Outcome of primary mediastinal large B-cell lymphoma using R-CHOP: impact of a PET-adapted approach.

Cure rates for primary mediastinal large B-cell lymphoma (PMBCL) have improved with the integration of rituximab. However, the type of primary therapy and role of radiotherapy (RT) remains ill-defined. Herein, we evaluated the outcome of PMBCL primarily treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and the impact of an end-of-treatment (EOT) 18F-fluorodeoxyglucose positron emission tomography (PET) scan to guide consolidative RT. Patients ≥18 years of age with PMBCL treated with curative intent rituximab-chemotherapy were identified. Prior to 2005, patients were recommended to receive R-CHOP + RT (RT era). Beginning in 2005, EOT PET was used to guide RT and only those with a PET-positive scan received RT (PET era). In total, 159 patients were identified, 94% were treated with R-CHOP and 44% received RT (78% in RT era, 28% in PET era). The 5-year time to progression (TTP) and overall survival (OS) for the entire cohort were 80% and 89%, respectively, similar across treatment eras. Overall, 10% had refractory disease. In total, 113 patients had an EOT PET scan: 63% negative and 37% positive with a 5-year TTP of 90% vs 71% and 5-year OS of 97% vs 88%, respectively. For those with Deauville (D)-scored PET scans (n = 103), the 5-year TTP for PET-negative cases by Deauville criteria (D1-D3, DX) was 91%, with inferior outcomes for D5 vs D4 (5-year TTP 33% vs 87%, P = .0002). Outcomes for PMBCL treated with RCHOP are favorable and use of a PET-adapted approach reduces RT in the majority of patients. A small proportion have refractory disease and may benefit from an alternate treatment.

Validation of a simplified international prognostic score (IPS-3) in patients with advanced-stage classic Hodgkin lymphoma.

A novel prognostic score (IPS-3), comprised of only three of the seven IPS-7 indicators (age ≥45, stage IV, haemoglobin <105 g/l), was recently proposed as a simplified model for advanced-stage classic Hodgkin lymphoma (cHL). We aimed to validate this model in advanced-stage cHL patients treated with doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) in British Columbia. The estimated five-year freedom from progression (FFP) for scores of 0, 1, 2 and 3 were very similar to the original report at 84%, 76%, 72% and 68% respectively. The IPS-3 score is highly reproducible in this independent dataset and its simplicity makes it appealing for everyday clinical practice.

Women's occupational exposure to polycyclic aromatic hydrocarbons and risk of breast cancer.

OBJECTIVE: To estimate the association between occupational polycyclic aromatic hydrocarbon (PAH) exposure and female breast cancer. METHODS: Lifetime work histories for 1130 cases and 1169 controls from British Columbia and Ontario (Canada) were assessed for PAH exposure using a job-exposure matrix based on compliance measurements obtained during US Occupational Safety and Health Administration workplace safety inspections. RESULTS: Exposure to any level of PAHs was associated with an increased risk of breast cancer (OR=1.32, 95% CI: 1.10 to 1.59), as was duration at high PAH exposure (for >7.4 years: OR=1.45, 95% CI: 1.10 to 1.91; ptrend=0.01), compared with women who were never exposed. Increased risk of breast cancer was most strongly associated with prolonged duration at high occupational PAH exposure among women with a family history of breast cancer (for >7.4 years: OR=2.79, 95% CI: 1.25 to 6.24; ptrend<0.01). CONCLUSIONS: Our study suggests that prolonged occupational exposure to PAH may increase breast cancer risk, especially among women with a family history of breast cancer.

Sedentary work and the risk of breast cancer in premenopausal and postmenopausal women: a pooled analysis of two case-control studies.

OBJECTIVES: There is limited research on the association between sedentary behaviour and breast cancer risk, particularly whether sedentary behaviour is differentially associated with premenopausal and postmenopausal breast cancer. We pooled data from 2 case-control studies from Australia and Canada to investigate this association. METHODS: This pooled analysis included 1762 incident breast cancer cases and 2532 controls. Participants in both studies completed a lifetime occupational history and self-rated occupational physical activity level. A job-exposure matrix (JEM) was also applied to job titles to assess sedentary work. Logistic regression analyses (6 pooled and 12 study-specific) were conducted to estimate associations between both self-reported and JEM-assessed sedentary work and breast cancer risk among premenopausal and postmenopausal women. RESULTS: No association was observed in the 6 pooled analyses, and 10 of the study-specific analyses also showed null results. 2 study-specific analyses provided inconsistent and contradictory results, with 1 showing statistically significant increased risk of breast cancer for self-reported sedentary work among premenopausal women cancer in the Canadian study, and the other a non-significant inverse association between JEM-assessed sedentary work and breast cancer risk among postmenopausal women in the Australian study. CONCLUSIONS: While a suggestion of increased risk was seen for premenopausal women in the Canadian study when using the self-reported measure, overall this pooled study does not provide evidence that sedentary work is associated with breast cancer risk.

Statistical Modeling of Occupational Exposure to Polycyclic Aromatic Hydrocarbons Using OSHA Data.

Polycyclic aromatic hydrocarbons (PAHs) are a group of pollutants with multiple variants classified as carcinogenic. The Occupational Safety and Health Administration (OSHA) provided access to two PAH exposure databanks of United States workplace compliance testing data collected between 1979 and 2010. Mixed-effects logistic models were used to predict the exceedance fraction (EF), i.e., the probability of exceeding OSHA's Permissible Exposure Limit (PEL = 0.2 mg/m3) for PAHs based on industry and occupation. Measurements of coal tar pitch volatiles were used as a surrogate for PAHs. Time, databank, occupation, and industry were included as fixed-effects while an identifier for the compliance inspection number was included as a random effect. Analyses involved 2,509 full-shift personal measurements. Results showed that the majority of industries had an estimated EF < 0.5, although several industries, including Standardized Industry Classification codes 1623 (Water, Sewer, Pipeline, and Communication and Powerline Construction), 1711 (Plumbing, Heating, and Air-Conditioning), 2824 (Manmade Organic Fibres), 3496 (Misc. Fabricated Wire products), and 5812 (Eating Places), and Major group's 13 (Oil and Gas Extraction) and 30 (Rubber and Miscellaneous Plastic Products), were estimated to have more than an 80% likelihood of exceeding the PEL. There was an inverse temporal trend of exceeding the PEL, with lower risk in most recent years, albeit not statistically significant. Similar results were shown when incorporating occupation, but varied depending on the occupation as the majority of industries predicted at the administrative level, e.g., managers, had an estimated EF < 0.5 while at the minimally skilled/laborer level there was a substantial increase in the estimated EF. These statistical models allow the prediction of PAH exposure risk through individual occupational histories and will be used to create a job-exposure matrix for use in a population-based case-control study exploring PAH exposure and breast cancer risk.

Beyond crosswalks: reliability of exposure assessment following automated coding of free-text job descriptions for occupational epidemiology.

Epidemiologists typically collect narrative descriptions of occupational histories because these are less prone than self-reported exposures to recall bias of exposure to a specific hazard. However, the task of coding these narratives can be daunting and prohibitively time-consuming in some settings. The aim of this manuscript is to evaluate the performance of a computer algorithm to translate the narrative description of occupational codes into standard classification of jobs (2010 Standard Occupational Classification) in an epidemiological context. The fundamental question we address is whether exposure assignment resulting from manual (presumed gold standard) coding of the narratives is materially different from that arising from the application of automated coding. We pursued our work through three motivating examples: assessment of physical demands in Women's Health Initiative observational study, evaluation of predictors of exposure to coal tar pitch volatiles in the US Occupational Safety and Health Administration's (OSHA) Integrated Management Information System, and assessment of exposure to agents known to cause occupational asthma in a pregnancy cohort. In these diverse settings, we demonstrate that automated coding of occupations results in assignment of exposures that are in reasonable agreement with results that can be obtained through manual coding. The correlation between physical demand scores based on manual and automated job classification schemes was reasonable (r = 0.5). The agreement between predictive probability of exceeding the OSHA's permissible exposure level for polycyclic aromatic hydrocarbons, using coal tar pitch volatiles as a surrogate, based on manual and automated coding of jobs was modest (Kendall rank correlation = 0.29). In the case of binary assignment of exposure to asthmagens, we observed that fair to excellent agreement in classifications can be reached, depending on presence of ambiguity in assigned job classification (κ = 0.5-0.8). Thus, the success of automated coding appears to depend on the setting and type of exposure that is being assessed. Our overall recommendation is that automated translation of short narrative descriptions of jobs for exposure assessment is feasible in some settings and essential for large cohorts, especially if combined with manual coding to both assess reliability of coding and to further refine the coding algorithm.

Interactions between exposure to polycyclic aromatic hydrocarbons and xenobiotic metabolism genes, and risk of breast cancer.

PURPOSE: Polycyclic aromatic hydrocarbons (PAHs) are a group of environmental pollutants associated with multiple cancers, including female breast cancer. Several xenobiotic metabolism genes (XMGs), including the CYP450 family, play an important role in activating and detoxifying PAHs, and variations in the activity of the enzymes they encode can impact this process. This study aims to examine the association between XMGs and breast cancer, and to assess whether these variants modify the effects of PAH exposure on breast cancer risk. METHODS: In a case-control study in Vancouver, British Columbia, and Kingston, Ontario, 1037 breast cancer cases and 1046 controls had DNA extracted from blood or saliva and genotyped for 138 single nucleotide polymorphisms (SNPs) and tagSNPs in 27 candidate XMGs. Occupational PAH exposure was assessed using a measurement-based job-exposure matrix. RESULTS: An association between genetic variants and breast cancer was observed among six XMGs, including increased risk among the minor allele carriers of AKR1C3 variant rs12387 (OR 2.71, 95% CI 1.42-5.19) and AKR1C4 variant rs381267 (OR 2.50, 95% CI 1.23-5.07). Heterogeneous effects of occupational PAH exposure were observed among carriers of AKR1C3/4 variants, as well as the PTGS2 variant rs5275. CONCLUSION: Our findings support an association between SNPs of XMGs and female breast cancer, including novel genetic variants that modify the toxicity of PAH exposure. These results highlight the interplay between genetic and environmental factors, which can be helpful in understanding the modifiable risks of breast cancer and its complex etiology.

Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women.

Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values < 5 × 10-8 as genome-wide significant, and p-values < 1 × 10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants. None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values < 1 × 105. The strongest evidence was found for rs4674019 (p-value = 2.27 × 10-7), which showed genome-wide significant interaction (p-value = 3.8 × 10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT-breast cancer risk association.

Genetic variants in genes related to inflammation, apoptosis and autophagy in breast cancer risk.

BACKGROUND: Inflammation contributes to breast cancer development through its effects on cell damage. This damage is usually dealt with by key genes involved in apoptosis and autophagy pathways. METHODS: We tested 206 single nucleotide polymorphisms (SNPs) in 54 genes related to inflammation, apoptosis and autophagy in a population-based breast cancer study of women of European (658 cases and 795 controls) and East Asian (262 cases and 127 controls) descent. Logistic regression was used to estimate odds ratios for breast cancer risk, and case-only analysis to compare breast cancer subtypes (defined by ER/PR/HER2 status), with adjustment for confounders. We assessed statistical interactions between the SNPs and lifestyle factors (smoking status, physical activity and body mass index). RESULTS AND CONCLUSION: Although no SNP was associated with breast cancer risk among women of European descent, we found evidence for an association among East Asians for rs1800925 (IL-13) and breast cancer risk (OR = 2.08; 95% CI: 1.32-3.28; p = 0.000779), which remained statistically significant after multiple testing correction (padj = 0.0350). This association was replicated in a meta-analysis of 4305 cases and 4194 controls in the Shanghai Breast Cancer Genetics Study (OR 1.12, 95% CI: 1.03-1.21, p = 0.011). Further, we found evidence of an interaction between rs7874234 (TSC1) and physical activity among women of East Asian descent.