Circulating inflammatory biomarkers, adipokines and breast cancer risk—a case-control study nested within the EPIC cohort

This work was funded by the French National Cancer Institute (grant number 2016-128) and the World Cancer Research Fund (grant number 2017/1614). Manon Cairat was supported by a PhD fellowship from la Ligue Nationale Contre le Cancer. The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition PotsdamRehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS) -Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology -ICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPICNorfolk; MR/M012190/1 to EPIC-Oxford). (United Kingdom). The funders were not involved in designing the study; collecting, analyzing or interpreting the data; or in writing or submitting the manuscript for publication.Background: Inflammation has been hypothesized to play a role in the development and progression of breast cancer and might differently impact breast cancer risk among pre and postmenopausal women. We performed a nested case-control study to examine whether pre-diagnostic circulating concentrations of adiponectin, leptin, c-reactive protein (CRP), tumour necrosis factor-α, interferon-γ and 6 interleukins were associated with breast cancer risk, overall and by menopausal status. Methods: Pre-diagnostic levels of inflammatory biomarkers were measured in plasma from 1558 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We used conditional logistic regression to estimate the odds ratios (ORs) of breast cancer at blood collection, per one standard deviation increase in biomarker concentration. Results: Cases were diagnosed at a mean age of 61.4 years on average 8.6 years after blood collection. No statistically significant association was observed between inflammatory markers and breast cancer risk overall. In premenopausal women, borderline significant inverse associations were observed for leptin, leptin-to-adiponectin ratio and CRP [OR= 0.89 (0.77–1.03), OR= 0.88 (0.76–1.01) and OR= 0.87 (0.75–1.01), respectively] while positive associations were observed among postmenopausal women [OR= 1.16 (1.05–1.29), OR= 1.11 (1.01–1.23), OR= 1.10 (0.99–1.22), respectively]. Adjustment for BMI strengthened the estimates in premenopausal women [leptin: OR = 0.83 (0.68– 1.00), leptin-to-adiponectin ratio: OR = 0.80 (0.66–0.97), CRP: OR = 0.85 (0.72–1.00)] but attenuated the estimates in postmenopausal women [leptin: OR = 1.09 (0.96–1.24), leptin-to-adiponectin ratio: OR = 1.02 (0.89–1.16), CRP: OR = 1.04 (0.92–1.16)]. Conclusions: Associations between CRP, leptin and leptin-to-adiponectin ratio with breast cancer risk may represent the dual effect of obesity by menopausal status although this deserves further investigation.Institut National du Cancer (INCA) France 2016-128World Cancer Research Fund International (WCRF) 2017/1614Ligue nationale contre le cancerWorld Health OrganizationNIHR Imperial Biomedical Research Centre (BRC)Danish Cancer SocietyLigue nationale contre le cancerInstitut Gustave RoussyMutuelle Generale de l'Education NationaleInstitut National de la Sante et de la Recherche Medicale (Inserm)Deutsche KrebshilfeHelmholtz AssociationFederal Ministry of Education & Research (BMBF)Fondazione AIRC per la ricerca sul cancroConsiglio Nazionale delle Ricerche (CNR)Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research FundsDutch Prevention FundsNetherlands Organization for Scientific Research (NWO)World Cancer Research Fund (WCRF), Statistics NetherlandsHealth Research Fund (FIS) -Instituto de Salud Carlos III (ISCIII)Catalan Institute of Oncology -ICO (Spain)Swedish Cancer SocietySwedish Research CouncilEuropean CommissionCounty Councils of SkaneVasterbotten (Sweden)Cancer Research UK 14136 C8221/A29017UK Research & Innovation (UKRI)Medical Research Council UK (MRC)European Commission 1000143 MR/M012190/

Circulating inflammatory biomarkers, adipokines and breast cancer risk—a case-control study nested within the EPIC cohort

Background Inflammation has been hypothesized to play a role in the development and progression of breast cancer and might differently impact breast cancer risk among pre and postmenopausal women. We performed a nested case-control study to examine whether pre-diagnostic circulating concentrations of adiponectin, leptin, c-reactive protein (CRP), tumour necrosis factor-alpha, interferon-gamma and 6 interleukins were associated with breast cancer risk, overall and by menopausal status. Methods Pre-diagnostic levels of inflammatory biomarkers were measured in plasma from 1558 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We used conditional logistic regression to estimate the odds ratios (ORs) of breast cancer at blood collection, per one standard deviation increase in biomarker concentration. Results Cases were diagnosed at a mean age of 61.4 years on average 8.6 years after blood collection. No statistically significant association was observed between inflammatory markers and breast cancer risk overall. In premenopausal women, borderline significant inverse associations were observed for leptin, leptin-to-adiponectin ratio and CRP [OR= 0.89 (0.77-1.03), OR= 0.88 (0.76-1.01) and OR= 0.87 (0.75-1.01), respectively] while positive associations were observed among postmenopausal women [OR= 1.16 (1.05-1.29), OR= 1.11 (1.01-1.23), OR= 1.10 (0.99-1.22), respectively]. Adjustment for BMI strengthened the estimates in premenopausal women [leptin: OR = 0.83 (0.68-1.00), leptin-to-adiponectin ratio: OR = 0.80 (0.66-0.97), CRP: OR = 0.85 (0.72-1.00)] but attenuated the estimates in postmenopausal women [leptin: OR = 1.09 (0.96-1.24), leptin-to-adiponectin ratio: OR = 1.02 (0.89-1.16), CRP: OR = 1.04 (0.92-1.16)]. Conclusions Associations between CRP, leptin and leptin-to-adiponectin ratio with breast cancer risk may represent the dual effect of obesity by menopausal status although this deserves further investigation

Inflammation and breast cancer risk in the EPIC cohort

Le cancer du sein pourrait être favorisé par l’inflammation chronique et par conséquent être prévenu par l’utilisation de médicaments agissant sur l’inflammation. L’objectif de ma thèse était de mieux comprendre le rôle de l’inflammation sur le développement du cancer du sein. J’ai d’abord évalué les associations entre onze biomarqueurs de l’inflammation (cytokines et adipokines) et le risque de cancer du sein chez environ 1600 paires cas-témoin de la cohorte EPIC. Le ratio leptine/adiponectine était associé à une diminution du risque de cancer du sein chez les femmes avant la ménopause alors que des niveaux élevés de TNF-α étaient associés à un risque accru de cancer du sein chez les femmes ménopausées. Ensuite, j’ai évalué les associations entre plusieurs médicaments anti-inflammatoires et antiagrégants plaquettaires et le risque de cancer du sein en utilisant des données auto-rapportées (cohorte EPIC) ou de remboursement de médicaments (cohorte E3N). Globalement, l’utilisation d’anti-inflammatoires non stéroïdiens n’était pas associée au risque de cancer du sein alors, alors qu’une durée d’utilisation longue d’aspirine, en tant qu’antiagrégant plaquettaire et donc à faible dose (≤325 mg), était associée à une diminution du risque de ce cancer. En revanche, un autre antiagrégant plaquettaire, le clopidogrel, était associé à une augmentation du risque de ce cancer, indépendamment de sa durée d’utilisation. L’utilisation de glucocorticoïdes était associée à une diminution du risque de cancer du sein infiltrants, dépendants aux œstrogènes et de stades 1 et 2 mais à une augmentation du risque de cancer in situ et de stades 3/4. Les résultats de cette thèse suggèrent que l’inflammation joue un rôle mineur dans le développement du cancer du sein. Cependant, elle pourrait être impliquée dans certains sous-groupes, et plus particulièrement chez les femmes ménopausées. Les effets des médicaments antiagrégants plaquettaires/anti-inflammatoires sur le risque de cancer du sein chez les femmes ménopausées semblent complexes et dépendre des sous-types et facteurs de risque de cancer du sein, de la durée d’utilisation ainsi que de l’utilisation d’autres médicamentsChronic inflammation might promote breast cancer development. Therefore, the possibility of stemming tumorigenic inflammatory effects with pharmacological compounds has drawn significant interest. The objective of my doctoral thesis was to better understand the role of inflammation on breast cancer development. First, I evaluated the associations of eleven inflammatory biomarkers (cytokines and adipokines) with breast cancer risk in about 1,600 case-control pairs from the EPIC cohort. The results suggested that a higher leptin-to-adiponectin ratio decreased the risk of peri/premenopausal breast cancer, while high levels of TNF-α increased postmenopausal breast cancer risk. Then, I evaluated the associations of several anti-inflammatory and antiplatelet drugs with breast cancer risk using self-reported (EPIC cohort) and drug reimbursement (E3N cohort) data. Nonsteroidal anti-inflammatory drugs were not associated with breast cancer risk. However, at antiplatelet dosage, a long duration of aspirin use was associated with a decreased risk of breast cancer. Another antiplatelet drug, clopidogrel, was associated with an increased breast cancer risk, regardless the duration of use. Glucocorticoid use was associated with a decreased risk of invasive breast cancer, that seemed restricted to oestrogen-dependant and stage 1 or 2 tumours and was associated with an increased risk of in situ and stage 3/4 breast cancers. The findings of this thesis suggest that inflammation plays a modest role in breast cancer development and that its impact on breast cancer could be limited to certain sub‐populations or certain breast cancer subtype

Inflammation et risque de cancer du sein dans la cohorte EPIC

Chronic inflammation might promote breast cancer development. Therefore, the possibility of stemming tumorigenic inflammatory effects with pharmacological compounds has drawn significant interest. The objective of my doctoral thesis was to better understand the role of inflammation on breast cancer development. First, I evaluated the associations of eleven inflammatory biomarkers (cytokines and adipokines) with breast cancer risk in about 1,600 case-control pairs from the EPIC cohort. The results suggested that a higher leptin-to-adiponectin ratio decreased the risk of peri/premenopausal breast cancer, while high levels of TNF-α increased postmenopausal breast cancer risk. Then, I evaluated the associations of several anti-inflammatory and antiplatelet drugs with breast cancer risk using self-reported (EPIC cohort) and drug reimbursement (E3N cohort) data. Nonsteroidal anti-inflammatory drugs were not associated with breast cancer risk. However, at antiplatelet dosage, a long duration of aspirin use was associated with a decreased risk of breast cancer. Another antiplatelet drug, clopidogrel, was associated with an increased breast cancer risk, regardless the duration of use. Glucocorticoid use was associated with a decreased risk of invasive breast cancer, that seemed restricted to oestrogen-dependant and stage 1 or 2 tumours and was associated with an increased risk of in situ and stage 3/4 breast cancers. The findings of this thesis suggest that inflammation plays a modest role in breast cancer development and that its impact on breast cancer could be limited to certain sub‐populations or certain breast cancer subtypesLe cancer du sein pourrait être favorisé par l’inflammation chronique et par conséquent être prévenu par l’utilisation de médicaments agissant sur l’inflammation. L’objectif de ma thèse était de mieux comprendre le rôle de l’inflammation sur le développement du cancer du sein. J’ai d’abord évalué les associations entre onze biomarqueurs de l’inflammation (cytokines et adipokines) et le risque de cancer du sein chez environ 1600 paires cas-témoin de la cohorte EPIC. Le ratio leptine/adiponectine était associé à une diminution du risque de cancer du sein chez les femmes avant la ménopause alors que des niveaux élevés de TNF-α étaient associés à un risque accru de cancer du sein chez les femmes ménopausées. Ensuite, j’ai évalué les associations entre plusieurs médicaments anti-inflammatoires et antiagrégants plaquettaires et le risque de cancer du sein en utilisant des données auto-rapportées (cohorte EPIC) ou de remboursement de médicaments (cohorte E3N). Globalement, l’utilisation d’anti-inflammatoires non stéroïdiens n’était pas associée au risque de cancer du sein alors, alors qu’une durée d’utilisation longue d’aspirine, en tant qu’antiagrégant plaquettaire et donc à faible dose (≤325 mg), était associée à une diminution du risque de ce cancer. En revanche, un autre antiagrégant plaquettaire, le clopidogrel, était associé à une augmentation du risque de ce cancer, indépendamment de sa durée d’utilisation. L’utilisation de glucocorticoïdes était associée à une diminution du risque de cancer du sein infiltrants, dépendants aux œstrogènes et de stades 1 et 2 mais à une augmentation du risque de cancer in situ et de stades 3/4. Les résultats de cette thèse suggèrent que l’inflammation joue un rôle mineur dans le développement du cancer du sein. Cependant, elle pourrait être impliquée dans certains sous-groupes, et plus particulièrement chez les femmes ménopausées. Les effets des médicaments antiagrégants plaquettaires/anti-inflammatoires sur le risque de cancer du sein chez les femmes ménopausées semblent complexes et dépendre des sous-types et facteurs de risque de cancer du sein, de la durée d’utilisation ainsi que de l’utilisation d’autres médicament

Use of menopausal hormone therapy and ovarian cancer risk in a French cohort study

International audienceAbstract Background Epidemiological studies have found that menopausal hormone therapy (MHT) use is associated with an increased ovarian cancer risk. However, whether different MHT types confer the same level of risk is unclear. We estimated the associations between different MHT types and the risk of ovarian cancer in a prospective cohort. Methods The study population included 75 606 postmenopausal women from the E3N cohort. Exposure to MHT was identified from self-reports in biennial questionnaires between 1992 and 2004 and from drug claim data matched to the cohort between 2004 and 2014. Hazard ratios and 95% confidence intervals (CIs) of ovarian cancer were estimated using multivariable Cox proportional hazards models with MHT as a time-varying exposure. Tests of statistical significance were 2-sided. Results Over an average 15.3 years follow-up, 416 ovarian cancers were diagnosed. Hazard ratios of ovarian cancer associated with ever use of estrogens combined with progesterone or dydrogesterone and ever use of estrogens combined with other progestagen were equal to 1.28 (95% CI = 1.04 to 1.57) and 0.81 (95% CI = 0.65 to 1.00), respectively (Phomogeneity = .003), compared with never use. The hazard ratio for unopposed estrogen use was 1.09 (95% CI = 0.82 to 1.46). We found no trend according to duration of use or time since last use except for estrogens combined with progesterone or dydrogesterone, which showed decreasing risk with increasing time since last use. Conclusion Different MHT types may impact ovarian cancer risk differentially. The possibility that MHT containing progestagens other than progesterone or dydrogesterone may confer some protection should be evaluated in other epidemiological studies

Use of nonsteroidal anti-inflammatory drugs and breast cancer risk in a prospective cohort of postmenopausal women

International audienceBackground: Although anti-inflammatory agents could theoretically have anticancer properties, results from cohort studies on nonsteroidal anti-inflammatory drugs (NSAIDs) and breast cancer (BC) risk are inconsistent. Methods: We investigated the association between NSAID use and BC incidence in the French E3N prospective cohort, which includes 98,995 women born between 1925 and 1950 and insured by a health insurance plan that covers mostly teachers. Self-reported information on lifestyle and medical history has been collected biennially by questionnaires and matched with data from a drug reimbursement database covering the period 2004–2014. Women who self-reported current NSAID use in the 2000 or 2002 questionnaires or with at least two reimbursements in any previous 3-month period were defined as exposed to NSAIDs. Multivariable Cox regression models were used to estimate hazard ratios (HRs) for the association of NSAID use with BC risk. Results: In the current analysis, 62,512 postmenopausal women were followed between 2004 and 2014 (9 years on average, starting at a mean age of 63 years; 2864 incident BC). In multivariable models, there was no statistically significant association between NSAID use and BC risk [HR = 1.00 (0.92–1.08), compared with non-exposed women]. The NSAID-BC associations did not differ by NSAID types, BC subtypes, risk factors, and comorbidities, nor by duration and dose of use. However, a statistically significant interaction was observed by proton pump inhibitor (PPI) drug use (Pinteraction = 0.01) whereby a decreased risk of BC with NSAID use was only observed among women who also used PPI before. Conclusion: Only women who used NSAIDs after having used PPI had a lower risk of BC. This result is novel and requires replication in other studies

Antiplatelet drug use and breast cancer risk in a prospective cohort of postmenopausal women

International audienceBackground: Epidemiologic evidence is insufficient to draw conclusions on the impact of low-dose aspirin use on breast cancer risk, and the potential impact of other antiplatelet drugs such as clopidogrel needs to be explored. Methods: We investigated the association between breast cancer risk and low-dose aspirin or clopidogrel use in the E3N cohort, which includes 98,995 women, with information on breast cancer risk factors collected from biennial questionnaires matched with drug reimbursement data available from 2004. Women with at least two reimbursements of the drug of interest in any previous 3-month period were considered "ever"exposed. Exposure was considered as time-varying and multivariable Cox regression models were used to estimate HRs of breast cancer. Results: Among 62,512 postmenopausal women followed during 9 years on average, 2,864 breast cancer cases were identified. Compared with never use, a transient higher breast cancer risk was observed during the third year of low-dose aspirin use [HR2-≤3 years of use = 1.49 (1.08.2.07)], followed by a lower risk [HR4+ years of use = 0.72 (0.52.0.99)]. Clopidogrel ever use was associated with a higher breast cancer risk [HR, 1.30 (1.02.1.68)], restricted to estrogen receptor negative (ER-) tumors [HRER+ = 1.14 (0.83.1.57), HRER- = 3.07 (1.64.5.76), Phomogeneity = 0.01]. Conclusions: Low-dose aspirin was associated with a lower breast cancer risk only after several years of use, while ever use of clopidogrel was associated with a higher ER- breast cancer risk. Impact: Antiplatelet drugs are not good pharmacologic candidates for breast cancer prevention

Mapping the European cancer prevention research landscape: a case for more prevention research funding

International audienceDespite the strong evidence of prevention as a prime defence against the disease, the majority of cancer research investment continues to be made in basic science and clinical translational research. Little quantitative data is available to guide decisions on the choice of research priorities or the allocation of research resources. The primary aim of the mapping of the European cancer prevention research landscape presented in this paper is to provide the evidence-base to inform future investments in cancer research. Using bibliometric data to identify funders that are active in prevention research in Europe and in the world, we have identified that 14% of cancer research papers had a focus on prevention research and those were funded by 16% of all the European cancer research funders. An important finding of our study is the lack of research on primary prevention with primary prevention funders accounting for 25% of European cancer prevention funders, meaning that less than 4% of all European cancer research funders identified show an interest in primary prevention. An additional analysis revealed that 7% of European cancer prevention research papers are categorised as implementation projects, meaning that only 1% of all cancer research publications are implementation research in cancer prevention. This paper highlights that the narrow focus on biology and treatment in Europe needs to be widened to include such areas as primary prevention and secondary prevention and a larger concentration on implementation research. These data can help support a more policy-focused cancer research agenda for individual European governments and charitable and philanthropic organisations and stimulate joining efforts across Europe to create a more systematic and structured approach to cancer prevention

Use of systemic glucocorticoids and risk of breast cancer in a prospective cohort of postmenopausal women

International audienceBackground: Glucocorticoids could theoretically decrease breast cancer risk through their anti-inflammatory effects or increase risk through immunosuppression. However, epidemiological evidence is limited regarding the associations between glucocorticoid use and breast cancer risk. Methods: We investigated the association between systemic glucocorticoid use and breast cancer incidence in the E3N cohort, which includes 98,995 women with information on various characteristics collected from repeated questionnaires complemented with drug reimbursement data available from 2004. Women with at least two reimbursements of systemic glucocorticoids in any previous 3-month period since January 1, 2004, were defined as exposed. We considered exposure as a time-varying parameter, and we used multivariable Cox regression models to estimate hazard ratios (HRs) of breast cancer. We performed a competing risk analysis using a cause-specific hazard approach to study the heterogeneity by tumour subtype/stage/grade. Results: Among 62,512 postmenopausal women (median age at inclusion of 63 years old), 2864 developed breast cancer during a median follow-up of 9 years (between years 2004 and 2014). Compared with non-exposure, glucocorticoid exposure was not associated with overall breast cancer risk [HR = 0.94 (0.85-1.05)]; however, it was associated with a higher risk of in situ breast cancer and a lower risk of invasive breast cancer [HR insitu = 1.34 (1.01-1.78); HR invasive = 0.86 (0.76-0.97); P homogeneity = 0.01]. Regarding the risk of invasive breast cancer, glucocorticoid exposure was inversely associated with oestrogen receptor (ER)-positive breast cancer [HR ER+ = 0.82 (0.72-0.94); HR ER− = 1.21 (0.88-1.66); P homogeneity = 0.03]; it was also inversely associated with the risk of stage 1 or stage 2 tumours but positively associated with the risk of stage 3/4 breast cancers [HR stage1 = 0.87 (0.75-1.01); HR stage2 = 0.67 (0.52-0.86); HR stage3/4 = 1.49 (1.02-2.20); P homogeneity = 0.01]. Conclusion: This study suggests that the association between systemic glucocorticoid use and breast cancer risk may differ by tumour subtype and stage