A case-control study of breast cancer risk in nurses from Northeastern Ontario, Canada.

PURPOSE: Previously published findings have documented increased breast cancer risks associated with the nursing profession. The aim of the present study was to assess whether an increased risk of breast cancer was associated with nursing in a population-based case-control breast cancer study of women in Northeastern Ontario, Canada. METHODS: A total of 1519 women (1380 never-nurses: 716 controls and 664 cases; 139 ever-nurses: 59 controls and 80 cases) were included in the present study. Study participants filled out a detailed questionnaire which included a history of smoking, general health information, breast cancer risk factors, and a detailed occupational history. RESULTS: Ever-nurses were at higher, but nonsignificant risk of breast cancer compared to never-nurses (adjusted OR 1.39, 95 % CI 0.93-2.07). Ever-nurses who worked for longer than 10 years were at a significantly increased risk of breast cancer compared to never-nurses (adjusted OR 1.70, 95 % CI 1.04-2.79). A nonsignificant, but increased risk of breast cancer was observed in ever-nurses who worked full-time compared to never-nurses (OR 1.52, 95 % CI 0.92-2.52), while nurses who worked part-time, or both part-time and full-time were not at increased risk. Ever-nurses who worked in a hospital setting had a significantly increased risk of breast cancer (OR 1.65, 95 % CI 1.04-2.62) compared to never-nurses. CONCLUSIONS: The results indicate that the nurses in the present study population are at increased risk of breast cancer. A prolonged duration of nursing years and prolonged intensity (being a full-time nurse) are factors associated with this increased risk.

Single nucleotide polymorphisms in CHRNA5 rs16969968, CHRNA3 rs578776, and LOC123688 rs8034191 are associated with heaviness of smoking in women in Northeastern Ontario, Canada.

INTRODUCTION: The development of nicotine dependence (ND) is an important final step in the development of nicotine addiction, is associated with substantial morbidity and mortality, and makes long-term smoking cessation difficult. METHODS: We used questionnaire data and DNA from buccal swabs previously collected from a population-based case-control study in Northeastern Ontario, Canada; an area with high smoking and smoking-related disease rates. Women smokers were classified into heavy and light phenotypes, a proxy for ND, and we assessed the association between phenotype and single nucleotide polymorphisms (SNPs) that have been associated with increased or decreased risk of ND. RESULTS: Women with the variant AA genotype of CHRNA5 rs16969968 or variant CC genotype of LOC123688 rs8034191 were at significantly increased risk of heavy smoking, with age-adjusted odds ratios (ORs) of 3.2 (95% CI: 1.05-10.0) and 2.8 (95% CI: 1.00-7.91), respectively. Women with the variant AA genotype of CHRNA3 rs578775 were at significantly decreased risk of heavy smoking, with an age-adjusted OR of 0.3 (95% CI: 0.12-0.90). CONCLUSION: SNPs from 2 distinct variant groups were significantly associated with heaviness of smoking in this homogeneous population of women with high smoking rates, and this study supports the interpretation that there are different mechanisms of nicotine addiction involving both increasing and decreasing risk.

Nucleotide excision repair polymorphisms and survival outcome for patients with metastatic breast cancer.

PURPOSE: Inter-individual variations in treatment efficacy may be influenced by polymorphisms in DNA repair genes. We investigated the association of 3 functional polymorphisms in the nucleotide excision repair (NER) pathway with survival outcome of 95 patients with metastatic breast cancer (MBC) treated with DNA-damaging chemotherapy. METHODS: ERCC1 8092 C/A, ERCC2 Asp312Asn and ERCC2 Lys751Gln were determined using Taqman-based genotyping assays. Genotype associations with breast cancer-specific survival (BCSS) and progression-free survival (PFS) were evaluated using Kaplan-Meier estimates and hazard ratios calculated using Cox regression analysis. Tests for trend were conducted by calculating P-values for the HR coefficient in proportional hazards regression models. RESULTS: ERCC2 Lys751Gln was significantly associated with BCSS (median: 24.8 months for AA/AC combined and 14.2 months for CC, HR: 1.9 (95% CI 1.06-3.26)). Median BCSS decreased with increasing number of designated adverse genotypes for the 3 polymorphisms (P (trend) = 0.003). Risk estimates for PFS were nonsignificantly elevated and were significantly elevated for BCSS for patients with 2 (HR = 2.21, 95% CI: 1.04-4.72) or 3 (HR = 6.67, 95% CI: 2.19-20.29) adverse genotypes. In treatment subgroup analysis, risk estimates for BCSS were significantly elevated for patients with 3 adverse genotypes treated with cyclophosphamide, mitoxantrone and vinblastine (HR: 11.9, 95% CI 1.77-79.51) and P (trend) = 0.02 for increasing number of adverse genotypes. Risk of progression was significantly increased for patients with 1 adverse genotype treated with cyclophosphamide, mitoxantrone and carboplatin (HR: 3.5, 95% CI 1.19-10.6) and P (trend) = 0.02 for increasing number of adverse genotypes. CONCLUSION: Polymorphisms in NER pathway may impact survival outcome for patients with MBC following treatment with DNA-damaging chemotherapy. These results provide support for a polygenic pathway approach for assessing the prognostic and predictive potential of polymorphisms in treatment outcome.

Smoking (active and passive), N-acetyltransferase 2, and risk of breast cancer.

BACKGROUND: The relationship between smoking and breast cancer remains controversial. The study aim was to assess the relationship of passive and active smoking to breast cancer risk by N-acetyltransferase 2 (NAT2) phenotype, using a comprehensive assessment of both passive and active smoking. METHODS: We undertook a population-based case-control study in Northeastern Ontario, Canada of 347 women diagnosed (2002-2004) with breast cancer and 775 population-based controls. The mailed study package included a questionnaire requesting information about established breast cancer risk factors, passive and active smoking, and a buccal swab for genetic analyses. RESULTS: Among never-active smokers, a long duration of passive smoking was associated with an increased risk of breast cancer (odds ratio (OR) 1.86 (95% confidence interval (95% CI) 1.01-3.44) (test for trend (p=0.07)); that risk was more elevated for NAT2 slow acetylators (OR 2.76, 95% CI 1.16-6.59) (and highest in extremely slow acetylators), but not elevated for NAT2 fast acetylators (OR 1.17, 95% CI 0.42-3.23). Among active smokers more than 20 pack-years of smoking was associated with an OR of 1.34 (95% CI 0.92-1.96); more elevated among NAT2 fast acetylators OR 1.93 (95% CI 1.01-3.69) but not elevated among NAT2 slow acetylators. Women who were NAT2 fast acetylators in the highest quartile for duration of active smoking had an OR of 2.74 (95% CI 1.42-5.27), with a significant test of trend (p=0.005). CONCLUSIONS: These findings suggest that passive and active smoking may be related to breast cancer, and the effect may be differentially modified by NAT2 phenotype. Further research into the genetic modification of a breast cancer-smoking relationship may help to reconcile earlier discrepant findings.

Polymorphisms in manganese superoxide dismutase, myeloperoxidase and glutathione-S-transferase and survival after treatment for metastatic breast cancer.

Treatments for metastatic breast cancer (MBC) are primarily palliative with variable efficacy and outcomes may be influenced by individual differences in drug metabolism. In this study, we examined the association of single nucleotide polymorphisms (SNPs) in genes involved in drug metabolism with progression free survival (PFS) and breast cancer specific survival (BCSS) in 95 patients with MBC that received high dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT). SNPs in the SOD2 (SOD2-01, Val16Ala), MPO (MPO-02, -463 promoter variant) and GSTP1 [GSTP1-01 (Ile105Val), GSTP1-02 (Ala114Val)] genes were examined in DNA isolated from cryopreserved blood products using genotyping assays. Survival was analysed using Cox proportional hazard models and Kaplan-Meier estimates. Patients with the SOD2-01 (TT) genotype had increased risk of disease progression [hazard ratio (HR): 2.52; 95% confidence interval (CI), 1.31-4.85] and breast cancer specific death (HR: 1.92; 95% CI: 1.03-3.57). Risks were increased for patients with both SOD2-01 (TT) and GSTP1-01 (GG or AG) genotypes (HR for disease progression: 2.57, 95% CI: 1.32-5.00 and HR for breast cancer specific death: 2.27; 95% CI: 1.18-4.34). In multivariable analysis, the combined genotype group of SOD2-01 and GSTP1-01 was an independent predictor of PFS and BCSS. HRs progressively increased with increasing number of genotypes associated with worse survival, with p(trend) of 0.005 and 0.006 for PFS and BCSS, respectively. These results suggest that SNPs in genes involved in drug metabolism may influence survival outcome for patients with MBC receiving HDC and ASCT.

Cell adhesion and cancer: is there a potential for therapeutic intervention?

Carcinogenesis involves a disruption in adhesion molecule expression and tissue architecture, and tumour invasion requires adhesion-dependent migration into surrounding tissues. Therefore, a variety of peptide and antibody-based reagents that block integrins, cadherins, immunoglobulin superfamily and selectin adhesion molecules have been developed to treat cancers. Therapeutics directed at adhesion molecules can block interactions between tumour cells, endothelial cells and immune cells to prevent tumour cell invasiveness and metastasis. Blocking the adhesion molecules that facilitate the invasion of tumours by endothelial cells and immune cells can prevent tumour-associated angiogenesis and the recruitment of immune-mediated growth factors which are required for tumour growth and spread. In addition, targeted therapies using anticancer agents attached to antibodies or peptides directed as tumour-specific adhesion molecules are being developed.

Polymorphisms in XRCC1, XRCC3, and CCND1 and survival after treatment for metastatic breast cancer.

PURPOSE: Single nucleotide polymorphisms (SNPs) in DNA repair and cell cycle control genes may alter protein function and therefore the efficacy of DNA damaging chemotherapy. We retrospectively evaluated the association of SNPs in DNA repair genes, XRCC1-01 (Arg399Gln) and XRCC3-01 (Thr241Met), and a cell cycle control gene, CCND1-02 (A870G), with progression-free survival (PFS) and breast cancer specific survival (BCSS) in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: SNPs in 95 patients with MBC enrolled onto one of five prospective clinical trials of high-dose chemotherapy and autologous stem-cell transplantation were evaluated using genotyping assays. RESULTS: For XRCC1-01, the hazard ratio (HR) for BCSS was 2.8 (95% CI, 1.60 to 5.00) and the HR for PFS was 2.0 (95%CI, 1.12 to 3.43). For XRCC3-01, the HR for BCSS was 2.0 (95%CI, 1.12 to 3.70) and the HR for PFS was 2.0 (95%CI, 1.09 to 3.59). For CCND1-02, the HR for BCSS was 1.8 (95%CI, 1.12 to 2.78) and the HR for PFS was 1.8 (95%CI, 1.15 to 2.85). Patients carrying one variant genotype (HR, 1.7; 95%CI, 1.07 to 2.82) or combinations of any two variant genotypes (HR, 4.7; 95% CI, 2.41 to 8.94) had significantly poorer BCSS compared with patients carrying zero variants. In multivariable analysis, XRCC1-01, presence of liver metastases, and bone metastases independently predicted BCSS. Combinations of any two variant genotypes were stronger independent predictors of BCSS and PFS than the presence of liver or bone metastases. CONCLUSION: XRCC1-01, XRCC3-01, and CCND1-01 may be predictive of survival outcome in patients with MBC treated with DNA damaging chemotherapy.

Adhesion dependent signalling in the tumour microenvironment: the future of drug targetting.

Cellular adhesion molecules are critical components during carcinogenesis and cancer metastasis and contribute to the mechanisms underlying resistance to chemotherapeutic drugs. Since drug resistance is associated with a very poor prognosis for patients with cancer, a better understanding of the role of adhesion molecules could improve patient outcome by identifying novel mechanisms that promote drug resistance. Epigenetic factors, such as cellular adhesion, are shown to promote the resistance of cancers to various chemotherapeutic drugs by altering cellular signalling pathways that activate cellular growth and inhibit apoptosis. In addition, cellular adhesion molecules can provide a means to specifically target more conventional chemotherapy to the unique tumour microenvironment. However, the expression and function of cellular adhesion molecules, and the signals activated by adhesion, are highly interrelated making the development of rational therapies more difficult.