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Background: Accumulating evidence suggests that statins affect diseases other than cardiovascular disease, including cancer, and that these effects may depend on the lipid solubility of specific statins. Though many studies have reported an association between statin use and breast cancer incidence, the relationship between statin use and breast cancer recurrence has not been well studied., Methods: We conducted a nationwide, population-based prospective cohort study of all female residents in Denmark diagnosed with stage I-III invasive breast carcinoma who were reported to the Danish Breast Cancer Cooperative Group registry between 1996 and 2003 (n = 18,769). Women were followed for a median of 6.8 years after diagnosis. Prescriptions for lipophilic and hydrophilic statins were ascertained from the national electronic pharmacy database. Associations between statin prescriptions and breast cancer recurrence were estimated with generalized linear models and Cox proportional hazards regression with adjustment for age and menopausal status at diagnosis; histological grade; estrogen receptor status; receipt of adjuvant therapy; type of primary surgery received; pre-diagnosis hormone replacement therapy; and co-prescriptions of aspirin, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or anticoagulants. All statistical tests were two-sided., Results: Most prescriptions for lipophilic statins in the study population were for simvastatin. Exclusive simvastatin users experienced approximately 10 fewer breast cancer recurrences per 100 women after 10 years of follow-up (adjusted 10-year risk difference = -0.10, 95% confidence interval = -0.11 to -0.08), compared with women who were not prescribed a statin. Exclusive hydrophilic statin users had approximately the same risk of breast cancer recurrence as women not prescribed a statin over follow-up (adjusted 10-year risk difference = 0.05, 95% confidence interval = -0.01 to 0.11)., Conclusions: Simvastatin, a highly lipophilic statin, was associated with a reduced risk of breast cancer recurrence among Danish women diagnosed with stage I-III breast carcinoma, whereas no association between hydrophilic statin use and breast cancer recurrence was observed.

Background: Cytochrome P450 2D6 (CYP2D6) inhibition reduces the concentration of 4-hydroxylated tamoxifen metabolites, but the clinical relevance remains uncertain., Methods: We conducted a large case-control study nested in the population of 11 251 women aged 35-69 years at diagnosis of stage I-III breast cancer between 1985 and 2001 on Denmark's Jutland Peninsula and registered with the Danish Breast Cancer Cooperative Group. We identified 541 recurrent or contralateral breast cancers among women with estrogen receptor-positive (ER+) disease treated with tamoxifen for at least 1 year and 300 cancers in women with ER-negative (ER-) disease never treated with tamoxifen. We matched one control subject per case patient on ER status, menopausal status, stage, calendar time, and county, genotyped the CYP2D6*4 allele to assess genetic inhibition, and ascertained prescription history to assess drug-drug inhibition. We estimated the odds ratio (OR), associating CYP2D6 inhibition with breast cancer recurrence and adjusted for potential confounding with logistic regression. To address bias from incomplete information on CYP2D6 function, we used Monte Carlo simulation to complete a record-level probabilistic bias analysis. All statistical tests were two-sided., Results: The frequency of the CYP2D6*4 minor allele was 24% in case patients with ER+ tumors, 23% in case patients with ER- tumors, and 22% each in control subjects with ER+ and ER- tumors. In women with ER+ tumors, the associations of one functional allele with recurrence (OR = 0.99; 95% confidence interval = 0.76 to 1.3) and no functional allele with recurrence (OR = 1.4; 95% confidence interval = 0.84 to 2.3) were near null, as were those for women with ER- tumors. The near-null associations persisted when evaluated by intake of medications, by combining genotype with medication history, in the probabilistic bias analysis, or by restricting the analysis to women with ER expression confirmed by re-assay., Conclusion: The association between CYP2D6 inhibition and recurrence in tamoxifen-treated patients is likely null or small.

Purpose: We analyzed data from a case-control study to assess the association between lifetime tobacco smoke exposure and breast cancer incidence., Methods: Incident breast cancer cases were identified in the Massachusetts Cancer Registry and population controls were sampled from state Medicare lists and driver's license rosters. Demographic, lifestyle, medical history, reproductive history, and passive and active smoking exposure variables were assessed by telephone interview. We defined passive and active tobacco smoke exposure categories reflective of lifetime exposure patterns, and compared breast cancer risk among these groups while adjusting for age, body mass index, menopausal status, parity, alcohol consumption, and family history of breast cancer. We also adjusted passive smoking associations for active smoking status and vice versa., Results: We observed no association between ever being passively exposed to tobacco smoke and risk of incident breast cancer (adjusted OR: 1.2; 95% CI: 0.8, 1.8) nor between active smoking and breast cancer (adjusted OR for [23 pack-years compared to nonsmokers: 0.9; 95% CI: 0.7, 1.3). Null effects persisted in finer categorizations of active and passive exposure., Conclusions: We observed no causal associations between active or passive tobacco smoke exposures and incident breast cancer, consistent with results from most prospective cohort studies.

Background: Breast cancer survivors with higher numbers of comorbidities at the time of primary treatment suffer higher rates of all-cause mortality than comparatively healthier survivors. The effect of time-varying comorbidity status on mortality in breast cancer survivors, however, has not been well investigated., Objective: We examined longitudinal comorbidity in a cohort of women treated for primary breast cancer to determine whether accounting for comorbidities acquired after baseline assessment influenced the hazard ratio of all-cause mortality compared with an analysis using only baseline comorbidity., Methods: Cox proportional hazards adjusted for age, race/ethnicity, and exercise habits were modeled using (1) only a baseline Charlson index; (2) 4 Charlson index values collected longitudinally and entered as time-varying covariates, with missing values addressed by carrying forward the prior observation; and (3) the 4 longitudinal Charlson scores entered as time-varying covariates, with missing values multiply imputed., Results: The 3 modeling strategies yielded similar results; Model 1 HR: 1.4 per unit increase in Charlson index, 95% confidence interval (CI): 1.2-1.7; Model 2 HR: 1.3, 95% CI: 1.1-1.5; and Model 3 HR: 1.4, 95% CI: 1.2-1.6., Conclusions: Our findings indicate that a unit increase in the Charlson comorbidity index raises the hazard rate for all-cause mortality by approximately 1.4-fold in older women treated for primary breast cancer. The conclusion is essentially the same whether accounting only for baseline comorbidity or accounting for acquired comorbidity over a median follow-up period of 85 months.

Using hospital discharge data from the counties in Northern Denmark and the Danish Cancer Registry, we examined the trend in the prevalence of breast-conserving surgery (BCS) to treat primary breast cancer from 1982 through 2002, with an emphasis on publications that may have influenced surgical practice in Denmark. Overall, the prevalence of BCS increased from less than 1% of breast cancer operations in 1982 to approximately 25% by 2002. The rise in prevalence was most pronounced for the treatment of young women and women with early-stage breast cancer. Of three pivotal clinical trials, the most significant trigger of the upward trend appeared to be a study conducted by the Danish Breast Cancer Cooperative Group, published in 1988. After 1988, there was a steep rise in the prevalence of BCS. By 2002, BCS prevalence appeared to reach a threshold at 25% of breast cancer operations, seemingly defined by the proportion of new breast cancer cases who are good candidates for BCS.