 0.02). This study provides new data indicating that EGFR may be important in the etiology of interval cancer and be a possible therapeutic target. Our data also suggest that biological differences between interval and screen-detected cancers are more defined in older women. Future studies to confirm this finding and to elucidate novel markers for characterizing interval cancers may be more beneficial to this subgroup.
PMCID: PMC4675131  PMID: 21431872
Interval breast cancer; Biomarkers; Tissue micro-arrays
6.  Lack of significant association between serum inflammatory cytokine profiles and the presence of colorectal adenoma 
BMC Cancer  2015;15:123.
Inflammatory cytokines in the colonic microenvironment have been shown to increase with advance colorectal cancer disease state. However, the contribution of inflammatory cytokines to pre-malignant disease, such as the formation of adenomas, is unclear.
Using the Milliplex® MAP Human Cytokine/ Chemokine Magnetic Bead Panel Immunoassay, serum cytokine and chemokine profiles were assayed among participants without an adenoma (n = 97) and those with an adenoma (n = 97) enrolled in the NCI-funded Insulin Resistance Atherosclerosis Colon Study. The concentrations of interleukin-10 (IL-10), IL-1β, IL-6, IL-17A, IL-2, IL-4, IL-7, IL-12(p70), interferon-γ (IFN-γ), macrophage chemoattractant protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted (RANTES), tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), granulocyte macrophage colony-stimulating factor (GM-CSF), and macrophage inflammatory protein-1β (MIP-1β) were determined. Multiple logistic regression analyses were used to evaluate the association between adenoma prevalence and cytokine levels.
The presence of colorectal adenomas was not associated with significant increases in the systemic levels of proinflammatory (TNF-α, IL-6, IL-1β) or T-cell polarizing (IL-12, IL-2, IL-10, IL-4, IL-17, IFN-γ) cytokines. Furthermore, MCP-1 and RANTES levels were equivalent in the serum of study participants with and without adenomas.
These findings suggest colorectal adenoma prevalence may not be associated with significant alterations in systemic inflammation.
PMCID: PMC4359784  PMID: 25884547
Colorectal cancer; Adenomas; Inflammation; Biomarkers; IRAS
7.  Association between Lifetime Exposure to Inorganic Arsenic in Drinking Water and Coronary Heart Disease in Colorado Residents 
Environmental Health Perspectives  2014;123(2):128-134.
Background: Chronic diseases, including coronary heart disease (CHD), have been associated with ingestion of drinking water with high levels of inorganic arsenic (> 1,000 μg/L). However, associations have been inconclusive in populations with lower levels (< 100 μg/L) of inorganic arsenic exposure.
Objectives: We conducted a case-cohort study based on individual estimates of lifetime arsenic exposure to examine the relationship between chronic low-level arsenic exposure and risk of CHD.
Methods: This study included 555 participants with 96 CHD events diagnosed between 1984 and 1998 for which individual lifetime arsenic exposure estimates were determined using data from structured interviews and secondary data sources to determine lifetime residence, which was linked to a geospatial model of arsenic concentrations in drinking water. These lifetime arsenic exposure estimates were correlated with historically collected urinary arsenic concentrations. A Cox proportional-hazards model with time-dependent CHD risk factors was used to assess the association between time-weighted average (TWA) lifetime exposure to low-level inorganic arsenic in drinking water and incident CHD.
Results: We estimated a positive association between low-level inorganic arsenic exposure and CHD risk [hazard ratio (HR): = 1.38, 95% CI: 1.09, 1.78] per 15 μg/L while adjusting for age, sex, first-degree family history of CHD, and serum low-density lipoprotein levels. The risk of CHD increased monotonically with increasing TWAs for inorganic arsenic exposure in water relative to < 20 μg/L (HR = 1.2, 95% CI: 0.6, 2.2 for 20–30 μg/L; HR = 2.2; 95% CI: 1.2, 4.0 for 30–45 μg/L; and HR = 3, 95% CI: 1.1, 9.1 for 45–88 μg/L).
Conclusions: Lifetime exposure to low-level inorganic arsenic in drinking water was associated with increased risk for CHD in this population.
Citation: James KA, Byers T, Hokanson JE, Meliker JR, Zerbe GO, Marshall JA. 2015. Association between lifetime exposure to inorganic arsenic in drinking water and coronary heart disease in Colorado residents. Environ Health Perspect 123:128–134;
PMCID: PMC4314243  PMID: 25350952
8.  A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010 
Lim, Stephen S | Vos, Theo | Flaxman, Abraham D | Danaei, Goodarz | Shibuya, Kenji | Adair-Rohani, Heather | Amann, Markus | Anderson, H Ross | Andrews, Kathryn G | Aryee, Martin | Atkinson, Charles | Bacchus, Loraine J | Bahalim, Adil N | Balakrishnan, Kalpana | Balmes, John | Barker-Collo, Suzanne | Baxter, Amanda | Bell, Michelle L | Blore, Jed D | Blyth, Fiona | Bonner, Carissa | Borges, Guilherme | Bourne, Rupert | Boussinesq, Michel | Brauer, Michael | Brooks, Peter | Bruce, Nigel G | Brunekreef, Bert | Bryan-Hancock, Claire | Bucello, Chiara | Buchbinder, Rachelle | Bull, Fiona | Burnett, Richard T | Byers, Tim E | Calabria, Bianca | Carapetis, Jonathan | Carnahan, Emily | Chafe, Zoe | Charlson, Fiona | Chen, Honglei | Chen, Jian Shen | Cheng, Andrew Tai-Ann | Child, Jennifer Christine | Cohen, Aaron | Colson, K Ellicott | Cowie, Benjamin C | Darby, Sarah | Darling, Susan | Davis, Adrian | Degenhardt, Louisa | Dentener, Frank | Des Jarlais, Don C | Devries, Karen | Dherani, Mukesh | Ding, Eric L | Dorsey, E Ray | Driscoll, Tim | Edmond, Karen | Ali, Suad Eltahir | Engell, Rebecca E | Erwin, Patricia J | Fahimi, Saman | Falder, Gail | Farzadfar, Farshad | Ferrari, Alize | Finucane, Mariel M | Flaxman, Seth | Fowkes, Francis Gerry R | Freedman, Greg | Freeman, Michael K | Gakidou, Emmanuela | Ghosh, Santu | Giovannucci, Edward | Gmel, Gerhard | Graham, Kathryn | Grainger, Rebecca | Grant, Bridget | Gunnell, David | Gutierrez, Hialy R | Hall, Wayne | Hoek, Hans W | Hogan, Anthony | Hosgood, H Dean | Hoy, Damian | Hu, Howard | Hubbell, Bryan J | Hutchings, Sally J | Ibeanusi, Sydney E | Jacklyn, Gemma L | Jasrasaria, Rashmi | Jonas, Jost B | Kan, Haidong | Kanis, John A | Kassebaum, Nicholas | Kawakami, Norito | Khang, Young-Ho | Khatibzadeh, Shahab | Khoo, Jon-Paul | Kok, Cindy | Laden, Francine | Lalloo, Ratilal | Lan, Qing | Lathlean, Tim | Leasher, Janet L | Leigh, James | Li, Yang | Lin, John Kent | Lipshultz, Steven E | London, Stephanie | Lozano, Rafael | Lu, Yuan | Mak, Joelle | Malekzadeh, Reza | Mallinger, Leslie | Marcenes, Wagner | March, Lyn | Marks, Robin | Martin, Randall | McGale, Paul | McGrath, John | Mehta, Sumi | Mensah, George A | Merriman, Tony R | Micha, Renata | Michaud, Catherine | Mishra, Vinod | Hanafiah, Khayriyyah Mohd | Mokdad, Ali A | Morawska, Lidia | Mozaff arian, Dariush | Murphy, Tasha | Naghavi, Mohsen | Neal, Bruce | Nelson, Paul K | Nolla, Joan Miquel | Norman, Rosana | Olives, Casey | Omer, Saad B | Orchard, Jessica | Osborne, Richard | Ostro, Bart | Page, Andrew | Pandey, Kiran D | Parry, Charles D H | Passmore, Erin | Patra, Jayadeep | Pearce, Neil | Pelizzari, Pamela M | Petzold, Max | Phillips, Michael R | Pope, Dan | Pope III, C Arden | Powles, John | Rao, Mayuree | Razavi, Homie | Rehfuess, Eva A | Rehm, Jürgen T | Ritz, Beate | Rivara, Frederick P | Roberts, Thomas | Robinson, Carolyn | Rodriguez-Portales, Jose A | Romieu, Isabelle | Room, Robin | Rosenfeld, Lisa C | Roy, Ananya | Rushton, Lesley | Salomon, Joshua A | Sampson, Uchechukwu | Sanchez-Riera, Lidia | Sanman, Ella | Sapkota, Amir | Seedat, Soraya | Shi, Peilin | Shield, Kevin | Shivakoti, Rupak | Singh, Gitanjali M | Sleet, David A | Smith, Emma | Smith, Kirk R | Stapelberg, Nicolas J C | Steenland, Kyle | Stöckl, Heidi | Stovner, Lars Jacob | Straif, Kurt | Straney, Lahn | Thurston, George D | Tran, Jimmy H | Van Dingenen, Rita | van Donkelaar, Aaron | Veerman, J Lennert | Vijayakumar, Lakshmi | Weintraub, Robert | Weissman, Myrna M | White, Richard A | Whiteford, Harvey | Wiersma, Steven T | Wilkinson, James D | Williams, Hywel C | Williams, Warwick | Wilson, Nicholas | Woolf, Anthony D | Yip, Paul | Zielinski, Jan M | Lopez, Alan D | Murray, Christopher J L | Ezzati, Majid
Lancet  2012;380(9859):2224-2260.
Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time.
We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden.
In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2–7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5–7·0]), and alcohol use (5·5% [5·0–5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8–9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6–8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4–6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2–10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water we and sanitation accounting for 0·9% (0·4–1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania.
Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children.
Bill & Melinda Gates Foundation.
PMCID: PMC4156511  PMID: 23245609
9.  Weight gain prior to entry into a weight-loss intervention study among overweight and obese breast cancer survivors 
Changes in cancer therapy, in addition to changes in obesity prevalence, suggest the need for a current assessment of weight gain patterns following breast cancer diagnosis. The aim of this study was to evaluate factors associated with weight gain among breast cancer survivors prior to enrolling into a behavioral weight loss intervention.
Anthropometric measures and data on weight-related factors were collected at baseline on 665 breast cancer survivors. Postdiagnosis weight gain was determined between entry into the trial and previous diagnosis up to 5 years. Multivariate logistic regression analyses were used to evaluate the association between weight gain and influencing factors.
The mean weight gain was 4.5 % body weight (standard deviation=10.6); 44 % of women experienced ≥5 % body weight gain. The risk of weight gain was inversely associated with age (adjusted odds ratio (ORadj)=0.97, 95 % confidence interval (95 % CI) 0.95–0.99), Hispanic ethnicity (ORadj=0.30, 95 % CI 0.13–0.68), and overweight (ORadj= 0.11, 95 % CI 0.05–0.23) or obese (ORadj=0.03, 95 % CI 0.02–0.07) status at diagnosis and positively associated with time elapsed since diagnosis (ORadj=1.19/year, 95 % CI 1.04–1.36). Women prescribed aromatase inhibitors were 46 % less likely to gain weight compared to women prescribed selective estrogen-receptor modulators (ORadj=0.54, 95 % CI 0.31–0.93). The risk of weight gain was positively associated with smoking at diagnosis (ORadj=2.69, 95 % CI 1.12–6.49) although this was attributable to women who subsequently quit smoking.
Postdiagnosis weight gain is common and complex and influenced by age, ethnicity, weight, smoking status, time elapsed since diagnosis, and endocrine-modulating therapy.
Implications for cancer survivors
Weight gain continues to be a concern following a diagnosis of breast cancer. Factors influencing this weight gain include age, ethnicity, weight, smoking status, time elapsed since diagnosis, and endocrine-modulating therapy. Effective weight management strategies are needed for this population of women.
PMCID: PMC4127359  PMID: 24599421
Breast cancer survivors; Weight gain; Women
10.  Reducing Breast Cancer Recurrence with Weight Loss, a Vanguard Trial: The Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) Trial 
Contemporary clinical trials  2012;34(2):282-295.
Breast cancer is the most common invasive cancer among women in developed countries. Obesity is a major risk factor for breast cancer recurrence and mortality in both pre-and postmenopausal women. Co-morbid medical conditions are common among breast cancer survivors. The Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) study is a 4-year randomized clinical trial of 693 overweight/obese women aged ≥21 years diagnosed with any early stage breast cancer (stages I[≥1 cm]-III) within the previous five years, designed to demonstrate the feasibility of achieving sustained weight loss and to examine the impact of weight loss on quality of life and co-morbidities, and to enable future exploration of biochemical mechanisms linking obesity to lower likelihood of disease-free survival. This trial is strategically designed as a vanguard for a fully-powered trial of women who will be evaluated for breast cancer recurrence and disease-free survival. Participants were recruited between 2010 and 2012 at four sites, had completed initial therapies, and had a body mass index between 25 and 45 kg/m2. The intervention featured a group-based cognitive-behavioral weight loss program with telephone counseling and tailored newsletters to support initial weight loss and subsequent maintenance, with the goal of 7% weight loss at two years. This study has high potential to have a major impact on clinical management and outcomes after a breast cancer diagnosis. This trial initiates the effort to establish weight loss support for overweight or obese breast cancer survivors as a new standard of clinical care.
PMCID: PMC3593786  PMID: 23266440
Obesity; Weight Reduction; Breast Cancer; Quality of Life; Co-Morbidities
11.  Mailed Intervention to Promote Sun Protection of Children 
Sun exposure, especially during childhood, is the most important preventable risk factor for skin cancer, yet few effective interventions to reduce exposure exist.
To test the effectiveness of a partially tailored mailed intervention based on the Precaution Adoption Process Model, delivered in the spring over 3 years to parents and children.
RCT, with data collection through telephone interviews of parents and skin exams of children at baseline (Summer 2004) and annually (Summer 2005–2007). The control group received no intervention.
Families recruited in the Denver CO area, through private pediatric clinics, a large MCO, and community settings. Children born in 1998 were aged approximately 6 years at baseline; 867 children met inclusion criteria; analysis is reported for 677 white, non-Hispanic participants at highest risk for skin cancer.
Main outcome measures
Primary outcomes were parent-reported child sun protection behaviors. Secondary outcomes included parents' risk perception, and perceived effectiveness of and barriers to prevention behaviors, stage of change, reported sunburns, and observed tanning and nevus development. The longitudinal mixed-model analysis was conducted between 2008 and 2011.
The intervention group reported more use of protective clothing and hats, shadeseeking, sunscreen and midday sun avoidance; fewer sunburns; more knowledge of the risk of skin cancer; higher perceived effectiveness of sun protection and stage of change; and lower perception of barriers to sun protection (all p<0.05). The intervention group had fewer nevi ≥2 mm in 1 year of the study, 2006 (p=0.03). No differences were found in tanning or nevi <2 mm.
The level of behavior change associated with this single-modality intervention is not likely sufficient to reduce skin cancer risk. However, the intervention shows promise for inclusion in longer-term, multicomponent interventions that have sufficient intensity to affect skin cancer incidence.
Trial registration
This study is registered at NCT01464957.
PMCID: PMC3888436  PMID: 22992358
It has been widely reported that individuals with a light phenotype (i.e., light hair color, light base skin color, and propensity to burn) have more nevi and are at greater risk for developing skin cancer. No studies have systematically investigated how phenotypic traits may interact in relation to nevus development.
We sought to systematically examine whether any combinations of phenotype are associated with a greater or lesser risk for nevus development in white children.
In the summer of 2007, 654 children were examined to determine full body nevus counts, skin color by colorimetry, and hair and eye color by comparison to charts. Interviews of parents were conducted to capture sun sensitivity, sun exposure and sun protection practices.
Among 9-year-old children with sun sensitivity rating type 2 (painful burn/light tan), those with light hair had lower nevus counts than did those with dark hair (p-value for interaction = 0.03). This relationship was independent of eye color, presence of freckling, gender, usual daily sun exposure, sunburn in 2004–2007, sun protection index and waterside vacation sun exposure. The difference in nevus counts was further determined to be specific to small nevi (less than 2 mm) and nevi in intermittently exposed body sites.
Geographic and genetic differences in other study populations may produce different results.
The standard acceptance that dark phenotype is a marker for low melanoma risk and light phenotype a marker for high risk may need to be reevaluated. In non-Hispanic white children, dark haired individuals who burn readily and then tan slightly are more prone to nevus development, and may therefore be a previously under-recognized high risk group for melanoma.
PMCID: PMC3888449  PMID: 20584558
children; nevus; phenotype; hair color; sun sensitivity; interaction; epidemiology
13.  ADRB2 G–G haplotype associated with breast cancer risk among Hispanic and non-Hispanic white women: interaction with type 2 diabetes and obesity 
Cancer causes & control : CCC  2012;23(10):1653-1663.
Polymorphisms in the beta-2-adrenergic receptor (ADRB2) gene have been studied in relation to risk of type 2 diabetes and obesity, risk factors that have received increased attention in relation to breast cancer. We evaluated the hypothesis that ADRB2 variants (rs 1042713, rs1042714) are associated with breast cancer risk in non-Hispanic white (NHW) and Hispanic (H) women using data from a population-based case–control study conducted in the southwestern United States.
Data on lifestyle and medical history, and blood samples, were collected during in-person interviews for incident primary breast cancer cases (1,244 NHW, 606 H) and controls (1,330 NHW, 728 H). ADRB2 genotypes for rs1042713(G/A) and rs1042714(G/C) were determined using TaqMan assays. The associations of each variant and corresponding haplotypes with breast cancer were estimated using multivariable logistic regression.
Two copies compared to one or zero copies of the ADRB2 G–G haplotype were associated with increased breast cancer risk for NHW women [odds ratio (OR), 1.95; 95 % confidence interval (95 % CI), 1.26–3.01], but with reduced risk for H women [OR, 0.74; 95 % CI, 0.50–1.09]. Effect estimates were strengthened for women with a body mass index (BMI) ≥25 kg/m2 [H: OR, 0.50; 95 % CI, 0.31–0.82; NHW: OR, 3.85; 95 % CI, 1.88–7.88] and for H women with a history of diabetes [H: OR, 0.32; 95 % CI, 0.12–0.89].
These data suggest that ethnicity modifies the association between the ADRB2 G–G haplotype and breast cancer risk, and being overweight or obese enhances the divergence of risk between H and NHW women.
PMCID: PMC3794465  PMID: 22864926
Breast cancer; Hispanic; Beta-2-adrenergic receptor; Haplotypes; Obesity; Diabetes
14.  Lack of Association Between Insulin Sensitivity and Colorectal Adenoma Risk 
Nutrition and cancer  2011;63(1):6-11.
Insulin resistance is thought to mediate the association between obesity and colorectal neoplasia, but no prior studies have assessed stimulated insulin sensitivity as a risk factor for colorectal neoplasia. This prospective study examined the association between insulin sensitivity measured directly using the frequently sampled intravenous glucose tolerance test (FSIGT) and later risk of colorectal adenomas. Among participants with a range of glucose tolerance levels enrolled in the Insulin Resistance Atherosclerosis Study, colonoscopies were conducted on 600 participants ages ≥ 50 yr, regardless of symptoms, about 10 yr after the first FSIGT and 5 yr after the second. Multiple logistic regression analyses were used. Within this cohort, diabetes was not associated with colorectal adenoma risk [~10 yr prior to colonoscopy adjusted odds ratio (ORadj) 1.00; 95% confidence interval (CI), 0.62–1.62 or ~5 yr prior to colonoscopy ORadj 0.96; 95% CI, 0.62–1.50]. Among non-diabetic participants, insulin sensitivity was not associated with colorectal adenoma risk at either prior study visit [lowest vs. highest insulin sensitivity, ~10 yr prior to colonoscopy ORadj 0.93; 95% CI 0.50–1.71 and ~5 yr prior to colonscopy ORadj 0.74; 95% CI, 0.38–1.46]. These results suggest that factors other than insulin sensitivity mediate the relationship between obesity and colorectal neoplasia.
PMCID: PMC3752663  PMID: 21154114
15.  Sex-specific association of sequence variants in CBS and MTRR with risk for promoter hypermethylation in the lung epithelium of smokers 
Carcinogenesis  2012;33(8):1542-1547.
Gene promoter hypermethylation is now regarded as a promising biomarker for the risk and progression of lung cancer. The one-carbon metabolism pathway is postulated to affect deoxyribonucleic acid (DNA) methylation because it is responsible for the generation of S-adenosylmethionine (SAM), the methyl donor for cellular methylation reactions. This study investigated the association of single nucleotide polymorphisms (SNPs) in six one-carbon metabolism-related genes with promoter hypermethylation in sputum DNA from non-Hispanic white smokers in the Lovelace Smokers Cohort (LSC) (n = 907). Logistic regression was used to assess the association of SNPs with hypermethylation using a high/low methylation cutoff. SNPs in the cystathionine beta synthase (CBS) and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) genes were significantly associated with high methylation in males [CBS rs2850146 (-8283G > C), 
OR = 4.9; 95% CI: 1.98, 12.2, P = 0.0006] and low methylation in females [MTRR rs3776467 (7068A > G), OR = 0.57, 95% CI: 0.42, 0.77, P = 0.0003]. The variant allele of rs2850146 was associated with reduced gene expression and increased plasma homocysteine (Hcy) concentrations. Three plasma metabolites, Hcy, methionine and dimethylglycine, were associated with increased risk for gene methylation. These studies suggest that SNPs in CBS and MTRR have sex-specific associations with aberrant methylation in the lung epithelium of smokers that could be mediated by the affected one-carbon metabolism and transsulfuration in the cells.
Abbreviations:CBScystathionine beta synthaseDNAdeoxyribonucleic acidHBEChuman bronchial epithelial cellHcyhomocysteineLD, linkage disequilibrium; LSClovelace Smokers CohortMAFminor allele frequencyMTHFRmethylenetetrahydrofolate reductaseMTRRmethyltransferase reductaseSNPsingle nucleotide polymorphismsSAHS-adenosylhomocysteineSAMS-adenosylmethionine
PMCID: PMC3499054  PMID: 22665368
16.  Increase in Circulating Levels of IGF-1 and IGF-1/IGFBP-3 Molar Ratio over a Decade is Associated with Colorectal Adenomatous Polyps 
High levels of circulating insulin-like growth factor-1 (IGF-1) have been associated with increased risk of several cancers. Regarding colorectal cancer, these associations are generally weak. We hypothesized that an increase in IGF-1 over time would be a stronger risk factor for cancer-related outcomes than the actual levels. In this analysis we utilized existing data from the Insulin Resistance and Atherosclerosis Study (IRAS). Circulating IGF-1 levels and molar ratios of IGF-1 to IGF binding protein 3 (IGFBP-3) were measured at three time points, within a 10-year follow-up period. We examined the associations of increase of the two variables with the presence of colorectal adenoma at the end of follow-up among participants with normal glucose tolerance at baseline. This included 143 individuals, from which 24 were diagnosed with adenomatous polyps. Although the mean levels of IGF-1 and IGF-1/IGFBP-3 decline with age, approximately 30% of the participants showed an increase of at least fifteen percent (“ever increase”) in one or both of these variables, compared to baseline. We found a positive association between “ever increase” in IGF-1 o r IGF-1/IGFBP-3 and the presence of colorectal adenoma: ORs were 3.81 (95% CI: 1.30-10.8) and 2.83 (95% CI: 1.00-8.22), respectively. No association was found when analyzing the actual levels of both variables at any time point. Our data suggest that an increase in circulating IGF-1 or IGF-1/IGFBP-3 may represent a disturbed GH/IGF1 homeostasis, which could favor the development of precancerous lesions, such as colorectal adenoma.
PMCID: PMC3314119  PMID: 21898383
IGF-1; colorectal adenoma; biomarkers
17.  Benefits and Harms of CT Screening for Lung Cancer: A Systematic Review 
Lung cancer is the leading cause of cancer death. Most patients are diagnosed with advanced disease, resulting in a very low five-year survival rate. Screening may reduce the risk of death from lung cancer.
A multi-society collaborative initiative (involving the American Cancer Society, the American College of Chest Physicians, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network) was undertaken to conduct a systematic review of the evidence regarding the benefits and harms of lung cancer screening using low dose computed tomography (LDCT), in order to create the foundation for development of an evidence-based clinical guideline.
Data Sources
MEDLINE (OVID: 1996 to April 2012), EMBASE (OVID: 1996 to April 2012), and the Cochrane Library (April 2012).
Study Selection
Of 591 citations identified and reviewed, eight randomized controlled trials and 13 cohort studies of LDCT screening met criteria for inclusion. Primary outcomes were lung cancer mortality and all-cause mortality, and secondary outcomes included nodule detection, invasive procedures, follow-up tests, and smoking cessation.
Data Extraction
Critical appraisal using pre-defined criteria was conducted on individual studies and the overall body of evidence. Differences in data extracted by reviewers were adjudicated by consensus.
Three randomized studies provided evidence on the impact of LDCT screening on lung cancer mortality, of which the National Lung Screening Trial was the most informative, demonstrating that among 53,454 enrolled, screening resulted in significantly fewer lung cancer deaths (356 vs 443 deaths; lung cancer-specific mortality, 247 vs 309 events per 100,000 person-years for LDCT and control groups, respectively; Relative Risk [RR] = 0.80, 95% Confidence Interval [CI] 0.73–0.93; Absolute Risk Reduction [ARR] = 0.33%, P=0.004). The other 2 smaller studies showed no such benefit. In terms of potential harms of LDCT screening, across all trials and cohorts, about 20% of individuals in each round of screening had positive results requiring some degree of follow-up, while approximately 1% had lung cancer. There was marked heterogeneity in this finding and in the frequency of follow-up investigations, biopsies, and the percent of surgical procedures performed in those with benign lesions. Major complications in those with benign conditions were rare.
LDCT screening may benefit individuals at an elevated risk for lung cancer, but uncertainty exists about potential harms and the generalizability of results.
PMCID: PMC3709596  PMID: 22610500
18.  Defining a Gene Promoter Methylation Signature in Sputum for Lung Cancer Risk Assessment 
To evaluate the methylation state of 31 genes in sputum as biomarkers in an expanded nested, case-control study from the Colorado Cohort and to assess the replication of results from the most promising genes in an independent case-control study of asymptomatic Stage I lung cancer patients from New Mexico.
Experimental Design
Cases and controls from Colorado and New Mexico were interrogated for methylation of up to 31 genes using nested, methylation specific PCR. Individual genes and methylation indices were used to assess the association between methylation and lung cancer with logistic regression modeling.
Seventeen genes with odds ratios of 1.4 – 3.6 were identified and selected for replication in the New Mexico study. Overall, the direction of effects seen in New Mexico was similar to Colorado with the largest increase in case discrimination (odds ratios, 3.2 – 4.2) seen for the PAX5α, GATA5, and SULF2 genes. ROC curves generated from seven gene panels from Colorado and New Mexico studies showed prediction accuracy of 71% and 77%, respectively. A 22-fold increase in lung cancer risk was seen for a subset of New Mexico cases with five or more genes methylated. Sequence variants associated with lung cancer did not improve the accuracy of this gene methylation panel.
These studies have identified and replicated a panel of methylated genes whose integration with other promising biomarkers could initially identify the highest risk smokers for computed tomography screening for early detection of lung cancer.
PMCID: PMC3483793  PMID: 22510351
gene methylation; sputum; lung cancer; biomarker
19.  Dietary Supplements and Cancer Prevention: Balancing Potential Benefits Against Proven Harms 
Nutritional supplementation is now a multibillion-dollar industry, and about half of all US adults take supplements. Supplement use is fueled in part by the belief that nutritional supplements can ward off chronic disease, including cancer, although several expert committees and organizations have concluded that there is little to no scientific evidence that supplements reduce cancer risk. To the contrary, there is now evidence that high doses of some supplements increase cancer risk. Despite this evidence, marketing claims by the supplement industry continue to imply anticancer benefits. Insufficient government regulation of the marketing of dietary supplement products may continue to result in unsound advice to consumers. Both the scientific community and government regulators need to provide clear guidance to the public about the use of dietary supplements to lower cancer risk.
PMCID: PMC3352833  PMID: 22534785
20.  Vitamin D intake, vitamin D receptor polymorphisms, and breast cancer risk among women living in the southwestern U.S. 
No studies of dietary vitamin D intake and vitamin D receptor (VDR) have been conducted comparing breast risk among Hispanic women and non-Hispanic white (NHW) women. We investigated the association between vitamin D intake and breast cancer in a population-based case–control study of 1,527 NHW and 791 Hispanic breast cancer cases diagnosed in 1999–2004 in Arizona, New Mexico, Utah, and Colorado, and 1,599 NHW and 922 Hispanic age-matched controls. Vitamin D intake was assessed using food frequency questionnaires, and associations with breast cancer were adjusted for age, ethnicity, state, education, body mass index, smoking, age at menarche, age at first birth, parity, hormone exposure, height, and physical activity using logistic regression. BsmI, Poly A and FokI vitamin D receptor (VDR) genotypes were also measured. Dietary vitamin D intake was positively associated with breast cancer (highest vs. lowest quartile (Q4 vs. Q1): odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.15–1.60; Ptrend = 0.003), whereas vitamin D supplement use was inversely associated with breast cancer (10+ µg/day vs. none: OR = 0.79, 95% CI = 0.65–0.96, Ptrend = 0.01). Similar patterns in risk were observed by ethnicity and menopausal status. Positive associations with dietary vitamin D intake and inverse associations with supplement use were observed for ER+/PR+ and ER−/PR− breast cancers, but not for ER+/PR−disease. BsmI genotype significantly modified the association between dietary vitamin D and breast cancer overall. Future research is needed to better understand potential differences in breast cancer risk by vitamin D source and hormone receptor status.
PMCID: PMC3390020  PMID: 22130867
Breast cancer; Vitamin D; Vitamin D receptor; Hispanics; Diet
21.  Dietary Intake of Folate, B-Vitamins and Methionine and Breast Cancer Risk among Hispanic and Non-Hispanic White Women 
PLoS ONE  2013;8(2):e54495.
Low dietary folate intake is associated with several neoplasias, but reports are inconsistent for breast cancer. Additionally, the association of folate with breast cancer estrogen receptor (ER) status is not well established.
To determine if dietary intakes of folate, B-vitamins (B2, B6, B12) and methionine are associated with breast cancer risk and ER status in Hispanic, and non-Hispanic White women in the southwestern US.
Materials and Methods
Primary breast cancer cases (n = 2,325) in the 4-Corners region (Arizona, Colorado, New Mexico and Utah), diagnosed between October 1999 and May 2004, were identified through state cancer registries. Controls (n = 2,525) were frequency-matched by ethnicity and age (±5 years). Dietary intake, physical activity and other exposures were assessed using in-person interviews. Risk was assessed through multivariable and multinomial logistic regression with adjustment for relevant covariates.
While there was no overall association with breast cancer, the highest quartile of folate intake was marginally inversely associated with ER− breast cancer (Odds Ratio (OR) = 0.50, 95%CI 0.25–1.00, p for trend = 0.07). Vitamin B12 intake was inversely associated with breast cancer also (OR = 0.73, 95%CI 0.53–1.00, p for trend = 0.06), particularly for the highest quartile of ER+ breast cancer (OR = 0.67, 95%CI 0.46–0.99, p for trend = 0.06), among NHW women (OR = 0.49, 95%CI 0.29–0.81, p for trend = 0.01) and invasive breast cancer (OR = 0.63; 95%CI: 0.42, 0.93, Ptrend = 0.01). Methionine intake was also inversely associated with ER+ breast cancer (OR for 4th quartile = 0.83, 95%CI 0.66–1.03, p for trend = 0.04), primarily among Hispanic women (OR = 0.71, 95%CI 0.47–1.06, and P for trend = 0.02).
Higher intake of folate is marginally associated with a lower risk for ER− breast cancer, and higher intakes of vitamin B-12 and methionine are marginally associated with a lower risk of ER+ breast cancer.
PMCID: PMC3569453  PMID: 23408942
22.  Behavioral risk factors and their relationship to tumor characteristics in Hispanic and non-Hispanic white long-term breast cancer survivors 
Hispanics are more likely to be diagnosed with breast cancer at a younger age, with more advanced stage at diagnosis, hormone receptor-negative tumors, and worse prognosis than non-Hispanic whites (NHW). Little is known regarding the association between behavioral risk factors and breast tumor characteristics and whether these associations vary by race/ethnicity. We evaluated the association between several behavioral risk factors and tumor phenotype in a population-based study of Hispanics and NHWs. Participants are cases (846 Hispanic and 1,625 NHW women) diagnosed with breast cancer between 1999 and 2004 in Arizona, Colorado, New Mexico, or Utah. The association between breast cancer characteristics and obesity, physical activity, smoking, alcohol intake, and reproductive factors was examined. Logistic regression was used to compute the ethnic-specific odds ratios for the association between these risk factors and estrogen receptor (ER) status, tumor size, and histologic grade. Hispanics had more ER-negative tumors (28 vs. 20%), tumors >2 cm (39 vs. 27%), and poorly differentiated tumors (84 vs. 77%) than NHW. Among premenopausal women, obesity was associated with more ER-negative cancers among NHW [OR = 2.47 (95% CI: 1.08, 5.67)] but less ER-negative cancers among Hispanics [OR = 0.29 (0.13, 0.66)]. Obesity was associated with larger tumors among NHW [OR = 1.58 (1.09, 2.29)], but not among Hispanics. Never using mammography was associated with larger tumors in both ethnic groups. Moderate alcohol drinking and moderate and vigorous physical activity were weakly associated with smaller tumors in both ethnic groups. Our findings suggest that the association of obesity and other behavioral risk factors with breast cancer characteristics differ by ethnicity. We observed a divergent pattern between Hispanic and NHW cases in the association between obesity and ER status and tumor size. These observations suggest that a complex set of metabolic and hormonal factors related to estrogen and insulin pathways influence tumor characteristics.
PMCID: PMC3390014  PMID: 21822637
Breast cancer; Tumor phenotype; Behavioral risk factors; Ethnicity; Obesity
23.  Ethnic Disparities in Breast Tumor Phenotypic Subtypes in Hispanic and Non-Hispanic White Women 
Journal of Women's Health  2011;20(10):1543-1550.
Hispanic women are at a lower risk of getting breast cancer than non-Hispanic white (NHW) women, yet they experience a higher risk of mortality after diagnosis. There is some evidence to suggest differences in tumor pathology; however, very limited research has been published on Hispanic women. This represents one of the first studies to evaluate the prevalence of tumor markers and phenotypic subtypes that are associated with poorer prognosis (human epidermal growth factor receptor 2 [HER2], triple negative and basal-like tumors) among Hispanic women.
We reviewed pathology reports, obtained paraffin blocks of breast cancer tissue, and established tissue microarrays from NHW (n=119) and Hispanic women (n=69) who were Colorado participants in the 4-Corners Breast Cancer Study. We evaluated ethnic differences in the prevalence of tumor markers and phenotypic subtypes and assessed the contribution of risk factors in explaining the observed differences.
Consistent with other studies, Hispanic women had a higher prevalence of estrogen receptor-negative tumors compared with NHWs (36.2% vs. 22.7%, p=0.05). Hispanics also had an unexpectedly higher proportion of HER2-positive tumors compared with NHWs (31.9% vs. 14.3%, p<0.01). Independent of other prognostic factors, Hispanics were 2.8 times more likely to have a HER2-positive tumor (95% confidence interval [CI] 0.98-7.86). Hispanics were less likely to have the more favorable luminal A subtype, but no significant differences were observed for the less favorable basal-like or triple negative subtypes. However, there were suggestive differences when considering menopausal status.
These findings provide evidence that breast cancers among Hispanic women comprise a distinct spectrum of tumor subtypes when compared with NHW women.
PMCID: PMC3186448  PMID: 21721934
24.  Replication of five GWAS-identified loci and breast cancer risk among Hispanic and non-Hispanic white women living in the Southwestern United States 
Genome-wide association studies (GWAS) have identified several loci as being associated with breast cancer in mostly European populations. We focus on TNRC9 rs3803662, FGFR2 rs1219648 and rs2981582, MAP3K1 rs889312, and 2q35 rs13387042, to replicate in the 4-Corner’s Breast Cancer Study of Hispanic (N = 565 cases and 714 controls) and non-Hispanic white (NHW) women (N = 1177 cases and 1330 controls). We evaluate associations by ethnicity, menopausal status, and tumor ER/PR status after adjusting for genetic admixture. TNRC9 AA genotype was associated with significant increased risk among NHW women (OR 1.54, 95% CI 1.14, 2.08; P trend 0.003). Both polymorphisms of FGFR2 were associated with statistically significant increased risk for NHW and Hispanic women; MAP3K1 was not associated with risk among either ethnic group. The polymorphism on 2q35 was associated with a statistically significant increased risk among Hispanic women (OR 1.53, 95% CI 1.08, 2.15 for the AA genotype; P trend = 0.004). Associations were significantly different among pre/peri-menopausal women for TNRC9 (P heterogeneity 0.008) and for 2q35 (P heterogeneity 0.08) for NHW and Hispanic women. Both FGFR2 polymorphisms reduced risk of ER−/PR− tumors in the presence of the minor allele among NHW women. Among Hispanic women, polymorphisms of the FGFR2 gene were associated with almost a twofold increase risk of an ER+/PR+ tumor, while non-significantly inversely associated with ER−/PR− tumors. Our data replicated some of the previously reported GWAS findings. Differences in associations were detected for NHW and Hispanic women by menopausal status and by ER/PR status of tumors.
PMCID: PMC3152602  PMID: 21475998
Breast cancer; Hispanic; TNRC9; MAP3K1; FGFR2; 2q35
25.  The Influence of Comorbidities on Overall Survival Among Older Women Diagnosed With Breast Cancer 
Previous studies have shown that summary measures of comorbid conditions are associated with decreased overall survival in breast cancer patients. However, less is known about associations between specific comorbid conditions on the survival of breast cancer patients.
The Surveillance, Epidemiology, and End Results–Medicare database was used to identify primary breast cancers diagnosed from 1992 to 2000 among women aged 66 years or older. Inpatient, outpatient, and physician visits within the Medicare system were searched to determine the presence of 13 comorbid conditions present at the time of diagnosis. Overall survival was estimated using age-specific Kaplan–Meier curves, and mortality was estimated using Cox proportional hazards models adjusted for age, race and/or ethnicity, tumor stage, cancer prognostic markers, and treatment. All statistical tests were two-sided.
The study population included 64 034 patients with breast cancer diagnosed at a median age of 75 years. None of the selected comorbid conditions were identified in 37 306 (58%) of the 64 034 patients in the study population. Each of the 13 comorbid conditions examined was associated with decreased overall survival and increased mortality (from prior myocardial infarction, adjusted hazard ratio [HR] of death = 1.11, 95% CI = 1.03 to 1.19, P = .006; to liver disease, adjusted HR of death = 2.32, 95% CI = 1.97 to 2.73, P < .001). When patients of age 66–74 years were stratified by stage and individual comorbidity status, patients with each comorbid condition and a stage I tumor had similar or poorer overall survival compared with patients who had no comorbid conditions and stage II tumors.
In a US population of older breast cancer patients, 13 individual comorbid conditions were associated with decreased overall survival and increased mortality.
PMCID: PMC3139585  PMID: 21719777

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