BackgroundTwo-thirds of U.S. adult women are overweight or obese. High body mass index (BMI) and adult weight gain are risk factors for a number of chronic diseases, including postmenopausal breast cancer. The higher postmenopausal breast cancer risk in women with elevated BMI is likely to be attributable to related metabolic disturbances including altered circulating sex steroid hormones and adipokines, elevated pro-inflammatory cytokines, and insulin resistance. Metformin is a widely used antidiabetic drug that has demonstrated favorable effects on metabolic disturbances and as such may lead to lower breast cancer risk in obese women. Further, the anti-proliferative effects of metformin suggest it may decrease breast density, an accepted biomarker of breast cancer risk.Methods/designThis is a Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have elements of metabolic syndrome. Eligible participants will be randomized to receive metformin 850 mg BID (n = 75) or placebo (n = 75) for 12 months. The primary endpoint is change in breast density, based on magnetic resonance imaging (MRI) acquired fat-water features. Secondary outcomes include changes in serum insulin levels, serum insulin-like growth factor (IGF)-1 to insulin-like growth factor binding protein (IGFBP)-3 ratio, serum IGF-2 levels, serum testosterone levels, serum leptin to adiponectin ratio, body weight, and waist circumference. Exploratory outcomes include changes in metabolomic profiles in plasma and nipple aspirate fluid. Changes in tissue architecture as well as cellular and molecular targets in breast tissue collected in a subgroup of participants will also be explored.DiscussionThe study will evaluate whether metformin can result in favorable changes in breast density, select proteins and hormones, products of body metabolism, and body weight and composition. The study should help determine the potential breast cancer preventive activity of metformin in a growing population at risk for multiple diseases.Trial registrationClinicalTrials.gov Identifier: NCT02028221. Registered on January 2, 2014. Grant #: 1R01CA172444-01A1 awarded on Sept 11, 2013.

Breast cancer prognosis is related to genetic and non-genetic risk factors. Distinct models for risk prediction have been reported to evaluate the 5-year overall survival at the time of diagnosis. However, those models do not account for non-genetic risk factors, like residential exposure to hazards. In this work, the residential exposure to hazards (gas power plants (GPP), residual water sites (RWS), hazardous air pollutants (HAPs)) has been included for assessing prognosis. We hypothesize that there is a statistically significant association between a 5-year breast cancer prognosis and residential exposure to hazards at Hermosillo city.The main findings include the association between 5-year prognosis and residential exposure to hazards in Hermosillo residents. Association models developed included, in addition to hazard exposure, the variables of age, high cholesterol and triglycerides, previous cancer(s), diabetes mellitus type 2, menopausal status, and the 5-year prognosis as the response variable. CMH test included the variables of residential exposure and 5-year prognosis in combination with one of the remaining risk factors. Non-significant models developed included hazard exposure, and the variables of familiar history of cancer, presence of chronic illness(es), presence of elements of metabolic syndrome, hypertension, elevated HDL-cholesterol, and LDL-cholesterol.The conclusions of this work are that the associations between residential exposure to hazards, in combination with other variables (age, previous cancer(s), diabetes mellitus type 2, and menopausal status), predict for a poor 5-year prognosis. Models including the factors of older age, the presence of previous cancer(s), and postmenopausal status; predict a poorer 5-year prognosis (overall survival of 69 % or less).

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Introduction: Breast cancer is the leading cause of female cancer-related deaths in Mexico. Residential exposure to environmental hazards, like air pollutants produced by industrial activities (HAPs), and contaminated sources of drinking water (CSW) may increase breast cancer risk. There is an interest in assessing environmental pollutants as risk factors, but there is no consensus on such an association. Hermosillo municipality is one of the regions with high breast cancer incidence at Sonora, Mexico. The role of environmental hazards on breast cancer risk in Hermosillo; however, has not been fully explored. This study aims at evaluating associations between breast cancer incidence rates and residential exposure to potentially hazardous sites (PHS). Objective: The aim is to determine breast cancer incidence rates in neighborhoods in the municipality of Hermosillo exposed to HAPs and/or CSW. Methods: Data (744 cases) is being collected from 5-year old clinical files of breast cancer patients residing in Hermosillo, and who were patients in private and public hospitals. Coordinates of PHS were obtained through government databases (INEGI, CONAGUA, SAGARPA) and projected onto a map by conversion to UTM zone 12 N. Cluster analysis was conducted to identify geographic regions of high breast cancer incidence. Neighborhoods were classified by their proximity to PHS, then calculated odds ratio (OR) and 95% confidence interval for breast cancer risk among residentially exposed inhabitants with that for non-exposed tenants. Results: Preliminary findings include high-high breast cancer clusters in five neighborhoods across Hermosillo, and from those, three are contiguous. In order to evaluate the association between neighborhoods with breast cancer cases, and the number of industries, an OR = 1.55 was obtained ((1.26 - 1.90), 95% CI, p-value = 0.00002). The previous comparison involved the location of 6 or more factories and those with less than 6 facilities (gas power industries excluded). We also examined an association between neighborhoods with breast cancer cases and their proximity (radio distance in km) to gas power industries-only. A comparison was made between neighborhoods within a radio of ≤ 2 km with those between a radio 2 - 4 km resulting in an OR = 0.68 ((0.56 - 0.83) CI, p-value = 0.00001). An additional comparison was carried out between residential locations within a radio of ≤ 2 km to those beyond 4 km, estimating an OR = 0.53 ((0.44 - 0.64), 95% CI, p-value < 0.00001). Furthermore, we evaluated associations for neighborhoods potentially exposed to CSW; particularly to residual waters within a radio of <1, between 1 - 2 km, and between 2 - 3 km. OR did not show significant differences for those comparisons. Conclusions: At this point in the study, a difference in breast cancer incidence rates has been observed in more industrialized neighborhoods or which are closer to potential sources of HAPs (gas power facilities). Residential proximity to CSW shows no association with incidence rates. Further studies with larger cohorts are needed to confirm findings. Citation Format: Diana Evelyn Villa-Guillen, Enrique Avila-Monteverde, Jose H Gonzalez-Zepeda, Luis F Munguia-Ibarra, Baldemar Corral-Villegas, Leticia Garcia-Rico, Martin Jara-Marini, Ana I Valenzuela-Quintanar, Graciela Caire-Juvera, Ivan Anduro-Corona, Eduardo Ruiz-Bustos, Jorge A Villa-Carrillo. Breast cancer risk and residential exposure to environmental hazards in Hermosillo, Sonora, Mexico [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-21.

Geographic heterogeneity of breast cancer prevalence suggests there are non-genetic factors related to cancer burden. Among those, residential exposure to pollutants, like hazardous waste sites, hazardous air pollutants, pesticides, and contaminated water sources, may contribute to breast cancer risk. This mini review discusses the main findings of several observational studies evaluating the association between historical exposure to contaminants and breast cancer development. The models used to evaluate breast cancer risk and hazardous contaminants are essential to reach a consensus in this highly debated field.