Thomas P. Ahern

Statin Prescriptions and Breast Cancer Recurrence Risk: A Danish Nationwide Prospective Cohort Study

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.

CYP2D6 Inhibition and Breast Cancer Recurrence in a Population-Based Study in Denmark

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 Denmarks 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.

Breast cancer recurrence risk related to concurrent use of SSRI antidepressants and tamoxifen

Abstract Background. Up to one-quarter of breast cancer patients suffer clinically significant depression in the year after diagnosis, which may respond to intervention. About half may be prescribed a psychotropic medication, such as a selective serotonin reuptake inhibitor (SSRI), while completing breast cancer therapy. Cytochrome P-450 2D6 (CYP2D6) metabolizes SSRIs and also metabolizes tamoxifen to more active forms. Therefore, concurrent use of SSRIs may reduce tamoxifen’s effectiveness at preventing breast cancer recurrence. The SSRI citalopram has limited potency to inhibit CYP2D6 activity, so has been recommended for breast cancer patients taking tamoxifen. This study provides epidemiologic evidence to support this recommendation. Material and methods. We conducted a case-control study of breast cancer recurrence nested in the population of female residents of Denmark who were diagnosed with non-metastatic estrogen-receptor positive breast cancers between 1994 and 2001 and who took tamoxifen for at least one year. We ascertained complete prescription histories by linking cases’ and controls’ civil registration numbers to the Danish national prescription registry. We estimated the association between SSRI use while taking tamoxifen and risk of recurrent breast cancer. Results. About the same proportion of recurrent cases (37 of 366) and matched controls (35 of 366) received at least one prescription for citalopram or its s-stereoisomer while taking tamoxifen (adjusted odds ratio = 1.1, 95% confidence interval = 0.7, 1.7). Breast cancer patients taking other SSRIs were also at no increased risk of recurrence (adjusted odds ratio = 0.9, 95% confidence interval = 0.5, 1.8). Discussion. Breast cancer patients with indications for an SSRI may be prescribed citalopram – and possibly other SSRI – without adversely affecting the outcome of adjuvant therapy with tamoxifen.

Statins and breast cancer prognosis: evidence and opportunities

Much preclinical and epidemiological evidence supports the anticancer effects of statins. Epidemiological evidence does not suggest an association between statin use and reduced incidence of breast cancer, but does support a protective effect of statins--especially simvastatin--on breast cancer recurrence. Here, we argue that the existing evidence base is sufficient to justify a clinical trial of breast cancer adjuvant therapy with statins and we advocate for such a trial to be initiated without delay. If a protective effect of statins on breast cancer recurrence is supported by trial evidence, then the indications for a safe, well tolerated, and inexpensive treatment can be expanded to improve outcomes for breast cancer survivors. We discuss several trial design opportunities--including candidate predictive biomarkers of statin safety and efficacy--and offer solutions to the key challenges involved in the enrolment, follow-up, and analysis of such a trial.

Use of β-Blockers, Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Risk of Breast Cancer Recurrence: A Danish Nationwide Prospective Cohort Study

PURPOSE To estimate associations between use of β-blockers, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs) and breast cancer recurrence in a large Danish cohort. PATIENTS AND METHODS We enrolled 18,733 women diagnosed with nonmetastatic breast cancer between 1996 and 2003. Patient, treatment, and 10-year recurrence data were ascertained from the Danish Breast Cancer Cooperative Group registry. Prescription and medical histories were ascertained by linkage to the National Prescription Registry and Registry of Patients, respectively. β-Blocker exposure was defined in aggregate and according to solubility, receptor selectivity, and individual drugs. ACE inhibitor and ARB exposures were defined in aggregate. Recurrence associations were estimated with multivariable Cox regression models in which time-varying drug exposures were lagged by 1 year. RESULTS Compared with never users, users of any β-blocker had a lower recurrence hazard in unadjusted models (unadjusted hazard ratio [HR] = 0.91; 95% CI, 0.81 to 1.0) and a slightly higher recurrence hazard in adjusted models (adjusted HR = 1.3; 95% CI, 1.1 to 1.5). Associations were similar for exposures defined by receptor selectivity and solubility. Although most individual β-blockers showed no association with recurrence, metoprolol and sotalol were associated with increased recurrence rates (adjusted metoprolol HR = 1.5, 95% CI, 1.2 to 1.8; adjusted sotalol HR = 2.0, 95% CI, 0.99 to 4.0). ACE inhibitors were associated with a slightly increased recurrence hazard, whereas ARBs were not associated with recurrence (adjusted ACE inhibitor HR = 1.2, 95% CI, 0.97 to 1.4; adjusted ARBs HR = 1.1, 95% CI, 0.85 to 1.3). CONCLUSION Our data do not support the hypothesis that β-blockers attenuate breast cancer recurrence risk.

No Increase in Breast Cancer Recurrence with Concurrent Use of Tamoxifen and Some CYP2D6-Inhibiting Medications

Tamoxifen reduces recurrence risk among women treated for estrogen receptor–positive breast cancer. Its effectiveness partly depends on metabolic activation via cytochrome P450 2D6 (CYP2D6). Some medications compromise CYP2D6 activity and may lower plasma concentrations of active tamoxifen metabolites. We studied the association between concurrent use of tamoxifen and CYP2D6-inhibiting medications and breast cancer recurrence among Danish women diagnosed with early-stage, estrogen receptor–positive breast cancer. Using the Danish Breast Cancer Cooperative Group Registry, we identified 366 cases with local or distant breast cancer recurrence and 366 matched breast cancer controls. We ascertained concurrent prescription of CYP2D6-inhibiting medications during tamoxifen treatment by linking to the national prescription database covering all Danish pharmacies. We computed the breast cancer recurrence odds ratio (OR) and 95% confidence interval for each medication. The pooled recurrence OR was null (OR, 1.0; 95% confidence interval, 0.8-1.3); recurrence ORs for individual drugs ranged from 0.3 to 3.4. The individual ORs followed the pattern expected under a null-centered Gaussian distribution. Null associations were apparent for all drugs after empirical Bayes adjustment for multiple comparisons. Together, these results provide evidence for a null association between drug-compromised CYP2D6 activity and breast cancer recurrence among tamoxifen-treated women. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2562–4)

Digoxin treatment is associated with an increased incidence of breast cancer: a population-based case-control study

IntroductionLaboratory and epidemiologic studies have suggested a modifying effect of cardiac glycosides (for example, digoxin and digitoxin) on cancer risk. We explored the association between digoxin treatment and invasive breast cancer incidence among postmenopausal Danish women.MethodsWe used Danish registries to identify 5,565 postmenopausal women diagnosed with incident invasive breast carcinoma between 1 January 1991 and 31 December 2007, and 55,650 matched population controls. Cardiac glycoside prescriptions were ascertained from county prescription registries. All subjects had at least 2 years of recorded prescription drug and medical history data. We estimated the odds ratio associating digoxin use with breast cancer in conditional logistic regression models adjusted for age, county of residence, and use of anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, and hormone replacement therapy. We also explored the impact of confounding by indication and detection bias.ResultsDigoxin was the sole cardiac glycoside prescribed to subjects during the study period. There were 324 breast cancer cases (5.8%) and 2,546 controls (4.6%) with a history of digoxin use at least 1 year before their index date (adjusted odds ratio (OR): 1.30; 95% confidence interval: 1.14 to 1.48). The breast cancer OR increased modestly with increasing duration of digoxin exposure (adjusted OR for 7 to 18 years of digoxin use: 1.39; 95% confidence interval: 1.10 to 1.74). The association was robust to adjustment for age, receipt of hormone replacement therapy, coprescribed drugs, and confounding by indication. A comparison of screening mammography rates between cases and controls showed no evidence of detection bias.ConclusionsOur results suggest that digoxin treatment increases the risk of invasive breast cancer among postmenopausal women.

Impact of Acquired Comorbidities on All-cause Mortality Rates Among Older Breast Cancer Survivors

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.

Lifetime tobacco smoke exposure and breast cancer incidence.

PurposeWe analyzed data from a case–control study to assess the association between lifetime tobacco smoke exposure and breast cancer incidence.MethodsIncident 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.ResultsWe 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.ConclusionsWe observed no causal associations between active or passive tobacco smoke exposures and incident breast cancer, consistent with results from most prospective cohort studies.

Opioids and breast cancer recurrence: A Danish population‐based cohort study

Opioids may alter immune function, thereby potentially affecting cancer recurrence. The authors investigated the association between postdiagnosis opioid use and breast cancer recurrence.