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Incidence of Venous Thromboembolism and the Impact on Survival in Breast Cancer Patients
Abstract
The incidence of venous thromboembolism (VTE) and the risk factors associated with development of VTE have not been reported in a large population-based study of breast cancer patients.
The California Cancer Registry was merged with the Patient Discharge Data Set, and the number of VTE events determined among patients diagnosed between 1993 and 1999.
Among 108,255 patients with breast cancer, the 2-year cumulative VTE incidence was 1.2%, with a rate of 1.2 and 0.6 events/100 patient-years during the first and second half-year, respectively. The 1-year incidence of VTE was significantly increased compared with the general population (standardized incidence ratio of VTE, 4.2; 95% CI, 3.9 to 4.4). In a multivariate model, significant predictors of developing VTE within 2 years were: age (hazard ratio [HR], 2.0 if > 75 years v < 45; 95% CI, 1.6 to 2.6), the number of chronic medical comorbidities (HR, 2.9 if 3 v 0; 95% CI, 2.4 to 3.5), and advancing cancer stage (HR, 6.3; 95% CI, 5.3 to 7.5 for metastatic v local disease). In multivariate models, VTE was a significant predictor of decreased 2-year survival (HR, 2.3; 95% CI, 2.1 to 2.6) and when stratified by initial cancer stage, the effect was highest in patients with localized (HR, 5.1; 95% CI, 3.6 to 7.1) or regional stage (HR, 3.5; 95% CI, 2.5 to 4.8) cancer compared with patients with metastatic disease (HR, 1.9; 95% CI, 1.5 to 2.4).
The incidence of venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, after breast cancer diagnosis is not well defined. An association between thromboembolic complications and specific treatments has been reported in large clinical trials. Specifically, a higher incidence of VTE has been reported in patients receiving tamoxifen therapy (0.9%), chemotherapy (2.1%), and the combination (4% to 13%), in either early stage1-4 or advanced breast cancer (4.4%).5 Although these clinical trials have documented an increased risk of VTE in patients receiving protocol treatment, differences in patient characteristics, the definition of thromboembolism applied, and the duration of follow-up make comparisons challenging. Furthermore, these studies have not analyzed the effect of VTE on survival.
We recently reported the incidence of VTE among patients with commonly diagnosed cancers using the California Cancer Registry merged with the state's Patient Discharge Data Set.6 Patients with metastatic breast cancer at diagnosis had an incidence rate in the first year of 2.8 VTE cases per 100 patient-years, compared with 20 VTE cases per 100 patient-years in the highest risk group with metastatic pancreas cancer. However, this study did not analyze the effects of comorbidities, cancer-related surgery, or histologic subtype on the incidence of VTE. The objectives of this study were to describe the incidence and time course of VTE in a population-based cohort with newly diagnosed breast cancer, and to determine the risk factors and outcomes associated with the development of VTE.
This study was conducted using two merged databases, the California Cancer Registry and the California Patient Discharge Data Set, which have been previously described.6,7 This study was approved by the California Health and Welfare Agency Committee for the Protection of Human Subjects and the University of California Davis Human Subjects Committee.
The breast cancer cohort included all breast cancer cases diagnosed in patients 18 years or older between January 1993 to December 1995 and January 1997 to December 1999. These dates were selected because during this time period outpatient use of low molecular weight heparin was rare, and patients with symptomatic VTE required hospitalization. Patients diagnosed at federal or military hospitals (n = 14) were excluded because of the absence of hospital discharge data. Registry information included basic demographics, Surveillance, Epidemiology and End Results (SEER) cancer stage, date of diagnosis, type and extent of major surgery, and cancer histology. SEER stage 1 is localized, confined to the breast; SEER stages 2 to 5 are regional, involving ipsilateral lymph nodes, direct extension, or both; and SEER stage 7 is remote, involving distant metastasis. Tumor histologies were categorized into distinct groups: adenocarcinoma NOS (not otherwise specified), lobular carcinoma, carcinoma NOS, and mucinous, tubular, papillary, and medullary carcinomas. Histologic types with fewer than 10 cases, sarcomas, adenocystic carcinomas, and malignant phyllodes tumors were excluded. The date of cancer diagnosis was defined as the earlier of: the cancer registry diagnosis date or the date of a hospital admission that included an International Classification of Diseases, ninth revision (ICD-9-CM) for primary or metastatic breast cancer.
The primary outcomes were the incidence of VTE and survival. Death was determined using the California master death registry linked to the Patient Discharge Data Set. Deep vein thrombosis and pulmonary embolism were defined using previously validated ICD-9-CM codes: 451.1x; 451.2; 451.81; 453.1; 453.2; 453.8; 453.9; 415.1x in the principal or a secondary position together with a hospital stay of 2 or more days, unless the patient died. Cases with superficial phlebitis or upper extremity VTE were identified but excluded in the primary analysis. To identify only first time VTE patients, records with a VTE diagnosis between July 1, 1990 and the date of breast cancer diagnosis were excluded.
The date of admission was considered the date of the VTE event for patients admitted with a principal diagnosis of VTE. If VTE was a secondary diagnosis and there was an associated code for a test to diagnose VTE, the VTE date was the procedure date. For patients with a secondary diagnosis of VTE and no test date, the VTE diagnosis date was assigned the median day of hospitalization.8
Using a hierarchical classification system, all first-time VTE patients were assigned a principal provoking risk factor based on the presence of specific ICD-9-CM codes. In order, these were: prior major breast cancer surgery (< 61 days); other malignancy (other cancer diagnosed < 6 months); pregnancy (< 40 weeks before or 6 weeks after delivery); trauma (< 61 days); other surgery (surgical diagnosis-related group [DRG] < 61 days); recent medical hospitalization (< 61 days with hospital stay of ≥ 4 days); concurrent medical hospitalization; and spontaneous (all remaining patients admitted with VTE).
In a prior study,9 the crude age, race, and sex-specific incidence of first-time VTE in California between 1995 and 1997 was determined using the California Patient Discharge Data Set and the identical ICD-9-CM codes and exclusion criteria used in this study to define VTE. The 2000 census figures for age, race, and sex were used to define the population distribution, adjusting the total population to published estimates for 1995 to 1997.10 All patients diagnosed with breast cancer were used to calculate the age-, sex-, and race-specific expected incidence of VTE in 1 year. Patients who died in year 1 were excluded when the year 2 expected incidence was calculated.
The presence of chronic comorbid medical conditions was determined using a variation of the Elixhauser comorbidity index, a comorbidity measure designed for use with large administrative inpatient data sets.11 Of the 29 conditions defined by this index, five conditions were excluded, three terms for cancer (tumor, metastatic, and lymphoma) and two terms for more acute conditions (electrolyte disturbance and coagulopathy). The number of comorbid conditions was based on diagnosis codes present during the index hospitalization and any hospitalizations 2 years before the cancer diagnosis.12
Incidence rates were calculated as both cumulative incidence and as person-time (events/100 patient-years). Standardized incidence ratios (SIRs) of VTE were calculated and CIs were computed assuming an underlying Poisson distribution for the number of VTE events. Cox proportional hazard models were used to analyze the effect of specified risk factors on the outcomes of VTE or death within 2 years of cancer diagnosis. In models predicting death, VTE was entered as a time-dependent covariate, as was major surgery in models predicting VTE. The significance of individual levels of polytomous variables was only interpreted after an overall test of significance using type III Sums of Squares tests. Proportionality assumptions of the models were checked and were met by the data. Kaplan-Meier plots were generated to compare survival among patients who developed VTE with patients who never developed VTE, matching four controls to each patient on survival from the cancer diagnosis date to the VTE diagnosis date, age (within 1 year), race (Asian v non-Asian), and cancer stage. Analyses were performed using SAS, S-plus (version 3.3; Statistical Sciences, Seattle, WA), or SISA (Simple Interactive Statistical Analysis, SMR Exact; http://home.clara.net/sisa/smr.htm). Given the large sample size, in multivariate models and comparisons of survival, P < .0001 was used to define statistical significance.
A total of 108,255 eligible breast cancer patients were identified in the 6-year study period. Ninety-nine percent were women with an average age of 62 ± 16 years. As presented in Table 1, white patients comprised 75% of the cohort. The majority of patients (61%) were diagnosed with localized breast cancer and 82% of the tumors were classified as adenocarcinomas.
The 1- and 2-year cumulative incidence of VTE was 0.9% and 1.2%, respectively. The 2-year incidence of upper extremity VTE was less than 0.5%. Table 1 summarizes the incidence of VTE, expressed as the rate per 100 patient-years, in the first and second 6 months after breast cancer diagnosis, and as the 2-year cumulative incidence. The VTE incidence rate between months 0 to 6 and 7 to 12 was 1.2 and 0.6 cases per 100 patient-years, respectively. The percentage of patients alive at 2 years is also shown. The incidence of VTE increased with advancing age and cancer stage. The highest incidence of VTE, 6.8 cases per 100 patient-years, was observed in the first 6 months after the diagnoses of metastatic cancer, with a 2-year cumulative incidence of 4.2%. For each age group, race, and cancer stage, the incidence rate of VTE was highest in the first 6 months after cancer diagnosis.
The SIR of VTE during the first and second year of follow-up for each cancer stage is presented in Appendix Table A1 (online only). The SIR for the breast cancer cohort was 4.2 (95% CI, 3.9 to 4.4) during the first year and 1.5 (95% CI, 1.4 to 1.7) during the second year. The 1-year SIR values for VTE among patients with local, regional, and metastatic breast cancer were 3, 6, and 15, respectively. Among women diagnosed with localized cancer, the SIR in the second year of follow-up was not statistically higher than expected (SIR, 1.1; 95% CI, 0.9 to 1.3).
Common provoking risk factors associated with the VTE events were identified, including surgery, pregnancy, trauma, and recent or concurrent medical hospitalizations. Twenty percent of patients underwent major surgery or had trauma within 61 days before the VTE event. However, breast cancer surgery accounted for only 9% of all VTE cases. Seventeen percent of the VTE cases were diagnosed during or within 61 days after a medical hospitalization. In 60% of the VTE patients, these provoking factors were not identified. During the 2-year follow-up, 186 women delivered a liveborn infant, but there was no VTE case associated with pregnancy.
The results of a multivariate analysis of potential risk factors associated with the development of VTE within 2 years after breast cancer diagnosis are presented in Table 2. Older age, increasing number of comorbidities, and advancing stage were associated with significantly higher risks of developing VTE. Breast cancer surgery and Asian/Pacific Islander ethnicity were associated with significantly lower risks of developing VTE. Metastatic disease at the time of diagnosis was the strongest risk factor, with a six-fold higher risk of VTE compared with localized disease (hazard ratio [HR], 6.3; 95% CI, 5.3 to 7.5). Histological subtype was not a predictor of VTE.
Figure 1 is a Kaplan-Meier plot of the 2-year incidence of VTE, stratified by cancer stage. In this plot, the day of VTE diagnosis was assigned as day 0 if the VTE was diagnosed during the same hospitalization as the cancer diagnosis. The incidence of VTE increased strikingly with advancing cancer stage.
Figure 2A is a Kaplan-Meier survival plot comparing all patients who developed VTE to a control sample of patients who never developed VTE, matching for survival to the date of the VTE diagnosis, age (within 1 year), race, and initial cancer stage. Figures 2B, 2C, and 2D are similar Kaplan-Meier survival plots stratified by the initial cancer stage. In the total cohort within each cancer stage, the development of VTE within 2 years of cancer diagnosis was associated with decreased survival compared with the matched cohort.
Results of a multivariate analysis of risk factors predicting death within 2 years of breast cancer diagnosis are presented in Table 3. Significant risk factors include advancing age, African American race, the number of chronic medical comorbidities, and advancing cancer stage. Asian ethnicity was associated with a significantly lower risk of death compared with whites. The histologic subtype of undifferentiated carcinoma was associated with a higher risk of death compared with adenocarcinoma (HR, 2.4; 95% CI, 2.2 to 2.5), whereas lobular and mucinous histologies were associated with a lower risk of death.
When adjusted for age, race, the number of comorbidities, and tumor histology, the development of VTE within 2 years of cancer diagnosis was associated with significant higher risk of death (HR, 2.3; 95% CI, 2.1 to 2.6). Stratified by cancer stage, the development of VTE remained a significant risk factor for death among patients with localized, regional, and metastatic stage breast cancer (HR, 5.1; 95% CI, 3.6 to 7.1; HR, 3.5; 95% CI, 2.5 to 4.8; and HR, 1.9; 95% CI, 1.5 to 2.4, respectively; P < .0001), but the effect of VTE on death diminished with advancing cancer stage.
The effect of VTE on survival was further analyzed according to the date of VTE diagnosis relative to the cancer diagnosis date among localized breast cancer. As shown in Figures 3A, 3B, and 3C, patients who developed VTE within 6 months of cancer diagnosis had a modestly decreased survival compared with matched patients without VTE, but the magnitude of the effect of VTE on survival increased as the time of VTE diagnosis increased to 7 to 12 months and to 1 to 2 years after cancer diagnosis. In corresponding multivariate models, using time of the VTE as a main effect, patients who were diagnosed with VTE at 7 to 12 months (HR, 3.5; 95% CI, 2.3 to 5.4) or 1 to 2 years (HR, 11.5; 95% CI, 8.1 to 16) after cancer diagnosis were significantly more likely to die than patients without VTE, whereas among the patients who developed VTE within 6 months of cancer diagnosis, the risk was not significantly increased (HR, 2.0; 95% CI, 1.4 to 2.8).
The observed 1- and 2-year incidence of VTE in this large population-based cohort was approximately 1%, a value consistent with the incidence reported in modern adjuvant endocrine studies.13,14 The incidence of VTE was not as high as reported among other types of cancers.6,15 This probably reflects the preponderance of patients who are diagnosed with local stage disease, as stage is a powerful predictor of VTE.6,16,17 However, breast cancer is the most common cancer in women in the United States18 and relative to the total population, the incidence of VTE was 4.2 times greater than expected during the first year after cancer diagnosis.
The incidence of VTE was highest in the first 6 months after cancer diagnosis, an observation also reported among common cancers6,16 and in clinical trials.4 The increased early incidence may reflect initial breast cancer treatment, as postulated by trials investigators,4 but may also be due to the biologic aggressiveness of some cancers, which has been reported to lead to activation of procoagulants.19 In support of this hypothesis is the finding that 60% of all the VTE cases were not associated with the common provoking risk factors of surgery, trauma, or medical hospitalization.
In risk-adjusted models, advancing cancer stage was the strongest predictor of VTE, an observation previously reported.6,16,17 In addition, the current study also examined the role of chronic illness and found a strong association between VTE and the presence of comorbidities. This finding is in agreement with prior reports of increasing VTE risk with medical illnesses in the general population.20,21
Interestingly, patients who underwent breast-related surgery had a 40% lower risk of developing VTE compared with those who did not have surgery, a finding also noted in patients with colon cancer.7 This observation likely reflects the exclusion of patients with advanced stage cancer or significant comorbidities from surgery. Asians with breast cancer had a lower risk of VTE compared with whites, consistent with prior publications of a lower prevalence of inherited thrombophilia in Asian patients compared with white patients.22
The development of VTE was associated with significantly reduced survival, a finding initially reported by Sorensen and colleagues23 using a linked Danish database that did not match for cancer stage. In this analysis, cancer patients who developed VTE had significantly shorter survival compared with matched patients who never developed VTE, and this difference was most pronounced in patients with local or regional stage disease. The results of multivariate models that were stratified by stage showed identical findings: the effect of VTE on survival was greatest in patients with local or regional stage disease. Moreover, among patients diagnosed with local stage cancer, the magnitude of the effect of VTE on decreased survival increased as the time between breast cancer diagnosis and development of VTE increased.
There are several potential explanations for these observations. First, the diagnosis of VTE may reflect more serious underlying medical conditions, thus leading to decreased survival in patients with less advanced disease. Multivariate modeling was used to adjust for chronic comorbidities, but no adjustment could be made for acute medical illness. Alternatively, VTE may be a marker of a biologically more aggressive cancer that would also result in earlier death. This may not be apparent in a cohort of patients with metastatic cancer who have a limited life expectancy. However, in patients with less advanced initial disease, VTE as a herald of more aggressive or recurrent cancer may have a more pronounced effect. Post hoc analyses of three recent randomized trials of low molecular weight heparin in cancer patients with24 or without25,26 VTE have suggested a survival benefit, but only among patients with less advanced disease. These findings, coupled with the results of this study, suggest that low molecular weight heparin may disrupt tumor-associated procoagulant activity and either impair the progression of cancer or render early stage cancers less biologically aggressive.27 Clearly, additional research in this area is needed.
The major limitations of this study were the absence of data on treatment with endocrine therapy or chemotherapy, and the lack of information regarding the progression of breast cancer over time. However, the observed 1% VTE incidence in this population-based study approached the incidence reported in large clinical trials.1,2 In addition, the mortality data at 2 years reassuringly mirrors SEER data,28 and findings of decreased survival among African Americans is consistent with prior studies.29 Another limitation was the absence of any information regarding primary thromboprophylaxis, although this was not common practice during the study period.30,31
In summary, the 1-year cumulative incidence of VTE after breast cancer diagnosis was approximately 1% with the highest incidence in the first 6 months of follow-up. Advancing cancer stage and increasing numbers of comorbidities were strong predictors of VTE. The diagnosis of VTE was associated with reduced survival within 2 years.
The authors indicated no potential conflicts of interest.
Conception and design: Helen K. Chew, Theodore Wun, Richard H. White
Provision of study materials or patients: Hong Zhou
Collection and assembly of data: Helen K. Chew, Danielle J. Harvey, Hong Zhou, Richard H. White
Data analysis and interpretation: Helen K. Chew, Theodore Wun, Danielle J. Harvey, Richard H. White
Manuscript writing: Helen K. Chew, Theodore Wun, Danielle J. Harvey, Richard H. White
Final approval of manuscript: Helen K. Chew, Theodore Wun, Danielle J. Harvey, Richard H. White
Fig 1. Kaplan-Meier plot of the incidence of venous thromboembolism (VTE) after breast cancer diagnosis, stratified by stage.
Fig 2. Kaplan and Meier plots of the incidence of death after venous thromboembolism (VTE) diagnosis and in a matched cohort without VTE, among the (A) entire cohort, and in (B) localized, (C) regional, and (D) metastatic stage breast cancer. Control and VTE patients were matched on survival from the cancer diagnosis date to the VTE diagnosis date, and survival was measured from this date.
Fig 3. Kaplan-Meier plots comparing the survival in localized breast cancer after venous thromboembolism (VTE) diagnosis and in a matched cohort without VTE, stratified by VTE diagnosis within (A) 6 months, (B) 7 to 12 months, and (C) 13 to 24 months of initial cancer diagnosis. Control and VTE patients were matched on survival from the cancer diagnosis date to the VTE diagnosis date, and survival was measured from this date.
|
| Variable | Patients | Rate of VTE per 100 Patient-Years | 2-Year Cumulative Incidence of VTE | Alive at 2 Years | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. | % | 0-6 Months | 95% CI | 7-12 Months | 95% CI | % | 95% CI | % | 95% CI | |||||||
| Total patients | 108,255 | 1.2 | 1.1 to 1.3 | 0.6 | 0.6 to 0.7 | 1.2 | 1.1 to 1.3 | 89.8 | 89.6 to 90.0 | |||||||
| Age, years | ||||||||||||||||
| < 45 | 14,767 | 14 | 0.7 | 0.5 to 0.9 | 0.3 | 0.2 to 0.5 | 0.7 | 0.6 to 0.9 | 92.8 | 92.4 to 93.2 | ||||||
| 45-64 | 45,276 | 42 | 1.1 | 1.0 to 1.3 | 0.5 | 0.4 to 0.6 | 1.0 | 0.9 to 1.1 | 93.4 | 93.2 to 93.6 | ||||||
| 65-74 | 24,886 | 23 | 1.3 | 1.1 to 1.5 | 0.9 | 0.7 to 1.0 | 1.5 | 1.3 to 1.6 | 91.2 | 90.9 to 91.6 | ||||||
| ≥ 75 | 23,326 | 21 | 1.6 | 1.4 to 1.9 | 0.9 | 0.7 to 1.1 | 1.6 | 1.4 to 1.7 | 79.4 | 78.9 to 79.9 | ||||||
| Race/ethnicity* | ||||||||||||||||
| White | 81,721 | 75 | 1.3 | 1.2 to 1.4 | 0.7 | 0.6 to 0.8 | 1.3 | 1.2 to 1.3 | 89.7 | 89.5 to 89.9 | ||||||
| Hispanic | 12,157 | 11 | 1.1 | 0.9 to 1.4 | 0.6 | 0.4 to 0.8 | 1.1 | 1.0 to 1.3 | 90.8 | 90.3 to 91.3 | ||||||
| Asian American | 7,490 | 7 | 0.4 | 0.2 to 0.6 | 0.2 | 0.1 to 0.3 | 0.3 | 0.2 to 0.4 | 93.8 | 93.3 to 94.4 | ||||||
| African American | 6,107 | 6 | 1.5 | 1.1 to 2.0 | 1.0 | 0.7 to 1.4 | 1.8 | 1.5 to 2.1 | 83.7 | 82.7 to 84.6 | ||||||
| Stage | ||||||||||||||||
| Localized | 66,475 | 61 | 0.8 | 0.7 to 0.9 | 0.4 | 0.4 to 0.5 | 0.8 | 0.8 to 0.9 | 95.6 | 95.5 to 95.8 | ||||||
| Regional | 32,990 | 30 | 1.5 | 1.3 to 1.7 | 0.9 | 0.8 to 1.0 | 1.6 | 1.4 to 1.7 | 88.9 | 88.6 to 89.3 | ||||||
| Metastatic | 4,499 | 4 | 6.8 | 5.7 to 8.1 | 2.4 | 1.7 to 3.3 | 4.2 | 3.6 to 4.8 | 40.5 | 39.0 to 41.9 | ||||||
| Unknown | 4,291 | 4 | 1.3 | 0.8 to 1.9 | 0.7 | 0.3 to 1.2 | 1.0 | 0.7 to 1.3 | 57.9 | 56.4 to 59.4 | ||||||
| Histologic subtype | ||||||||||||||||
| Adenocarcinoma NOS | 88,793 | 82 | 1.2 | 1.1 to 1.3 | 0.6 | 0.5 to 0.7 | 1.2 | 1.1 to 1.3 | 91.0 | 90.9 to 91.2 | ||||||
| Lobular carcinoma | 9,066 | 8 | 1.1 | 0.9 to 1.5 | 0.7 | 0.5 to 1.0 | 1.2 | 1.0 to 1.4 | 92.7 | 92.2 to 93.2 | ||||||
| Carcinoma NOS | 4,042 | 4 | 2.2 | 1.5 to 3.0 | 1.6 | 1.0 to 2.4 | 1.6 | 1.3 to 2.1 | 48.5 | 47.0 to 50.0 | ||||||
| Mucinous | 2,822 | 3 | 1.0 | 0.6 to 1.7 | 0.7 | 0.4 to 1.3 | 1.1 | 0.8 to 1.5 | 94.4 | 93.6 to 95.2 | ||||||
| Tubular | 1,594 | 1 | 0.4 | 0.1 to 1.0 | 0.4 | 0.1 to 1.0 | 0.8 | 0.4 to 1.3 | 96.8 | 96.0 to 97.7 | ||||||
| Medullary | 1,248 | 1 | 1.5 | 0.7 to 2.7 | 0.5 | 0.1 to 1.4 | 1.1 | 0.6 to 1.8 | 94.2 | 92.9 to 95.5 | ||||||
| Papillary | 690 | 1 | 0.9 | 0.2 to 2.4 | 1.2 | 0.4 to 2.9 | 1.3 | 0.6 to 2.4 | 93.6 | 91.8 to 95.4 | ||||||
Abbreviations: VTE, venous thromboembolism; NOS, not otherwise specified.
*< 1% of the cohort classified as other are not included.
|
| Variable | Hazard Ratio | 95% CI | P |
|---|---|---|---|
| Age (v < 45), years | < .0001* | ||
| 45-64 | 1.4 | 1.2 to 1.8 | .0009 |
| 65-74 | 1.9 | 1.5 to 2.4 | < .0001 |
| >75 | 2.0 | 1.6 to 2.6 | < .0001 |
| Race/ethnicity (v white) | < .0001* | ||
| African American | 1.3 | 1.0 to 1.5 | .022 |
| Hispanic | 0.9 | 0.8 to 1.1 | .49 |
| Asian American | 0.3 | 0.2 to 0.4 | < .0001 |
| No. of chronic comorbid conditions (v 0) | < .0001* | ||
| 1 | 1.9 | 1.6 to 2.2 | < .0001 |
| 2 | 2.3 | 1.9 to 2.7 | < .0001 |
| 3 | 2.9 | 2.4 to 3.5 | < .0001 |
| SEER stage (v localized) | < .0001* | ||
| Regional | 2.1 | 1.8 to 2.3 | < .0001 |
| Metastatic | 6.3 | 5.3 to 7.5 | < .0001 |
| Histologic subtype (v adenocarcinoma) | .41* | ||
| Lobular | 0.8 | 0.7 to 1.0 | .09 |
| Carcinoma NOS | 1.2 | 0.9 to 1.6 | .19 |
| Mucinous | 1.0 | 0.7 to 1.4 | .91 |
| Tubular | 0.8 | 0.4 to 1.4 | .43 |
| Medullary | 1.2 | 0.7 to 2.0 | .52 |
| Papillary | 1.1 | 0.6 to 2.1 | .77 |
| Breast-related surgery | |||
| Yes v no | 0.6 | 0.5 to 0.7 | < .0001 |
Abbreviations: VTE, venous thromboembolism, SEER, Surveillance, Epidemiology and End Results; NOS, not otherwise specified.
*Overall test of significance for polytomous variable.
|
| Variable | Hazard Ratio | 95% CI | P |
|---|---|---|---|
| Age (v < 45), years | < .0001* | ||
| 45-64 | 1.0 | 0.9 to 1.1 | .80 |
| 65-74 | 1.3 | 1.2 to 1.4 | < .0001 |
| >75 | 2.9 | 2.7 to 3.1 | < .0001 |
| Race/ethnicity (v white) | < .0001* | ||
| African American | 1.4 | 1.3 to 1.5 | < .0001 |
| Hispanic | 1.0 | 0.9 to 1.0 | .41 |
| Asian American | 0.8 | 0.7 to 0.9 | < .0001 |
| No. of chronic comorbid conditions (v 0) | < .0001* | ||
| 1 | 1.3 | 1.2 to 1.4 | < .0001 |
| 2 | 1.8 | 1.7 to 1.9 | < .0001 |
| 3 | 2.7 | 2.6 to 2.9 | < .0001 |
| SEER stage (v localized) | < .0001* | ||
| Regional | 2.8 | 2.7 to 3.0 | < .0001 |
| Metastatic | 18.4 | 17.4 to 19.4 | < .0001 |
| Histologic subtype (v adenocarcinoma) | < .0001* | ||
| Lobular | 0.7 | 0.6 to 0.7 | < .0001 |
| Carcinoma NOS | 2.4 | 2.2 to 2.5 | < .0001 |
| Mucinous | 0.7 | 0.6 to 0.8 | < .0001 |
| Tubular | 0.6 | 0.5 to 0.8 | .001 |
| Medullary | 1.0 | 0.8 to 1.2 | .68 |
| Papillary | 0.7 | 0.5 to 0.9 | .008 |
| VTE | 2.3 | 2.1 to 2.6 | < .0001 |
Abbreviations: VTE, venous thromboembolism; SEER, Surveillance, Epidemiology and End Results; NOS, not otherwise specified.
*Overall test of significance for polytomous variable.
|
| SEER Stage | VTE | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Year 1 | Year 2 | ||||||||||||||
| Observed | Expected | SIR | 95% CI | Observed | Expected | SIR | 95% CI | ||||||||
| Localized | 401 | 150 | 2.7* | 2.4 to 2.9 | 161 | 145 | 1.1 | 0.9 to 1.3 | |||||||
| Regional | 387 | 62 | 6.2* | 5.7 to 6.9 | 125 | 56 | 2.2* | 1.9 to 2.7 | |||||||
| Metastatic | 156 | 10 | 15.6* | 13.3 to 18.2 | 33 | 5 | 6.6* | 4.7 to 9.3 | |||||||
| Total | 975 | 234 | 4.2* | 3.9 to 4.4 | 331 | 214 | 1.5* | 1.4 to 1.7 | |||||||
NOTE. Unclassified stage not included in the breakdown, but it is included in the total.
Abbreviations: SIR, standardized incidence ratios; VTE, venous thromboembolism; SEER, Surveillance, Epidemiology, and End Results.
*P < .001.
Supported in part by National Institutes of Health Grant No. 1-RO3- CA99527-01 (H.K.C.).
Presented in part at the 28th Annual San Antonio Breast Cancer Symposium December 8-11, 2005.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
| 1. | Fisher B, Costantino J, Redmond C, et al: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 320::479,1989-484, Crossref, Medline, Google Scholar |
| 2. | Clahsen PC, van de Velde CJ, Julien JP, et al: Thromboembolic complications after perioperative chemotherapy in women with early breast cancer: A European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group study. J Clin Oncol 12::1266,1994-1271, Link, Google Scholar |
| 3. | Fisher B, Dignam J, Wolmark N, et al: Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89::1673,1997-1682, Crossref, Medline, Google Scholar |
| 4. | Pritchard KI, Paterson AH, Paul NA, et al: Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer: National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. J Clin Oncol 14::2731,1996-2737, Link, Google Scholar |
| 5. | Levine M, Hirsh J, Gent M, et al: Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 343::886,1994-889, Crossref, Medline, Google Scholar |
| 6. | Chew HK, Wun T, Harvey D, et al: Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 166::458,2006-464, Crossref, Medline, Google Scholar |
| 7. | Alcalay A, Wun T, Khatri V, et al: Venous thromboembolism in patients with colorectal cancer: Incidence and effect on survival. J Clin Oncol 24::1112,2006-1118, Link, Google Scholar |
| 8. | White RH, Romano PS, Zhou H, et al: Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med 158::1525,1998-1531, Crossref, Medline, Google Scholar |
| 9. | White RH, Zhou H, Murin S, et al: Effect of ethnicity and gender on the incidence of venous thromboembolism in a diverse population in California in 1996. Thromb Haemost 93::298,2005-305, Crossref, Medline, Google Scholar |
| 10. | California Department of Finance: E-4 Revised Historical City, County, and State Population Estimates, 1991-2000, with 1990 and 2000 Census Counts. Sacramento, CA, California Department of Finance, 2002 Google Scholar |
| 11. | Elixhauser A, Steiner C, Harris DR, et al: Comorbidity measures for use with administrative data. Med Care 36::8,1998-27, Crossref, Medline, Google Scholar |
| 12. | Stukenborg GJ, Wagner DP, Connors AF Jr: Comparison of the performance of two comorbidity measures, with and without information from prior hospitalizations. Med Care 39::727,2001-739, Crossref, Medline, Google Scholar |
| 13. | Baum M, Budzar AV, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359::2131,2002-2139, Crossref, Medline, Google Scholar |
| 14. | Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350::1081,2004-1092, Crossref, Medline, Google Scholar |
| 15. | Levitan N, Dowlati A, Remick SC, et al: Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy: Risk analysis using Medicare claims data. Medicine (Baltimore) 78::285,1999-291, Crossref, Medline, Google Scholar |
| 16. | Blom JW, Doggen CJ, Osanto S, et al: Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 293::715,2005-722, Crossref, Medline, Google Scholar |
| 17. | Stein PD, Beemath A, Meyers FA, et al: Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med 119::60,2006-68, Crossref, Medline, Google Scholar |
| 18. | Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55::10,2005-30, Crossref, Medline, Google Scholar |
| 19. | Rickles FR, Patierno S, Fernandez PM: Tissue factor, thrombin, and cancer. Chest 124::58S,2003–68S, (suppl 3) Crossref, Medline, Google Scholar |
| 20. | Haas S: Venous thromboembolism in medical patients: The scope of the problem. Semin Thromb Hemost 29::17,2003-21, (suppl 1) Crossref, Medline, Google Scholar |
| 21. | Alikhan R, Cohen AT, Combe S, et al: Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: Analysis of the MEDENOX study. Arch Intern Med 164::963,2004-968, Crossref, Medline, Google Scholar |
| 22. | Gregg JP, Yamane AJ, Grody WW: Prevalence of the factor V-Leiden mutation in four distinct American ethnic populations. Am J Med Genet 73::334,1997-336, Crossref, Medline, Google Scholar |
| 23. | Sorensen HT, Mellemkjaer L, Olsen JH, et al: Prognosis of cancers associated with venous thromboembolism. N Engl J Med 343::1846,2000-1850, Crossref, Medline, Google Scholar |
| 24. | Lee AY, Rickles FR, Julian JA, et al: Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 23::2123,2005-2129, Link, Google Scholar |
| 25. | Kakkar AK, Levine MN, Kadziola Z, et al: Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: The fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol 22::1944,2004-1948, Link, Google Scholar |
| 26. | Klerk CP, Smorenburg SM, Otten HM, et al: The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 23::2130,2005-2135, Link, Google Scholar |
| 27. | Petralia GA, Lemoine NR, Kakkar AK: Mechanisms of disease: The impact of antithrombotic therapy in cancer patients. Nat Clin Pract Oncol 2::356,2005-363, Crossref, Medline, Google Scholar |
| 28. | National Cancer Institute: Surveillance, Epidemiology and End Results. http://seer.cancer.gov Google Scholar |
| 29. | Newman LA, Griffith KA, Jatoi I, et al: Meta-analysis of survival in African American and white American patients with breast cancer: Ethnicity compared with socioeconomic status. J Clin Oncol 24::1342,2006-1349, Link, Google Scholar |
| 30. | Levine M, Gent M, Hirsh J, et al: A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 334::677,1996-681, Crossref, Medline, Google Scholar |
| 31. | Koopman MM, Prandoni P, Piovella F, et al: Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home: The Tasman Study Group. N Engl J Med 334::682,1996-687, Crossref, Medline, Google Scholar |
