Risk of breast cancer and residential proximity to industrial installations: New findings from a multicase-control study (MCC-Spain)

Breast cancer is the most frequent tumor in women worldwide, although well-established risk factors account for 53%-55% of cases. Therefore, other risk factors, including environmental exposures, may explain the remaining variation. Our objective was to assess the relationship between risk of breast cancer and residential proximity to industries, according to categories of industrial groups and specific pollutants released, in the context of a population-based multicase-control study of incident cancer carried out in Spain (MCC-Spain). Using the current residence of cases and controls, this study was restricted to small administrative divisions, including both breast cancer cases (452) and controls (1511) in the 10 geographical areas recruiting breast cancer cases. Distances were calculated from the respective woman's residences to the 116 industries located in the study area. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance (between 1 km and 3 km) to industrial plants, adjusting for matching variables and other confounders. Excess risk (OR; 95%CI) of breast cancer was found near industries overall (1.30; 1.00-1.69 at 3 km), particularly organic chemical industry (2.12; 1.20-3.76 at 2.5 km), food/beverage sector (1.87; 1.26-2.78 at 3 km), ceramic (4.71; 1.62-13.66 at 1.5 km), surface treatment with organic solvents (2.00; 1.23-3.24 at 3 km), and surface treatment of plastic and metals (1.51; 1.06-2.14 at 3 km). By pollutants, the excess risk (OR; 95%CI) was detected near industries releasing pesticides (2.09; 1.14-3.82 at 2 km), and dichloromethane (2.09; 1.28-3.40 at 3 km). Our results suggest a possible increased risk of breast cancer in women living near specific industrial plants and support the need for more detailed exposure assessment of certain agents released by these plants.The authors thank all those who took part in this study providing questionnaire data. The study was partially funded by the “Acción Transversal del Cáncer", approved on the Spanish Ministry Council on the 11th October 2007, by the Scientific Foundation of the Spanish Association Against Cancer (Fundación Científica de la Asociación Española Contra el Cáncer (AECC) – EVP-1178/14), by the Spain's Health Research Fund (Fondo de Investigación Sanitaria - FIS 12/01416), by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359 PS09/01286-León, PS09/00773-Cantabria, PS09/02078-Huelva, PS09/01903-Valencia, PS09/01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/00613, PI15/00069, PI15/00914, PI15/01032), by the ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII) and Red Temática de Investigación del Cáncer (RTICC) del ISCIII (RD12/0036/0036)), by the Fundación Marqués de Valdecilla (API 10/09), by the Consejería de Salud of the Junta de Andalucía (PI-0571-2009, PI-0306-2011, salud201200057018tra), by the Junta de Castilla y León (LE22A10-2), by the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), by the Regional Government of the Basque Country, by the Recercaixa (2010ACUP 00310), by the European Commission grants FOOD-CT-2006-036224-HIWATE, by the Spanish Association Against Cancer (AECC) Scientific Foundation, by the Catalan Government DURSI grant 2017SGR723, by the University of Oviedo, and by the Fundación Caja de Ahorros de Asturias. ISGlobal is a member of the CERCA Program, Generalitat de Catalunya.S

Menstrual and Reproductive Factors and Risk of Gastric and Colorectal Cancer in Spain

BACKGROUND: Sex hormones play a role in gastric cancer and colorectal cancer etiology, however, epidemiological evidence is inconsistent. This study examines the influence of menstrual and reproductive factors over the risk of both tumors. METHODS: In this case-control study 128 women with gastric cancer and 1293 controls, as well as 562 female and colorectal cancer cases and 1605 controls were recruited in 9 and 11 Spanish provinces, respectively. Population controls were frequency matched to cases by age and province. Demographic and reproductive data were directly surveyed by trained staff. The association with gastric, colon and rectal cancer was assessed using logistic and multinomial mixed regression models. RESULTS: Our results show an inverse association of age at first birth with gastric cancer risk (five-year trend: OR = 0.69; p-value = 0.006). Ever users of hormonal contraception presented a decreased risk of gastric (OR = 0.42; 95%CI = 0.26-0.69), colon (OR = 0.64; 95%CI = 0.48-0.86) and rectal cancer (OR = 0.61; 95%CI = 0.43-0.88). Postmenopausal women who used hormone replacement therapy showed a decreased risk of colon and rectal tumors. A significant interaction of educational level with parity and months of first child lactation was also observed. CONCLUSION: These findings suggest a protective role of exogenous hormones in gastric and colorectal cancer risk. The role of endogenous hormones remains unclear

Reasons for participating in the Valencian Community Colorectal Cancer Screening Programme by gender, age, and social class

Objective: To know the reasons to participate or not in a colorectal cancer (CCR) screening programme and to analyze the differences by sex, age and social class. Methods: Cross-sectional study by a telephone survey directed to a sample of men and women aged between 50-74 year old, participants (n = 383) and non participants (n = 383) in the CCR screening programme of Valencian Community. Descriptive analysis and logistic regression models estimating the Odds Ratio (p < 0.05). Results: The main reasons to participate are "it is important for health" (97.9 %) and "the test is easy" (97.6 %); and to non participate are "no CCR symptoms" (49.7 %) and "didn't receive invitation letter" (48.3 %). Women are more likely not to participate if the reason was to consider the "test unpleasant" (OR: 1.82; IC: 1.00-3.28), and men if the reason was "lack of time" (OR 0.51; IC: 0.27-0.97); persons 60 or more years old if the reason was "diagnostic fear" (OR: 2.31; IC: 1.11-4.80), and persons 50-59 years old if was "lack of time" (OR 0.44; IC: 0.23-0.85); non manual social class persons if the reason was "lack of time" (OR: 2.66; IC: 1.40-5.10); manual women if the reason was "embarrassment to perform the test" (OR: 0.37; IC: 0.14-0.97); and non manual men if was "lack of time" (OR: 4.78; IC: 1.96-11.66). Conclusions: There are inequalities in the reasons for not participating in CCR screening programmes by sex, age and social class. It would be advisable to design actions that incorporate specific social group needs in order to reduce inequalities in participation

Association of diabetes and diabetes treatment with incidence of breast cancer

AIMS: The aim of this study was to evaluate the association of diabetes and diabetes treatment with risk of postmenopausal breast cancer. METHODS: Histologically confirmed incident cases of postmenopausal breast (N = 916) cancer were recruited from 23 Spanish public hospitals. Population-based controls (N = 1094) were randomly selected from primary care center lists within the catchment areas of the participant hospitals. ORs (95 % CI) were estimated using mixed-effects logistic regression models, using the recruitment center as a random effect term. Breast tumors were classified into hormone receptor positive (ER+ or PR+), HER2+ and triple negative (TN). RESULTS: Diabetes was not associated with the overall risk of breast cancer (OR 1.09; 95 % CI 0.82-1.45), and it was only linked to the risk of developing TN tumors: Among 91 women with TN tumors, 18.7 % were diabetic, while the corresponding figure among controls was 9.9 % (OR 2.25; 95 % CI 1.22-4.15). Regarding treatment, results showed that insulin use was more prevalent among diabetic cases (2.5 %) as compared to diabetic controls (0.7 %); OR 2.98; 95 % CI 1.26-7.01. They also showed that, among diabetics, the risk of developing HR+/HER2- tumors decreased with longer metformin use (ORper year 0.89; 95 % CI 0.81-0.99; based on 24 cases and 43 controls). CONCLUSION: This study reinforces the need to correctly classify breast cancers when studying their association with diabetes. Given the low survival rates in women diagnosed with TN breast tumors and the potential impact of diabetes control on breast cancer prevention, more studies are needed to better characterize this association.This work was supported by research Grants from Spain´s Health Research Fund Fondo de Investigación Sanitaria (PI12/00488, PI08/1770, PI08/0533, PI08/1359, PS09/00773, PS09/01286, PS09/01903, PS09/02078, PS09/01662, PI11/01403, PI11/01889, PI11/00226, PI11/01810, PI11/02213, PI12/00265, PI12/01270, PI12/00715, PI12/00150), Fundación Marqués de Valdecilla (API 10/09), ICGC International Cancer Genome Consortium CLL, Junta de Castilla y León (LE22A10-2), Consejería de Salud of the Junta de Andalucía (PI-0571), Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), Recercaixa (2010ACUP 00310), Regional Government of the Basque Country by European Commission GrantsFOOD-CT-2006-036224-HIWATE, Spanish Association Against Cancer (AECC) Scientific Foundation and the Catalan Government DURSI Grant 2014SGR647S

Long-term exposure to trihalomethanes in drinking water and breast cancer in the Spanish multicase-control study on cancer (MCC-SPAIN)

Background: Exposure to trihalomethanes (THMs) in drinking water has consistently been associated with an increased risk of bladder cancer, but evidence on other cancers including the breast is very limited. Objectives: We assessed long-term exposure to THMs to evaluate the association with female breast cancer (BC) risk. Methods: A multi case-control study was conducted in Spain from 2008 to 2013. We included 1003 incident BC cases (women 20–85 years old) recruited from 14 hospitals and 1458 population controls. Subjects were interviewed to ascertain residential histories and major recognized risk factors for BC. Mean residential levels of chloroform, brominated THMs (Br-THMs) and the sum of both as total THM (TTHMs) during the adult-lifetime were calculated. Results: Mean adult-lifetime residential levels ranged from 0.8 to 145.7 μg/L for TTHM (median = 30.8), from 0.2 to 62.4 μg/L for chloroform (median = 19.7) and from 0.3 to 126.0 μg/L for Br-THMs (median = 9.7). Adult-lifetime residential chloroform was associated with BC (adjusted OR = 1.47; 95%CI = 1.05, 2.06 for the highest (> 24 μg/L) vs. lowest ( 31 μg/L vs. 48 μg/L vs. < 22 μg/L). Conclusions: At common levels in Europe, long-term residential total THMs were not related to female breast cancer. A moderate association with chloroform was suggested at the highest exposure category. This large epidemiological study with extensive exposure assessment overcomes several limitations of previous studies but further studies are needed to confirm these results

Evaluating the association between artificial light-at-night exposure and breast and prostate cancer risk in Spain (MCC-Spain study).

BACKGROUND: Night shift work, exposure to light at night (ALAN) and circadian disruption may increase the risk of hormone-dependent cancers. OBJECTIVES: We evaluated the association of exposure to ALAN during sleeping time with breast and prostate cancer in a population based multicase-control study (MCC-Spain), among subjects who had never worked at night. We evaluated chronotype, a characteristic that may relate to adaptation to light at night. METHODS: We enrolled 1,219 breast cancer cases, 1,385 female controls, 623 prostate cancer cases, and 879 male controls from 11 Spanish regions in 2008-2013. Indoor ALAN information was obtained through questionnaires. Outdoor ALAN was analyzed using images from the International Space Station (ISS) available for Barcelona and Madrid for 2012-2013, including data of remotely sensed upward light intensity and blue light spectrum information for each geocoded longest residence of each MCC-Spain subject. RESULTS: Among Barcelona and Madrid participants with information on both indoor and outdoor ALAN, exposure to outdoor ALAN in the blue light spectrum was associated with breast cancer [adjusted odds ratio (OR) for highest vs. lowest tertile, OR=1.47; 95% CI: 1.00, 2.17] and prostate cancer (OR=2.05; 95% CI: 1.38, 3.03). In contrast, those exposed to the highest versus lowest intensity of outdoor ALAN were more likely to be controls than cases, particularly for prostate cancer. Compared with those who reported sleeping in total darkness, men who slept in "quite illuminated" bedrooms had a higher risk of prostate cancer (OR=2.79; 95% CI: 1.55, 5.04), whereas women had a slightly lower risk of breast cancer (OR=0.77; 95% CI: 0.39, 1.51). CONCLUSION: Both prostate and breast cancer were associated with high estimated exposure to outdoor ALAN in the blue-enriched light spectrum. https://doi.org/10.1289/EHP1837.The study was partially funded by the Accion Transversal del Cancer, approved by the Spanish Ministry Council on 11 October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PS09/00773-Cantabria, PS09/01286-León, PS09/01903-Valencia, PS09/02078-Huelva, PS09/01662-Granada, PI11/01889-FEDER, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI14/0613), by the Fundación Marqués de Valdecilla (API 10/09), by the ICGC International Cancer Genome Consortium CLL [the ICGC CLL-Genome Project is funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII) and Red Temática de Investigación del Cáncer (RTICC) del ISCIII (RD12/0036/0036)], by the Junta de Castilla y León (LE22A10-2), by the Consejería de Salud of the Junta de Andalucía (PI-0571-2009, PI-0306-2011, salud201200057018tra), by the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), by the Regional Government of the Basque Country, by the Consejería de Sanidad de la Región de Murcia, by the European Commission grants FOOD-CT-2006-036224-HIWATE, by the Spanish Association Against Cancer (AECC) Scientific Foundation, by the Catalan Government–Agency for Management of University and Research Grants (AGAUR) grants 2014SGR647 and 2014SGR850, by the Fundación Caja de Ahorros de Asturias, and by the University of Oviedo. ISGlobal is a member of the Centres de Recerca de Catalunya (CERCA) Programme, Generalitat de Catalunya. This research was also supported in part by the STARS4ALL project funded by the H2020-ICT-2015-688135 program of the European Union, the ORISON project funded by the H2020-INFRASUPP-2015-2 program of the European Union, and through the resources of researchers and collaborators of the Cities at Night project. J.G.-P. was funded by the Scientific Foundation of the Spanish Association against Cancer (Fundación Científica de la Asociación Española Contra el Cáncer (AECC), EVP-1178/14)

Colorectal Cancer and Long-Term Exposure to Trihalomethanes in Drinking Water: A Multicenter Case–Control Study in Spain and Italy

BACKGROUND: Evidence on the association between colorectal cancer and exposure to disinfection by-products in drinking water is inconsistent. OBJECTIVES: We assessed long-term exposure to trihalomethanes (THMs), the most prevalent group of chlorination by-products, to evaluate the association with colorectal cancer. METHODS: A multicenter case-control study was conducted in Spain and Italy in 2008-2013. Hospital-based incident cases and population-based (Spain) and hospital-based (Italy) controls were interviewed to ascertain residential histories, type of water consumed in each residence, frequency and duration of showering/bathing, and major recognized risk factors for colorectal cancer. We estimated adjusted odds ratios (OR) for colorectal cancer in association with quartiles of estimated average lifetime THM concentrations in each participant's residential tap water (micrograms/liter; from age 18 to 2 years before the interview) and estimated average lifetime THM ingestion from drinking residential tap water (micrograms/day). RESULTS: We analyzed 2,047 cases and 3,718 controls. Median values (ranges) for average lifetime residential tap water concentrations of total THMs, chloroform, and brominated THMs were 30 (0-174), 17 (0-63), and 9 (0-145) μg/L, respectively. Total THM concentration in residential tap water was not associated with colorectal cancer (OR = 0.92, 95% CI: 0.66, 1.28 for highest vs. lowest quartile), but chloroform concentrations were inversely associated (OR = 0.31, 95% CI: 0.24, 0.41 for highest vs. lowest quartile). Brominated THM concentrations showed a positive association among men in the highest versus the lowest quartile (OR = 1.43, 95% CI: 0.83, 2.46). Patterns of association were similar for estimated average THM ingestion through residential water consumption. CONCLUSIONS: We did not find clear evidence of an association between detailed estimates of lifetime total THM exposure and colorectal cancer in our large case-control study population. Negative associations with chloroform concentrations and ingestion suggest differences among specific THMs, but these findings should be confirmed in other study populations. Citation: Villanueva CM, Gracia-Lavedan E, Bosetti C, Righi E, Molina AJ, Martín V, Boldo E, Aragonés N, Perez-Gomez B, Pollan M, Gomez Acebo I, Altzibar JM, Jiménez Zabala A, Ardanaz E, Peiró R, Tardón A, Chirlaque MD, Tavani A, Polesel J, Serraino D, Pisa F, Castaño-Vinyals G, Espinosa A, Espejo-Herrera N, Palau M, Moreno V, La Vecchia C, Aggazzotti G, Nieuwenhuijsen MJ, Kogevinas M. 2017. Colorectal cancer and long-term exposure to trihalomethanes in drinking water: a multicenter case---control study in Spain and Italy. Environ Health Perspect 125:56-65; http://dx.doi.org/10.1289/EHP155.We appreciate the contribution of the institutions and local governments that provided data on municipal water in Spain, particularly to J. Lázaro Arias Paredes (Mancomunidad de Canales del Taibilla, Murcia, Spain). We also thank F. Gallino (IRCCS, Istituto Nazionale dei Tumori, Milan, Italy), A. Tonini and C. Dellanoce (Ospedale Niguarda Cà Granda, Milan, Italy) for their collaboration in conducting the study. We appreciate the contribution of G. Sesana and D. Ravetta of the regional Environmental Health Agency “Arpa Lombardia” and the contribution of E. Zamparo and F. del Bianco of the Health Authority n.5 “Friuli Occidentale” for providing data on DBPs (disinfection by-products) in Italian drinking water. We thank L. Font-Ribera and L.A. Salas for comments on the draft manuscript and X. Basagaña for the contribution to the statistical approach.S

Helicobacter pylori serological biomarkers of gastric cancer risk in the MCC-Spain case-control Study

BACKGROUND: Helicobacter pylori infection is one of the main risk factors for non-cardia gastric cancer. However, only a minority of infected persons develop the disease. This study aims at identifying H. pylori related serological biomarkers of risk for gastric cancer. METHODS: Incident gastric cancer cases and population controls (age, sex and region frequency-matched) from the MCC-Spain multicase-control Study were included. Seroreactivities against 16H. pylori proteins were determined using multiplex serology. Infection was defined as seropositivity against≥4 proteins. Relation of serological results to non-cardia and cardia gastric cancer was assessed using multivariable mixed logistic regression and principal components analysis. RESULTS: Seroprevalence was 88% among 2071 controls, 95% among 202 non-cardia gastric cancer cases (OR=1.9 (95% CI: 1.0-3.6)) and 85% among 62 cardia cancer cases (OR=0.5 (95% CI: 0.3-1.1)). In infected subjects, seropositivity for UreA, HP231, NapA and Cagδ was associated with lower non-cardia gastric cancer risk, while seropositivity for CagA and VacA was associated with higher risk. Seropositivity for CagA and seronegativity for Cagδ maintained the association after additional adjustment by serostatus of significant proteins. We identified two antibody reactivity patterns: the "virulent-pattern", related to a threefold higher risk of non-cardia gastric cancer and the "non-virulent pattern", related to a 60% decreased risk (4th vs. first quartile). CONCLUSIONS: In our population, people seropositive for H. pylori were characterized by two patterns of antibody reactivity against H. pylori proteins: 1) Combined high seroreactivity against several proteins, associated with a lower non-cardia gastric cancer risk, and 2) High seroreactivity against CagA and VacA, associated with an increased risk

Ingested Nitrate and Breast Cancer in the Spanish Multicase-Control Study on Cancer (MCC-Spain).

BACKGROUND: Ingested nitrate leads to endogenous formation of N-nitroso compounds that are breast carcinogens in animals, but human evidence is limited. OBJECTIVE: We evaluated ingested nitrate as a risk factor for breast cancer (BC) in a multicase-control study. METHODS: Hospital-based incident BC cases and population-based controls were recruited in eight Spanish regions in 2008-2013; participants provided residential and water consumption from 18 years of age and information on known BC risk factors. Long-term nitrate levels (1940-2010) were estimated and linked with residential histories and water consumption to calculate waterborne ingested nitrate (milligrams/day). Dietary ingested nitrate (milligrams/day) was calculated using food frequency questionnaires and published dietary nitrate contents. Interactions with endogenous nitrosation factors and other variables were evaluated. A total of 1,245 cases and 1,520 controls were included in the statistical analysis. RESULTS: Among the study regions, average ± SD waterborne ingested nitrate ranged from 2.9 ± 1.9 to 13.5 ± 7.5 mg/day, and dietary ingested nitrate ranged from 88.5 ± 48.7 to 154 ± 87.8 mg/day. Waterborne ingested nitrate was not associated with BC overall, but among postmenopausal women, those with both high nitrate (> 6 vs. < 2.6 mg/day) and high red meat intake (≥ 20 vs. < 20 g/day) were more likely to be cases than women with low nitrate and low red meat intake (adjusted odds ratio = 1.64; 95% confidence interval: 1.08, 2.49; overall interaction p-value = 0.17). No association was found with dietary nitrate. CONCLUSIONS: Waterborne ingested nitrate was associated with BC only among postmenopausal women with high red meat consumption. Dietary nitrate was not associated with BC regardless of the animal or vegetable source or of menopausal status.This study was funded by the “Acción Transversal del Cáncer del Consejo de Ministros del 11/10/2007” from the “Instituto de Salud Carlos III-FEDER” (PI08/1770, PI08/0533, PI11/00226), ISCIII FIS grants. N.E.H. received financial support for the Ph.D. program from the “Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR FI-DGR 2013) Generalitat de Cataluña.