Monika Izano

Chronic inflammation and risk of colorectal and other obesity‐related cancers: The health, aging and body composition study

Evidence of the association between chronic inflammation and the risk of colorectal cancer (CRC) and other obesity‐related cancers (OBRC) remains inconsistent, possibly due to a paucity of studies examining repeated measures of inflammation. In the Health ABC prospective study of 2,490 adults aged 70–79 years at baseline, we assessed whether circulating levels of three markers of systemic inflammation, IL‐6, CRP and TNF‐α, were associated with the risk of CRC and OBRC, a cluster including cancers of pancreas, prostate, breast and endometrium. Inflammatory markers were measured in stored fasting blood samples. While only baseline measures of TNF‐α were available, IL‐6 and CRP were additionally measured at Years 2, 4, 6 and 8. Multivariable Cox models were fit to determine whether tertiles and log‐transformed baseline, updated and averaged measures of CRP and IL‐6 and baseline measures of TNF‐α were associated with the risk of incident cancer(s). During a median follow‐up of 11.9 years, we observed 55 and 172 cases of CRC and OBRC, respectively. The hazard of CRC in the highest tertile of updated CRP was more than double that in the lowest tertile (HR = 2.29; 95% CI: 1.08–4.86). No significant associations were seen between colorectal cancer and IL‐6 or TNF‐α. Additionally, no significant associations were found between obesity‐related cancers and the three inflammatory markers overall, but we observed a suggestion of effect modification by BMI and NSAID use. In summary, in this population, higher CRP levels were associated with increased risk of CRC, but not of OBRC. The findings provide new evidence that chronically elevated levels of CRP, as reflected by repeated measures of this marker, may play a role in colorectal carcinogenesis in older adults.

Smoking and mortality after breast cancer diagnosis: the health and functioning in women study.

We examined the effect of smoking on long‐term mortality from breast cancer and other causes among a cohort of women with breast cancer. A total of 975 women diagnosed with breast cancer and aged 40–84 years were followed for a median follow‐up of 11 years in the U.S. Health and Functioning in Women (HFW) study. The impact of the individual smoking status and smoking intensity reported in the first few months following breast cancer diagnosis on the risk of mortality from breast cancer and other causes was examined using Cox proportional hazards models. In this study, former smoking was associated with increased risk of other‐cause mortality (hazard ratio [HR] = 1.47, 95% confidence interval [CI]: 1.13–1.90), and the risk doubled with increased intensity (HR for <50 pack‐years [py]: 1.36, 95% CI: 1.03–1.79; HR for ≥50 py: 2.45, 95% CI: 1.41–4.23). Current smoking (HR = 2.45, 95% CI: 1.81–3.32) and each additional 10 py smoked (HR = 1.16, 95% CI: 1.11–1.22) were associated with statistically significant increases in the risk of other‐cause mortality. The effect of current smoking on other‐cause mortality decreased with advancing stage and increasing body mass index (BMI). Breast cancer‐specific mortality was associated with current smoking of ≥50 py (HR = 2.36, 95% CI: 1.26–4.44), and each additional 10 py smoked (HR = 1.07, 95% CI: 1.01–1. 14). Current smoking, but not former smoking, was associated with increased risk of breast cancer‐specific mortality in women with local disease (HR = 2.32, 95% CI: 1.32–4.09), but not in those with regional and distant disease (HR = 1.10, 95% CI: 0.73–1.68). Our findings suggest that current smoking at the time of breast cancer diagnosis may be associated with increased risk of breast‐cancer specific and other‐cause mortality, whereas former smoking is associated with increased risk of other‐cause mortality. Smoking cessation at the time of diagnosis may lead to better prognosis among women with breast cancer.

Long-term outcomes among African-American and white women with breast cancer: What is the impact of comorbidity?

OBJECTIVES We examined the association between comorbidity and long-term mortality from breast cancer and other causes among African-American and white women with breast cancer. METHODS A total of 170 African-American and 829 white women aged 40-84years were followed for up to 28years with median follow-up of 11.3years in the Health and Functioning in Women (HFW) study. The impact of the Charlson Comorbidity Score (CCS) in the first few months following breast cancer diagnosis on the risk of mortality from breast cancer and other causes was examined using extended Cox models. RESULTS Median follow-up was significantly shorter for African-American women than their white counterparts (median 8.5years vs. 12.3years). Compared to white women, African-American women had significantly fewer years of education, greater body mass index, were more likely to have functional limitations and later stage at breast cancer diagnosis, and fewer had adequate financial resources (all P<0.05). Proportionately more African-American women died of breast cancer than white women (37.1% vs. 31.4%, P=0.15). A positive and statistically significant time-varying effect of the Charlson Comorbidity Score (CCS) on other-cause mortality persisted throughout the first 5years of follow-up (P<0.001) but not for its remainder. CONCLUSIONS Higher CCS was associated with increased risk of other-cause mortality, but not breast cancer specific mortality; the association did not differ among African-American and white women.

Benefits and Harms of Screening Mammography by Comorbidity and Age: A Qualitative Synthesis of Observational Studies and Decision Analyses

ObjectiveWe conducted a systematic review to assess the quality and limitations of published studies examining benefits and harms of screening mammography in relation to comorbidity and age.MethodsWe searched MEDLINE and EMBASE from January 1980 through June 2013 for studies that examined benefits or harms of screening mammography in women aged 65 years or older in relation to comorbidity. For each study, we extracted data regarding setting, design, quality, screening schedule, measure of comorbidity, and estimates of benefits and/or harms. We reviewed 1760 titles, identifying 7 articles that met the inclusion criteria: prospective cohort (two studies), retrospective cohort (two studies), and decision analyses (three studies). No randomized controlled trials were identified.ResultsAt least one measure of life expectancy or reduction in the risk of breast cancer death as a marker of benefit was examined in four studies, whereas three studies addressed the harms of screening mammography, including false-positive results. Both cohort studies and decision analyses showed that screening benefits decreased with increasing age and comorbidity burden.ConclusionsThe limited evidence currently available suggests that, apart from older women with severe comorbidity, women 65 and older may experience improvements in life expectancy from screening. Given the potential for harm, it is unclear whether the magnitude of the benefit is sufficient to warrant regular screening. Women, clinicians and policymakers should consider these factors in deciding whether continue screening.

The impact of functional limitations on long-term outcomes among African-American and white women with breast cancer: a cohort study

Objectives We examined the impact of functional limitations and functional decline during the first year following breast cancer diagnosis on the risk of mortality from breast cancer and other causes among African-American and white women, respectively. Design The Health and Functioning in Women (HFW) cohort study. Setting Detroit, Michigan, USA. Participants A total of 162 African-American and 813 white women aged 40–84 years with newly diagnosed breast cancer identified through the Metropolitan Detroit Cancer Surveillance System over a 7-month period between 1984 and 1985 and followed for up to 28 years (median 11 years). Outcome measures Risk of mortality from breast cancer and other causes. Results Statistically significant increases in the risk of other-cause mortality were found for each unit increase in the number of self-reported functional limitations (HR=1.08, 95% CI 1.03 to 1.14), 0 vs ≥1 functional limitations (HR=1.47, 95% CI 1.13 to 1.91), difficulty in pushing or pulling large objects (HR=1.34, 95% CI 1.04 to 1.73), writing or handling small objects (HR=1.56, 95% CI 1.00 to 2.44), and walking half a mile (HR=1.60, 95% CI 1.19 to 2.14). Functional limitations and functional decline did not explain racial disparities in the survival of this cohort. Functional decline was associated with increased risk of other-cause mortality in women with regional and remote disease but not in women with localised disease. Whereas measures of functional limitation were not associated with breast cancer-specific mortality, each unit of functional decline (HR=1.17, 95% CI 1.05 to 1.31) and decline in the ability to sit ≥1 h (HR=2.06, 95% CI 1.13 to 3.76) were associated with increased risk of breast cancer-specific mortality. Measures of functional decline were associated with increased risk of breast cancer mortality in overweight and obese women, but not in women of normal weight. Conclusions Whereas functional limitations were associated with increased risk of other-cause mortality, functional decline was associated with increased risk of breast cancer mortality.

The Healthy Worker Survivor Effect: Target Parameters and Target Populations

Purpose of ReviewWe offer an in-depth discussion of the time-varying confounding and selection bias mechanisms that give rise to the healthy worker survivor effect (HWSE).Recent FindingsIn this update of an earlier review, we distinguish between the mechanisms collectively known as the HWSE and the statistical bias that can result. This discussion highlights the importance of identifying both the target parameter and the target population for any research question in occupational epidemiology. Target parameters can correspond to hypothetical workplace interventions; we explore whether these target parameters’ true values reflect the etiologic effect of an exposure on an outcome or the potential impact of enforcing an exposure limit in a more realistic setting. If a cohort includes workers hired before the start of follow-up, HWSE mechanisms can limit the transportability of the estimates to other target populations.SummaryWe summarize recent publications that applied g-methods to control for the HWSE, focusing on their target parameters, target populations, and hypothetical interventions.

Chronic inflammation and risk of lung cancer in older adults in the health, aging and body composition cohort study

OBJECTIVES We examined the association between three inflammatory markers (Interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) and incident lung cancer using baseline, updated, and averaged inflammatory measures in older adults. METHODS We fitted multivariable Cox models to assess whether circulating levels of inflammation markers were associated with incident lung cancers in the Health Aging, Body and Composition (HealthABC) prospective cohort of 3075 older adults aged 70-79 years at baseline. IL-6 and CRP were measured biennially, whereas TNF-α was measured at baseline. RESULTS Baseline levels of IL-6 were significantly associated with incident lung cancer risk in a model that adjusted for age, gender, race, and site (Model 1) (Hazard RatioT3 vs. T1: 3.34, 95% Confidence Interval: 1.91, 5.85) and in a model adjusted for health factors linked to chronic inflammation (Model 2) (HR T3 vs. T1: 2.57, 95% CI: 1.41, 4.65). The associations observed in time-updated IL-6 (HR T3 vs. T1: 2.47, 95% CI: 1.43, 4.28), cumulatively averaged IL-6 (HR T3 vs. T1: 2.47, 95% CI: 1.43, 4.35), and baseline CRP levels (HR T3 vs. T1: 1.85, 95% CI: 1.11, 3.08) with incident lung cancer in Model 1 were not statistically significant in Model 2. CONCLUSIONS Baseline CRP and IL-6 levels were associated with increased risk of lung cancer in Model 1 and both models, respectively. Chronic IL-6 inflammation, as quantified by repeated measures was associated with incident lung cancer in Model 1, but not Model 2. Further research is needed to understand the role of CRP and IL-6 in lung carcinogenesis.

The association of early life socioeconomic position on breast cancer incidence and mortality: a systematic review

ObjectivesWe conducted a systematic review of the literature relating early life socioeconomic position (SEP) to breast cancer incidence and mortality from a critical period and life-course trajectory perspective.MethodsPubMed, EMBASE and Web of Science were searched to identify cohort studies that evaluated the impact of early life SEP indicators on the incidence and/or mortality from breast cancer in adulthood.ResultsNine distinct studies evaluated the relationship between early life SEP and breast cancer between 1990 and 2016. Five reports assessed breast cancer incidence and five assessed breast cancer mortality as outcomes; one study assessed both incidence and mortality. While lower early life SEP was associated with reduced breast cancer incidence and increased breast cancer mortality in the US, studies conducted in Europe were unable to establish a consistent association.ConclusionsWe found moderate support for the association between early life SEP and incidence and mortality from breast cancer. The impact of early life SEP on breast cancer incidence and mortality appeared to vary between countries. We urge further investigation of the role of lifelong SEP trajectories in breast cancer outcomes.

O26-1 An analytical approach for the estimation of causal effects of occupational exposures in left censored cohorts

Metalworking fluids (MWFs) – complex mixtures of mineral oils, PAHs, and chemical additives widely used to cool and lubricate metal machining operations – have been linked to a number of cancers. With an estimated 4.4 million U.S. workers exposed to MWFs in 1997, and millions more worldwide, MWF exposure poses a major potential cancer hazard. The United Autoworkers-General Motors (UAW-GM) mortality study of 46,000 workers in the automotive manufacturing industry, followed from 1941 to 2009, provides a unique opportunity to examine the causal relationship between quantitative exposure metrics for MFWs and incident cancers. Cancer incidence follow-up in the UAW-GM cohort starts when the Michigan Cancer Registry was established in 1985, up to decades after all workers were hired. Since only workers still alive in 1985 are eligible for incidence follow-up, the sub-cohort may be a biassed sample of the full cohort. Because we have data on all subjects in the mortality, the UAW-GM study offers an opportunity to address the potential bias in the left-censored cancer incidence sub-cohort. We establish an analytical framework for the estimation of effects of MFW exposure on incident cancers, under specific assumptions. First, we show in a simulation study that analyses based on left censored subgroups tend to be biassed and that the bias may increase when aspects of the healthy worker survivor effect (HWSE), such as heterogeneous susceptibility and time-varying confounding, are present. Next, we apply an estimation approach designed to reduce left-censoring bias and report its performance in the presence of the HWSE. We conclude with a roadmap for the application of the procedure in the UAW-GM cohort to estimate the causal effects of MWF on incident cancers, under dynamic interventions that satisfy the experimental treatment assignment assumption.