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. 2011 Mar 10;22(11):2394–2402. doi: 10.1093/annonc/mdq777

Risk factors and incidence of thromboembolic events (TEEs) in older men and women with breast cancer

M Chavez-MacGregor 1, H Zhao 2, M Kroll 3, S Fang 2, N Zhang 2, G N Hortobagyi 2, T A Buchholz 4, Y-C Shih 5, S H Giordano 2,*
PMCID: PMC3200221  PMID: 21393379

Abstract

Background: The purpose of this study is to evaluate the risk factors and the prevalence of thromboembolic events (TEEs) in breast cancer patients.

Patients and methods: This is a retrospective cohort study using the Surveillance, Epidemiology, and End Results-Medicare database. Breast cancer patients diagnosed from 1992 to 2005 ≥66 years old were identified. International Classification of Diseases, Ninth Revision, and Healthcare Common Procedure Coding System codes were used to identify TEEs within 1 year of the breast cancer diagnosis. Analyses were conducted using descriptive statistics and logistic regression.

Results: A total of 89 841 patients were included, of them 2658 (2.96%) developed a TEE. In the multivariable analysis, males had higher risk of a TEE than women [odd ratio (OR) = 1.57; confidence interval (CI) 1.10–2.25] and blacks had higher risk than whites (OR = 1.20; CI 1.04–1.40). Compared with stage I patients, patients with stage II, III and IV had 22%, 39% and 98% increase, respectively, in risk. Placement of central catheters (OR = 2.71; CI 2.43–3.02), chemotherapy treatment (OR = 1.66; CI 1.48–1.86) or treatment with erythropoiesis-stimulating agents (ESAs) (OR = 1.33; CI 1.33–1.52) increase the risk. Other significant predictors included comorbidities, age, receptor status, marital status and year of diagnosis. Similar estimates were seen for pulmonary embolism, deep vein thromboembolism and other TEEs.

Conclusions: In total, 2.96% of patients in this cohort developed a TEE within 1 year from breast cancer diagnosis. Stage, gender, race, use of chemotherapy and ESAs, comorbidities, receptor status and catheter placement were associated with the development of TEEs.

Keywords: breast cancer, cancer-associated thrombosis, deep venous thrombosis, population-based study, thromboembolic events, thrombosis

introduction

Thromboembolic events (TEEs) are a common complication and a life-threatening condition in cancer patients [1, 2]. Trousseau [3] described in 1868 the relationship between malignancy and venous thrombosis. Today, it is well recognized that thrombosis and cancer are linked by multiple pathophysiological mechanisms and that tumor biology and coagulation processes are integrally connected [4].

Population-based studies have showed that the presence of cancer increases the risk of TEEs by four- and sevenfold [2, 5]. Furthermore, advanced age, race, stage, comorbidities and the use of systemic therapies and intravascular catheters are factors that have been associated with an increased risk of TEE in patients with cancer [1, 5–11]. Different risk estimates have been observed among different primary cancer sites; for example gastric, pancreatic, kidney cancers and astrocytomas are associated with a higher risk of developing a TEE than other cancers [1, 6].

Breast cancer patients are considered to be at relatively low risk of developing a TEE; a recent study reported an incidence rate of 1.2% within 2 years of diagnosis [12]. Data from clinical trials suggest that the risk is higher in patients receiving chemotherapy (2.1%) [13] or in those with metastatic disease (4.4%) [14]. Breast cancer is the most common cancer in women in the United States[15]; therefore, the occurrence of a TEE represents a common clinical problem in patients with breast cancer. In this retrospective study, we sought to explore the incidence and the risk factors associated with TEEs in a large cohort of older patients with newly diagnosed breast cancer.

patients and methods

data source

We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. The SEER program, supported by the USA National Cancer Institute (NCI), collects data from tumor registries; during the years included in this study, the database covered 14%–25% of the USA population. The Medicare program is administered by the Centers for Medicare and Medicaid Services and covers 97% of the USA population aged ≥65 years [16]. Of SEER participants who were diagnosed with cancer at age ≥65 years, 94% are matched with their Medicare enrollment records [16].

Patient demographics, tumor characteristics, and treatment information were extracted from the SEER-Medicare Patient Entitlement and Diagnosis Summary File (PEDSF); Medicare claims files for durable medical equipment (DME), physician/supplier [National Claims History (NCH)], inpatient service [Medicare Provider Analysis and Review (MEDPAR)], and outpatient service files.

study population

This study included patients ≥66 years old with a diagnosis of stage I–IV breast cancer (American Joint Committee on Cancer Staging third edition). Patients were required to have Medicare Part A and B and not to be members of a Health Maintenance Organization (HMO) for 1 year prior and after their breast cancer diagnosis, because Medicare claims are not complete for HMO members. From the initial 319 395 patients with breast cancer diagnosed from 1992 to 2005, 32 256 had history of prior or subsequent malignancies; 1 089 had an unknown month of diagnosis; 103 599 were <66 years old; 37 389 were unstaged or had an unknown initial stage; 45 511 did not have full coverage of Medicare A and B or were members of an HMO, and 193 had non-carcinoma histology. From them, only the 90 153 patients who developed a TEE within the first year of diagnosis and those not developing a TEE were included. Three hundred and twelve patients with an unknown education level were excluded, in order to preserve confidentiality and maintain at least 15 patients per cell in subgroup analyses, per NCI regulations. A total of 89 841 patients were included.

data extraction and definitions

The main outcome of this study was a TEE within the first year of breast cancer diagnosis. TEEs were defined as pulmonary embolism (PE), deep vein thromboembolism (DVT), or other/unclassified TEEs. To identify TEE cases, the study period for each patient was from 1 year before breast cancer diagnosis to 1 year after breast cancer was diagnosed or death (if within 1 year from breast cancer diagnosis). We identified cases of TEEs using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes from the Medicare claims files DME, NCH, MEDPAR, and outpatient service files. Diagnosis code 415.1x was identified as PE; codes 451, 453.1, 453.2, and 453.4 were identified as DVT; and codes 452, 453, 453.0, 453.3, 453.5, 453.6, 453.7, 453.8, and 453.9 were identified as other/unclassified TEEs. In the MEDPAR files, a patient was identified as having a TEE if there was a claim of PE, DVT, or other TEEs as primary diagnosis. In the other three claims files, a patient was classified as having a TEE if the diagnosis appeared in at least two claims with 30 days apart. After we identified the TEE cases, we merged them and chose the earliest date as the TEE diagnosis date.

Demographic and tumor characteristics were obtained from the PEDSF. For the census tract variables of education and poverty level, quartiles were calculated in increasing order. Chemotherapy was identified from Medicare claims; surgery and radiation therapy were identified from the SEER dataset and Medicare claims. Central venous catheter (CVC) placement in the first year after cancer diagnosis was identified from Medicare claims files DME, MEDPAR, NCH, and outpatient service files. Also the use of erythropoiesis-stimulating agents (ESAs) in the same time period was recorded. Using ICD-9-CM diagnosis and procedure codes, the presence of comorbid conditions from 12 to 1 month before the diagnosis of breast cancer was identified in the Medicare inpatient, outpatient and physicians claims data. A comorbidity score was calculated using Klabunde's adaptation of the Charlson comorbidity index from the SAS macro provided by NCI [12,17–19]. The comorbidities included in the score are myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, diabetes (with and without end-organ damage), chronic pulmonary disease, connective tissue disease, ulcer disease, liver disease, renal disease, hemiplegia, and acquired immunodeficiency syndrome.

statistical analysis

Descriptive statistics was used. Chi-square tests were used to compare the frequency of demographic and tumor characteristics between patients who experienced at least one TEE and those who did not. Logistic regression was used to identify risk factors associated with the development of TEE within 1 year of breast cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The variables entered in the multivariable logistic regression model included age, gender, race, marital status, education level, poverty level, geographical location, year of diagnosis, stage at diagnosis, estrogen receptor (ER) and progesterone receptor (PR) status, comorbidities (Charlson index), surgery, radiation therapy, chemotherapy, presence of a CVC and the use of ESAs. All computer programming and statistical analyses were carried out with the SAS system (SAS Institute Inc., Cary, NC), and all tests were two sided.

results

Our final cohort included 89 841 patients; the median age was 75.8 years. The stage distribution was 52.1%, 34.1%, 7.5% and 6.3% for stages I–IV, respectively. Patient characteristics are shown in Table 1. A total of 2658 (2.96%) patients developed at least one TEE within the first year of breast cancer diagnosis. Among the total study samples, 773 (0.86%) had a PE; 1259 (1.4%) had a DVT; and 1829 (2.04%) had other/unclassified TEEs. Some patients had more than one event; the total number of observed events was 3861. Among the patients who experienced an event, 1646 (62%) had only one type, 821 (31%) had two types, and 191 (7%) had three types of TEE. The majority of the events occurred during the first 3 months after breast cancer diagnosis (39.5%). A total of 26.5% of the events were diagnosed between the third and the sixth month and 34% of the events were seen from months 6 to 12 after diagnosis (Figure 1).

Table 1.

Characteristics of the study cohort

Frequency %
Age (years)
    66–70 22 289 24.81
    71–75 22 989 25.59
    76–80 20 630 22.96
    >80 23 933 26.64
Gender
    Female 89 172 99.26
    Male 669 0.74
Race
    White 77 776 86.57
    Black 5646 6.28
    Other 6419 7.14
Year of diagnosis
    1992 4756 5.29
    1993 4439 4.94
    1994 4283 4.77
    1995 4359 4.85
    1996 4306 4.79
    1997 4371 4.87
    1998 4308 4.80
    1999 4452 4.96
    2000 8833 9.83
    2001 9186 10.22
    2002 9236 10.28
    2003 9211 10.25
    2004 9036 10.06
    2005 9065 10.09
Stage
    I 46 831 52.13
    II 30 652 34.12
    III 6710 7.47
    IV 5648 6.29
Estrogen receptor
    Positive 61 660 68.63
    Negative 12 108 13.48
    Unknown 16 073 17.89
Charlson comorbidity score
    0 69 349 77.19
    1 14 516 16.16
    2+ 5976 6.65
Surgery
    Breast conserving 42 518 47.33
    Mastectomy 42 773 47.61
    No surgery/unknown 4550 5.06
Radiation therapy
    No 45 405 50.54
    Yes 43 123 48.0
    Unknown 1313 1.46
Chemotherapy
    No 71 279 79.34
    Yes 18 562 20.66
CVC placement
    No 80 425 89.52
    Yes 9416 10.48
ESAs use
    No 83 596 93.05
    Yes 6245 6.95
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CVC, central venous catheter; ESA, erythropoiesis-stimulating agent.

Figure 1.

Figure 1.

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Time of TEE after breast cancer diagnosis. TEE, thromboembolic event; PE, pulmonary embolism; DVT, deep vein thromboembolism.

We observed that men with breast cancer were more likely to develop a TEE than women (5.08% versus 2.94%). Black patients had TEEs more frequently than whites or other races (4.96% versus 2.89% versus 2.01%, respectively). Stage had a clear association with the development of TEE with higher rates seen in more advanced stages (1.87% for stage I, 3.3% for stage II, 5.02% for stage III and 7.63% for stage IV). Increased comorbidities as well as the use of chemotherapy (6.09%), CVC placement (9.23%) and the use of ESAs (7.7%) were all associated with a higher event frequency. Similar results were seen when PEs, DVTs and other TEEs were analyzed separately. The frequency of the distribution of risk factors is shown in Table 2.

Table 2.

Distribution of demographic characteristics and risk factors according to TEE

Any TEE
 PE
 DVT
 Other TEEs
N = 89 841
 Cases = 2658
 N = 87 956
 Cases = 773
 N = 88 442
 Cases = 1259
 N = 89 012
 Case = 1829
Total Nocases % P Total Nocases % P Total Nocases % P Total Nocases % P
Age (years)
    66–70 22 289 676 3.03 0.172 21 802 189 0.87 0.659 21 950 337 1.54 0.081 22 073 460 2.08 0.119
    71–75 22 989 715 3.11 22 482 208 0.93 22 616 342 1.51 22 776 502 2.2
    76–80 20 630 601 2.91 20 212 183 0.91 20 304 275 1.35 20 448 419 2.05
    >80 23 933 666 2.78 23 460 193 0.82 23 572 305 1.29 23 715 448 1.89
Gender
    Female 89 172 2624 2.94 0.001 87 308 760 0.87 0.002 87 791 1243 1.42 0.025 88 359 1811 2.05 0.205
    Male 669 34 5.08 648 13 2.01 651 16 2.46 653 18 2.76
Race
    White 77 776 2249 2.89 <0.0001 76 193 666 0.87 <0.0001 76 600 1073 1.4 <0.0001 77 071 1544 2 <0.0001
    Black 5646 280 4.96 5444 78 1.43 5491 125 2.28 5567 201 3.61
    Other 6419 129 2.01 6319 29 0.46 6351 61 0.96 6374 84 1.32
Year of diagnosis
    1992 4756 127 2.67 0.346 4661 32 0.69 0.441 4681 52 1.11 0.002 4724 95 2.01 <0.0001
    1993 4439 117 2.64 4354 32 0.73 4381 59 1.35 4402 80 1.82
    1994 4283 113 2.64 4202 32 0.76 4231 61 1.44 4244 74 1.74
    1995 4359 125 2.87 4272 38 0.89 4298 64 1.49 4325 91 2.1
    1996 4306 127 2.95 4207 28 0.67 4245 66 1.55 4268 89 2.09
    1997 4371 119 2.72 4289 37 0.86 4314 62 1.44 4335 83 1.91
    1998 4308 135 3.13 4211 38 0.9 4238 65 1.53 4274 101 2.36
    1999 4452 135 3.03 4361 44 1.01 4378 61 1.39 4407 90 2.04
    2000 8833 298 3.37 8602 67 0.78 8666 131 1.51 8765 230 2.62
    2001 9186 295 3.21 8968 77 0.86 9026 135 1.5 9112 221 2.43
    2002 9236 267 2.89 9057 88 0.97 9060 91 1 9178 209 2.28
    2003 9211 274 2.97 9034 97 1.07 9048 111 1.23 9134 197 2.16
    2004 9036 272 3.01 8843 79 0.89 8897 133 1.49 8925 161 1.8
    2005 9065 254 2.8 8895 84 0.94 8979 168 1.87 8919 108 1.21
Stage
    I 46 831 878 1.87 <0.0001 46 237 284 0.61 <0.0001 46 405 452 0.97 <0.0001 46 545 592 1.27 <0.0001
    II 30 652 1012 3.3 29 918 278 0.93 30 158 518 1.72 30 327 687 2.27
    III 6710 337 5.02 6470 97 1.5 6512 139 2.13 6609 236 3.57
    IV 5648 431 7.63 5331 114 2.14 5367 150 2.79 5531 314 5.68
Estrogen receptor
    Positive 61 660 1717 2.78 <0.0001 60 445 502 0.83 0.007 60 796 853 1.4 61 138 1195 1.95 0.008
    Negative 12 108 421 3.48 11 820 133 1.13 11 870 183 1.54 0.503 11 961 274 2.29
    Unknown 16 073 520 3.24 15 691 138 0.88 15 776 223 1.41 15 913 360 2.26
Charlson comorbidity
    0 69 349 1992 2.87 <0.0001 67 931 574 0.84 0.120 68 294 937 1.37 0.001 68 738 1381 2.01 0.008
    1 14 516 435 3 14 219 138 0.97 14 286 205 1.43 14 375 294 2.05
    2+ 5976 231 3.87 5806 61 1.05 5862 117 2 5899 154 2.61
Surgery
    Breast conserving 42 518 999 2.35 41 842 323 0.77 <0.0001 42 016 497 1.18 <0.0001 42 217 698 1.65 <0.0001
    Mastectomy 42 773 1331 3.11 41 797 355 0.85 42 092 650 1.54 42 345 903 2.13
    No/unknown 4550 328 7.21 4317 95 2.2 4334 112 2.58 4450 228 5.12
Radiotherapy
    No 45 405 1307 2.88 0.067 44 438 340 0.77 0.001 44 718 620 1.39 0.523 44 971 873 1.94 0.016
    Unknown 1313 51 3.88 1277 15 1.17 1278 16 1.25 1298 36 2.77
    Yes 43 123 1300 3.01 42 241 418 0.99 42 446 623 1.47 42 743 920 2.15
Chemotherapy
    No 71 279 1527 2.14 <0.0001 70 208 456 0.65 <0.0001 70 495 743 1.05 <0.0001 70 781 1029 1.45 <0.0001
    Yes 18 562 1131 6.09 17 748 317 1.79 17 947 516 2.88 18 231 800 4.39
CVC
    No 80 425 1789 2.22 <0.0001 79 169 533 0.67 <0.0001 79 537 901 1.13 <0.0001 79 851 1215 1.52 <0.0001
    Yes 9416 869 9.23 8787 240 2.73 8905 358 4.02 9161 614 6.7
ESAs
    No 83 596 2177 2.6 <0.0001 82 069 650 0.79 <0.0001 82 447 1028 1.25 <0.0001 82 912 1493 1.8 <0.0001
    Yes 6245 481 7.7 5887 123 2.09 5995 231 3.85 6100 336 5.51
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TEE, thromboembolic event; PE, pulmonary embolism; DVT, deep vein thromboembolism; Nocases, number of cases; CVC, central venous catheter; ESA, erythropoiesis-stimulating agent.

In the multivariable analysis, we observed that men had an increased risk of developing a TEE compared with women (OR 1.57, 95% CI 1.10–2.25); blacks had higher risk (OR 1.20; 95% CI 1.04–1.40), and other races had reduced risk (OR 0.75; 95% CI 0.62–0.90) when compared with whites. More advanced stages were associated with higher risk; using stage I as a reference, patients with stage II, III and IV breast cancer had 22%, 39% and 98% increased risk, respectively. Patients that did not undergo any breast surgery (OR 1.60, 95% CI 1.34–1.91), and those who had CVC placed (OR 2.71, 95% CI 2.43–3.02), received chemotherapy (OR 1.66, 95% CI 1.48–1.86) or ESAs (OR 1.33, 95% CI 1.17–1.52), had increased risk for developing a TEE. Patients who had ER-negative tumors were less likely to have a TEE (OR 0.84, 95% CI 0.73–0.96). When the analysis was carried out according to the different TEE categories, the observed estimates were similar; however, some of the associations did not achieve statistical significance. The multivariable analyses are shown in Table 3.

Table 3.

Multivariable analysisa of risk factors associated with different TEEs

TEE (events = 2658), OR (95% CI) PE (events = 773), OR (95% CI) DVT (events = 1259), OR (95% CI) Other/unclassified (events = 1829), OR (95% CI)
Age (years)
    66–70 Reference Reference Reference Reference
    71–75 1.14 (1.03–1.28) 1.20 (0.98–1.47) 1.09 (0.94–1.27) 1.18 (1.03–1.34)
    76–80 1.19 (1.06–1.33) 1.31 (1.06–1.62) 1.08 (0.91–1.27) 1.22 (1.06–1.40)
    >80 1.26 (1.12–1.43) 1.36 (1.09–1.71) 1.15 (0.96–1.37) 1.27 (1.10–1.48)
Gender
    Female Reference Reference Reference Reference
    Male 1.57 (1.10–2.25) 2.27 (1.29–3.99) 1.50 (0.90–2.49) 1.25 (0.77–2.02)
Race
    White Reference Reference Reference Reference
    Black 1.20 (1.04–1.40) 1.23 (0.94–1.60) 1.29 (1.04–1.60) 1.20 (1.01–1.43)
    Other 0.75 (0.62–0.90) 0.56 (0.38–0.83) 0.72 (0.55–0.94) 0.73 (0.58–0.92)
Year of diagnosis
    1992 Reference Reference Reference Reference
    1993 0.97 (0.75–1.25) 1.03 (0.63–1.69) 1.19 (0.82–1.74) 0.88 (0.65–1.19)
    1994 0.95 (0.73–1.23) 1.06 (0.64–1.73) 1.26 (0.87–1.83) 0.83 (0.61–1.14)
    1995 1.03 (0.80–1.32) 1.22 (0.76–1.96) 1.29 (0.89–1.87) 1.00 (0.74–1.34)
    1996 1.03 (0.80–1.32) 0.87 (0.52–1.45) 1.34 (0.92–1.93) 0.97 (0.72–1.30)
    1997 0.91 (0.71–1.18) 1.08 (0.67–1.75) 1.19 (0.82–1.74) 0.84 (0.62–1.14)
    1998 1.04 (0.81–1.33) 1.11 (0.69–1.79) 1.25 (0.86–1.81) 1.03 (0.78–1.38)
    1999 0.95 (0.74–1.23) 1.18 (0.75–1.88) 1.07 (0.74–1.56) 0.84 (0.63–1.14)
    2000 0.90 (0.72–1.12) 0.80 (0.52–1.24) 0.95 (0.68–1.33) 0.90 (0.70–1.17)
    2001 0.85 (0.68–1.06) 0.89 (0.58–1.36) 0.91 (0.65–1.27) 0.84 (0.65–1.08)
    2002 0.74 (0.59–0.93) 0.98 (0.65–1.50) 0.59 (0.42–0.85) 0.76 (0.58–0.98)
    2003 0.75 (0.60–0.94) 1.07 (0.71–1.62) 0.72 (0.51–1.01) 0.71 (0.54–0.92)
    2004 0.72 (0.57–0.90) 0.84 (0.55–1.29) 0.84 (0.60–1.18) 0.55 (0.42–0.72)
    2005 0.66 (0.53–0.83) 0.88 (0.57–1.35) 1.05 (0.75–1.46) 0.37 (0.27–0.49)
Stage
    I Reference Reference Reference Reference
    II 1.22 (1.10–1.35) 1.08 (0.90–1.30) 1.24 (1.08–1.42) 1.21 (1.07–1.36)
    III 1.39 (1.20–1.62) 1.26 (0.96–1.65) 1.13 (0.91–1.41) 1.47 (1.23–1.76)
    IV 1.98 (1.68–2.33) 1.55 (1.14–2.10) 1.50 (1.17–1.93) 2.15 (1.78–2.59)
Estrogen receptor
    Positive Reference Reference Reference Reference
    Negative 0.84 (0.73–0.96) 0.92 (0.72–1.18) 0.72 (0.59–0.88) 0.77 (0.65–0.92)
    Unknown 0.80 (0.61–1.04) 1.18 (0.67–2.06) 0.77 (0.52–1.13) 0.68 (0.50–0.92)
Charlson comorbidity
    0 Reference Reference Reference Reference
    1 1.03 (0.92–1.14) 1.13 (0.94–1.37) 1.03 (0.88–1.20) 1.01 (0.89–1.15)
    2+ 1.21 (1.05–1.40) 1.14 (0.87–1.49) 1.34 (1.10–1.64) 1.17 (0.99–1.40)
Surgery
    Breast conserving Reference Reference Reference Reference
    Mastectomy 1.05 (0.95–1.16) 0.98 (0.81–1.18) 1.09 (0.94–1.27) 1.02 (0.90–1.15)
    No surgery/unknown 1.60 (1.34–1.91) 1.88 (1.36–2.60) 1.43 (1.08–1.89) 1.52 (1.23–1.87)
Radiation theorapy
    No Reference Reference Reference Reference
    Unknown 1.15 (0.84–1.57) 1.37 (0.78–2.39) 0.83 (0.49–1.41) 1.13 (0.78–1.63)
    Yes 1.07 (0.97–1.17) 1.29 (1.08–1.53) 1.07 (0.93–1.23) 1.12 (1.00–1.26)
Chemotherapy
    No Reference Reference Reference Reference
    Yes 1.66 (1.48–1.86) 1.70 (1.38–2.08) 1.72 (1.47–2.03) 1.71 (1.50–1.96)
CVC placement
    No Reference Reference Reference Reference
    Yes 2.71 (2.43–3.02) 2.71 (2.23–3.30) 2.14 (1.83–2.51) 2.79 (2.46–3.17)
ESAs use
    No Reference Reference Reference Reference
    Yes 1.33 (1.17–1.52) 1.08 (0.85–1.37) 1.52 (1.27–1.83) 1.39 (1.19–1.61)
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a

Adjusted for age, gender, race, marital status, education level, poverty level, geographical location, year of diagnosis, stage at diagnosis, estrogen and progesterone receptor status, comorbidities (Charlson index), surgery, radiation therapy, chemotherapy, CVC placement and the use of ESAs.

TEE, thromboembolic event; PE, pulmonary embolism; DVT, deep vein thromboembolism; OR, odds ratio; CI, confidence interval; CVC, central venous catheter; ESAs, erythropoiesis-stimulating agents.

discussion

Our study shows that among patients ≥66 years old with breast cancer, the incidence of TEE is 2.96% in the first year of diagnosis. We observed that the incidence is even higher among males and black patients; those with stage IV disease, CVC placement and those receiving chemotherapy and ESAs were at even higher risk. The magnitude of the observed risk was notable. In a multivariable analysis, patients with stage II, III and IV disease had 22%, 39% and 98% increase in risk. The risk among males and black patients was increased 57% and 20%, respectively. The associations with different treatment modalities were also significant; the use of chemotherapy increased the risk by 66%, ESAs increased it by 33% and the use of CVC increased the risk by 170%.

The observed incidence of TEEs is higher than that previously reported. In a large population-based study, Chew et al. [12] observed that among 108 255 patients with breast cancer, the 2-year cumulative risk of a TEE was 1.2%. These results are similar to those observed in clinical trials of patients receiving adjuvant hormonal therapy (1.3%) [20]. The reported incidence of TEE in breast cancer patients receiving adjuvant chemotherapy is 2.1% [13], and for patients with metastatic disease it is 4.4% [14]. This contrasts with our observed TEE incidence of 6.09% in patients receiving chemotherapy and 7.63% in those with metastatic disease. Different studies use different definitions for TEEs, and inter-study comparisons are difficult. Also, it is important to note that our patient population included exclusively patients aged ≥66 years, representing a high-risk cohort, therefore they are not comparable with younger and healthier patients included in clinical trials.

The first months after a cancer diagnosis are considered the highest risk period for developing TEEs [6, 12]. Consistent with prior reports, we observed that 39.5% of the events occurred during the first 3 months after diagnosis. Some of the hypotheses to explain this phenomenon include the possibility that cancer cells cause activation of the clotting system via humoral and mechanical effects [2]. Other explanations include that in the early months after the diagnosis of cancer, surgery may take place and the inflammatory response can favor a procoagulant state; surgery is also associated with increased risk of TEEs secondary to immobility. Another possible explanation to this peak in the early months after diagnosis is the beginning of active treatment, in particular chemotherapy; the possible invasive interventions to complete the diagnosis work-up and the direct effect of injury after a CVC placement or infections may also play a role [9, 21–24].

A notable finding of this analysis is the increased risk of TEE in male patients. Observational studies including patients with different types of cancer report similar rates of TEE among males and females [1, 6, 22, 25]. In a large study [8] evaluating risk factors for TEE in 1 015 598 hospitalized cancer patients, gender was a predictor of venous thromboembolism, with females having a 14% increase in risk compared with males. It should be noted that a different pattern was observed in our study. Male breast cancer is a rare disease, and ∼1% of all the breast cancers are diagnosed in men. Breast cancer in males is more likely to express ER and PR, with rates as high as 90% [26]. It is accepted that two major factors involved in the stimulation of ER-positive breast cancers are ER signaling and circulating estrogen [27, 28]. There is evidence that extraglandularly produced estradiol-17β and estrone stimulate breast growth in males [29] and that male patients with breast cancer have significantly higher circulating levels of total and free estradiol than non-cancer males [30]. It is possible that risk factors or hormonal variations associated with male breast cancer are also associated with TEE. A study by Kyrle et al. [31] in non-cancer patients reported that males had a higher incidence of recurrent idiopathic venous thromboembolism than women. Similarly, Christiansen et al. [32] observed that in a young non-cancer cohort, males had higher rates of recurrent TEE compared with women. To the best of our knowledge, our observation has not been studied specifically in patients with breast cancer and represents an interesting finding that needs to be confirmed.

In our study, rates of TEE appear to be higher in black patients compared with whites. This observation has been reported by others [7, 8]. Some have suggested that such differences may be related to the type of cancer [6]. However, in a large cohort of breast cancer patients, black patients had a borderline significant increase of 30% in the risk of TEE compared with whites [12]. Comorbidities are another well-studied risk factor for the development of TEEs. The presence of comorbid conditions influences the development of TEEs in patients with different types of cancer. Our data confirm this supposition and provide evidence that the observed increase in risk is associated with an increased number of comorbidities [6, 7, 12, 22, 33–36]. To evaluate comorbidities, we used Klabunde's adaptation of the Charlson index; this scoring system was developed to incorporate the diagnostic and procedure data contained in Medicare claims, to model the 2-year non-cancer mortality [17]. We observed that patients with a Charlson score of 1 did not have a significant increase in risk; however, those with a score ≥2 had 21% higher probability of developing a TEE.

Different treatment strategies have been associated with TEEs, and patients receiving systemic chemotherapy are considered to be at increased risk [1, 2, 37]. In a retrospective study evaluating patients receiving chemotherapy, the reported TEE rate for breast cancer patients was 6% [38], a number nearly identical to what we observed in our study. The exact pathophysiological mechanisms to explain the observed excess of TEEs in patients receiving chemotherapy are not well elucidated, but prothrombotic alterations in coagulation factors, anticoagulant proteins and endothelial cells have been shown to occur following the administration of cytotoxic agents [39–43]. It has been suggested that a prechemotherapy platelet count ≥350 000 and a hemoglobin level <10 g/dl are risk factors for the development of chemotherapy-associated TEEs [7, 25, 35]. Unfortunately, in the SEER-Medicare dataset, no information is available on patients' hematological parameters, so it was not possible to take these factors into consideration in our analysis.

ESAs have been widely used to increase hemoglobin values and reduce transfusion requirements in cancer patients [44–46]. Reports have raised safety concerns as results suggest that the use of ESAs is associated with TEEs [47–49]. In a recent meta-analysis that included 4610 cancer patients, Bennett et al. [48] reported that patients who received ESAs had a higher risk of TEEs (hazard ratio 1.57; 95% CI 1.31–1.87). Our results are consistent with such a risk estimate; we observed that patients who received ESAs had a 33% increase of developing a TEE and a 52% higher risk of DVT compared with patients that did not receive ESAs.

CVC placement is another intervention that has consistently been associated with an increased risk for TEE [10, 50]; we observed that it conferred a 2.7-fold increase in risk. Some of the factors associated with this phenomenon are venous stasis and endothelial injury. However, recent reports associate number of attempts, left side placement and catheter tip position with an increased risk [9]. Unfortunately, we were not able to include those factors in our analysis. Despite the clear relationship between CVC placement and the development of a TEE, no differences in CVC-related TEE rates have been seen in double-blind placebo-controlled trials in cancer patients randomly assigned to receive enoxaparin [51] for 6 weeks or dalteparin [52] for 16 weeks. Current guidelines do not recommend prophylaxis for cancer patients with a CVC [53] but clinical trials should continue to address this question given the important morbidity associated with CVCs.

Our results raise the question of the use of primary prophylaxis in high-risk patients. Our study describes the risk of TEEs in a high-risk breast cancer patient population, and does not represent a valid scoring system, therefore no treatment recommendations can be made based on our results. However, as the National Comprehensive Cancer Network guidelines suggest, inpatient prophylactic therapy should be administered to all patients with active diagnosis of cancer who do not have a contraindication to such therapy [53]. There is unfortunately no data to support extended prophylaxis for medical oncology patients in the outpatient setting [53]. Different scoring systems are available in which individual risk factors are assigned weighted scores, and they provide support for the use of prophylaxis in cancer patients [54–56]; however, none of those score systems have been validated in cancer patients. Khorana et al. [35] reported on a model in cancer patients receiving chemotherapy; if validated in future studies, this score could help identify patients in whom primary prophylaxis should be recommended. Importantly, randomized clinical trials evaluating this concept are warranted.

To the best of our knowledge, this is the largest study examining the risk factors associated with different TEEs within the first year of diagnosis in breast cancer patients aged ≥66 years. One of the strengths of this study is that it involves a large unselected population-based cohort of patients, likely reflecting real clinical practice. It is important to mention that, for the same reasons, our cohort includes a high-risk population, and it is likely that age and comorbidities contributed to the higher incidence of TEEs seen.

A limitation of our study is that the SEER-Medicare data do not allow for assessment of the extent of the disease, the severity of outcomes, or an analysis that takes into account the use of thromboprophylaxis, the patient's history of prior TEEs and performance status or hematological parameters. It is possible that factors such as a large tumor burden or genetic predisposition may impact TEE incidence, but we were not able to adjust for such factors. An inherent limitation of claims-based research is the possible heterogeneity in the diagnosis methods used to identify events. We used established diagnosis codes to identify TEE cases and do not believe that the possible heterogeneity in the diagnosis methods could have caused a significant change in our estimates. A limitation of our study is that we could not include data on tamoxifen use, a medication with known prothrombotic effects. It is possible that the lower rate of TEE seen in patients with ER-negative tumors is a reflection of the increased risk seen in ER+ patients as a result of tamoxifen treatment. As a way to take this into account, we adjusted for ER status in the multivariable model and also included the year of diagnosis as we suspect that the proportion of patients taking tamoxifen decreased in recent years as the use of aromatase inhibitors has become the standard of care in postmenopausal patients. We also carried out a stratified analysis according to ER status (data not shown) and observed that the magnitude and direction of the estimates remained very similar. The effect of age, race, stage, comorbidities, chemotherapy and ESAs use and CVC placement was similar when patients with ER-positive, ER-negative and ER-unknown tumors were analyzed separately, validating our results. Also, the results of our study may not be applicable to a population of younger, and in general, healthier patients. Additional studies are needed to confirm these findings and assess the risk of different TEEs in younger breast cancer patients.

In summary, our results demonstrate that TEEs are a complication seen in patients with breast cancer. In this cohort of patients, the first 3 months after diagnosis were associated with the highest event incidence. Males, black patients and those with advanced stages or positive hormone receptor status are at increased risk. Other subgroups of patients at significant risk are those receiving chemotherapy or ESAs and those with CVC placement. TEEs in breast cancer patients represent a substantial clinical problem and much work needs to be done to reduce the burden of TEEs. Better risk assessment tools need to be developed to identify high-risk populations who could benefit from pharmacological prophylactic treatment.

funding

National Institutes of Health (K07-CA109064) to S.H.G.

diclosure

The authors declare no conflict of interest.

Acknowledgments

This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the Applied Research Program, NCI; the Office of Research, Development and Information, Centers for Medicare and Medicaid Services; Information Management Services Inc.; and the SEER Program tumor registries in the creation of the SEER-Medicare database.

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