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1.  Treatment and survival in a population-based sample of patients diagnosed with gastroesophageal adenocarcinoma 
AIM: To examine the extent of use of specific therapies in clinical practice, and their relationship to therapies validated in clinical trials.
METHODS: The US National Cancer Institutes’ Patterns of Care study was used to examine therapies and survival of patients diagnosed in 2001 with histologically-confirmed gastroesophageal adenocarcinoma (n = 1356). The study re-abstracted data and verified therapy with treating physicians for a population-based stratified random sample.
RESULTS: Approximately 62% of patients had stomach adenocarcinoma (SAC), while 22% had gastric-cardia adenocarcinoma (GCA), and 16% lower esophageal adenocarcinoma (EAC). Stage IV/unstaged esophageal cancer patients were most likely and stage I-III stomach cancer patients least likely to receive chemotherapy as all or part of their therapy; gastric-cardia patients received chemotherapy at a rate between these two. In multivariable analysis by anatomic site, patients 70 years and older were significantly less likely than younger patients to receive chemotherapy alone or chemoradiation for all three anatomic sites. Among esophageal and stomach cancer patients, receipt of chemotherapy was associated with lower mortality; but no association was found among gastric-cardia patients.
CONCLUSION: This study highlights the relatively low use of clinical trials-validated anti-cancer therapies in community practice. Use of chemotherapy-based treatment was associated with lower mortality, dependent on anatomic site. Findings suggest that physicians treat lower esophageal and SAC as two distinct entities, while gastric-cardia patients receive a mix of the treatment strategies employed for the two other sites.
PMCID: PMC2712847  PMID: 18506920
Adenocarcinoma; Esophageal adeno-carcinoma; Gastroesophageal; Gastric adenocarcinoma; Survival; Chemotherapy; Radiotherapy
2.  Methods and rationale used in a matched cohort study of the incidence of new primary cancers following prostate cancer 
Clinical Epidemiology  2013;5:429-437.
We describe several methodological issues that were addressed in conducting a Danish population-based matched cohort study comparing rates of new primary cancers (NPCs) in men with and without prostate cancer (PC).
We matched 30,220 men with PC to 151,100 men without PC (comparators) on age (±2 years) and PC diagnosis/index date. We focused on several methodological issues: 1) to address survival differences between the cohorts we compared rates with and without censoring comparators on the date their matched PC patient died or was censored; 2) to address diagnostic bias, we excluded men with a history of cancer from the comparator cohort; 3) to address prostate cancer immunity, we graphed the hazard of NPC in both cohorts, with and without prostate cancer as an outcome; 4) we used empirical Bayes methods to explore the effect of adjusting for multiple comparisons.
After 18 months of follow-up, cumulative person-time was lower in the PC than comparator cohort due to higher mortality among PC patients. Terminating person-time in comparators at the matched PC patient’s death or loss to follow-up resulted in comparable person-time up to 30 months of follow-up and lower person-time among comparators thereafter. The hazard of NPC was lower among men with PC than comparators throughout follow-up. There was little difference in rates beyond the first four years of follow-up after removing PC as an outcome. Empirical Bayes adjustment for multiple comparisons had little effect on the estimates.
Addressing the issues of competing risks, treatment interference or diagnostic bias, prostate cancer immunity due to radical prostatectomy, and multiple comparisons lowered the deficit rate of NPCs among men with a history of PC compared with those without PC. However, the differing rates of NPCs may also be due to risk factor differences between the cohorts.
PMCID: PMC3817011  PMID: 24204172
prostate cancer; cohort study; cancer epidemiology; new primary cancer; incidence rate; competing risks; multiple comparisons
3.  Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy 
Future oncology (London, England)  2014;10(1):107-122.
Tamoxifen reduces the rate of breast cancer recurrence by approximately a half. Tamoxifen is metabolized to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6). Tamoxifen is a substrate for ATP-binding cassette transporter proteins. We review tamoxifen's clinical pharmacology and use meta-analyses to evaluate the clinical epidemiology studies conducted to date on the association between CYP2D6 inhibition and tamoxifen effectiveness. Our findings indicate that the effect of both drug-induced and/or gene-induced inhibition of CYP2D6 activity is likely to be null or small, or at most moderate in subjects carrying two reduced function alleles. Future research should examine the effect of polymorphisms in genes encoding enzymes in tamoxifen's complete metabolic pathway, should comprehensively evaluate other biomarkers that affect tamoxifen effectiveness, such as the transport enzymes, and focus on subgroups of patients, such as premenopausal breast cancer patients, for whom tamoxifen is the only guideline endocrine therapy.
PMCID: PMC4319217  PMID: 24328412
ATP-binding cassette transporter; breast cancer; breast cancer recurrence; cytochrome P450 2D6; multiple drug resistance; P-glycoprotein; polymorphism; selective serotonin reuptake inhibitor; tamoxifen
4.  Statins and breast cancer prognosis: evidence and opportunities 
The Lancet. Oncology  2014;15(10):e461-e468.
Much preclinical and epidemiologic evidence supports anticancer effects of HMG-CoA reductase inhibitors (statins). Epidemiologic evidence does not support an association between statin use and reduced breast cancer incidence, but does support a protective effect of statins—particularly simvastatin—on breast cancer prognosis. We argue that the current evidence base is sufficient to justify a clinical trial of breast cancer adjuvant therapy with statins. 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 in expensive treatment can be expanded to improve outcomes for breast cancer survivors. We discuss several design opportunities—including candidate predictive biomarkers of statin safety and efficacy—and offer solutions to key challenges to enrolment, follow-up, and analysis of such a trial.
PMCID: PMC4167822  PMID: 25186049
5.  Use of β-Blockers, Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Risk of Breast Cancer Recurrence: A Danish Nationwide Prospective Cohort Study 
Journal of Clinical Oncology  2013;31(18):2265-2272.
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.
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).
Our data do not support the hypothesis that β-blockers attenuate breast cancer recurrence risk.
PMCID: PMC3677839  PMID: 23650417
6.  Manganese Superoxide Dismutase and Breast Cancer Recurrence: A Danish Clinical Registry-Based Case-Control Study, and a Meta-Analysis 
PLoS ONE  2014;9(1):e87450.
Manganese superoxide dismutase (MnSOD) inhibits oxidative damage and cancer therapy effectiveness. A polymorphism in its encoding gene (SOD2: Val16Ala rs4880) may confer poorer breast cancer survival, but data are inconsistent. We examined the association of SOD2 genotype and breast cancer recurrence (BCR) among patients treated with cyclophosphamide-based chemotherapy (Cyclo). We compared our findings with published studies using meta-analyses.
We conducted a population-based case-control study of BCR among women in Jutland, Denmark. Subjects were diagnosed with non-metastatic breast cancer from 1990–2001, received adjuvant Cyclo, and were registered in the Danish Breast Cancer Cooperative Group. We identified 118 patients with BCR and 213 matched breast cancer controls. We genotyped SOD2 and used conditional logistic regression to compute the odds ratio (OR) and associated 95% confidence intervals (95% CI) of BCR. We used random-effects meta-analytic models to evaluate the association of SOD2 polymorphisms and BCR.
The frequency of the SOD2-Ala allele was 70% in cases versus 71% in controls; 40% versus 44% were heterozygotes, and 30% versus 25% were homozygotes, respectively. Heterozygote and homozygote carriers of the Ala allele had no increased rate of BCR (OR = 1.1, 95%CI = 0.65, 2.0, and OR = 0.87, 95%CI = 0.47, 1.6, respectively). Five studies informed the meta-analytic models; summary estimates associating BCR for homozygote, or any inheritance of the variant Ala allele were 1.18 (95%CI = 0.74, 1.88), and 1.18, (95%CI = 0.91, 1.54), respectively.
Our findings do not suggest that MnSOD enzymatic activity, as measured by SOD2 genotype, affects rates of BCR among patients treated with Cyclo.
PMCID: PMC3909115  PMID: 24498107
7.  Comorbidity and survival of Danish breast cancer patients from 2000–2011: a population-based cohort study 
Clinical Epidemiology  2013;5(Suppl 1):39-46.
Previous studies have suggested that breast cancer survival in Denmark has improved, primarily in cancer patients without comorbidity. We therefore conducted a population-based cohort study to examine recent temporal changes in survival and mortality among breast cancer patients with different extents of comorbidity.
We used population-based medical and administrative registries to identify breast cancer patients diagnosed between 2000 and 2011 in the Central Denmark Region. We defined comorbid diseases according to the Charlson Comorbidity Index (CCI), including a history of hospitalization for comorbid disease up to 10 years before breast cancer diagnosis. We studied the impact of comorbidities on overall 1- and 5-year survival in different calendar time periods, using a hybrid analysis for survival prediction in the most recent calendar periods.
We included 9,329 breast cancer patients. The proportion of patients within different comorbidity categories remained stable from 2000 to 2011. One-year survival improved from 91% in 2000–2002 to 95% in 2009–2011, while 5-year survival improved from 72% to a predicted 78%. During the entire study period, comorbidity was a strong predictor of the survival of breast cancer patients. However, we observed improvements over time in 1- and 5-year survival for all comorbidity groups. During the 12-year study period, the estimated 5-year survival for patients with a high comorbidity disease burden (CCI score ≥3) increased from 25% to a predicted 50%, and their 5-year age-adjusted mortality hazard ratio (HR) fell from 4.0 (95% confidence interval [CI]: 3.0, 5.4) to 2.7 (95% CI: 2.0, 3.6), respectively, compared with patients with no comorbid disease.
Survival of breast cancer patients diagnosed in the Central Denmark Region improved from 2000 to 2011, regardless of the extent of comorbid disease.
PMCID: PMC3820476  PMID: 24227922
breast neoplasm; survival; mortality; comorbidity; prognosis
8.  Statin Prescriptions and Breast Cancer Recurrence Risk: A Danish Nationwide Prospective Cohort Study 
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.
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.
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).
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.
PMCID: PMC3186780  PMID: 21813413
9.  Functional polymorphisms in UDP-glucuronosyltransferases and recurrence in tamoxifen-treated breast cancer survivors 
Tamoxifen is oxidized by cytochrome-P450 enzymes (e.g., CYP2D6) to two active metabolites, which are eliminated via glucuronidation by UDP-glucuronosyltransferases (UGTs). We measured the association between functional polymorphisms in key UGTs (UGT2B15*2, UGT2B7*2, and UGT1A8*3) and the recurrence rate among breast cancer survivors.
We used the Danish Breast Cancer Cooperative Group registry to identify 541 cases of recurrent breast cancer among women with estrogen receptor-positive tumors treated with tamoxifen for at least one year (ER+/TAM+), and 300 cases of recurrent breast cancer among women with estrogen receptor-negative tumors who were not treated with tamoxifen (ER−/TAM−). We matched 1 control to each case on ER status, menopausal status, stage, calendar period, and county. UGT polymorphisms were genotyped from archived primary tumors. We estimated the recurrence odds ratio for the UGT polymorphisms using logistic regression models, with and without stratification on CYP2D6*4 genotype.
No UGT polymorphism was associated with breast cancer recurrence in either the ER+/TAM+ or ER-/TAM- groups [in the ER+TAM+ group, compared with two normal alleles: adjusted OR for two UGT2B15*2 variant alleles = 1.0 (95% CI: 0.70, 1.5); adjusted OR for two for UGT2B7*2 variant alleles = 0.91 (95% CI: 0.65, 1.3); adjusted OR for 1 or 2 UGT1A8*3 variant alleles = 0.75 (0.41, 1.4)]. Associations were similar within strata of CYP2D6*4 genotype.
Functional polymorphisms in key tamoxifen-metabolizing enzymes were not associated with breast cancer recurrence risk.
Our results do not support the genotyping of key metabolic enzyme polymorphisms to predict response to tamoxifen therapy.
PMCID: PMC3169710  PMID: 21750172
Epidemiology; breast neoplasms; UDP-glucuronosyltransferases; tamoxifen
10.  Clinical epidemiology and pharmacology of CYP2D6 inhibition related to breast cancer outcomes 
Adjuvant tamoxifen therapy of breast cancer patients with estrogen receptor-positive tumors reduces the rate of breast cancer recurrence by approximately a half. Tamoxifen is metabolized by several polymorphic enzymes, including cytochrome P450 2D6 (CYP2D6), to more active metabolites. We have reviewed the clinical pharmacology of tamoxifen and evaluated the evidence from clinical epidemiology studies regarding the association between CYP2D6 inhibition and tamoxifen effectiveness. We conclude that the impact of CYP2D6 inhibition on tamoxifen effectiveness is likely to be null or small, at least in the populations studied so far. Understanding the effect of variations in tamoxifen metabolism on breast cancer outcomes, if any, will likely require a broader perspective, including examination of the complete metabolic pathway and subgroups of patients with other markers of potentially poor tamoxifen response.
PMCID: PMC3119576  PMID: 21709817
breast cancer; breast cancer recurrence; cytochrome P450 2D6; selective serotonin reuptake inhibitors; tamoxifen
11.  Use of glucocorticoids and risk of breast cancer: a Danish population-based case-control study 
Glucocorticoids are widely prescribed drugs. In the human body, glucocorticoid is the main stress hormone and controls a variety of physiological and cellular processes, including metabolism and immune response. It belongs to the same steroid superfamily as estrogens, which are known to play a role in breast cancer. However, the effect of glucocorticoid use on the risk of breast cancer is not clear.
We conducted a case-control study using population-based medical databases from Northern Denmark (1.8 million inhabitants) to investigate the association between glucocorticoid prescriptions and breast cancer risk. The study included 9,488 incident breast cancer cases diagnosed between 1994 and 2008 and 94,876 population controls. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) associating glucocorticoid use with breast cancer occurrence, controlling for prescriptions of postmenopausal hormone replacement therapy, anti-diabetics, immunosuppressive drugs, and hospital diagnosis of obesity, diabetes, chronic pulmonary diseases and autoimmune diseases.
We found no effect on breast cancer risk in ever users (> 2 prescriptions) of any glucocorticoids (adjusted odds ratio (aOR) = 1.0; 95% CI: 0.96, 1.1), systemic glucocorticoids (aOR = 1.0; 95% CI: 0.96, 1.1), or inhaled glucocorticoids (aOR = 1.0; 95% CI: 0.95, 1.1), each compared to never users of any glucocorticoids. Associations for recent use (preceding two years) and former use (more than two years earlier) were near null in all dose categories (low, medium and high number of prescriptions). Intensity of systemic glucocorticoid use (cumulative prednisolone equivalent doses), regardless of duration (< 1, 1 to 5, 5+ years), was also not associated with breast cancer risk.
Overall, our study provides no evidence that glucocorticoid use affects the risk of breast cancer.
PMCID: PMC3496139  PMID: 22305057
12.  Factors associated with concordant estrogen receptor expression at diagnosis and centralized re-assay in a Danish population-based breast cancer study 
Estrogen receptor (ER) expression predicts tamoxifen response, which halves the risk of breast cancer recurrence. We examined clinical factors associated with concordance between ER expression at diagnosis and centralized re-assay, and the association of concordance with breast cancer recurrence.
Materials and Methods
We used immunohistochemistry to assess ER expression on archived fixed, paraffin-embedded breast carcinoma tissue excised from women aged 35–69 years, diagnosed 1985–2001 in Jutland, Denmark. We calculated the percentage agreement, positive predictive value (PPV) and negative predictive value (NPV) of ER status at diagnosis and re-assay. We used logistic regression to investigate factors associated with concordance, and its association with recurrence (odds ratios (OR) and associated 95% confidence intervals (95%CI)).
ER was re-assayed in 91% of patients (n=1530). Concordance was better in ER+ than ER− tumors (PPV=94% versus NPV=75%). Factors associated with concordance included menopausal status, tumor size, surgical procedure, diagnostic period, lymph node status and time to recurrence. ER+ women at diagnosis who re-assayed ER+ were less likely to have recurrent disease (OR=0.49, 95% CI=0.28, 0.86) than those who re-assayed ER−. In originally ER− women, concordance was not associated with recurrence (OR=0.97, 95% CI=0.66, 1.42).
Several clinical factors were associated with ER assay concordance. Some women were ineffectively treated with tamoxifen, or required but did not receive tamoxifen. We observed almost exactly the protective effect of endocrine therapy among tamoxifen-treated ER+ women whose tumors expressed the ER on re-assay, compared with those ER− on re-assay. Diagnostic pathology results for ER+ tumors appear a valid and useful resource for research studies. However, those for ER− tumors have lower validity. Study-specific considerations regarding the aims, diagnostic period, and consequences of including ER− patients with truly ER+ disease ought to be examined when using diagnostic pathology results for ER− tumors in research studies.
PMCID: PMC3264781  PMID: 22129357
Estrogen receptor; concordance; formalin-fixed paraffin-embedded; case-control; breast cancer
13.  Pancreatic cancer survival in central and northern Denmark from 1998 through 2009: a population-based cohort study 
Clinical Epidemiology  2011;3(Suppl 1):19-25.
Pancreatic cancer has a relatively low incidence but ranks fourth among cancer- related deaths in western countries. In Denmark, cancer survival generally is lower than in other countries with comparable health care systems. As a result, in 2000, a national strategy to improve cancer survival was introduced. Here we examine time trends in survival and relative mortality among pancreatic cancer patients, using Danish population and medical databases.
Using the Danish National Patient Registry (DNPR), we identified all incident pancreatic cancer patients (n = 2968) diagnosed between 1998 and 2009 in the Central and North Denmark Regions. We computed the 1-, 3-, and 5-year survival and relative mortality (MRR) and associated 95% confidence intervals (CI) adjusting for age and gender. Among surgical patients, we also computed 30-day mortality and 30-day MRR.
Median age at diagnosis was approximately 71 years. The annual number of patients increased from 189 in 1998–2000 to 302 in 2007–2009. There was a slight improvement in 1-, 3-, and 5-year survival over time from 14.8% to 17.7%; 3.5% to a predicted 5.6%; and from 2.0% to a predicted 3.8%, from 1998–2000 to 2007–2009, respectively. Correspondingly, the adjusted relative mortality decreased from 1998–2000 to 2007–2009. Thirty-day post-operative mortality decreased from 12.2% in 1998–2000 to 5.8% in 2007–2009, corresponding to a 30-day MRR of 0.38, 95% CI = 0.09, 1.6 in 2007–2009.
There was a slight, albeit modest, improvement in survival and relative mortality in pancreatic cancer patients between 1998 and 2009. As we lacked staging information, it is not clear if this improvement is attributable to earlier stage at diagnosis. However, these improvements likely reflect the national cancer strategy which aimed to centralize cancer services and involved the introduction of palliative and adjuvant chemotherapy for pancreatic cancer in Denmark. The dismal prognosis of pancreatic cancer means that efforts to improve survival need to be intensified.
PMCID: PMC3144774  PMID: 21814466
pancreatic cancer; survival; relative mortality; epidemiology
14.  Aspirin and other non-steroidal anti-inflammatory drugs in relation to Hodgkin lymphoma risk in Northern Denmark 
There are few known modifiable risk factors for Hodgkin lymphoma (HL), but the recent finding of an inverse association between routine regular-strength aspirin use and HL risk suggests that aspirin may protect against HL development. To further investigate this association using prospectively collected data, we conducted a population-based case-control study in Northern Denmark. A total of 478 incident HL cases were identified in nationwide health care databases from 1991 through 2008. Ten population controls were matched to each case on age, sex, and county using risk-set sampling. Use of aspirin, selective cyclooxygenase-2 (sCOX-2) inhibitors, and other NSAIDs from 1989 through 2007 was ascertained by linkage to a population-based prescription database. Conditional logistic regression was used to estimate odds ratios (ORs) for associations between medication use and risk of HL. The OR for ever use (>2 prescriptions) compared with never/rare use (≤2 prescriptions) of low-dose aspirin was 0.7 (95% confidence interval [CI]: 0.5–1.2). The association with low-dose aspirin use did not vary appreciably by recentness, duration, or intensity of use. Recent use (>2 prescriptions in the 1–2 years before the index date), short-term use (<7 years), and medium/high-intensity use (≥25% of duration of use covered by prescription) of sCOX-2 inhibitors or other NSAIDs was associated with increased HL risk, possibly due to prodromal symptoms among cases. In conclusion, our results provide some evidence of a protective effect of low-dose aspirin, but not other NSAIDs, against HL development.
PMCID: PMC2837543  PMID: 20056623
non-steroidal anti-inflammatory drugs; Hodgkin lymphoma; epidemiology; risk; prevention
15.  Concordance of metabolic enzyme genotypes assayed from paraffin-embedded, formalin-fixed breast tumors and normal lymphatic tissue 
Clinical Epidemiology  2010;2:241-246.
Translational epidemiology studies often use archived tumor specimens to evaluate genetic hypotheses involving cancer outcomes. When the exposure of interest is a germline polymorphism, a key concern is whether the genotype assayed from tumor-derived DNA is representative of the germline. We evaluated the concordance between breast tumor-derived and normal lymph node-derived genotypes for three polymorphic tamoxifen-metabolizing enzymes.
We assayed paired DNA samples extracted from archived tumor and normal lymph node tissues from 106 breast cancer patients. We used TaqMan assays to determine the genotypes of three enzyme variants hypothesized to modify tamoxifen effectiveness, ie, CYP2D6*4, UGT2B15*2, and UGT1A8*2. We assessed genotype agreement between the two DNA sources by calculating the percent agreement and the weighted kappa statistic.
We successfully obtained genotypes for CYP2D6*4, UGT2B15*2, and UGT1A8*2 in 99%, 100%, and 84% of the paired samples, respectively. Genotype concordance was perfect for the CYP2D6*4 and UGT1A8*2 variants (weighted kappa for both = 1.00; 95% confidence interval [CI] 1.00, 1.00). For UGT2B15*2, one pair out of 106 gave a discordant result that persisted over several assay repeats.
We observed strong agreement between DNA from breast tumors and normal lymphatic tissue in the genotyping of polymorphisms in three tamoxifen-metabolizing enzymes. Genotyping DNA extracted from tumor tissue avoids the time-consuming practice of microdissecting adjacent normal tissue when other normal tissue sources are not available. Therefore, the demonstrated reliability of tumor-derived DNA allows resources to be spent instead on increasing sample size or the number of polymorphisms examined.
PMCID: PMC2998813  PMID: 21152250
molecular epidemiology; breast neoplasms; cytochrome P450 CYP2D6; glucuronosyltransferase
16.  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 (DBCG) 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 (95% CI) for each medication. The pooled recurrence odds ratio was null (OR: 1.0; 95% CI: 0.8, 1.3); recurrence odds ratios for individual drugs ranged from 0.3 to 3.4. The individual odds ratios 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.
PMCID: PMC2742564  PMID: 19690182
Epidemiology; breast neoplasms; tamoxifen; pharmacology and therapeutic use; tamoxifen; antagonists and inhibitors; cytochrome P-450 2D6
17.  Prescriptions for selective cyclooxygenase-2 inhibitors, non-selective non-steroidal anti-inflammatory drugs, and risk of breast cancer in a population-based case-control study 
Non-steroidal anti-inflammatory drugs (NSAIDs) prevent the growth of mammary tumours in animal models. Two population-based case-control studies suggest a reduced risk of breast cancer associated with selective cyclooxygenase-2 (sCox-2) inhibitor use, but data regarding the association between breast cancer occurrence and use of non-selective NSAIDs are conflicting.
We conducted a population-based case-control study using Danish healthcare databases to examine if use of NSAIDs, including sCox-2 inhibitors, was associated with a reduced risk of breast cancer. We included 8,195 incident breast cancer cases diagnosed in 1991 through 2006 and 81,950 population controls.
Overall, we found no reduced breast cancer risk in ever users (>2 prescriptions) of sCox-2 inhibitors (odds ratio (OR) = 1.08, 95% confidence interval (95% CI) = 0.99, 1.18), aspirin (OR = 0.98, 95% CI = 0.90-1.07), or non-selective NSAIDs OR = 1.04, (95% CI = 0.98, 1.10)). Recent use (>2 prescriptions within two years of index date) of sCox-2 inhibitors, aspirin, or non-selective NSAIDs was likewise not associated with breast cancer risk (Ors = 1.06 (95% CI = 0.96, 1.18), 0.96 (95% CI = 0.87, 1.06) and 0.99 (95% CI = 0.85, 1.16), respectively). Risk estimates by duration (<10, 10 to 15, 15+ years) or intensity (low/medium/high) of NSAID use were also close to unity. Regardless of intensity, shorter or long-term NSAID use was not significantly associated with breast cancer risk.
Overall, we found no compelling evidence of a reduced risk of breast cancer associated with use of sCox-2 inhibitors, aspirin, or non-selective NSAIDs.
PMCID: PMC2879557  PMID: 20193065

Results 1-17 (17)