Incident cardiovascular disease in patients diagnosed with multiple sclerosis: A multi-database study.

BACKGROUND: Recent data on rates of cardiovascular disease (CVD) in patients after MS diagnosis are sparse. OBJECTIVE: To describe incident CVD in MS patients after diagnosis compared with a matched non-MS population. METHODS: We conducted a matched cohort study in two separate electronic medical databases, the United States Department of Defense military health care system and the United Kingdom's Clinical Practice Research Datalink GOLD. The study population included all patients with a first recorded diagnosis of MS and no history of CVD or selected measurable comorbidities associated with CVD and matched non-MS patients who were also free of CVD and the CVD associated comorbidities. We identified incident CVD outcomes first recorded after the MS diagnosis / matched date and calculated incidence rates and incidence rate ratios by type of CVD. RESULTS: Rates of venous thromboembolism and peripheral vascular disease were 2-fold higher among MS than non-MS patients in both databases and the risk of myocardial infarction was 2.5 times higher among female MS patients compared with non-MS females in both databases. Other CVD outcomes were not consistent between databases. CONCLUSION: MS patients in the UK and the US have increased risk of venous thromboembolism and peripheral vascular disease. The risk of myocardial infarction is increased among female MS patients.

Multi-database study of multiple sclerosis: identification, validation and description of MS patients in two countries.

OBJECTIVE: To describe the resources and methods used to identify and validate multiple sclerosis (MS) and match non-MS patients in each of the two databases, and to characterize their demographics, comorbidities and concomitant medications. METHODS: This study was conducted in two separate electronic medical databases, the United States Department of Defense (DOD) military health care system and the United Kingdom's Clinical Practice Research Datalink (CPRD) GOLD. We identified patients with a first recorded diagnosis of MS in 2001-2016 (CPRD) or 2004-2017 (DOD) and matched non-MS patients using algorithms appropriate to each database. We describe patient symptoms, comorbidities, and medication use at the time of the MS diagnosis and compared them to the non-MS cohort. RESULTS: We identified 8695 patients with MS and 86,934 matched non-MS patients in the DOD database and 6932 patients with MS and 68,526 matched non-MS patients in CPRD GOLD. Most MS patients were female (around 70%) and were diagnosed before age 60 (88%). MS patients had higher prevalence of depression and other psychiatric conditions at MS diagnosis compared to non-MS patients. Epilepsy, fractures and infections were also more common. MS patients had many expected symptoms and treatments documented in their records prior to the MS diagnosis. CONCLUSION: These results are consistent between the two databases, as well as with previous studies of MS. Future analyses of these patients' experience after MS diagnosis will provide valuable insights into disease and treatment patterns in relation to risk of chronic diseases and mortality.

Risk of diabetes complications among those with diabetes receiving androgen deprivation therapy for localized prostate cancer.

PURPOSE: Androgen deprivation therapy (ADT), used increasingly in the treatment of localized prostate cancer, is associated with substantial long-term adverse consequences, including incident diabetes. While previous studies have suggested that ADT negatively influences glycemic control in existing diabetes, its association with diabetes complications has not been investigated. In this study, we examined the association between ADT use and diabetes complications in prostate cancer patients. METHODS: A retrospective cohort study was conducted among men with newly diagnosed localized prostate cancer between 1995 and 2008, enrolled in three integrated health care systems. Men had radical prostatectomy or radiotherapy (curative intent therapy), existing type II diabetes mellitus (T2DM), and were followed through December 2010 (n = 5,336). Cox proportional hazards models were used to examine associations between ADT use and diabetes complications (any complication), and individual complications (diabetic neuropathy, diabetic retinopathy, diabetic amputation or diabetic cataract) after prostate cancer diagnosis. RESULTS: ADT use was associated with an increased risk of any diabetes complication after prostate cancer diagnosis (adjusted hazard ratio, AHR, 1.12, 95% CI 1.03-1.23) as well as an increased risk of each individual complication compared to non-use. CONCLUSION: ADT use in men with T2DM, who received curative intent therapy for prostate cancer, was associated with an increased risk of diabetes complications. These findings support those of previous studies, which showed that ADT worsened diabetes control. Additional, larger studies are required to confirm these findings and to potentially inform the development of a risk-benefit assessment for men with existing T2DM, before initiating ADT.

Serum cholesterol trajectories in the 10 years prior to lymphoma diagnosis.

PURPOSE: Many studies suggest a role for cholesterol in cancer development. Serum cholesterol levels have been observed to be low in newly diagnosed lymphoma cases. The objective of these analyses was to examine the time-varying relationship of cholesterol with lymphomagenesis in the 10 years prior to diagnosis by lymphoma subtype. METHODS: Participants were selected from the combined membership of six National Cancer Institute-funded Cancer Research Network health plans from 1998 to 2008, excluding members with human immunodeficiency virus, cancer (except lymphoma), or organ transplants. Incident lymphoma cases within this population were ascertained and matched with up to five controls. Total serum cholesterol, high-density lipoprotein, and low-density lipoprotein were collected from plan databases. Multilevel, multivariable longitudinal models were fit after choosing the best polynomial order by deviance statistics for selected lymphoma histotypes to examine pre-diagnosis cholesterol trajectories: Hodgkin lymphoma (n = 519) and all non-Hodgkin lymphomas combined (n = 12,635) as well as six subtypes of the latter. RESULTS: For all categories, lymphoma cases had statistically significantly lower estimated total serum cholesterol, high-density lipoprotein, and low-density lipoprotein levels than controls in the years prior to diagnosis/index date. Between-group differences were most pronounced 3-4 years prior to diagnosis, when cases' cholesterol levels declined steeply. CONCLUSIONS: This analysis is the first to examine changes in serum cholesterol for a decade prior to lymphoma diagnosis. A drop in cholesterol levels was evident several years before diagnosis. Our results suggest that cholesterol-related pathways have an important relationship with lymphomagenesis and low cholesterol could be a preclinical lymphoma marker.

Influence of NSAID Use Among Colorectal Cancer Survivors on Cancer Outcomes.

PURPOSE: Colorectal cancer (CRC) is the third most common cancer diagnosed in men and women in the United States. Given the availability of effective screening, most tumors are found early enough to offer patients substantial long-term survival. Thus there is a resulting significant population of CRC survivors for whom modifiable risk factors for recurrence and survival would be of interest. METHODS: We conducted a population-based retrospective cohort study among patients enrolled in 2 large Midwestern health plans for which claims data, including pharmacy fill data, and medical record data were available. Men and women who were 40 years of age or older at the time of CRC diagnosis with disease less than stage IV and no history of Crohn disease, ulcerative colitis, and irritable bowel syndrome were included. CRC cases diagnosed between January 1, 1990 and December 31, 2000 were included if they met the inclusion criteria. Adjusted Cox proportional hazard models were used with exposure modeled as a time-dependent covariate. We assessed progression-free survival, defined as an aggressive polyp or invasive disease, and overall survival. RESULTS: After adjustment for age at diagnosis, sex, race, body mass index, stage, side of initial tumor, and tumor histology, we found that current users of nonsteroidal anti-inflammatory drugs had a 3-fold decreased risk of recurrence and a >7-fold decreased risk of death. Our results are statistically significant with P-values <0.05. CONCLUSIONS: Our results suggest that current use of nonsteroidal anti-inflammatory drugs provides significant improvements in CRC outcomes.

Mortality and Androgen Deprivation Therapy as Salvage Treatment for Biochemical Recurrence after Primary Therapy for Clinically Localized Prostate Cancer.

PURPOSE: Androgen deprivation therapy is often used as salvage treatment in men with rising prostate specific antigen after initial radical prostatectomy or radiotherapy for clinically localized prostate cancer. Given the lack of evidence from general practice, we examined the association of salvage androgen deprivation therapy with mortality in an observational cohort study. MATERIALS AND METHODS: From 3 managed care organizations we assembled a retrospective cohort of all 5,804 men with newly diagnosed localized prostate cancer from 1995 to 2009 who had a prostate specific antigen increase (biochemical recurrence) after primary radical prostatectomy or radiotherapy. The main outcomes were all-cause and prostate cancer specific mortality. We used Cox proportional hazards models to estimate mortality with salvage androgen deprivation therapy as a time dependent predictor. RESULTS: Overall salvage androgen deprivation therapy was not associated with all-cause or prostate cancer specific mortality in the prostatectomy cohort (HR 0.97, 95% CI 0.70-1.35 or HR 1.18, 95% CI 0.68-2.07) or in the radiotherapy cohort (HR 0.84, 95% CI 0.70-1.01 or HR 1.06, 95% CI 0.80-1.40, respectively). Among men with prostate specific antigen doubling time less than 9 months after the prostate specific antigen rise, salvage androgen deprivation therapy was statistically significantly associated with a decreased risk of all-cause and prostate cancer specific mortality in the prostatectomy cohort (HR 0.35, 95% CI 0.20-0.63 and HR 0.43, 95% CI 0.21-0.91) and in the radiotherapy cohort (HR 0.62, 95% CI 0.48-0.80 and HR 0.65, 95% CI 0.47-0.90, respectively). CONCLUSIONS: We found no association of salvage androgen deprivation therapy with all-cause or cause specific mortality in most men with biochemical recurrence after primary radical prostatectomy or radiotherapy for clinically localized prostate cancer. Men with quickly progressed disease may derive a clinical benefit from salvage androgen deprivation therapy.

Statin use and risk of hepatocellular carcinoma in a U.S. population.

PURPOSE: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are medications widely prescribed to reduce cholesterol levels. Observational studies in high-risk populations, mostly in Asia, have suggested that statins are associated with a reduced risk of hepatocellular carcinoma (HCC). The current study sought to evaluate the association of statin use and HCC in a U.S.-based, low-risk, general population. METHODS: A nested case-control study was conducted among members of the Health Alliance Plan HMO of the Henry Ford Health System enrolled between 1999 and 2010. Electronic pharmacy records of statin use were compared among tumor registry-confirmed cases of HCC (n=94) and controls (n=468) matched on age, sex, diagnosis date, and length of HMO enrolment. RESULTS: In multivariate analyses, ever-use of statins was significantly inversely associated with development of HCC (Odds ratio (OR): 0.32, 95%CI: 0.15-0.67). No clear dose-response relationship was evident as statin use for <2 years (OR=0.32, 95%CI=0.13-0.83) and >2 years (OR=0.31, 95CI%=0.12-9.81) resulted in very similar ORs. CONCLUSIONS: The use of statins among populations in low-risk HCC areas may be associated with decreased risk of HCC.

Incident comorbidities and all-cause mortality among 5-year survivors of Stage I and II breast cancer diagnosed at age 65 or older: a prospective-matched cohort study.

Five-year breast cancer survivors, diagnosed after 65 years of age, may develop more incident comorbidities than similar populations free of cancer. We investigated whether older breast cancer survivors have a similar comorbidity burden 6-15 years after cancer diagnosis to matched women free of breast cancer at start of follow-up and whether incident comorbidities are associated with all-cause mortality. In this prospective cohort study, 1,361 older 5-year early-stage breast cancer survivors diagnosed between 1990 and 1994 and 1,361 age- and health system-matched women were followed for 10 years. Adjudicated medical record review captured prevalent and incident comorbidities during follow-up or until death as collected from the National Death Index. Older 5-year breast cancer survivors did not acquire incident comorbidities more often than matched women free of breast cancer in the subsequent 10 years [hazard ratio (HR) 1.0, 95 % confidence interval (95 % CI) 0.93, 1.1]. Adjusted for cohort membership, women with incident comorbidities had a higher mortality rate than those without incident comorbidities (HR 4.8, 95 % CI 4.1, 5.6). A breast cancer history continued to be a hazard for mortality 6-15 years after diagnosis (HR 1.3, 95 % CI 1.1, 1.4). We found that older breast cancer survivors who developed comorbidities had an increased all-cause mortality rate even after adjusting for age and prevalent comorbidity burden. Additionally, survivors acquire comorbidities at a rate similar to older women free of breast cancer. These results highlight the association between comorbidity burden and long-term mortality risk among older breast cancer survivors and their need for appropriate oncology and primary care follow-up.

Treatment patterns and clinical outcomes for patients with de novo versus recurrent HER2-positive metastatic breast cancer.

Improvements in screening and adjuvant therapy for breast cancer are associated with decreased recurrence, which may have the effect of increasing the proportion of patients presenting with first-line de novo versus recurrent metastatic breast cancer (MBC). Here, we describe and compare patients with de novo versus recurrent human epidermal growth factor 2 (HER2)-positive MBC. registHER was a prospective observational cohort study (late 2003-early 2006) of 1,023 patients with HER2-positive MBC. Baseline characteristics, treatment patterns, and clinical outcomes were examined in patients with newly diagnosed de novo (n = 327) compared with recurrent HER2-positive MBC after prior treatment for early-stage disease (n = 674). Patients with de novo HER2-positive MBC were less likely to have lung metastases, more likely to have lymph node, bone, and/or liver metastases and >4 sites of metastases and more likely to receive combined or concurrent chemotherapy and hormonal therapy with or without trastuzumab than those with recurrent HER2-positive MBC. Median follow-up was 29 months. Median progression-free survival was 12.1 versus 9.3 months [hazard ratio = 0.716 (95 % confidence interval (CI) 0.617-0.831)], and overall survival was 41.7 versus 32.8 months [hazard ratio = 0.766 (95 % CI 0.633-0.928)] for patients with de novo versus recurrent HER2-positive MBC, respectively. Patients with recurrent HER2-positive MBC had similar outcomes regardless of whether they received prior adjuvant therapy, excluding hormonal therapy. Despite presenting with more advanced-stage disease and higher tumor burdens, patients with de novo HER2-positive MBC have more favorable clinical outcomes than those with recurrent HER2-positive MBC. These differences may be due to effects of prior drug exposure and could have implications for designing and interpreting clinical trials.

Comprehensive evaluation of the incidence of late effects in 5-year survivors of breast cancer.

Late effects of breast cancer affect the quality of survivorship. Using administrative data, we compared the occurrence of almost all ICD9 codes among older breast cancer survivors to that among a matched comparison cohort to generate new hypotheses. Breast cancer patients 65 years or older diagnosed 1990-1994 in 6 integrated care settings and who survived at least 5 years were matched with a cohort of women without a history of breast cancer on care setting, age, and calendar time. We collected data on the occurrence of incident ICD9 codes beginning 6 years after the breast cancer diagnosis date and continuing to year 15, and comparable data for the matched woman. We calculated hazard ratios (HRs) and 95 % confidence intervals associating breast cancer survivorship with incidence of each ICD9 code. We used semi-Bayes methods to address multiple comparisons. Older breast cancer survivors had about the same occurrence of diseases and conditions 6-15 years after breast cancer diagnosis as comparable women. The median of 564 adjusted HRs equaled 1.06, with interquartile range 0.92-1.3. The distribution of HRs pertaining to cancer-related ICD codes was shifted toward positive associations, and the distribution pertaining to cardiovascular-related ICD codes was shifted toward negative associations. In this hypothesis-scanning study, we observed little difference in the occurrence of non-breast cancer-related diseases and conditions among older, long-term breast cancer survivors, and comparable women without a history of breast cancer.

Comorbidities and cardiovascular disease risk in older breast cancer survivors.

OBJECTIVE: To evaluate cardiovascular disease (CVD) risk factors in older breast cancer survivors compared with a group of women without breast cancer. STUDY DESIGN: The retrospective study included (1) women aged 65 or more years who were initially diagnosed with stage I or II breast cancer from 1990 to 1994 in 6 US health plans and who survived at least 5 years post-diagnosis (cases) and (2) a matched comparison group. They were followed for a maximum of 15 years. METHODS: Data sources included medical charts and electronic health records. Cases (n = 1361) were matched on age, health plan site, and enrollment year to women in the comparison group (n = 1361). Subjects were followed to the first CVD outcome, health plan disenrollment, death, or study end. We compared rates of CVD in these 2 groups and used Cox proportional hazard models to estimate the hazard ratio (HR), considering body mass index, smoking history, diabetes, and hypertension. RESULTS: The strongest predictors of CVD were smoking history (HR = 1.29; 95% confidence interval [CI], 1.15-1.46), diabetes (HR = 1.72; 95% CI, 1.48-1.99), and hypertension (HR = 1.48; 95% CI, 1.31-1.67) rather than breast cancer case-comparison status (HR = 0.97; 95% CI, 0.87-1.09). CONCLUSION: Results suggest that long-term prognosis in breast cancer patients is affected by management of preexisting conditions. Assessment of comorbid conditions and effective management of diabetes and hypertension in older breast cancer survivors may lead to longer overall survival.

Patient characteristics and participation in a genetic study: a type 2 diabetes cohort.

BACKGROUND: Recruitment of large, diverse populations into genetic studies remains challenging. Potential strategies to overcome limitations include leveraging electronic health data and minimizing patient burden. We sought to describe the overall participation rate and identify characteristics associated with participation in a genetic substudy of patients with type 2 diabetes mellitus, in which patients were identified via electronic hospital data and asked to participate by providing DNA samples by mail. METHODS: During a phone interview, participants (n = 455) were asked to take part in a genetic substudy. Subjects verbally consenting were mailed saliva collection kits and written consent forms. We examined demographic and clinical variables associated with verbal consent and DNA kit return using logistic regression. RESULTS: Overall, 90% (n = 410) verbally consented to the genetic substudy during interviews. However, of those consenting, only 70% returned the DNA kit (n = 287). Among those consenting, after covariate adjustment, male sex (odds ratio [OR], 1.70; 95% confidence interval [CI], 1.09-2.65), African American race (OR, 0.61; 95% CI, 0.39-0.95), hemoglobin A1c (HbA1c) (OR, 0.87; 95% CI, 0.75-1.00), and physical activity (OR, 0.58; 95% CI, 0.37-0.91) were significantly associated with DNA kit return. CONCLUSIONS: To our knowledge, we are the first to demonstrate an inverse association between HbA1c and participation in genetic research, potentially indicating a compliance-related trait needing further exploration. The DNA kit return rate being notably lower than the verbal consent rate suggests that the greater convenience of a telephone/mail-in process did not drastically enhance full participation. Direct comparison to in-person donation may be warranted.

Performance of claims-based algorithms for identifying heart failure and cardiomyopathy among patients diagnosed with breast cancer.

BACKGROUND: Cardiotoxicity is a known complication of certain breast cancer therapies, but rates come from clinical trials with design features that limit external validity. The ability to accurately identify cardiotoxicity from administrative data would enhance safety information. OBJECTIVE: To characterize the performance of clinical coding algorithms for identification of cardiac dysfunction in a cancer population. RESEARCH DESIGN: We sampled 400 charts among 6460 women diagnosed with incident breast cancer, tumor size ≥ 2 cm or node positivity, treated within 8 US health care systems between 1999 and 2007. We abstracted medical records for clinical diagnoses of heart failure (HF) and cardiomyopathy (CM) or evidence of reduced left ventricular ejection fraction. We then assessed the performance of 3 different International Classification of Diseases, 9th Edition (ICD-9)-based algorithms. RESULTS: The HF/CM coding algorithm designed a priori to balance performance characteristics provided a sensitivity of 62% (95% confidence interval, 40%-80%), specificity of 99% (range, 97% to 99%), positive predictive value (PPV) of 69% (range, 45% to 85%), and negative predictive value (NPV) of 98% (range, 96% to 99%). When applied only to incident HF/CM (ICD-9 codes and gold standard diagnosis both occurring after breast cancer diagnosis) in patients exposed to anthracycline and/or trastuzumab therapy, the PPV was 42% (range, 14% to 76%). CONCLUSIONS: Claims-based algorithms have moderate sensitivity and high specificity for identifying HF/CM among patients with invasive breast cancer. As the prevalence of HF/CM among the breast cancer population is low, ICD-9 codes have high NPV but only moderate PPV. These findings suggest a significant degree of misclassification due to HF/CM overcoding versus incomplete clinical documentation of HF/CM in the medical record.

Long-term surveillance mammography and mortality in older women with a history of early stage invasive breast cancer.

Annual surveillance mammograms in older long-term breast cancer survivors are recommended, but this recommendation is based on little evidence and with no guidelines on when to stop. Surveillance mammograms should decrease breast cancer mortality by detecting second breast cancer events at an earlier stage. We examined the association between surveillance mammography beyond 5 years after diagnosis on breast cancer-specific mortality in a cohort of women aged ≥ 65 years diagnosed 1990-1994 with early stage breast cancer. Our cohort included women who survived disease free for ≥ 5 years (N = 1,235) and were followed from year 6 through death, disenrollment, or 15 years after diagnosis. Asymptomatic surveillance mammograms were ascertained through medical record review. We used Cox proportional hazards regression stratified by follow-up year to calculate the association between time-varying surveillance mammography and breast cancer-specific and other-than-breast mortality adjusting for site, stage, primary surgery type, age and time-varying Charlson Comorbidity Index. The majority (85 %) of the 1,235 5-year breast cancer survivors received ≥ 1 surveillance mammogram in years 5-9 (yearly proportions ranged from 48 to 58 %); 82 % of women received ≥ 1 surveillance mammogram in years 10-14. A total of 120 women died of breast cancer and 393 women died from other causes (average follow-up 7.3 years). Multivariable models and lasagna plots suggested a modest reduction in breast cancer-specific mortality with surveillance mammogram receipt in the preceding year (IRR 0.82, 95 % CI 0.56-1.19, p = 0.29); the association with other-cause mortality was 0.95 (95 % CI 0.78-1.17, p = 0.64). Among older breast cancer survivors, surveillance mammography may reduce breast cancer-specific mortality even after 5 years of disease-free survival. Continuing surveillance mammography in older breast cancer survivors likely requires physician-patient discussions similar to those recommended for screening, taking into account comorbid conditions and life-expectancy.

First-line treatment patterns and clinical outcomes in patients with HER2-positive and hormone receptor-positive metastatic breast cancer from registHER.

BACKGROUND: Limited data are available describing the natural history of patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer (MBC). We examined first-line treatment patterns and clinical outcomes in patients with HER2-positive, HR-positive MBC in a real-world setting. METHODS: registHER is a prospective, observational cohort of 1,023 patients with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up time: 27 months). Demographics, first-line treatment patterns, and clinical outcomes were examined for 530 HER2-positive, HR-positive patients. Progression-free survival (PFS) and overall survival (OS) times were examined. Multivariate analyses adjusted for baseline demographic and prognostic factors. RESULTS: HER2-positive, HR-positive patients receiving first-line trastuzumab plus hormonal therapy had significantly longer PFS times than patients who received hormonal therapy only (13.8 vs. 4.8 months; adjusted hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.22-0.60); a nonsignificant reduction in OS time was observed (adjusted HR: 0.55, 95% CI: 0.27-1.14). Compared with patients who received first-line trastuzumab plus chemotherapy, patients who received first-line trastuzumab plus chemotherapy and hormonal therapy had longer median PFS times (20.4 months vs. 9.5 months; adjusted HR: 0.53, 95% CI: 0.42-0.68); a statistically significant reduction in risk of death was observed (adjusted HR: 0.50, 95% CI: 0.36-0.70). Sequential use of chemotherapy and hormonal therapy was associated with improved OS times when compared with concurrent use (adjusted PFS HR: 0.81, 95% CI: 0.54-1.21; adjusted OS HR: 0.48, 95% CI: 0.26-0.89). CONCLUSIONS: These real-world data in patients with HER2-positive/HR-positive MBC provide evidence that, with or without chemotherapy, dual targeting of HRs and HER2 receptors is associated with significantly prolonged PFS and OS times.

Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study.

BACKGROUND: Clinical trials demonstrated that women treated for breast cancer with anthracycline or trastuzumab are at increased risk for heart failure and/or cardiomyopathy (HF/CM), but the generalizability of these findings is unknown. We estimated real-world adjuvant anthracycline and trastuzumab use and their associations with incident HF/CM. METHODS: We conducted a population-based, retrospective cohort study of 12,500 women diagnosed with incident, invasive breast cancer from January 1, 1999 through December 31, 2007, at eight integrated Cancer Research Network health systems. Using administrative procedure and pharmacy codes, we identified anthracycline, trastuzumab, and other chemotherapy use. We identified incident HF/CM following chemotherapy initiation and assessed risk of HF/CM with time-varying chemotherapy exposures vs no chemotherapy. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age at diagnosis, stage, Cancer Research Network site, year of diagnosis, radiation therapy, and comorbidities. RESULTS: Among 12 500 women (mean age = 60 years, range = 22-99 years), 29.6% received anthracycline alone, 0.9% received trastuzumab alone, 3.5% received anthracycline plus trastuzumab, 19.5% received other chemotherapy, and 46.5% received no chemotherapy. Anthracycline and trastuzumab recipients were younger, with fewer comorbidities than recipients of other chemotherapy or none. Compared with no chemotherapy, the risk of HF/CM was higher in patients treated with anthracycline alone (adjusted HR = 1.40, 95% CI = 1.11 to 1.76), although the increased risk was similar to other chemotherapy (adjusted HR = 1.49, 95% CI = 1.25 to 1.77); the risk was highly increased in patients treated with trastuzumab alone (adjusted HR = 4.12, 95% CI = 2.30 to 7.42) or anthracycline plus trastuzumab (adjusted HR = 7.19, 95% CI = 5.00 to 10.35). CONCLUSIONS: Anthracycline and trastuzumab were primarily used in younger, healthier women and associated with increased HF/CM risk compared with no chemotherapy. This population-based observational study complements findings from clinical trials on cancer treatment safety.

Treatment patterns and clinical outcomes in elderly patients with HER2-positive metastatic breast cancer from the registHER observational study.

Limited data exist regarding treatment patterns and outcomes in elderly patients with HER2-positive metastatic breast cancer (MBC). registHER is an observational study of patients (N = 1,001) with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up 27 months). Outcomes were analyzed by age at MBC diagnosis: younger (<65 years), older (65-74 years), elderly (≥75 years). For progression-free survival (PFS) and overall survival (OS) analyses of first-line trastuzumab versus nontrastuzumab, older and elderly patients were combined. Cox regression analyses were adjusted for baseline characteristics and treatments. Estrogen receptor/progesterone receptor status was similar across age groups. Underlying cardiovascular disease was most common in elderly patients. In patients receiving trastuzumab-based first-line treatment, elderly patients were less likely to receive chemotherapy. In trastuzumab-treated patients, incidence of left ventricular dysfunction (LVD) and congestive heart failure (CHF) (grades ≥ 3) were highest in elderly patients (LVD: elderly 4.8 %, younger 2.8 %, older 1.5 %; CHF: elderly 3.2 %, younger 1.9 %, older 1.5 %). Unadjusted median PFS (months) was significantly higher in patients treated with first-line trastuzumab than those who were not (<65 years: 11.0 vs. 3.4, respectively; ≥65 years: 11.7 vs. 4.8, respectively). In patients <65 years, unadjusted median OS (months) was significantly higher in trastuzumab-treated patients; in patients ≥65 years, median OS was similar (<65 years: 40.4 vs. 25.9; ≥65 years: 31.2 vs. 28.5). In multivariate analyses, first-line trastuzumab use was associated with significant improvement in PFS across age. For OS, significant improvement was observed for patients <65 years and nonsignificant improvement for patients ≥65 years. Elderly patients with HER2-positive MBC had higher rates of underlying cardiovascular disease than their younger counterparts and received less aggressive treatment, including less first-line trastuzumab. These real-world data suggest improved PFS across all age groups and similar trends for OS.

Cardiovascular outcomes in women with advanced breast cancer exposed to chemotherapy.

PURPOSE: To quantify incidence of cardiovascular outcomes in patients with advanced breast cancer receiving cardiotoxic and non-cardiotoxic chemotherapy. METHODS: This study identified all women at a Midwestern health system with initial diagnosis of American Joint Commission on Cancer Stage III/IV breast cancer (1995-2003) and random sample of 50 women initially diagnosed with Stage I/II who progressed to Stage III/IV. The rate of new cardiovascular outcomes (heart failure, dysrhythmia, and ischemia events) for cardiotoxic (anthracycline or trastuzumab) and non-cardiotoxic agents was calculated. RESULTS: Of 315 patients, 90.5% (n = 285) received systemic cancer therapy; 67.7% (n = 193) received cardiotoxic drugs. Older patients were less likely to receive cardiotoxic agents (86.4%, ≤59 years vs. 31.9%, 70+ years). Adjusting for age, race, stage, surgery/radiation, estrogen receptor/progesterone receptor status, and diagnosis year, rate of new cardiac events was higher in patients exposed to cardiotoxic drugs compared with those exposed to non-cardiotoxic drugs (adjusted hazard ratio = 2.5, 95%CI = 0.9-7.2). Patients with cardiac event history (relative risk = 3.2, 95%CI = 2.0-5.1) and those with heart failure history (relative risk = 5.9, 95%CI = 2.4-14.6) were more likely to receive non-cardiotoxic treatment. Heart failure events occurred steadily over time; after 3 years of follow-up, 16% exposed to cardiotoxic drugs experienced an event, and 8% of those exposed to non-cardiotoxic drugs experienced an event. CONCLUSIONS: Patients with cardiac comorbidity are less likely to receive cardiotoxic agents. Use of cardiotoxic agents is common; treatment is related to patient and tumor characteristics and is associated with substantial risk of cardiotoxicity that persists during patients' remaining lifespan.

Validity of eight integrated healthcare delivery organizations' administrative clinical data to capture breast cancer chemotherapy exposure.

BACKGROUND: Cancer Research Network (CRN) sites use administrative data to populate their Virtual Data Warehouse (VDW). However, information on VDW chemotherapy data validity is limited. The purpose of this study was to assess the validity of VDW chemotherapy data. METHODS: This was a retrospective cohort study of women ≥18 years with incident, invasive breast cancer diagnosed between January 1999 and December 2007. Pharmacy and procedure chemotherapy data were extracted from each site's VDW. Random samples of 50 patients stratified on trastuzumab, anthracyclines, and no chemotherapy exposure was selected from each site for detailed chart abstraction. Weighted sensitivities and specificities of VDW compared with abstracted data were calculated. Cumulative doses calculated from VDW data were compared with doses obtained from the medical chart review. RESULTS: The cohort included 13,497 patients with 6,456 (48%) chart review eligible. Patients in the sample (N = 400) had a mean age of 65 years. Trastuzumab, anthracycline, and other chemotherapy weighted sensitivities were 95%, 97%, and 100%, respectively; specificities were 99%, 99%, and 93%, respectively; positive predictive values were 96%, 99%, and 55%, respectively; and negative predictive values were 99%, 96%, and 100%. Trastuzumab and anthracyclines VDW mean doses were 873 and 386 mg, respectively, whereas abstracted mean doses were 1,734 and 369 mgs, respectively (R(2) = 0.14, P < 0.01 and R(2) = 0.05, P = 0.03, respectively). CONCLUSIONS: Sensitivities and specificities for CRN chemotherapy VDW data were high and dosages were correlated with chart information. IMPACT: The findings support the use of CRN data in evaluating chemotherapy exposures and related outcomes.

Adherence to treatment with second-line therapies, dasatinib and nilotinib, in patients with chronic myeloid leukemia.

BACKGROUND AND OBJECTIVE: Previous studies have shown that long-term outcomes are more favorable for patients newly diagnosed with chronic myeloid leukemia (CML) if a complete cytogenetic response is achieved within ≤12 months of diagnosis. Because continuous and adequate dosing is important to achieve this outcome, it is important to understand treatment adherence as part of managing long-term CML therapy. While studies regarding imatinib suggest that adherence varies widely, data addressing adherence to newer breakpoint cluster region-Abelson (BCR-ABL) inhibitors (dasatinib and nilotinib) are sparse. This study evaluates real-world adherence in patients diagnosed with CML receiving dasatinib or nilotinib as second-line therapy. RESEARCH DESIGN AND METHODS: Using the HealthCore Integrated Research Database (HIRD(SM)), patients with ≥1 International Classification of Diseases, 9th edition/revision, Clinical Modification (ICD-9-CM) code for CML (205.1x ) and ≥1 prescription for imatinib from January 1, 2001 to June 30, 2010 were identified. Analysis was limited to patients who switched to second-line dasatinib or nilotinib. Dasatinib exposure was stratified by dose (≤100 mg/day or ≥140 mg/day) to account for dasatinib label changes. MAIN OUTCOME MEASURES: Medication possession ratio (MPR) was used to calculate adherence and Cox proportional hazard models were used to quantify poor rates of adherence (i.e., MPR <85%). RESULTS: Of 2064 imatinib-exposed patients, 197 received dasatinib (≤100 mg/day, n = 112; ≥140 mg/day, n = 85) and 53 received nilotinib (400 mg BID, n = 46; 400 mg QD, n = 7) as second-line therapy. Mean exposure durations were 276 days for dasatinib (≤100 mg, 275 days; ≥140 mg, 276 days) and 170 days for nilotinib. Cox proportional hazard models quantifying rates of poor adherence (MPR < 85%) comparing nilotinib with dasatinib (adjusted for age, sex, duration of previous imatinib exposure, number of concomitant medications, presence of cardiovascular disease or diabetes) calculated hazard ratios of 1.6 (95% confidence interval [CI], 1.0-2.4) for nilotinib versus dasatinib overall, 1.9 (95% CI, 1.2-3.0) for nilotinib versus dasatinib ≤100 mg, and 1.2 (95% CI, 0.7-2.0) for nilotinib versus dasatinib ≥140 mg. CONCLUSIONS: While this study is limited by use of claims data to identify CML and adherence, claims based data have been widely used to evaluate the association between treatment use and clinical outcomes. When stratified by dose, patients receiving second-line nilotinib were almost two times more likely to have poor adherence compared with patients receiving second-line dasatinib at the current approved dose of 100 mg once daily.